olanzapine and Weight-Gain

The endogenous opioid system affects metabolism, including weight regulation. Evidence from preclinical and clinical studies provides a rationale for targeting this system to mitigate weight-related side effects of antipsychotics. This review describes the role of the opioid system in regulating weight and metabolism, examines the effects of opioid receptor antagonism on those functions, and explores the use of opioid antagonists to mitigate antipsychotic-associated weight gain and/or metabolic effects.. A PubMed literature search was conducted to identify representative opioid antagonists and associated preclinical and clinical studies examining their potential for the regulation of weight and metabolism.. The mu opioid receptor (MOR), delta opioid receptor (DOR), and kappa opioid receptor (KOR) types have overlapping but distinct patterns of central and peripheral expression, and each contributes to the regulation of body weight and metabolism. Three representative opioid antagonists (eg, naltrexone, samidorphan, and LY255582) were identified for illustration. These opioid antagonists differed in their receptor binding and pharmacokinetic profiles, including oral bioavailability, systemic clearance, and half-life, and were associated with varying effects on food intake, energy utilization, and metabolic dysregulation.. Preclinical and clinical data suggest that antagonism of the endogenous opioid system is a mechanism to address antipsychotic-associated weight gain and metabolic dysregulation. However, evidence suggests that the differing roles of MOR, DOR, and KOR in metabolism, together with the differences in receptor binding, pharmacokinetic, and functional activity profiles of the opioid receptor antagonists discussed in this review, likely contribute to their differential pharmacodynamic effects and clinical outcomes observed regarding antipsychotic-associated weight gain.

Topics: Analgesics, Opioid; Antipsychotic Agents; Humans; Naltrexone; Narcotic Antagonists; Olanzapine; Receptors, Opioid, kappa; Weight Gain

Antipsychotic (AP) drugs are efficacious treatments for various psychiatric disorders, but excessive weight gain and subsequent development of metabolic disease remain serious side effects of their use. Increased food intake leads to AP-induced weight gain, but the underlying molecular mechanisms remain unknown. In previous studies, we identified the neuropeptide Agrp and the transcription factor nuclear receptor subfamily 5 group A member 2 (Nr5a2) as significantly upregulated genes in the hypothalamus following AP-induced hyperphagia. While Agrp is expressed specifically in the arcuate nucleus of the hypothalamus and plays a critical role in appetite stimulation, Nr5a2 is expressed in both the CNS and periphery, but its role in food intake behaviors remains unknown. In this study, we investigated the role of hypothalamic Nr5a2 in AP-induced hyperphagia and weight gain. In hypothalamic cell lines, olanzapine treatment resulted in a dose-dependent increase in gene expression of Nr5a2 and Agrp. In mice, the pharmacological inhibition of NR5A2 decreased olanzapine-induced hyperphagia and weight gain, while the knockdown of Nr5a2 in the arcuate nucleus partially reversed olanzapine-induced hyperphagia. Chromatin-immunoprecipitation studies showed for the first time that NR5A2 directly binds to the Agrp promoter region. Lastly, the analysis of single-cell RNA seq data confirms that Nr5a2 and Agrp are co-expressed in a subset of neurons in the arcuate nucleus. In summary, we identify Nr5a2 as a key mechanistic driver of AP-induced food intake. These findings can inform future clinical development of APs that do not activate hyperphagia and weight gain.

Topics: Agouti-Related Protein; Animals; Antipsychotic Agents; Eating; Humans; Hyperphagia; Hypothalamus; Mice; Olanzapine; Receptors, Cytoplasmic and Nuclear; Weight Gain

Psychosis is a state of mind that makes it difficult to determine what is real and what is not. Psychosis can have serious negative effects. Like many psychiatric phenomena, psychosis has a variety of causes, such as schizophrenia, bipolar disorder, and psychotic depression. Antipsychotic medications, psychotherapy, and social support are the most common treatments. Antipsychotic drugs reduce the symptoms of psychosis by changing brain chemistry. Based on the mechanism of action, antipsychotics have two groups, typical and atypical. Most people who take antipsychotics experience side effects. People taking typical antipsychotics tend to have higher rates of extrapyramidal side effects, but some atypical drugs, especially olanzapine, are associated with the risk of significant weight gain, diabetes, and metabolic syndrome, which, in turn, increases the risk of atherosclerotic cardiovascular disease and premature death. Physical exercise, diet regimen, psychoeducation, monotherapy, or switching to an alternative antipsychotic are strategies to correct metabolic aberrates in atypical antipsychotic users. In light of several successful studies on the use of medicinal plants to control metabolic syndrome, this article briefly reviews the studies on some herbal medications for the management of metabolic disorders associated with atypical antipsychotics and discusses probable mechanisms. Therefore, we searched the Cochrane, Scopus, PubMed, and Google Scholar databases for works published before July, 2022, on the effect of herbal medications on antipsychotic-related metabolic abnormalities in animals or humans. We recommend that some herbal medicines may be efficient for regulating the metabolic changes related to atypical antipsychotics due to their multipotential action, and more efforts should be made to make herbal drug treatments more effective. We hope this review will be a reference for research on developing herbal therapeutics for metabolic alterations in antipsychotic customers.

Topics: Animals; Antipsychotic Agents; Humans; Metabolic Syndrome; Olanzapine; Schizophrenia; Weight Gain

Patients with first-episode psychosis or early-phase schizophrenia are susceptible to olanzapine-associated weight gain and cardiometabolic dysregulation. This meta-analysis characterized weight and metabolic effects observed during olanzapine treatment in randomized clinical trials in this vulnerable patient population.. PubMed, EMBASE, and Dialog were searched for randomized controlled trials (RCTs) reporting weight or cardiometabolic outcomes associated with olanzapine treatment in first-episode psychosis or early-phase schizophrenia. Random-effects meta-analysis and meta-regression were conducted using R v4.0.5.. Of 1203 records identified, 26 RCTs informed the analyses. The meta-analytic mean (95% CI) weight gain was 7.53 (6.42-8.63) kg in studies (n = 19) that reported weight gain with olanzapine treatment. Stratified by duration, the mean (95% CI) weight gain was significantly higher in studies >13 weeks in duration than in those lasting ≤13 weeks: 11.35 (10.05-12.65) vs 5.51 (4.73-6.28) kg, respectively. Despite between-study variability, increases from baseline in most glycemic and lipid parameters were generally small in studies of both ≤13 and >13 weeks. There were no correlations, however, between weight gain and metabolic parameter changes when stratified by study duration.. In RCTs enrolling patients with first-episode psychosis or early-phase schizophrenia, olanzapine was consistently associated with weight gain that was greater in studies lasting >13 weeks compared with those of ≤13 weeks. Metabolic changes observed across studies suggest that RCTs may underestimate metabolic sequelae vs real-world treatment observations. Patients with first-episode psychosis or early-phase schizophrenia are vulnerable to olanzapine-associated weight gain; strategies minimizing olanzapine-associated weight gain should be carefully considered.

Topics: Antipsychotic Agents; Benzodiazepines; Cardiovascular Diseases; Humans; Olanzapine; Psychotic Disorders; Schizophrenia; Weight Gain

Schizophrenia, a serious psychiatric disorder, is among the top 10 global causes of disability and affects nearly 1% of the world population. Antipsychotics constitute the best treatment for patients with schizophrenia, however, this treatment class carries a high risk of metabolic syndrome, including lipid abnormalities. Indeed, the risk of metabolic syndrome would be increased in the population with schizophrenia compared to the general population. The objective is to summarize the prevalence, the mechanisms, and the potential treatments of antipsychotic-induced metabolic syndrome. This is a narrative review of the literature. We searched the electronic database Medline, accessed through PubMed, to find studies that investigated the prevalence and treatments of metabolic syndrome in the adult population using antipsychotics. The prevalence of metabolic syndrome in patients treated with antipsychotics ranges from 37% to 63%. Antipsychotic iatrogenic effects include weight gain/increased waist circumference, dyslipidemia, insulin resistance/type 2 diabetes, and hypertension. Clozapine and olanzapine are reported to precipitate the onset of metabolic syndrome features. In patients with metabolic syndrome, an antipsychotic with less metabolic side effects such as lurasidone, lumateperone, ziprasidone, and aripiprazole should be prioritized. Unlike medications, aerobic exercise and dietetic counseling were found to be efficient as the nonpharmacologic treatment of antipsychotic-induced metabolic syndrome. Few pharmacological treatments were proven effective against weight gain in this patient population. The risk of metabolic syndrome induced by antipsychotics should be early recognized and closely monitored. Primary and secondary prevention of metabolic syndrome or onset of its feature might help reduce the risk of death for patients using antipsychotics.

Topics: Adult; Antipsychotic Agents; Clozapine; Diabetes Mellitus, Type 2; Dyslipidemias; Humans; Hypertension; Metabolic Syndrome; Olanzapine; Schizophrenia; Weight Gain

Weight gain is among the most important side-effects of antipsychotics. It is, however, unclear whether it is associated with antipsychotic doses. We aimed to fill this gap with a dose-response meta-analysis.. We searched multiple electronic databases (last update search June 2021) for all fixed-dose studies that investigated 16 second-generation antipsychotics and haloperidol in adults with acute exacerbation of schizophrenia or with negative symptoms. We estimated the dose-response curves by conducting random-effects dose-response meta-analyses. We used the restricted cubic spline to model the dose-response relationship. The primary outcome was mean weight gain in kg from baseline to endpoint, the secondary outcome was the number of patients with clinically important weight gain.. Ninety-seven studies with 333 dose arms (36 326 participants) provided data for meta-analyses. Most studies were short-term with median duration of 6 weeks (range 4 to 26 weeks). In patients with acute exacerbation, amisulpride, aripiprazole, brexpiprazole, cariprazine, haloperidol, lumateperone, and lurasidone produced mild weight gain in comparison to placebo (mean difference at any dose≤1 kg), while more significant weight gain was observed by all other drugs. For most drugs, dose-response curves showed an initial dose-related increase in weight which plateaued at higher doses, while for others there was no plateau and some even had bell-shaped curves, meaning less weight gain to be associated with higher doses.. Second-generation antipsychotics do not only differ in their propensity to produce weight gain, but also in the shapes of their dose-response curves. This information is important for dosing decisions in clinical practice.

Topics: Adult; Antipsychotic Agents; Haloperidol; Humans; Olanzapine; Randomized Controlled Trials as Topic; Weight Gain

Although olanzapine remains one of the most efficacious antipsychotic medications for the treatment of schizophrenia, there are significant tolerability concerns related to its weight and metabolic profile. Olanzapine-samidorphan combination tablets (OLZ/SAM), branded as Lybalvi, is a newly FDA approved formulation aimed at attenuating antipsychotic induced weight gain via modulation of the endogenous opioid system with samidorphan, while retaining the robust antipsychotic efficacy of olanzapine.. We reviewed the published literature of OLZ/SAM for the management of schizophrenia using the US National Library of Medicine's PubMed.gov resource. Topics covered in this narrative review include the pharmacokinetics, pharmacodynamics, efficacy, and tolerability of OLZ/SAM.. OLZ/SAM is an effective and well-tolerated pharmacologic option in mitigating olanzapine induced weight gain while retaining olanzapine's efficacy. OLZ/SAM cumulatively tends to attenuate weight gain rather than promote weight loss. Effect on metabolic laboratory variables appears limited. Additional research will be needed to determine its effectiveness compared to alternative strategies to attenuate antipsychotic induced weight gain.

Topics: Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Humans; Naltrexone; Narcotic Antagonists; Olanzapine; Schizophrenia; Tablets; Weight Gain

Identifying medications that may be used as therapeutic agents for eating disorders is a longstanding focus of research, with varying degrees of success. The present review consolidates the most recent findings on pharmacological treatment of three eating disorders, including anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED).. Recent research suggests that olanzapine demonstrates positive effects on weight gain among outpatients with AN. There are fewer recent advances in psychopharmacological treatment for BN and BED, likely due to the relative success of prior medication trials. Olanzapine is the first medication to safely promote weight gain among individuals with AN. Fluoxetine is FDA-approved for BN treatment, and lisdexamfetamine is FDA-approved for BED treatment. BN and BED also generally respond well to SSRIs prescribed off-label. Research on psychopharmacological treatments for other eating disorders, such as avoidant-restrictive food intake disorder and other specified feeding and eating disorders, are sorely needed.

Topics: Anorexia Nervosa; Binge-Eating Disorder; Bulimia Nervosa; Feeding and Eating Disorders; Humans; Olanzapine; Weight Gain

Olanzapine is a second-generation antipsychotic with established efficacy in several psychiatric disease states, but its use is limited because of weight gain and metabolic side effects. Samidorphan is a novel opioid antagonist that binds to mu-opioid, kappa-opioid, and delta-opioid receptors and is hypothesized to reduce cravings for high-calorie foods thus attenuating antipsychotic-induced weight gain. The combination product olanzapine/samidorphan was approved by the US Food and Drug Administration in June 2021 for the treatment of schizophrenia and bipolar I disorder; this article reviews the pharmacological properties of oral olanzapine/samidorphan and its clinical efficacy and tolerability with a focus on mitigation of olanzapine-induced weight gain in these patient populations. In clinical trials, the combination of olanzapine/samidorphan was associated with significantly less weight gain and smaller increases in waist circumference as compared with olanzapine monotherapy. Olanzapine/samidorphan demonstrated similar efficacy as olanzapine monotherapy and was well tolerated. Weight gain and metabolic side effects associated with olanzapine monotherapy can result in tolerability issues and potentially medication nonadherence. Olanzapine/samidorphan is an effective treatment for schizophrenia and bipolar I disorder with less weight gain than olanzapine monotherapy.

Topics: Analgesics, Opioid; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Humans; Naltrexone; Olanzapine; Schizophrenia; Weight Gain

Topics: Antipsychotic Agents; Cardiometabolic Risk Factors; Drug Therapy, Combination; Female; Humans; Male; Metabolic Syndrome; Naltrexone; Olanzapine; Schizophrenia; Weight Gain

Topics: Antipsychotic Agents; Bipolar Disorder; Drug Combinations; Humans; Naltrexone; Narcotic Antagonists; Olanzapine; Schizophrenia; Weight Gain

The approvals of psychotropics for bipolar disorder (BD) are mainly based on randomized, double-blind, placebo-controlled trials (RCTs) from North America. It remains unknown whether approved psychotropics have similar efficacy, tolerability, and safety for Asians with BD. The aim of this systematic review was to compare those differences of psychotropics between Asians and North Americans with BD.. MEDLINE, EMBASE, and PsycINFO were searched for RCTs studied in two regions. The effect size, remission/response rate, and risk for discontinuation due to adverse events (AEs), weight gain (WG), nervous systems and gastrointestinal AEs were assessed and compared between two regions with Cohen's d or number needed to treat/harm.. Eleven studies of aripiprazole, olanzapine, risperidone, and quetiapine in BD were included. Similar efficacy and relatively benign tolerability of atypical antipsychotics (AAPs) between Asians and Americans with BD were observed in most studies. The risk for AAP-related WG was similar between two regions. Asians with mania or bipolar depression were more vulnerable to akathisia/tremor or constipation. Japanese and Chinese with bipolar depression were more sensitive to somnolence and dizziness, respectively. Americans were more likely to have dry mouth, nausea, and vomiting.. The number of included psychotropics and papers was small.. Differences in AAP-related efficacy and tolerability were minimal between the two regions, but some AEs appeared to be different. Clinicians should pay attention to these differences to optimize treatment strategies in different races/ethnicities with BD.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Asian People; Bipolar Disorder; Female; Humans; North America; Olanzapine; Quetiapine Fumarate; Risperidone; United States; Weight Gain

Disturbed eating behaviours have been widely reported in psychotic disorders since the early 19th century. There is also evidence that antipsychotic (AP) treatment may induce binge eating or other related compulsive eating behaviours. It is therefore possible that abnormal eating patterns may contribute to the significant weight gain and other metabolic disturbances observed in patients with psychosis. In this scoping review, we aimed to explore the underlying psychopathological and neurobiological mechanisms of disrupted eating behaviours in psychosis spectrum disorders and the role of APs in this relationship. A systematic search identified 35 studies that met our eligibility criteria and were included in our qualitative synthesis. Synthesizing evidence from self-report questionnaires and food surveys, we found that patients with psychosis exhibit increased appetite and craving for fatty food, as well as increased caloric intake and snacking, which may be associated with increased disinhibition. Limited evidence from neuroimaging studies suggested that AP-naïve first episode patients exhibit similar neural processing of food to healthy controls, while chronic AP exposure may lead to decreased activity in satiety areas and increased activity in areas associated with reward anticipation. Overall, this review supports the notion that AP use can lead to disturbed eating patterns in patients, which may contribute to AP-induced weight gain. However, intrinsic illness-related effects on eating behaviors remain less well elucidated, and many confounding factors as well as variability in study designs limits interpretation of existing literature in this field and precludes firm conclusions from being made.

Topics: Antipsychotic Agents; Appetite; Brain; Bulimia; Case-Control Studies; Clozapine; Craving; Diet Surveys; Energy Intake; Feeding Behavior; Food Preferences; Humans; Hunger; Neuroimaging; Olanzapine; Psychotic Disorders; Reward; Satiation; Self Report; Snacks; Weight Gain

Multiple drugs are known to induce metabolic malfunctions, among them second-generation antipsychotics (SGAs). The pathogenesis of such adverse effects is of multifactorial origin.. We investigated whether SGAs drive dysbiosis, assessed whether gut microbiota alterations affect body weight and metabolic outcomes, and looked for the possible mechanism of metabolic disturbances secondary to SGA treatment in animal and human studies.. A systematic literature search (PubMed/Medline/Embase/ClinicalTrials.gov/PsychInfo) was conducted from database inception until 03 July 2018 for studies that reported the microbiome and weight alterations in SGA-treated subjects.. Seven articles reporting studies in mice (experiments = 8) and rats (experiments = 3) were included. Olanzapine was used in five and risperidone in six experiments. Only three articles (experiments = 4) in humans fit our criteria of using risperidone and mixed SGAs. The results confirmed microbiome alterations directly (rodent experiments = 5, human experiments = 4) or indirectly (rodent experiments = 4) with predominantly increased Firmicutes abundance relative to Bacteroidetes, as well as weight gain in rodents (experiments = 8) and humans (experiments = 4). Additionally, olanzapine administration was found to induce both metabolic alterations (adiposity, lipogenesis, plasma free fatty acid, and acetate levels increase) (experiments = 3) and inflammation (experiments = 2) in rodents, whereas risperidone suppressed the resting metabolic rate in rodents (experiments = 5) and elevated fasting blood glucose, triglycerides, LDL, hs-CRP, antioxidant superoxide dismutase, and HOMA-IR in humans (experiment = 1). One rodent study suggested a gender-dependent effect of dysbiosis on body weight.. Antipsychotic treatment-related microbiome alterations potentially result in body weight gain and metabolic disturbances. Inflammation and resting metabolic rate suppression seem to play crucial roles in the development of metabolic disorders.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Gastrointestinal Microbiome; Humans; Hyperglycemia; Metabolic Diseases; Olanzapine; Risperidone; Weight Gain

Modeling dose-response relationships of drugs is essential to understanding their safety effects on patients under realistic circumstances. While intention-to-treat analyses of clinical trials provide the effect of assignment to a particular drug and dose, they do not capture observed exposure after factoring in nonadherence and dropout. We develop a Bayesian method to flexibly model the dose-response relationships of binary outcomes with continuous treatment, permitting multiple evidence sources, treatment effect heterogeneity, and nonlinear dose-response curves. In an application, we examine the risk of excessive weight gain for patients with schizophrenia treated with the second-generation antipsychotics paliperidone, risperidone, or olanzapine in 14 clinical trials. We define exposure as total cumulative dose (daily dose × duration) and convert to units equivalent to 100 mg of olanzapine (OLZ doses). Averaging over the sample population of 5891 subjects, the median dose ranged from 0 (placebo randomized participants) to 6.4 OLZ doses (paliperidone randomized participants). We found paliperidone to be least likely to cause excessive weight gain across a range of doses. Compared with 0 OLZ doses, at 5.0 OLZ doses, olanzapine subjects had a 15.6% (95% credible interval: 6.7, 27.1) excess risk of weight gain; corresponding estimates for paliperidone and risperidone were 3.2% (1.5, 5.2) and 14.9% (0.0, 38.7), respectively. Moreover, compared with nonblack participants, black participants had a 6.8% (1.0, 12.4) greater risk of excessive weight gain at 10.0 OLZ doses of paliperidone. Nevertheless, our findings suggest that paliperidone is safer in terms of weight gain risk than risperidone or olanzapine for all participants at low to moderate cumulative OLZ doses.

Topics: Adult; Antipsychotic Agents; Bayes Theorem; Dose-Response Relationship, Drug; Female; Humans; Male; Markov Chains; Medication Adherence; Middle Aged; Olanzapine; Paliperidone Palmitate; Risperidone; Schizophrenia; Weight Gain

Bipolar disorder places a significant burden on the affected individuals, their family, healthcare systems and the overall economy. More treatment options are needed, especially those with better efficacy and tolerability. Asenapine is a second-generation antipsychotic approved in Europe (brand name Sycrest

Topics: Antimanic Agents; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Dibenzocycloheptenes; Dizziness; Heterocyclic Compounds, 4 or More Rings; Humans; Olanzapine; Quality of Life; Randomized Controlled Trials as Topic; Treatment Outcome; Weight Gain

A plethora of data deriving from single studies as well as meta-analyses demonstrates that weight gain is associated with the exposure to the majority of antipsychotics (AP). However, potential sex differences have widely evaded the attention of AP treatment trials. It is hypothesised that female patients gain more weight compared with male patients due to their enhanced susceptibility to adverse drug reactions.. A meta-analysis was conducted using clinical trials of AP that reported weight change separately for female and male patients. Duration of AP use was stratified in four categories: <6 weeks, 6-16 weeks, 16-38 weeks and >38 weeks. Forest plots were generated for men and women separately, stratified by AP as well as by duration of use. Sex differences were tested by performing meta-regression.. Data of 26 studies were used in the present analysis because sufficient data were available only for olanzapine, risperidone and the no-medication group. Both female and male patients showed considerable weight gain after switch or initiate of olanzapine or risperidone, but meta-regression analyses did not show significant sex differences.. The present meta-analysis revealed that sex differences in AP-related weight gain have been under investigated hampering the detection of sex-specific patterns. In chronic patients switching to olanzapine or risperidone receiving short-or middle-term treatment, AP were associated with weight gain in both sex subgroups and no significant differences were reported.

Topics: Adult; Aged; Antipsychotic Agents; Body Mass Index; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Observational Studies as Topic; Olanzapine; Psychotic Disorders; Randomized Controlled Trials as Topic; Risperidone; Weight Gain

Second generation antipsychotic drugs (SGAs) cause substantial body weight gain/obesity and other metabolic side-effects such as dyslipidaemia. Their antagonistic affinity to the histaminergic H1 receptor (H1R) has been identified as one of the main contributors to weight gain/obesity side-effects. The effects and mechanisms of betahistine (a histaminergic H1R agonist and H3 receptor antagonist) have been investigated for ameliorating SGA-induced weight gain/obesity in both animal models and clinical trials. It has been demonstrated that co-treatment with betahistine is effective in reducing weight gain, associated with olanzapine in drug-naïve patients with schizophrenia, as well as in the animal models of both drug-naïve rats and rats with chronic, repeated exposure to olanzapine. Betahistine co-treatment can reduce food intake and increase the effect of thermogenesis in brown adipose tissue by modulating hypothalamic H1R-NPY-AMPKα (NPY: neuropeptide Y; AMPKα: AMP-activated protein kinase α) pathways, and ameliorate olanzapine-induced dyslipidaemia through modulation of AMPKα-SREBP-1-PPARα-dependent pathways (SREBP-1: Sterol regulatory element binding protein 1; PPARα: Peroxisome proliferator-activated receptor-α) in the liver. Although reduced locomotor activity was observed from antipsychotic treatment in rats, betahistine did not affect locomotor activity. Importantly, betahistine co-treatment did not influence the effects of antipsychotics on serotonergic receptors in the key brain regions for antipsychotic therapeutic efficacy. However, betahistine co-treatment reverses the upregulated dopamine D2 binding caused by chronic olanzapine administration, which may be beneficial in reducing D2 supersensitivity often observed in chronic antipsychotic treatment. Therefore, these results provide solid evidence supporting further clinical trials in treating antipsychotics-induced weight gain using betahistine in patients with schizophrenia and other mental disorders.

Topics: AMP-Activated Protein Kinases; Animals; Antipsychotic Agents; Benzodiazepines; Betahistine; Histamine Agonists; Humans; Olanzapine; Receptors, Histamine H1; Weight Gain

The second-generation antipsychotic drug olanzapine has become a widely prescribed drug in the treatment of schizophrenia and bipolar disorder. Unfortunately, its therapeutic benefits are partly outweighed by significant weight gain and other metabolic side effects, which increase the risk for diabetes and cardiovascular disease. Because olanzapine remains superior to other antipsychotic drugs that show less weight gain liability, insight into the mechanisms responsible for olanzapine-induced weight gain is crucial if it is to be effectively addressed. Over the past few decades, several groups have investigated the effects of olanzapine on energy balance using rat models. Unfortunately, results from different studies have not always been consistent and it remains to be determined which paradigms should be used in order to model olanzapine-induced weight gain most accurately. This review summarizes the effects of olanzapine on energy balance observed in different rat models and discusses some of the factors that appear to contribute to the inconsistencies in observed effects. In addition it compares the effects reported in rats with clinical findings to determine the predictive validity of different paradigms.

Topics: Animals; Benzodiazepines; Disease Models, Animal; Energy Intake; Energy Metabolism; Humans; Models, Biological; Olanzapine; Predictive Value of Tests; Rats; Weight Gain

To describe weight changes and metabolic effects of asenapine compared with placebo and olanzapine in adults.. Post hoc analyses were performed using data from 17 asenapine trials (13 schizophrenia and 4 bipolar mania trials) with placebo (5-10 mg twice daily; n = 1,748; 1-6 weeks) and/or olanzapine (5-20 mg, once daily; n = 3,430; 3-100 weeks). Data were pooled based on treatment into placebo-controlled and olanzapine-controlled trials. For trials with placebo and olanzapine treatment groups, the asenapine population was included in both pools. Changes from baseline for weight, body mass index, and fasting lipid and glucose levels were determined. The Medical Dictionary for Regulatory Activities was used to define metabolic adverse events.. Mean (standard error [SE]) weight change was greater with asenapine than with placebo (1.2 [0.2] vs 0.14 [0.2] kg; P < .0001) and similar in schizophrenia and bipolar disorder. Mean changes differed for asenapine versus placebo in triglycerides (1.8 [6.3] vs -12.2 [5.9] mg/dL; P < .01) and fasting glucose (1.9 [1.7] vs -1.6 [1.5] mg/dL; P < .05). In the olanzapine-controlled trials, weight change was significantly lower with asenapine than with olanzapine (0.9 [0.1] vs 3.1 [0.2] kg; P < .0001). Changes associated with asenapine were lower than those with olanzapine in fasting glucose (2.0 vs 3.3 mg/dL), total cholesterol (-0.4 [1.1] vs 6.2 [1.2] mg/dL; P < .0001), low-density lipoprotein cholesterol (-0.3 [1.1] vs 3.1 [1.2] mg/dL; P < .01), and triglycerides (-0.9 [5.4] vs 24.3 [5.8] mg/dL; P < .0001).. Asenapine was associated with greater weight gain and glucose changes than placebo and not associated with a meaningful change in triglycerides or cholesterol levels. Asenapine was not significantly different from olanzapine in change in glucose levels and lower than olanzapine with respect to triglycerides, weight gain, and increased cholesterol.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Blood Glucose; Body Mass Index; Body Weight; Cholesterol; Cholesterol, LDL; Controlled Clinical Trials as Topic; Dibenzocycloheptenes; Female; Hematologic Tests; Heterocyclic Compounds, 4 or More Rings; Humans; Male; Middle Aged; Olanzapine; Schizophrenia; Treatment Outcome; Triglycerides; Weight Gain

Olanzapine is frequently prescribed in young children for psychiatric conditions. It may be an option for chemotherapy-induced nausea and vomiting (CINV) control in children. The objective of this review was to describe the safety of olanzapine in children less than 13 years of age to determine if safety concerns would be a barrier to its use for CINV prevention.. Electronic searches were performed in MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science and Scopus. All studies in English reporting adverse effects associated with olanzapine use in children younger than 13 years or with a mean/median age less than 13 years were included. Adverse outcomes were synthesized for prospective studies.. A total of 47 studies (17 prospective) involving 387 children aged 0.6-18 years were included; nine described olanzapine poisonings. Weight gain or sedation were reported in 78 % [95 % confidence interval (CI) 63-95] and 48 % (95 % CI 35-67), respectively. Extrapyramidal symptoms or electrocardiogram abnormalities were reported in 9 % (95 % CI 4-21) and 14 % (95 % CI 7-26), respectively. Elevation in liver function tests or blood glucose abnormalities were reported in 7 % (95 % CI 2-20) and 4 % (95 % CI 1-17), respectively. No deaths were attributed to olanzapine.. No studies were identified with a primary focus on evaluating safety, and the adverse effects reported in the included studies were heterogeneous.. Most adverse events associated with olanzapine use in children less than 13 years of age are of minor clinical significance. These findings support the exploration of olanzapine for the prevention of CINV in children in future trials.

Topics: Antipsychotic Agents; Appetite; Benzodiazepines; Child; Child, Preschool; Conscious Sedation; Humans; Infant; Nausea; Olanzapine; Vomiting; Weight Gain

To conduct meta-analyses of all published association studies on the HTR2C -759C/T (rs3813829) polymorphism and olanzapine-induced weight gain in schizophrenia patients and on the HTR2C -759C/T, -697G/C (rs518147) and rs1414334:C> G polymorphisms and olanzapine/clozapine/risperidone-induced metabolic syndrome in schizophrenia patients.. Eligible studies were identified by searching PubMed and Web of Science databases. Meta-analyses were performed using Cochrane Review Manager (RevMan, version 5.2) to calculate the pooled odds ratio (OR) and its corresponding 95% confidence interval (CI).. Our meta-analyses revealed both a significant positive association between the rs1414334 C allele and olanzapine/clozapine/risperidone-induced metabolic syndrome and a marginally significant positive association between the -697C allele and the induced metabolic syndrome in schizophrenia patients, but no significant association between the -759C/T polymorphism and the induced metabolic syndrome in schizophrenia patients. Our analysis further revealed a pronounced trend toward a significant negative association between the -759T allele and high olanzapine-induced weight gain and a trend toward a significant positive association between the -759C allele and high olanzapine-induced weight gain in Caucasian schizophrenia patients.. Our results support that HTR2C polymorphisms play a role in antipsychotic-induced metabolic disturbance. More association studies are needed to further elucidate association of different HTR2C polymorphisms and antipsychotic-induced metabolic disturbance.

Topics: Alleles; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Genetic Association Studies; Humans; Male; Metabolic Syndrome; Olanzapine; Polymorphism, Single Nucleotide; Receptor, Serotonin, 5-HT2C; Risperidone; Schizophrenia; Weight Gain

The aims of this study were to provide a systematic review and meta-analysis of the effects of atypical antipsychotics in children and adolescents on weight gain (primary objective) and other metabolic parameters (secondary objective).. A systematic literature review and meta-analysis of double-blind, randomized, controlled trials were conducted. The data sources used were as follows: EMBASE, PubMed, BIOSIS, International Pharmaceutical Abstracts, The Cochrane database (Clinical Trials), Clinical Trials Government Registry, The metaRegister of Controlled Trials, WHO (World Health Organization) Clinical Trials Registry Platform, and PsycINFO(®). Hand searching was also carried out by examining the reference lists of identified studies. Double-blind, randomized, controlled trials investigating the metabolic adverse effects (weight gain, lipid, glucose, and prolactin level abnormalities) associated with atypical antipsychotic use in children and adolescents aged ≤ 18 years were included, irrespective of whether the investigation of adverse effects was a primary or secondary endpoint.. We identified 21 studies of drug versus placebo that met the inclusion criteria, with a total of 2,455 patients, 14 studies for risperidone (1,331 patients), three for olanzapine (276 patients), and four for aripiprazole (848 patients). Compared with placebo, the mean weight increases for each drug were olanzapine 3.45 kg (95 % CI 2.93-3.98), risperidone 1.77 kg (95 % CI 1.35-2.20), and aripiprazole 0.94 kg (95 % CI 0.65-1.24). Regarding other metabolic abnormalities, eight studies reported statistically significant increases in prolactin with risperidone; two reported a statistically significant increase in glucose, total cholesterol, and prolactin with olanzapine; and three studies reported a statistically significant decrease in prolactin with aripiprazole. Data on lipid, glucose, and prolactin level changes were too limited to allow us to perform a meta-analysis.. Olanzapine, risperidone, and aripiprazole were all associated with statistically significant weight gain. Olanzapine was associated with the most weight gain and aripiprazole the least. For the secondary outcome, although a number of active comparator trials were identified, data were not available for meta-analysis and were too limited to allow firm conclusions to be drawn.

Topics: Adolescent; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Child; Humans; Olanzapine; Piperazines; Quinolones; Randomized Controlled Trials as Topic; Risperidone; Weight Gain

Treatment with second generation antipsychotics (SGAs), notably olanzapine and clozapine, causes severe obesity side effects. Antagonism of histamine H1 receptors has been identified as a main cause of SGA-induced obesity, but the molecular mechanisms associated with this antagonism in different stages of SGA-induced weight gain remain unclear. This review aims to explore the potential role of hypothalamic histamine H1 receptors in different stages of SGA-induced weight gain/obesity and the molecular pathways related to SGA-induced antagonism of these receptors. Initial data have demonstrated the importance of hypothalamic H1 receptors in both short- and long-term SGA-induced obesity. Blocking hypothalamic H1 receptors by SGAs activates AMP-activated protein kinase (AMPK), a well-known feeding regulator. During short-term treatment, hypothalamic H1 receptor antagonism by SGAs may activate the AMPK-carnitine palmitoyltransferase 1 signaling to rapidly increase caloric intake and result in weight gain. During long-term SGA treatment, hypothalamic H1 receptor antagonism can reduce thermogenesis, possibly by inhibiting the sympathetic outflows to the brainstem rostral raphe pallidus and rostral ventrolateral medulla, therefore decreasing brown adipose tissue thermogenesis. Additionally, blocking of hypothalamic H1 receptors by SGAs may also contribute to fat accumulation by decreasing lipolysis but increasing lipogenesis in white adipose tissue. In summary, antagonism of hypothalamic H1 receptors by SGAs may time-dependently affect the hypothalamus-brainstem circuits to cause weight gain by stimulating appetite and fat accumulation but reducing energy expenditure. The H1 receptor and its downstream signaling molecules could be valuable targets for the design of new compounds for treating SGA-induced weight gain/obesity.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Clozapine; Histamine H1 Antagonists; Humans; Hypothalamus; Obesity; Olanzapine; Receptors, Histamine H1; Weight Gain

Patients with schizophrenia have a shorter life expectancy and their risk of dying from a cardiovascular disease is higher than the general population. Both facts have been attributed to the raised presence of metabolic syndrome. There is a big amount of scientific publications that deals with the relationship between schizophrenia, antipsychotic treatment, and the development of metabolic syndrome. There is also information about recommendations and clinical guides to achieve an adequate prevention, screening, and treatment of the disease. The aim of this review is to update the current information about this issue and to understand related etiologic factors, differences between antipsychotic drugs, and the current recommendations for patient's care.

Topics: Antipsychotic Agents; Benzodiazepines; Blood Glucose; Cardiovascular Diseases; Clozapine; Comorbidity; Follow-Up Studies; Humans; Hypothalamus; Incidence; Life Expectancy; Lipid Metabolism; Metabolic Syndrome; Obesity, Abdominal; Olanzapine; Practice Guidelines as Topic; Schizophrenia; Weight Gain

Weight gain as a result of atypical anti-psychotic treatment is a common issue with different atypical anti-psychotic treatments causing differing magnitudes of weight gain. Although differing amounts of weight gain result from different atypical agents little is known about the temporal course of weight gain in anti-psychotic treatment. Specifically is the time course of weight gain comparable across different agents. Therefore this article reviews the temporal course of weight gain for three common atypical anti-psychotics namely; clozapine, olanzapine and risperidone. It is evident that all three of these agents exhibit similar although at distinct magnitudes temporal courses of weight gain. That is an initial rapid increase from baseline to 3 months (stage 1), a steady increase from 3 months to 18 months (stage 2) and a plateau after this point (stage 3) with continued anti-psychotic treatment. It is postulated that each of these stages of weight gain result from distinct neural mechanisms. The hypothesized neural correlates for each stage of weight gain are reviewed and discussed. The article concludes with recommendations for future research.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Humans; Nervous System Physiological Phenomena; Olanzapine; Psychotic Disorders; Risperidone; Time Factors; Weight Gain

Several analytical approaches were used to characterize time progression of weight changes observed in adults treated with olanzapine from a 12,425-patient database of 86 studies of oral and depot formulations of olanzapine (mean modal dose 13.3 mg/day). Descriptive mean profile plots for completer and modified completer groups showed weight increasing throughout each observed period, with apparent slowing in rate of change after 3 or 4 months. Mixed-effects model repeated measures analyses also showed that weight increased most rapidly early in treatment and slowed within 2 to 4 months. The slowing in rate of change was greatest for patients obese at baseline and least for patients underweight at baseline. This pattern was also observed in a nonparametric regression-based profile. Based on visual inspection of profile plots, 2, 3, 4, and 5 months were postulated as potential 'change points' beyond which rate of increase might slow, and the proportions of patients whose slope after each change point was ≤ 90% of the slope before change point were calculated. Over 85% of patients who gained weight showed slowing rate of weight change after each postulated change point. Potential consequences of weight gain should be considered prior to starting olanzapine. Olanzapine-treated patients should receive regular weight monitoring.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Benzodiazepines; Body Weight; Databases, Factual; Delayed-Action Preparations; Female; Humans; Male; Middle Aged; Models, Statistical; Obesity; Olanzapine; Regression Analysis; Time Factors; Weight Gain; Young Adult

Olanzapine is an atypical antipsychotic that is useful in schizophrenia and bipolar affective disorder, but its use is associated with troublesome weight gain and metabolic syndrome. A variety of pharmacological agents has been studied in the efforts to reverse weight gain induced by olanzapine, but current evidence is insufficient to support any particular pharmacological approach. We conducted a systematic review and meta-analysis of randomized controlled trials of metformin for the treatment of olanzapine-induced weight gain. Systematic review of the literature revealed 12 studies that had assessed metformin for antipsychotic-induced weight gain. Of these, four studies (n= 105) met the review inclusion criteria and were included in the final analysis. Meta-analysis was performed to see the effect size of the treatment on body weight, waist circumference and body-mass index (BMI). Weighted mean difference (WMD) for body weight was 5.02 (95% CI 3.93, 6.10) kg lower with metformin as compared with placebo at 12 weeks. For waist circumference, the test for heterogeneity was significant (P= 0.00002, I(2) = 85.1%). Therefore, a random effects model was used to calculate WMD, which was 1.42 (95% CI 0.29, 3.13) cm lower with metformin as compared with placebo at 12 weeks. For BMI, WMD was 1.82 (95% CI 1.44, 2.19) kg m(-2) lower with metformin as compared with placebo at 12 weeks. Existing data suggest that short term modest weight loss is possible with metformin in patients with olanzapine-induced weight gain.

Topics: Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Blood Glucose; Body Mass Index; Humans; Hypoglycemic Agents; Metformin; Olanzapine; Overweight; Randomized Controlled Trials as Topic; Schizophrenia; Weight Gain

Antipsychotic therapy forms the cornerstone of treatment for people with severe mental illness. Second-generation (atypical) antipsychotics are associated with a significantly lower incidence of extrapyramidal symptoms than the typical, first-generation agents; however, changes in metabolic variables -- including impaired glucose metabolism, diabetes mellitus, weight gain and dyslipidaemia -- have been reported during treatment with second-generation antipsychotics. Understanding any potential link between antipsychotic treatment and the incidence of these events is complicated by the increasing prevalence of obesity and diabetes occurring in the general population and the increased risk of diabetes and changes in metabolic variables in people with schizophrenia. While relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucose level appears to fall on a continuum, with olanzapine appearing to have a greater association than some other atypical antipsychotics. The PubMed database was used to search for publications that included any information on measures of changes in weight, body mass index (BMI) and/or metabolic variables in randomized studies of olanzapine published between 1992 and 2010. In long-term (≥48 weeks) studies of olanzapine, the mean weight gain was 5.6 kg (last observation carried forward; median exposure 573 days). The proportions of patients who gained at least 7%, 15% or 25% of their baseline weight with long-term exposure were 64%, 32% and 12%, respectively. Some studies have suggested that weight gain early during the course of olanzapine treatment may predict clinically significant weight gain following long-term exposure to the drug. Changes in metabolic variables, such as elevated indices of glucose metabolism and triglyceride level, have also been observed during treatment with olanzapine. Consensus guidelines emphasize the importance of appropriate baseline screening and ongoing monitoring of weight gain and metabolic variables for people receiving all antipsychotic treatments. Long-term weight management programmes have been shown to reduce weight gain in some patients.

Topics: Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Cardiovascular Diseases; Dyslipidemias; Glucose Metabolism Disorders; Humans; Incidence; Olanzapine; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Risk Factors; Schizophrenia; Weight Gain

The atypical antipsychotics (AAPs) are associated with weight gain and an increased incidence of metabolic disease including type 2 diabetes mellitus. Epidemiological, cross-sectional and prospective studies suggest that two of the AAPs, olanzapine and clozapine, cause the most dramatic weight gain and metabolic impairments including increased fasting glucose, insulin and triglycerides. Relative to the other AAPs, both olanzapine and clozapine exhibit a particularly high antagonistic affinity for histamine and muscarinic receptors which have been hypothesized as mediators of the reported increase in weight and glucose abnormalities. In this article, we review the current evidence for the AAP associated weight gain and abnormal glucose metabolism. We postulate that the effects of the AAPs on food intake and peripheral metabolism are initially independently regulated but with increasing body adiposity, the early AAP-induced impairments in peripheral metabolism will be exacerbated, thereby establishing a vicious cycle such that the effects of the AAP are magnified by the known pathophysiological consequences of obesity. Furthermore, we examine how inhibition of the histaminergic pathway may mediate increases in food intake and the potential role of the vagus nerve in the reported peripheral metabolic effects.

Topics: Animals; Antipsychotic Agents; Appetite Regulation; Benzodiazepines; Clozapine; Glucose; Histamine; Histamine Antagonists; Humans; Models, Biological; Muscarinic Antagonists; Obesity; Olanzapine; Receptors, Histamine; Vagus Nerve; Weight Gain

Although atypical antipsychotics have beneficial efficacy and tolerance, non-adherence and partial adherence remain in patients treated for schizophrenia. Long-acting injectable or depot atypical antipsychotics offer better medication adherence and tolerability advantages. Currently, two drugs are available for the treatment of schizophrenia, risperidone long-acting injectable (RLAI) and olanzapine pamoate (OP).. Short- and long-term safety and tolerability data on RLAI and OP from January 2006 through September 2009 were reviewed by performing Medline and PubMed searches, reviewing abstracts and poster presentations, and viewing available material from the FDA and European Medicines Agency.. RLAI and OP show good short- and long-term safety when treating patients with schizophrenia, with uncommon discontinuation due to adverse effects. RLAI and OP data show rare problems with injection site reactions and patients exposed to injectable treatments prefer to continue injections. Infrequent but serious post-injection delirium sedation syndrome occurred after 1% of OP injections. Weight gain was generally higher among patients treated with OP versus RLAI.. Healthcare providers, patients and family members should be made aware of the safety and benefits of long-acting injectable atypical antipsychotics in order to diminish the unnecessary restrictions of these therapies for patients with schizophrenia.

Topics: Administration, Oral; Antipsychotic Agents; Benzodiazepines; Delayed-Action Preparations; Dyslipidemias; Humans; Hyperglycemia; Hyperprolactinemia; Injections; Medication Adherence; Movement Disorders; Olanzapine; Pain; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Weight Gain

The metabolic side effects of second-generation antipsychotics (SGA) are serious and have not been compared head to head in a meta-analysis. We conducted a meta-analysis of studies comparing the metabolic side effects of the following SGAs head-to-head: amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone, zotepine.. We searched the register of the Cochrane schizophrenia group (last search May 2007), supplemented by MEDLINE and EMBASE (last search January 2009) for randomized, blinded studies comparing the above mentioned SGA in the treatment of schizophrenia or related disorders. At least three reviewers extracted the data independently. The primary outcome was weight change. We also assessed changes of cholesterol and glucose. The results were combined in a meta-analysis.. We included 48 studies with 105 relevant arms. Olanzapine produced more weight gain than all other second-generation antipsychotics except for clozapine where no difference was found. Clozapine produced more weight gain than risperidone, risperidone more than amisulpride, and sertindole more than risperidone. Olanzapine produced more cholesterol increase than aripiprazole, risperidone and ziprasidone. (No differences with amisulpride, clozapine and quetiapine were found). Quetiapine produced more cholesterol increase than risperidone and ziprasidone. Olanzapine produced more increase in glucose than amisulpride, aripiprazole, quetiapine, risperidone and ziprasidone; no difference was found with clozapine.. Some SGAs lead to substantially more metabolic side effects than other SGAs. When choosing an SGA for an individual patient these side effects with their potential cause of secondary diseases must be weighed against efficacy and characteristics of the individual patient.

Topics: Amisulpride; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Blood Glucose; Cholesterol; Clinical Trials as Topic; Clozapine; Dibenzothiazepines; Humans; Imidazoles; Indoles; Olanzapine; Piperazines; Quetiapine Fumarate; Quinolones; Risperidone; Schizophrenia; Sulpiride; Thiazoles; Weight Gain

Metabolic syndrome and cardiovascular diseases are important causes of morbidity and mortality among patients with severe mental illnesses. Atypical or second-generation antipsychotics (SGAs) are associated with obesity and other components of metabolic syndrome, particularly abnormal glucose and lipid metabolism. This review aims to provide a summary of recent evidence on metabolic risks associated with SGAs, current recommendations for metabolic monitoring, and efficacy of treatment options currently available.. Studies have identified younger, antipsychotic-naive patients with first-episode psychosis as a population vulnerable to adverse metabolic effects from SGAs. These patients gained more weight and developed evident lipid and glucose abnormalities as soon as 8-12 weeks after treatment initiation. Findings are more striking among children and adolescents. The differential effects of various SGAs are well described, with clozapine and olanzapine associated with the highest metabolic risk. In addition to behavioral therapy, emerging data suggest that pharmacological therapy, most notably metformin, is efficacious in the treatment and possibly prevention of SGA-associated metabolic derangements.. More data have become available on the burden from metabolic complications associated with SGAs. New and effective treatment options are required in the near future to improve cardiovascular health in this susceptible population.

Topics: Antipsychotic Agents; Benzodiazepines; Cardiovascular Diseases; Clozapine; Humans; Metabolic Syndrome; Metformin; Obesity; Olanzapine; Practice Guidelines as Topic; Psychotic Disorders; Severity of Illness Index; Weight Gain

To examine potential differences in efficacy and safety of treatment with olanzapine in patients with schizophrenia of white and black descent.. A post-hoc, pooled analysis of 6 randomized, double-blind trials in the treatment of schizophrenia, schizophreniform disorder, or schizoaffective disorder compared white (N = 605) and black (N = 375) patients treated with olanzapine (5 to 20 mg/day) for 24 to 28 weeks. Efficacy measurements included the Positive and Negative Syndrome Scale (PANSS) total score; and positive, negative, and general psychopathology scores; and the Clinical Global Impression of Severity (CGI-S) scores at 6 months. Safety measures included differences in the frequencies of adverse events along with measures of extrapyramidal symptoms, weight, glucose, and lipid changes over time.. 51% of black patients and 45% of white patients experienced early study discontinuation (P = .133). Of those who discontinued, significantly more white patients experienced psychiatric worsening (P = .002) while significantly more black patients discontinued for reasons other than efficacy or tolerability (P = .014). Discontinuation for intolerability was not different between groups (P = .320). For the estimated change in PANSS total score over 6 months, there was no significant difference in efficacy between white and black patients (P = .928), nor on the estimated PANSS positive (P = .435), negative (P = .756) or general psychopathology (P = .165) scores. Overall, there was no significant difference in the change in CGI-S score between groups from baseline to endpoint (P = .979). Weight change was not significantly different in white and black patients over 6 months (P = .127). However, mean weight change was significantly greater in black versus white patients at Weeks 12 and 20 only (P = .028 and P = .026, respectively). Additionally, a significantly greater percentage of black patients experienced clinically significant weight gain (≥ 7%) at anytime compared to white patients (36.1% vs. 30.4%, P = .021). Changes across metabolic parameters (combined fasting and random lipids and glucose) were also not significantly different between groups, with the exception of a greater categorical change in total cholesterol from borderline to high among white subjects and a categorical change from normal to low in high density lipoprotein (HDL) cholesterol among white males.. The findings did not demonstrate overall substantive differences in efficacy or safety between white and black patients diagnosed with schizophrenia or related disorders treated with olanzapine. However, a significantly greater percentage of black patients (36.1%) experienced clinically significant weight gain compared to white patients (30.4%).

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Black or African American; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Obesity; Olanzapine; Psychiatric Status Rating Scales; Psychotic Disorders; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome; Weight Gain; White People

Topics: Adult; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Decision Making; Female; Humans; Olanzapine; Piperazines; Polypharmacy; Psychotic Disorders; Quinolones; Schizophrenia; Schizophrenic Psychology; Weight Gain

Weight gain is common for people with schizophrenia and this has serious implications for a patient's health and well being. Switching strategies have been recommended as a management option.. To determine the effects of antipsychotic medication switching as a strategy for reducing or preventing weight gain and metabolic problems in people with schizophrenia.. We searched key databases and the Cochrane Schizophrenia Group's trials register (January 2005 and June 2007), reference sections within relevant papers and contacted the first author of each relevant study and other experts to collect further information.. All clinical randomised controlled trials comparing switching of antipsychotic medication as an intervention for antipsychotic induced weight gain and metabolic problems with continuation of medication and/or other weight loss treatments (pharmacological and non pharmacological) in people with schizophrenia or schizophrenia-like illnesses.. Studies were reliably selected, quality assessed and data extracted. For dichotomous data we calculated risk ratio (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis, based on a fixed-effect model. The primary outcome measures were weight loss, metabolic syndrome, relapse and general mental state.. We included four studies for the review with a total of 636 participants. All except one study had a duration of 26 weeks or less. There was a mean weight loss of 1.94 kg (2 RCT, n = 287, CI -3.9 to 0.08) when switched to aripiprazole or quetiapine from olanzapine. BMI also decreased when switched to quetiapine (1 RCT, n = 129, MD -0.52 CI -1.26 to 0.22) and aripiprazole (1 RCT, n = 173, RR 0.28 CI 0.13 to 0.57) from olanzapine.Fasting blood glucose showed a significant decrease when switched to aripiprazole or quetiapine from olanzapine. (2 RCT, MD -2.53 n = 280 CI -2.94 to -2.11). One RCT also showed a favourable lipid profile when switched to aripiprazole but these measures were reported as percentage changes, rather than means with standard deviation.People are less likely to leave the study early if they remain on olanzapine compared to switching to quetiapine or aripiprazole.There was no significant difference in outcomes of mental state, global state, and adverse events between groups which switched medications and those that remained on previous medication. Three different switching strategies were compared and no strategy was found to be superior to the others for outcomes of weight gain, mental state and global state.. Evidence from this review suggests that switching antipsychotic medication to one with lesser potential for causing weight gain or metabolic problems could be an effective way to manage these side effects, but the data were weak due to the limited number of trials in this area and small sample sizes. Poor reporting of data also hindered using some trials and outcomes. There was no difference in mental state, global state and other treatment related adverse events between switching to another medication and continuing on the previous one. When the three switching strategies were compared none of them had an advantage over the others in their effects on the primary outcomes considered in this review. Better designed trials with adequate power would provide more convincing evidence for using medication switching as an intervention strategy.

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Blood Glucose; Body Mass Index; Body Weight; Dibenzothiazepines; Drug Substitution; Fasting; Humans; Olanzapine; Piperazines; Quetiapine Fumarate; Quinolones; Schizophrenia; Weight Gain

The prevalence of Diabetes Mellitus (DM) is becoming a serious public health problem. The use of atypical antipsychotics has been associated with disruption of the glucose metabolism and therefore with causing DM. The underlying mechanisms are unknown, but knowledge of the differences between the pharmacological features of various antipsychotics combined with their diabetogenic profile might help us to understand those mechanisms. This article describes how the binding of various essential receptors or transporters in essential body tissues, adipose tissue, pancreatic tissue and liver and skeletal muscle tissue can cause disruption of the glucose metabolism. With such knowledge in mind one can try to explain the differences between the diabetogenic propensities of various antipsychotics. It is well known that clozapine and olanzapine cause weight gain and DM, whereas aripiprazole and ziprasidone have much less disruptive clinical profiles. The most significant risk factor for adiposity seems to be strong blocking of histaminergic receptors. An agonistic activity on serotonergic-1a receptors, with a very low affinity for muscarinergic-3 receptors, might protect against the development of DM. More data will become available which may help to solve the puzzle.

Topics: Adiponectin; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Blood Glucose; Clozapine; Diabetes Mellitus; Humans; Leptin; Obesity; Olanzapine; Piperazines; Quinolones; Receptor, Muscarinic M3; Receptor, Serotonin, 5-HT1A; Receptors, Dopamine D2; Receptors, Histamine; Serotonin 5-HT1 Receptor Agonists; Thiazoles; Weight Gain

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Brain; Cardiomyopathies; Child; Clozapine; Dyskinesia, Drug-Induced; Energy Metabolism; Feeding Behavior; Female; Gene Expression; Genetic Association Studies; Humans; Male; Myocarditis; Olanzapine; Pericarditis; Risperidone; Tourette Syndrome; Twin Studies as Topic; Weight Gain

Topics: Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Diabetes Mellitus, Type 2; Humans; Olanzapine; Receptors, Adrenergic; Receptors, Dopamine; Receptors, Serotonin; Schizophrenia; Secondary Prevention; Weight Gain

Olanzapine is a second-generation antipsychotic approved for the treatment of schizophrenia, bipolar mania and associated agitation.. To assess the safety profile of olanzapine, including its propensity to be associated with weight gain, diabetes mellitus and dyslipidemias.. Review of English-language reports located through PubMed and information available on regulatory agency websites.. The use of olanzapine can pose a therapeutic dilemma in that on one hand, a number of large scale studies have found effectiveness advantages for olanzapine in comparison to other first-line second-generation medications. On the other hand, olanzapine is associated with substantial weight gain and the development of dyslipidemia. Regarding other important safety concerns, olanzapine has a favorable profile in terms of extra-pyramidal side effects and is also relatively prolactin-sparing. The effectiveness benefits may outweigh the risks, particularly in patients with low baseline risk for metabolic syndrome but monitoring for untoward metabolic effects crucial. Switch-or-stay and other intervention decisions need to be made early before substantial weight gain has occurred.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Clinical Trials as Topic; Diabetes Mellitus; Dyslipidemias; Humans; Olanzapine; Prolactin; Risk Factors; Weight Gain

Early-onset schizophrenia-spectrum (EOSS) disorders (onset of psychotic symptoms before 18 years of age) represent a severe variant associated with significant chronic functional impairment and poor response to antipsychotic treatment. All drugs with proven antipsychotic effects block dopamine D(2) receptors to some degree. The ongoing development of the dopamine and other neurotransmitter receptor systems during childhood and adolescence may affect clinical response and susceptibility to side effects in youth. A literature search was conducted of clinical trials of antipsychotics in children and adolescents with EOSS disorders between 1980 and 2007 from the Medline database, reference lists, and conference proceedings. Trials were limited to double-blind studies of duration of 4 or more weeks that included 15 or more patients. Ten clinical trials were identified. Antipsychotic medications were consistently found to reduce the severity of psychotic symptoms in children and adolescents when compared with placebo. The superiority of clozapine has been now demonstrated relative to haloperidol, standard-dose olanzapine, and "high-dose" olanzapine for EOSS disorders. However, limited comparative data are available regarding whether there are differences among the remaining second-generation antipsychotics (SGAs) in clinical effectiveness. The available data from short-term studies suggest that youth might be more sensitive than adults to developing antipsychotic-related adverse side effects (eg, extrapyramidal side effects, sedation, prolactin elevation, weight gain). In addition, preliminary data suggest that SGA use can lead to the development of diabetes in some youth, a disease which itself carries with it significant morbidity and mortality. Such a substantial risk points to the urgent need to develop therapeutic strategies to prevent and/or mitigate weight gain and diabetes early in the course of treatment in this population.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Disorders of Excessive Somnolence; Haloperidol; Humans; Olanzapine; Prolactin; Schizophrenia, Childhood; Treatment Outcome; Weight Gain

The second-generation antipsychotic olanzapine has been shown to be efficacious as a treatment for adults with bipolar disorder and is approved by the United States Food and Drug Administration for the treatment of acute manic or mixed episodes as well as for maintenance treatment in bipolar adults.. This review examines the use of olanzapine for the treatment of children and adolescents with bipolar disorder and presents a discussion of the mechanism of action, pharmacokinetic and pharmacodynamic properties of olanzapine in children and adolescents. In addition, efficacy and safety data are reviewed and the risks and benefits of using olanzapine in bipolar youth are summarized.. Articles published in English were identified using a search of the National Library of Medicine from 1990 to 2007 with manual review of references of each article as well as review of the US Clinical Trials database. Articles describing the use of olanzapine in children or adolescents were included.. Olanzapine appears to have a rapid onset of action for mixed and manic episodes, but is associated with metabolic side effects including hyperprolactinemia, diabetes and weight gain. Therefore, olanzapine may best be used in the acute treatment of children and adolescents experiencing a manic or mixed episode as its side-effect profile may limit its use as a maintenance agent in this population.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Child; Diabetes Mellitus; Humans; Hyperprolactinemia; Olanzapine; Weight Gain

Several papers and communications have reported possible weight reduction or less weight gain when patients start or switch to orally disintegrating olanzapine, as contrasted with standard oral olanzapine tablets. In this paper, the current literature is reviewed and hypothesized mechanisms of action are discussed. The data are still preliminary and mechanisms of action are not well understood. Randomized controlled trials are needed to further evaluate change in weight during treatment with orally disintegrating olanzapine.

Topics: Administration, Oral; Antipsychotic Agents; Benzodiazepines; Drug Delivery Systems; Humans; Olanzapine; Patient Compliance; Schizophrenia; Solubility; Tablets; Weight Gain

The mechanisms underlying olanzapine-induced weight gain have not yet been fully elucidated. To examine the effects of long-term treatment with olanzapine on different aspects of energy balance, we administered olanzapine to male rats. Osmotic minipumps were chosen as preferred mode of administration because the half-life of olanzapine is only 2(1/2) h in rats compared to 30 h in humans. We discovered that, within one week, degradation of olanzapine occurred in the solution used to fill the minipump reservoir. This resulted in a decrease in delivered olanzapine and declining plasma levels over the course of the experiment. Therefore, we caution other researchers for the limitations of using osmotic minipumps to administer olanzapine for longer periods of time.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Disease Models, Animal; Drug Administration Schedule; Eating; Infusion Pumps, Implantable; Male; Olanzapine; Pharmaceutical Solutions; Rats; Rats, Wistar; Weight Gain

Compared with the first-generation, or "typical" antipsychotic drugs, second-generation or atypical antipsychotics cause fewer extrapyramidal (motor) problems, but they pose new challenges, as they often contribute to metabolic disturbances such as weight gain, hyperlipidemia, insulin resistance, and type 2 diabetes mellitus. Patients taking atypical antipsychotics should be monitored for glycemic and cardiovascular risk factors and should receive treatment for such problems as they arise.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Diabetes Mellitus; Humans; Olanzapine; Psychotic Disorders; Risk Factors; Risperidone; Weight Gain

The decision to stay with a treatment or switch to a different one depends on the balance between overall effectiveness, efficacy, and tolerability. One of the challenges with antipsychotic medication treatment of serious mental illness is the risk of weight gain, which can be considerable for some patients. This article reviews the issue of weight gain associated with antipsychotics and places it within the context of metabolic issues in general. The concept of "number needed to treat" is introduced to interpret the results of the Clinical Antipsychotic Trials of Intervention Effectiveness for schizophrenia, particularly to examine the balance between overall effectiveness, efficacy, and tolerability of the different antipsychotic treatments tested. Predictors of weight gain for olanzapine are reviewed for schizophrenia and bipolar disorder, as is a monitoring plan applicable for all patients receiving antipsychotic therapy.

Topics: Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Humans; Olanzapine; Schizophrenia; Weight Gain

Management of bipolar disorder (BPD) may require multiple medications, including lithium, anticonvulsants, and antipsychotics (both conventional and atypical). Updated treatment guidelines reflect an expanded role for atypical antipsychotics (AAPs) in BPD treatment. Five AAPs--olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole--are approved by the US Food and Drug Administration (FDA) as monotherapy for first-line treatment of acute manic and (except for quetiapine) mixed episodes. Two AAPs--olanzapine (in fixed-dose combination with fluoxetine) and quetiapine--are also FDA approved for bipolar depression. For long-term maintenance therapy, one option is to continue effective, well-tolerated acute phase treatment; however, only olanzapine and aripiprazole are FDA approved for maintenance, based on evidence from randomized, placebo-controlled clinical trials. Although head-to-head comparisons are scarce, meta-analysis data suggest that olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole have similar antimanic efficacy; therefore, AAP selection for this indication should be guided by other considerations such as safety, tolerability, and cost. Safety and tolerability issues to consider when selecting an AAP include metabolic dysfunction (weight gain, type 2 diabetes, and dyslipidemia); hyperprolactinemia; extrapyramidal symptoms; QTc prolongation; and pharmacokinetic drug interactions.

Topics: Antipsychotic Agents; Aripiprazole; Arrhythmias, Cardiac; Benzodiazepines; Bipolar Disorder; Diabetes Mellitus, Type 2; Dibenzothiazepines; Drug Evaluation; Drug Interactions; Drug Therapy, Combination; Dyslipidemias; Humans; Hyperprolactinemia; Olanzapine; Piperazines; Quetiapine Fumarate; Quinolones; Risperidone; Thiazoles; Treatment Outcome; Weight Gain

To evaluate options for the management of weight gain associated with olanzapine therapy.. MEDLINE (1966-May 2004), International Pharmaceutical Abstracts (1970-August 2003), The Cochrane Library, and EMBASE (1974-August 2003) databases were searched using the key words antipsychotics, atypical antipsychotics, olanzapine, and weight gain. Bibliographies of cited articles were reviewed.. All articles identified from the data sources were evaluated and all information deemed relevant was included for this review.. Weight gain is a common adverse effect of olanzapine, a member of the atypical antipsychotic class. Data are limited supporting a specific therapeutic approach to the management of weight gain with olanzapine treatment. Reversal of weight gain with lifestyle modifications and adjunctive pharmacologic therapies such as nizatidine and amantadine has been modest. Experience with adjunctive pharmacologic treatment has been limited to small, observational studies and case reports. Although data are limited, weight reduction has been observed in select patients switching from olanzapine to an alternative atypical antipsychotic.. At this time, targeting lifestyle modifications provides the most reasonable approach to minimize weight gain observed with olanzapine therapy. Preliminary evidence evaluating adjunctive pharmacologic treatment for this indication has demonstrated minimal clinical benefit. Switching to an alternative atypical antipsychotic agent associated with less significant weight gain may be appropriate in select patients. Further clinical trials are needed to support a specific therapeutic approach to managing weight gain with olanzapine.

Topics: Benzodiazepines; Disease Management; Histamine Antagonists; Humans; Life Style; Olanzapine; Selective Serotonin Reuptake Inhibitors; Weight Gain

Among the atypical antipsychotics, clozapine and olanzapine are known to cause significant weight gain. Along with quetiapine, they may impair glucose metabolism and increase the risk for type 2 diabetes. They are also associated with a rise in triglyceride levels and an increased risk for coronary artery disease. Clinicians should take these risks seriously in prescribing these antipsychotics and employ intelligent safeguards if and when they use them.

Topics: Antipsychotic Agents; Benzodiazepines; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Humans; Hypertriglyceridemia; Leptin; Neurotransmitter Agents; Olanzapine; Weight Gain

Atypical antipsychotics, including olanzapine, have been associated with clinically significant weight gain in some patients. The purpose of this study was to determine if weight gain was associated with increasing plasma concentrations during olanzapine treatment in subjects with schizophrenia. This study included 39 acutely ill subjects with schizophrenia, schizoaffective disorder, or schizophreniform disorder (DSM-III-R or DSM-IV). Assessments included the Brief Psychiatric Rating Scale (BPRS), the Scale for Assessment of Negative Symptoms (SANS), and weight measurements. Olanzapine was titrated to a dose of 5 to 20 mg/d for 2 to 6 weeks. A 24-hour plasma concentration was obtained after 6 weeks of treatment. Analysis using a receiver operator characteristic curve identified a threshold dose-weighted plasma concentration of 20.6 ng/mL being associated with an increased likelihood of clinically significant weight gain (> or =7% baseline weight) during olanzapine treatment. The associations remained significant after adjusting for age, gender, baseline body mass index, baseline symptom severity, and symptom improvement (OR = 10.1; 95% CI, 1.3-75.0; P = 0.024). Similar analysis determined that a threshold olanzapine dose of 13.3 mg/d was associated with > or =7% weight gain. However, after adjusting for potential confounders, the results did not remain significant. The association of weight gain with plasma concentrations during treatment with olanzapine may support the utilization of plasma drug concentration as a marker for antipsychotic-induced weight gain in the treatment of schizophrenia.

Topics: Adult; Benzodiazepines; Clinical Trials as Topic; Confidence Intervals; Female; Humans; Male; Middle Aged; Odds Ratio; Olanzapine; Schizophrenia; Weight Gain

Novel 'atypical' antipsychotic drugs represent a substantial improvement on older 'typical' drugs. However, clinical experience has shown that some, but not all, of these drugs can induce substantial weight gain. This interferes with compliance with drug taking and has expected effects on morbidity and mortality. In this review, we summarize current thinking on: (i) the extent to which different 'atypical' drugs induce weight gain; (ii) the possible roles of various neurotransmitters and neuropeptides in this adverse drug reaction; and (iii) the state of development of animal models in this area. We also outline major areas for future research.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Disease Models, Animal; Female; Humans; Male; Neuropeptides; Obesity; Olanzapine; Rats; Receptors, Biogenic Amine; Weight Gain

Weight overload and obesity became these last years a major health problem. However gain weight is a frequent side effect of a large number of psychotropics. This article proposes to discuss this potential while reviewing various molecules. This reveals that the atypical antipsychotics are most likely to induce weight gain, in particular clozapine and olanzapine. The tricyclic antidepressants and mirtazapine come next, with the majority of the mood stabilizers. The old antipsychotics seem to involve less gain of weight. The SSRI make lose weight in the first weeks of treatment, but induce a moderate weight gain on the long term.

Topics: Adolescent; Adult; Amisulpride; Antidepressive Agents; Antimanic Agents; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Body Mass Index; Child; Clozapine; Dibenzothiazepines; Double-Blind Method; Female; Fructose; Haloperidol; Humans; Imidazoles; Indoles; Male; Obesity; Olanzapine; Piperazines; Placebos; Psychotropic Drugs; Quetiapine Fumarate; Quinolones; Randomized Controlled Trials as Topic; Risperidone; Socioeconomic Factors; Sulpiride; Thiazoles; Time Factors; Topiramate; Valproic Acid; Weight Gain

Five new antipsychotic drugs introduced in the United States in the last decade offer physicians the ability to treat patients with schizophrenia and bipolar mania without the adverse effects of the first-generation antipsychotics. In this article, the authors discuss the advantages and side effects of these agents and present a guide to help physicians choose the optimal drug in the most favorable formulation for each patient.

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clozapine; Diabetes Mellitus, Type 2; Dibenzothiazepines; Drug Administration Schedule; Humans; Hyperprolactinemia; Mental Disorders; Olanzapine; Patient Compliance; Piperazines; Practice Guidelines as Topic; Prescription Fees; Quetiapine Fumarate; Quinolones; Risk Assessment; Risperidone; Thiazoles; Torsades de Pointes; Treatment Outcome; Weight Gain

Dyslipidemia is an increasing problem in most industrialized societies and is a risk factor for coronary heart disease (CHD). Imbalances in individual lipid components, including total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and serum triglycerides, have each been shown to contribute to this increased risk. Certain psychiatric patient populations, such as those afflicted with schizophrenia, are of particular concern. Psychiatric patients with schizophrenia are naturally at increased risk for dyslipidemia and obesity, in part due to poor diet and sedentary lifestyle, but these conditions can be exacerbated by some antipsychotic medications. Clozapine and olanzapine, for example, appear to be associated with hyperlipidemia, which may be associated with changes in body weight. Other, newer antipsychotic agents may exhibit less liability for weight gain and the development of dyslipidemia. This review is intended to briefly highlight the association between dyslipidemia and cardiovascular disease, the changes in serum lipids associated with some antipsychotic agents, and how these changes in serum lipids affect the monitoring of schizophrenia patients.

Topics: Antipsychotic Agents; Benzodiazepines; Cardiovascular Diseases; Cholesterol; Cholesterol, VLDL; Clozapine; Coronary Disease; Diabetes Mellitus, Type 2; Humans; Hyperlipidemias; Obesity; Olanzapine; Risk Factors; Schizophrenia; Triglycerides; Weight Gain

Topics: Antimanic Agents; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Clozapine; Diabetes Mellitus; Dibenzothiazepines; Dyskinesias; Haloperidol; Humans; Hyperglycemia; Hyperprolactinemia; Olanzapine; Pirenzepine; Quetiapine Fumarate; Risperidone; Thioridazine; Weight Gain

Topics: Adolescent; Adult; Age Factors; Aged; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Clinical Trials as Topic; Clozapine; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dibenzothiazepines; Female; Glucose; Haloperidol; Humans; Intellectual Disability; Male; Mental Disorders; Metabolic Syndrome; Middle Aged; Olanzapine; Quetiapine Fumarate; Retrospective Studies; Risk Factors; Risperidone; Schizophrenia; Sex Factors; Time Factors; Weight Gain

The atypical antipsychotics have been shown to have superior efficacy compared with typical antipsychotics such as haloperidol, particularly in the treatment of negative symptoms of schizophrenia. Furthermore, they induce less extrapyramidal effects. However, following clinical use, marked bodyweight gain has been frequently observed with some of the atypical antipsychotic drugs. In order to examine and compare the frequency, amount and conditions of bodyweight gain during treatment with atypical antipsychotics, studies concerning bodyweight gain with these agents were identified through a MEDLINE search from 1966 to March 2000. Although comparison is limited by the different designs and recruitment procedures of the reviewed studies, the available data support the notion that the frequency as well as the amount of bodyweight gain is high in patients treated with olanzapine (average bodyweight gain 2.3 kg/month), clozapine (1.7 kg/month), quetiapine (1.8 kg/month), and possibly also zotepine (2.3 kg/month). Moderate changes in bodyweight have been observed in the treatment with risperidone (average bodyweight gain 1.0 kg/month). Ziprasidone seems to induce only slight bodyweight changes (0.8 kg/month). Bodyweight gain most frequently occurs in the first 12 weeks of treatment. Patients who were underweight at the beginning of treatment are at highest risk of gaining bodyweight. The underlying pathomechanism still remains largely unclear. The relative receptor affinities of the atypical antipsychotics for histamine H1 receptors as well as the ratio of their affinity for serotonin 5-HT2 and dopamine D2 receptors appear to be the most robust correlate of bodyweight gain. Furthermore, the induction of leptin secretion may have an important impact on bodyweight gain in patients treated with atypical antipsychotics. Although many questions concerning the pathogenesis of bodyweight gain remain unresolved, this adverse effect has to be taken into consideration when prescribing the atypical antipsychotics, particularly in view its affect on compliance during long term treatment and the long term effects of obesity on mortality and morbidity.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Humans; Mental Disorders; Olanzapine; Pirenzepine; Quetiapine Fumarate; Receptors, Dopamine D2; Receptors, Histamine H1; Receptors, Serotonin; Risk Factors; Smoking Cessation; Weight Gain

Schizophrenic patients who have been prescribed atypical antipsychotics have a potential risk of gaining weight. The implications of weight gain for clinical care may differ depending on whether a patient is underweight or overweight at baseline. The exact mechanism for weight gain is not known, but several factors have been identified that can help predict which patients are at risk for gaining weight. These factors include better clinical outcome, increased appetite, and low baseline body mass index. In patients treated with olanzapine for up to 3 years, weight gain trended toward a plateau at approximately 36 weeks. Weight gain interventions, including behavioral modifications, show promise in controlling or reducing weight in patients treated with antipsychotics.

Topics: Antipsychotic Agents; Behavior Therapy; Benzodiazepines; Dose-Response Relationship, Drug; Follow-Up Studies; Haloperidol; Health Behavior; Humans; Obesity; Olanzapine; Pirenzepine; Risperidone; Schizophrenia; Weight Gain

With the availability of the so-called novel antipsychotic agents, extrapyramidal symptoms are becoming decreasingly problematic for patients with schizophrenia, and simultaneously, a new symptom is emerging as a preeminent concern. This side effect is weight gain and its metabolic concomitants. This article reviews what is currently known about antipsychotic-induced weight gain, describes the magnitude of the problem, briefly touches on mechanisms of action, and addresses the correlation of interindividual variations in magnitude of weight gain. In addition, we address questions about the effects of weight gain on compliance and whether or not there is a correlation between weight gain and therapeutic efficacy. Finally, we address medical consequences of weight gain and review the literature supporting various treatment options for antipsychotic-induced weight gain. As will be seen, this is an area of research in its infancy, and much work remains to be done.

Topics: Adult; Antipsychotic Agents; Behavior Therapy; Benzodiazepines; Body Mass Index; Female; Humans; Male; Middle Aged; Obesity; Olanzapine; Patient Compliance; Pirenzepine; Schizophrenia; Weight Gain

In general, antipsychotic agents have diverse actions on a wide range of neurotransmitter systems. Data strongly suggest that a number of these systems may play a role in the regulation of body weight. In addition to having very distinct pharmacologic profiles, individual agents possess discrete weight gain liabilities. This article briefly reviews the evidence for the involvement of specific neurotransmitter systems in the control of body weight and describes the relevant pharmacologic characteristics of individual antipsychotic agents. By comparing the pharmacologic profiles of specific antipsychotic agents with their respective weight gain liabilities, this article attempts to gain an insight into the specific receptors underlying a drug's propensity to induce weight gain. However, there is still much to be learned concerning weight control mechanisms, and the role of many of the receptors at which antipsychotic agents are active remains unclear. In spite of this, an overview of current knowledge in the field may facilitate prediction of a potential novel antipsychotic agent's weight gain liability.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Eating; Humans; Olanzapine; Piperazines; Pirenzepine; Psychotic Disorders; Quetiapine Fumarate; Rats; Receptors, Neurotransmitter; Schizophrenia; Thiazoles; Weight Gain

Prescribing an antipsychotic for a patient with schizophrenia requires a risk-benefit analysis. Weight gain has become an issue recently as a result of reports that 2 of the atypical antipsychotic agents, clozapine and olanzapine, are associated with a higher risk than other drugs of causing excessive weight gain. Some degree of weight gain may occur with any atypical antipsychotic agent, particularly early in treatment. A more important consideration is the long-term effects of the atypical antipsychotic on body weight, since many of the patients in this population require chronic therapy. This is important because weight gain is an adverse effect that is associated with noncompliance and medical problems. In this article, I review recent reports about the weight effects of different atypical antipsychotic drugs. To provide accurate understanding of the effects of atypical antipsychotic agents, data analyses should include both short-term and long-term findings, the relationship of changes in body weight to pretreatment body mass index (BMI), relationship to dose, both intent-to-treat and complete analyses, and presentation of both mean and median changes in weight. It is also important to know whether the studies have been done in an inpatient or outpatient setting, since patients who are institutionalized may be less likely to exhibit increases in body weight. Such complete information and multidimensional analysis would minimize obfuscation about the true nature of a drug's impact on body weight.

Topics: Ambulatory Care; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clinical Trials as Topic; Clozapine; Dibenzothiazepines; Dose-Response Relationship, Drug; Hospitalization; Humans; Olanzapine; Piperazines; Pirenzepine; Quetiapine Fumarate; Research Design; Schizophrenia; Thiazoles; Weight Gain

Olanzapine is an effective and safe antipsychotic drug. Its pharmacokinetic properties are comparable to those of classical antipsychotics. Oxidative processes are mediated by the cytochrome P450 isoenzyme CYP1A2 and to a minor degree by CYP2D6. Olanzapine's main route of metabolism is by glucuronidation. Therapeutic doses result in a wide variability of serum levels; dose and serum concentration are linearly correlated. Smoking and carbamazepine induce cytochrome P450 isoenzymes and thus decrease olanzapine serum levels. Inhibition of CYP1A2 by fluvoxamine yields increased concentrations; however, clinically relevant CYP2D6 inhibition was observed only in combination with additional disposition factors, such as female gender or old age. As a rule dose adjustment is not necessary but moderate renal or hepatic impairment calls for control of serum levels to provide maximal safety during olanzapine therapy. Therapeutic drug monitoring (TDM) and toxicology studies are carried out by HPLC methods using UV or MS detection. The optimal therapeutic range of olanzapine serum levels is 20 to 40 ng/ml. Concentrations of 80 ng/ml are considered threshold for the occurrence of adverse events; however, toxicological studies showed that postmortem plasma levels are higher than antemortem levels. Lethality of high olanzapine was only observed in combination with other drugs. Moderate increases of prolactin levels were detected during administration of olanzapine. In relation to olanzapine therapy, several case reports of neutropenia and agranulocytosis appeared in the literature. Weight gain in olanzapine-treated patients does not correlate with serum levels. Olanzapine response is augmented when patients' serum levels are titrated to 20 to 40 ng/ml thereby minimizing the occurrence of side effects, thus TDM is recommended for patients treated with olanzapine.

Topics: Antipsychotic Agents; Benzodiazepines; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2D6; Dose-Response Relationship, Drug; Drug Evaluation; Drug Interactions; Drug Monitoring; Humans; Olanzapine; Pirenzepine; Selective Serotonin Reuptake Inhibitors; Smoking; Weight Gain

The overall effectiveness of traditional antipsychotics has been hindered by their extrapyramidal side effects, which contribute to noncompliance and relapse in patients with schizophrenia. The side effects associated with traditional antipsychotic treatment are generally minimal in patients who take risperidone, a combined 5-HT2/D2 antagonist, but the literature is sparse on adverse events among the newer atypical antipsychotics. Risperidone is associated with relatively few motor side effects compared with the traditional antipsychotics, and weight gain is less likely with risperidone than with either clozapine or olanzapine. While increased prolactin levels have been reported in patients taking risperidone, little correlation has been found between prolactin levels and adverse events. As antipsychotic treatment options expand to include the new agents, it is important for clinicians to anticipate side effects and to query patients about specific adverse events.

Topics: Antipsychotic Agents; Benzodiazepines; Drug Administration Schedule; Humans; Hyperprolactinemia; Incidence; Movement Disorders; Olanzapine; Pirenzepine; Risperidone; Schizophrenia; Schizophrenic Psychology; Weight Gain

Olanzapine, a serotonin-dopamine receptor antagonist, is one of the novel atypical antipsychotics that is effective against the positive and negative symptoms of schizophrenia with significantly fewer treatment-emergent extrapyramidal symptoms and less akathisia associated with traditional antipsychotics. Compared with traditional agents, olanzapine shows only a few adverse events such as dry mouth, sedation, and increase in appetite. Compared with risperidone, olanzapine causes greater increases in weight gain and body mass index but less hyperprolactinemia. Transient, non-dose-dependent, asymptomatic elevations in liver enzymes have also been noted in olanzapine-treated patients. Because of the comparative efficacy and improved side effect profiles of the atypical antipsychotics, consideration should be given to using the newer agents as preferred treatment for schizophrenia and related psychoses.

Topics: Akathisia, Drug-Induced; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Body Mass Index; Clinical Trials as Topic; Humans; Olanzapine; Pirenzepine; Psychotic Disorders; Risperidone; Schizophrenia; Weight Gain

To review systematically data relating to weight changes with atypical antipsychotics.. We conducted a Medline search on October 29 1999 and covered the period 1980-99. All recovered papers were examined for further relevant reports. In addition, we wrote to pharmaceutical manufacturers and 10 practising clinicians to ask them to provide other relevant reports known to them.. Eighty reports mentioning change in body weight were retrieved. Data relating to weight changes were of variable quality. Weight changes were indicated by a variety of measures. The majority of reports related to short-term changes.. All atypical drugs, with the exception of ziprasidone, have been associated with weight increases. Clozapine seems to have the highest risk of weight gain, followed by olanzapine and quetiapine. There is probably a lower risk with risperidone, sertindole and zotepine and a still lower risk with amisulpride. Ziprasidone appears not to be associated with weight gain. In the absence of more compelling data, these rankings must be considered approximate and preliminary. Longer, more robust trials are needed.

Topics: Amisulpride; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Dibenzothiepins; Humans; Imidazoles; Indoles; Olanzapine; Piperazines; Pirenzepine; Quetiapine Fumarate; Risperidone; Sulpiride; Thiazoles; Weight Gain

Adverse effects of antipsychotics often lead to noncompliance. Thus, clinicians should address patients' concerns about adverse effects and attempt to choose medications that will improve their patients' quality of life as well as overall health. The side effect profiles of the atypical antipsychotics are more advantageous than those of the conventional neuroleptics. Conventional agents are associated with unwanted central nervous system effects, including extrapyramidal symptoms (EPS), tardive dyskinesia, sedation, and possible impairment of some cognitive measures, as well as cardiac effects, orthostatic hypotension, hepatic changes, anticholinergic side effects, sexual dysfunction, and weight gain. The newer atypical agents have a lower risk of EPS, but are associated in varying degrees with sedation, cardiovascular effects, anticholinergic effects, weight gain, sexual dysfunction, hepatic effects, lowered seizure threshold (primarily clozapine), and agranulocytosis (clozapine only). Since the incidence and severity of specific adverse effects differ among the various atypicals, the clinician should carefully consider which side effects are most likely to lead to the individual's dissatisfaction and noncompliance before choosing an antipsychotic for a particular patient.

Topics: Agranulocytosis; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Central Nervous System Diseases; Clozapine; Dibenzothiazepines; Drug Interactions; Dyskinesia, Drug-Induced; Health Status; Humans; Hypotension, Orthostatic; Olanzapine; Pirenzepine; Quality of Life; Quetiapine Fumarate; Receptors, Cholinergic; Risperidone; Schizophrenia; Sexual Dysfunctions, Psychological; Sleep Wake Disorders; Treatment Refusal; Weight Gain

Clinical safety data for treatment of acute schizophrenia with olanzapine, a new atypical antipsychotic agent, are summarized. The primary clinical trial safety database included 2500 patients treated with olanzapine, 810 with haloperidol, and 236 with placebo. The overall discontinuation rate from olanzapine treatment was low. Significant adverse events included somnolence, weight gain, and asymptomatic treatment-emergent transaminase elevation. Minimal parkinsonism and akathisia with rare dystonia were noted. No hematotoxicity was noted. The incidence of seizures and sexual dysfunction was rare.

Topics: Acute Disease; Akathisia, Drug-Induced; Antipsychotic Agents; Benzodiazepines; Blood Pressure; Clinical Trials as Topic; Cross-Over Studies; Dizziness; Double-Blind Method; Dystonia; Haloperidol; Heart Rate; Humans; Liver; Olanzapine; Parkinson Disease, Secondary; Pirenzepine; Placebos; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Schizophrenia; Schizophrenic Psychology; Sleep; Transaminases; Treatment Outcome; Weight Gain

Most traditional neuroleptics have a narrow therapeutic-to-toxic index, and thus, the novel antipsychotics are the result of a search to substantially widen the distance between the dose that treats psychosis and the one that produces adverse effects. In vitro binding profiles have been created for the atypical antipsychotics that have been approved by the U.S. Food and Drug Administration (FDA)-clozapine, olanzapine, and risperidone and those that are under FDA review-quetiapine and sertindole. These profiles, which were compared with that of the typical neuroleptic haloperidol, provide guidance for predicting the adverse effects produced by these drugs. Most conventional antipsychotics have central nervous system effects, particularly extrapyramidal symptoms (EPS) and tardive dyskinesia, sedation, and dulling of cognition. Other adverse effects of the typical antipsychotics include the neuroleptic malignant syndrome, orthostatic hypotension, changes in liver function, anticholinergic and antiadrenergic side effects, sexual dysfunction, and weight gain. The newer agents have a lower incidence of EPS and tardive dyskinesia, while weight gain and changes in blood pressure and liver function tests are adverse effects that have been associated with the use of the newer agents. The favorable side effect profile of these new antipsychotics is likely to make patients more willing to continue treatment, and thus these agents represent a step forward in the treatment of patients with severe, chronic mental illness.

Topics: Akathisia, Drug-Induced; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Haloperidol; Humans; Olanzapine; Parkinson Disease, Secondary; Pirenzepine; Receptors, Neurotransmitter; Seizures; Sleep; Weight Gain

Although neuroleptic drugs have become the mainstay of treating acute and chronic psychosis, they are substantially limited by troublesome side effects. The traditional neuroleptic drugs have a wide array of central nervous system and peripheral system side effects that often lead to problems in management or patient noncompliance. Of particular difficulty are the extrapyramidal symptoms and tardive dyskinesia. However, other side effects of seizures, sedation, neuroleptic malignant syndrome and cardiovascular, hematologic, endocrinological, and weight gain problems remain as clinical management challenges posed by existing antipsychotic drug therapy. Considerable progress has been made in improving the motor side effect profile with the advent of clozapine and risperidone. However, each of these drugs has its own dose-limiting side effect profile. Two new drugs, olanzapine and sertindole, are now added to the pharmacopeia for treating psychosis. They further improve the benefit/ risk ratio because they have even fewer EPS and other side effects. Overall, these new antipsychotic agents greatly improve the treatment of psychosis by reducing drug-induced morbidity and improving the quality of life for patients.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Dyskinesia, Drug-Induced; Humans; Imidazoles; Indoles; Neuroleptic Malignant Syndrome; Olanzapine; Pirenzepine; Psychotic Disorders; Risperidone; Schizophrenia; Seizures; Sleep; Weight Gain

Weight gain and adverse cardiometabolic effects often limit the clinical utility of olanzapine. In ENLIGHTEN-2, combining olanzapine with the opioid receptor antagonist samidorphan (OLZ/SAM) mitigated olanzapine-associated weight gain. These analyses tested the hypothesis that OLZ/SAM would be associated with reduced adverse cardiometabolic effects compared with olanzapine.. This phase 3 double-blind study randomized adults with schizophrenia to OLZ/SAM or olanzapine for 24 weeks. Post hoc analyses assessed changes from baseline to week 24 in cardiometabolic risk parameters, including body mass index (BMI), risk of developing obesity (BMI ≥30 kg/m2) or metabolic syndrome, waist circumference, along with mean and potentially clinically significant changes in blood pressure, glucose, and lipids.. After 24 weeks' treatment, compared with olanzapine, OLZ/SAM was associated with smaller least-squares mean (LSM) changes from baseline in systolic blood pressure (LSM difference, -2.63 mm Hg; 95% CI: -4.78, -0.47), diastolic blood pressure (LSM difference, -0.75 mm Hg; 95% CI: -2.31, 0.80), and BMI (LSM difference, -0.65 kg/m2; 95% CI: -1.01, -0.28). OLZ/SAM treatment was also associated with reduced risk of shifting from normal blood pressure to stage 1/2 hypertension (odds ratio [OR], 0.48; 95% CI: 0.24, 0.96), becoming obese (OR, 0.52; 95% CI: 0.32, 0.82), and developing metabolic syndrome (OR, 0.55; 95% CI: 0.31, 0.99) compared with olanzapine. No treatment group differences were noted for risk of hyperglycemia or hyperlipidemia.. OLZ/SAM treatment was associated with lower risk of worsening cardiometabolic risk factors related to obesity, hypertension, and metabolic syndrome relative to olanzapine. NCT02694328, https://clinicaltrials.gov/ct2/show/NCT02694328.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Cardiometabolic Risk Factors; Cardiovascular Diseases; Humans; Hypertension; Metabolic Syndrome; Obesity; Olanzapine; Weight Gain

Weight gain is a frequent side effect of treatment with SGAs (second-generation antipsychotics) and a leading cause for nonadherence. Several candidate genes have been identified that could influence the amount of AIWG (antipsychotic-induced weight gain). The polymorphism rs17782313 near the MC4R (human melanocortin 4 receptor gene) was strongly associated with obesity in a large scale GWAS (genome wide association study), yet previous studies investigating its impact on AIWG did not lead to a definite conclusion regarding its effect. In particular, they were all relatively short and had a naturalistic design.. We therefore examined the influence of the rs17782313 polymorphism on SGA-related weight gain.. Participants of a multicenter randomized, controlled, double-blind study comparing two treatment strategies in individuals with schizophrenia or schizoaffective disorder were genotyped using a rapid-cycle polymerase chain reaction. Up to 252 individuals completed the first 2 weeks (phase I), 212 the entire 8 weeks (hence 'completers'). Patients received either amisulpride or olanzapine or both consecutively. Thirty-seven had their first episode. Weight gain occurring in different genotypes was statistically compared and confounding factors were adjusted by stepwise multiple linear regression. A correction for multiple testing was included.. Within 212 'completers', carriers of the C allele had a higher absolute weight gain than those homozygous for the T allele (2.6 kg vs. 1.2 kg), though this observation was not significant (P = 0.063). In the amisulpride subpopulation, this association appeared stronger and reached significance (2.5 kg vs. 0.7 kg, P = 0.043), though failed to remain significant after correction for multiple testing. A stepwise multiple linear regression showed a significant association in both the whole study population (P < 0.001) and the amisulpride subpopulation (P < 0.001).. Our results indicate that the rs17782313 polymorphism might influence antipsychotic-induced weight gain and therefore confirm some of the earlier conclusions.

Topics: Amisulpride; Antipsychotic Agents; Genome-Wide Association Study; Humans; Olanzapine; Polymorphism, Single Nucleotide; Weight Gain

Anorexia occurs in 30%-80% of patients with advanced malignancies, which may be worsened with chemotherapy. This trial assessed the efficacy of olanzapine in stimulating appetite and improving weight gain in patients receiving chemotherapy.. Adults (≥18 years) with untreated, locally advanced, or metastatic gastric, hepatopancreaticobiliary (HPB), and lung cancers were randomly assigned (double-blind) to receive olanzapine (2.5 mg once a day for 12 weeks) or placebo along with chemotherapy. Both groups received standard nutritional assessment and dietary advice. The primary outcomes were the proportion of patients with weight gain > 5% and the improvement in appetite (assessed by the visual analog scale [VAS] and the Functional Assessment of Chronic Illness Therapy system of Quality-of-Life questionnaires Anorexia Cachexia subscale [FAACT ACS]). Secondary end points were change in nutritional status, quality of life (QOL), and chemotherapy toxicity.. We enrolled 124 patients (olanzapine, 63 and placebo, 61) with a median age of 55 years (18-78 years), of whom 112 (olanzapine, 58 and placebo, 54) were analyzable. The majority (n = 99, 80%) had metastatic cancer (gastric [n = 68, 55%] > lung [n = 43, 35%] > HPB [n = 13, 10%]). The olanzapine arm had a greater proportion of patients with a weight gain of > 5% (35 of 58 [60%]. Low-dose, daily olanzapine is a simple, inexpensive, well-tolerated intervention that significantly improves appetite and weight gain in newly diagnosed patients on chemotherapy.

Topics: Adult; Anorexia; Double-Blind Method; Humans; Lung Neoplasms; Middle Aged; Olanzapine; Quality of Life; Weight Gain

Antipsychotic-induced weight gain is associated with alterations to the composition of the gut microbiota. The purpose of this study was to determine the effect of probiotics plus dietary fiber on antipsychotic-induced weight gain.. Two sequential, randomized clinical trials were conducted. In Study 1, 90 drug-naïve, first-episode schizophrenia patients were randomized to receive either olanzapine plus probiotics or olanzapine monotherapy for 12 weeks. In Study 2, 60 drug-naïve, first-episode schizophrenia patients were randomly assigned to receive either olanzapine plus probiotics and dietary fiber or olanzapine monotherapy for 12 weeks.. In Study 1, no significant differences in weight gain were observed between the two groups. The insulin resistance index (IRI) was lower in the olanzapine plus probiotics group compared with the olanzapine monotherapy group at week 12 (estimated mean difference, -0.65, [95% confidence interval (CI), -1.10 to -0.20]; p = .005). In Study 2, weight gain was lower in the probiotics plus dietary fiber group than in the olanzapine monotherapy group at week 12 (estimated mean difference -3.45 kg, [95% CI, -5.91 to -1.00]; p = .007). At week 12, IRI increased significantly in the olanzapine monotherapy group (mean, 1.74; standard deviation (SD) = 1.11, p < .001), but not in the olanzapine plus probiotics and dietary fiber group (mean 0.47, SD = 2.16, p = .35) with an estimated mean difference of -0.95 between the two groups [95% CI, -1.77 to -0.14]; p = .022).. These results provide support for the efficacy and safety of probiotics plus dietary fiber in attenuating antipsychotic-induced weight gain in drug-naïve, first-episode schizophrenia patients.

Topics: Antipsychotic Agents; Dietary Fiber; Humans; Olanzapine; Probiotics; Schizophrenia; Weight Gain

A combination of olanzapine and the opioid receptor antagonist samidorphan is under development for the treatment of schizophrenia and bipolar I disorder. The single-tablet combination treatment is intended to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain. In this phase 3 double-blind trial, the authors evaluated the weight profile of combined olanzapine/samidorphan compared with olanzapine in patients with schizophrenia.. Adults (ages 18‒55 years) with schizophrenia were randomly assigned to receive either combination treatment with olanzapine and samidorphan or olanzapine treatment for 24 weeks. Primary endpoints were percent change from baseline in body weight and proportion of patients with ≥10% weight gain at week 24. The key secondary endpoint was the proportion of patients with ≥7% weight gain. Waist circumference and fasting metabolic laboratory parameters were also measured.. Of 561 patients who underwent randomization (olanzapine/samidorphan combination, N=280; olanzapine, N=281), 538 had at least one postbaseline weight assessment. At week 24, the least squares mean percent weight change from baseline was 4.21% (SE=0.68) in the olanzapine/samidorphan group and 6.59% (SE=0.67) in the olanzapine group (the difference of -2.38% [SE=0.76] was significant). Significantly fewer patients in the olanzapine/samidorphan combination group compared with the olanzapine group had weight gain ≥10% (17.8% and 29.8%, respectively; number needed to treat [NNT]=7.29; odds ratio=0.50) and weight gain ≥7% (27.5% and 42.7%, respectively; NNT=6.29; odds ratio=0.50). Increases in waist circumference were smaller in the olanzapine/samidorphan combination group compared with the olanzapine group. Schizophrenia symptom improvement was similar between treatment groups. Adverse events (in ≥10% of the groups) in the olanzapine/samidorphan and olanzapine groups included weight gain (24.8% and 36.2%), somnolence (21.2% and 18.1%), dry mouth (12.8% and 8.0%), and increased appetite (10.9% and 12.3%). Metabolic changes were small and similar between treatments.. Olanzapine/samidorphan combination treatment was associated with significantly less weight gain and smaller increases in waist circumference than olanzapine and was well tolerated. The antipsychotic efficacy of the combination treatment was similar to that of olanzapine monotherapy.

Topics: Adolescent; Adult; Antipsychotic Agents; Double-Blind Method; Drug Combinations; Female; Humans; Male; Middle Aged; Naltrexone; Narcotic Antagonists; Olanzapine; Schizophrenia; Weight Gain; Young Adult

Amisulpride, aripiprazole, and olanzapine are first-line atypical antipsychotics that have not previously been compared head-to-head in a pragmatic trial. We aimed to compare the efficacy and safety of these agents in a controlled trial.. This pragmatic, rater-blind, randomised controlled trial was done in three academic centres of psychiatry in Norway, and one in Austria. Eligible patients were aged 18 years or older, met ICD-10 criteria for schizophrenia-spectrum disorders (F20-29), and had symptoms of active psychosis. Eligible patients were randomly assigned to receive oral amisulpride, aripiprazole, or olanzapine. Treatment allocation was open to patients and staff, and starting dose, treatment changes, and adjustments were left to the discretion of the treating physician. Computer-generated randomisation lists for each study centre were prepared by independent statisticians. Patients were followed up for 52 weeks after random assignment, during which assessments were done 8 times by researchers masked to treatment. The primary outcome was reduction of the Positive And Negative Syndrome Scale (PANSS) total score at 52 weeks, and primary analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01446328.. Between Oct 20, 2011, and Dec 30, 2016, we assessed 359 patients for eligibility. 215 patients were excluded (107 did not meet inclusion criteria, 82 declined to participate, 26 other reasons). 144 patients (mean baseline PANSS total estimated score 78·4 [SD 1·4]) were randomly assigned 1:1:1 to receive amisulpride (44 patients), aripiprazole (48 patients) or olanzapine (52 patients). After 52 weeks, the patients allocated to amisulpride had a PANSS total score reduction of 32·7 points (SD 3·1) compared with 21·9 points reduction with aripiprazole (SD 3·9, p=0·027) and 23·3 points with olanzapine (2·9, p=0·025). We observed weight gain and increases of serum lipids and prolactin in all groups. 26 serious adverse events (SAEs) among 20 patients were registered (four [9%] of 44 patients allocated to amisulpride, ten [21%] of 48 patients allocated to aripiprazole, and six [12%] of 52 patients allocated to olanzapine), with no statistically significant differences between the study drugs. 17 (65%) of the 26 SAEs occurred during the use of the study drug, with readmission or protracted hospital admission accounting for 13 SAEs. One death by suicide, one unspecified death, and one life-threatening accident occurred during follow-up, after cessation of treatment.. Amisulpride was more efficacious than aripiprazole or olanzapine for reducing the PANSS total scores in adults with schizophrenia-spectrum disorders. Side-effect differences among the groups were generally small. This study supports the notion that clinically relevant efficacy differences exist between antipsychotic drugs. Future research should aim to compare first-line antipsychotics directly in pragmatic clinical trials that reflect everyday clinical practice.. The Research Council of Norway, the Western Norway Regional Health Trust, and participating hospitals and universities.

Topics: Adolescent; Adult; Aged; Amisulpride; Antipsychotic Agents; Aripiprazole; Female; Humans; Male; Middle Aged; Norway; Olanzapine; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Treatment Outcome; Weight Gain; Young Adult

The study objective was to examine whether and when antipsychotic-induced weight gain in first episode psychosis (FEP) stabilizes over a 12-month exposure to the same antipsychotic in a sample of previously untreated FEP patients.. In this prospective naturalistic outcome study, 109 patients diagnosed with non-affective or affective psychosis (DSM-IV) were treated with the same antipsychotic medication (olanzapine n = 45, risperidone n = 39, or aripiprazole n = 25) throughout the first year of treatment. Body weight was measured and body mass index calculated at baseline and 1, 2, 3, 6, 9, and 12 months. Additional weight data over the second year were available, making extending the comparison for a second year possible.. Linear mixed model analysis showed a significant main effect of time (Type III test P < .001) after adjusting for baseline weight values. Post hoc pairwise comparisons showed that incremental weight changes subsequent to month 6 were insignificant, suggesting weight stabilization by month 9. No significant difference (P = .243) between groups or time × group interaction (P = .111) was observed. Similar findings were obtained with BMI. A follow-up analysis, of a subsample who continued treatment with the same antipsychotic for an additional 12 months (n = 57), confirmed weight stabilization in the second year. There was no significant main effect of time (P = .641), group (P = .539), or time × group interaction (P = .250).. Antipsychotic-induced weight gain occurs mostly in the first few months of treatment. Preventive interventions concurrent to second-generation antipsychotic treatment initiation in medication-naive FEP patients might be warranted.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Body Mass Index; Female; Humans; Male; Olanzapine; Prospective Studies; Psychotic Disorders; Risperidone; Time Factors; Weight Gain; Young Adult

Second-generation antipsychotics are associated with moderate benefits in terms of improved schizophrenia symptoms, but also with higher rates of side-effects such as excessive weight gain (WG); a consensus on their efficacy has not been reached. To date, no study has evaluated the interplay of treatments and side-effects in a single framework, which is a critical step to clarify the role of side-effects in explaining the efficacy of these antipsychotics. We used recent methods for mediation and interaction to clarify the role of WG in explaining the effects of second-generation drugs on schizophrenia symptoms. We used data from 1460 participants in the CATIE trial, assigned to either perphenazine (first-generation comparison drug), olanzapine, quetiapine, risperidone, or ziprasidone. The primary outcome was an individual's score on the Positive and Negative Syndrome Scale (PANSS) for symptoms of schizophrenia after 9 months, separately evaluated as positive (PANSS+), negative (PANSS-), and total PANSS score. WG after 6 months was investigated as a potential mediator and effect modifier. Results showed that, by limiting WG, patients would benefit of a considerably better improvement in terms of PANSS symptoms. In the scenario of weight change being controlled between -2% and 1% for all participants, patients assigned to olanzapine would experience the highest significant improvements in both PANSS+ (-2.66 points; 95% CI: -4.98, -0.35), PANSS- (-1.59; 95% CI: -4.31, 1.14), and total PANSS (-6.11; 95% CI: -13.13, 0.92). In conclusion, occurrence of excessive WG hampers the potentially beneficial effects of second-generation antipsychotics, thus suggesting future directions for treatment and interventions.

Topics: Adult; Antipsychotic Agents; Body-Weight Trajectory; Female; Humans; Male; Middle Aged; Olanzapine; Perphenazine; Piperazines; Quetiapine Fumarate; Risperidone; Schizophrenia; Schizophrenic Psychology; Thiazoles; Treatment Outcome; Weight Gain

This study evaluated the benefits of olanzapine compared with placebo for adult outpatients with anorexia nervosa.. This randomized double-blind placebo-controlled trial of adult outpatients with anorexia nervosa (N=152, 96% of whom were women; the sample's mean body mass index [BMI] was 16.7) was conducted at five sites in North America. Participants were randomly assigned in a 1:1 ratio to receive olanzapine or placebo and were seen weekly for 16 weeks. The primary outcome measures were rate of change in body weight and rate of change in obsessionality, assessed with the Yale-Brown Obsessive Compulsive Scale (YBOCS).. Seventy-five participants were assigned to receive olanzapine and 77 to receive placebo. A statistically significant treatment-by-time interaction was observed, indicating that the increase in BMI over time was greater in the olanzapine group (0.259 [SD=0.051] compared with 0.095 [SD=0.053] per month). There was no significant difference between treatment groups in change in the YBOCS obsessions subscale score over time (-0.325 compared with -0.017 points per month) and there were no significant differences between groups in the frequency of abnormalities on blood tests assessing potential metabolic disturbances.. This study documented a modest therapeutic effect of olanzapine compared with placebo on weight in adult outpatients with anorexia nervosa, but no significant benefit for psychological symptoms. Nevertheless, the finding on weight is notable, as achieving change in weight is notoriously challenging in this disorder.

Topics: Adolescent; Adult; Ambulatory Care; Anorexia Nervosa; Body Mass Index; Double-Blind Method; Female; Humans; Male; Middle Aged; Obsessive Behavior; Olanzapine; Selective Serotonin Reuptake Inhibitors; Time Factors; Weight Gain; Young Adult

Preclinical evidence and data from a proof-of-concept study in healthy volunteers suggest that samidorphan, an opioid antagonist, mitigates weight gain associated with olanzapine. This study prospectively compared combination therapy of olanzapine plus either samidorphan or placebo for the treatment of schizophrenia.. This was an international, multicenter, randomized phase 2 study of olanzapine plus samidorphan in patients with schizophrenia. The study had a 1-week open-label olanzapine lead-in period followed by a 12-week double-blind treatment phase in which patients were randomly assigned in a 1:1:1:1 ratio to receive olanzapine plus placebo (N=75) or olanzapine plus 5 mg (N=80), 10 mg (N=86), or 20 mg (N=68) of samidorphan. The primary aims were to confirm that the antipsychotic efficacy of olanzapine plus samidorphan was comparable to olanzapine plus placebo, to assess the effect of combining olanzapine with samidorphan on olanzapine-induced weight gain, and to assess the overall safety and tolerability of olanzapine plus samidorphan.. Antipsychotic efficacy, as assessed by total score on the Positive and Negative Syndrome Scale (PANSS), was equivalent across all treatment groups. Treatment with olanzapine plus samidorphan resulted in a statistically significant lower weight gain (37% lower weight gain compared with olanzapine plus placebo). The least square mean percent change from baseline in body weight was 4.1% (2.9 kg) for the olanzapine plus placebo group and 2.6% (1.9 kg) for the olanzapine plus samidorphan group (2.8% [2.1 kg] for the 5 mg group, 2.1% [1.5 kg] for the 10 mg group, and 2.9% [2.2 kg] for the 20 mg group). Adverse events reported at a frequency ≥5% in any of the olanzapine plus samidorphan groups and occurring at a rate ≥2 times greater than in the olanzapine plus placebo group were somnolence, sedation, dizziness, and constipation. Other safety measures were comparable between the olanzapine plus samidorphan groups and the olanzapine plus placebo group.. The antipsychotic efficacy of olanzapine plus samidorphan was equivalent to that of olanzapine plus placebo, and olanzapine plus samidorphan was associated with clinically meaningful and statistically significant mitigation of weight gain compared with olanzapine plus placebo. Olanzapine plus samidorphan was generally well tolerated, with a safety profile similar to olanzapine plus placebo.

Topics: Adult; Antipsychotic Agents; Constipation; Dizziness; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Least-Squares Analysis; Male; Middle Aged; Naltrexone; Narcotic Antagonists; Olanzapine; Schizophrenia; Sleepiness; Weight Gain

A combination of the atypical antipsychotic olanzapine and opioid receptor antagonist samidorphan (OLZ/SAM) is in development for the treatment of schizophrenia. The goal of OLZ/SAM is to provide the antipsychotic efficacy of olanzapine while mitigating olanzapine-induced weight gain and many associated long-term metabolic consequences. The primary metabolic pathways for olanzapine are direct glucuronidation via uridine 5'-diphospho-glucuronosyltransferase (UGT)1A4 and cytochrome P450 (CYP)-mediated oxidation, mainly by CYP1A2. In contrast, the samidorphan metabolic pathway is mediated predominantly by CYP3A4.. The aim of this study was to evaluate the effects of CYP3A4 induction on the single-dose pharmacokinetics of OLZ/SAM in healthy subjects.. In this phase I, single-center, open-label, two-period study, 24 healthy volunteers received a single oral dose of OLZ/SAM 10/10 (10 mg olanzapine/10 mg samidorphan) on day 1. After a 14-day washout, 600 mg of rifampin (rifampicin), a strong CYP3A4 inducer, as well as an inducer of UGT enzymes and a weak inducer of CYP1A2, was administered once daily on days 15‒21. A single oral dose of OLZ/SAM 10/10 was coadministered with rifampin 600 mg on day 22. Olanzapine and samidorphan pharmacokinetic parameters were determined after OLZ/SAM dosing on days 1 and 22. The geometric mean ratio of maximum plasma concentration (C. Coadministration with rifampin decreased total systemic exposure (based on AUC

Topics: Adult; Antipsychotic Agents; Cytochrome P-450 CYP3A Inducers; Drug Interactions; Drug Therapy, Combination; Female; Healthy Volunteers; Humans; Male; Middle Aged; Naltrexone; Narcotic Antagonists; Olanzapine; Rifampin; Weight Gain; Young Adult

Antipsychotic induced weight gain is a frequent reason for treatment discontinuation in psychosis, subsequently increasing the risk of relapse and negatively affecting patient well-being. The metabolic effect of weight gain and the subsequent risk of obesity constitute a major medical problem on the long term. Despite its consequences, to date few risk factors have been identified (age, gender, body mass index at baseline), with some authors suggesting the implication of early life stressful events, such as perinatal conditions. We aim to describe if a surrogate marker of intrauterine environment (birth weight) might predict weight gain in a cohort of 23 antipsychotic naïve patients at the onset of the psychotic disease evaluated during 16 weeks with olanzapine treatment and in another cohort of 24 psychosis-resistant patients initiating clozapine assessed for 18 weeks. Two independent linear mixed model analyses were performed in each cohort of patients, with prospective weight gain as the dependent variable, age, gender, body mass index, duration of treatment and time as independent variables. Only in naïve patients, weight gain due to antipsychotics was significantly associated with birth weight, while male gender and body mass index at baseline were associated in both cohorts of patients. Treatment-resistant psychotic patients under clozapine were older, had previous antipsychotic treatment and more years of disease, confounders that might have influence a non significant association. Our results suggest that early environmental events might be playing a role in weight evolution in naïve patients treated with antipsychotics.

Topics: Adult; Antipsychotic Agents; Birth Weight; Body Mass Index; Clozapine; Cohort Studies; Female; Humans; Male; Models, Biological; Olanzapine; Pregnancy; Prenatal Exposure Delayed Effects; Psychotic Disorders; Sex Factors; Weight Gain; Young Adult

It is unknown whether there are differences in efficacy and safety between quetiapine extended-release, 300 mg/d (QUEXR300), and olanzapine, 5-20 mg/d (OLA), for Japanese patients with bipolar depression.. We conducted a Bayesian analysis of data from phase 3 studies in Japan of QUEXR300 and OLA. Outcomes were remission rate (primary), response rate, improvement on the Montgomery-Åsberg Depression Rating Scale and 17-item Hamilton Depression Rating Scale scores, discontinuation rate, and incidence of individual adverse events. We calculated the standardized mean difference (SMD) and the risk ratio (RR) and 95% credible interval (95% CrI) for continuous and dichotomous data, respectively.. There were no significant differences between QUEXR300 and OLA for any of the efficacy outcomes. QUEXR300 was associated with a higher incidence of somnolence than OLA (RR = 5.517; 95% CrI = 1.563, 19.787), while OLA was associated with greater increase body weight (SMD = -0.488; 95% CrI = -0.881, -0.089) and blood prolactin levels (SMD = -0.642; 95% CrI = -1.073, -0.213) than QUEXR300, and a greater decrease in high-density lipoprotein cholesterol levels (SMD = -0.408; 95% CrI = -0.785, -0.030) than QUEXR300.. Although the two drugs' efficacy did not differ, OLA increased the risk of metabolic syndrome and QUEXR300 the risk of somnolence. A large scale, long-term, head-to-head comparison study of QUEXR300 vs OLA for Japanese patients with bipolar depression is needed to confirm the results of the current study.

Topics: Adolescent; Adult; Antipsychotic Agents; Bayes Theorem; Bipolar Disorder; Cholesterol, HDL; Delayed-Action Preparations; Female; Humans; Japan; Male; Metabolic Syndrome; Middle Aged; Olanzapine; Prolactin; Quetiapine Fumarate; Weight Gain

Antipsychotic medications are associated with weight gain and adverse metabolic effects that complicate the treatment and management of schizophrenia. Olanzapine (OLZ) in particular is associated with significant weight gain and adverse metabolic effects. The present Phase 1, proof of concept, multicenter, randomized, double-blind, placebo-controlled study investigated the safety and effect on weight of a combination of OLZ (10mg) and the opioid modulator samidorphan (SAM; 5mg) in comparison to OLZ alone in healthy, male normal weight volunteers. Altogether, 106 male subjects with stable body weight and BMI 18-25kg/m

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Double-Blind Method; Female; Healthy Volunteers; Humans; Male; Naltrexone; Narcotic Antagonists; Olanzapine; Time Factors; Weight Gain; Young Adult

Atypical antipsychotic drugs have been associated with the development of obesity and diabetes. In particular, olanzapine can induce peripheral insulin resistance and compensatory hyperinsulinemia independent of weight gain or psychiatric disease. To determine if this compensatory increase in insulin is mediated by parasympathetic muscarinic stimulation, we randomized 15 healthy subjects 2:1 to receive double-blind olanzapine or placebo for 9 days under diet- and activity-controlled inpatient conditions. Before and after 7 days of study drug administration, subjects underwent frequently sampled intravenous glucose tolerance tests with either saline or atropine infused on subsequent days to assess insulin secretion and hepatic insulin extraction in the absence or presence of muscarinic blockade. We found that olanzapine led to an increase in the acute insulin response to glucose, which was not seen with placebo, and was attenuated in the olanzapine group by atropine. Deconvolution of C-peptide data confirmed an increase in insulin secretion with olanzapine, which was blocked by atropine, with a modest reduction in hepatic insulin extraction with olanzapine. These results support the contribution of muscarinic augmentation of insulin secretion to olanzapine-induced hyperinsulinemia, and provide a mechanism for the compensatory hyperinsulinemia that normally serves to prevent deterioration of glucose tolerance under conditions of metabolic challenge.

Topics: Adolescent; Adult; Antipsychotic Agents; C-Peptide; Diet; Double-Blind Method; Female; Glucose Tolerance Test; Healthy Volunteers; Humans; Hyperinsulinism; Insulin Secretion; Liver; Male; Muscarinic Antagonists; Olanzapine; Weight Gain; Young Adult

Second generation antipsychotics are prescribed for an increasing number of psychiatric conditions, despite variable associations with weight gain, dyslipidemia, and impaired glucose tolerance. The mechanism(s) of the apparent causal relationships between these medications and metabolic effects have been inadequately defined and are potentially confounded by genetic risk of mental illness, attendant lifestyle, and concomitant medications. Therefore, we conducted a study in which 24 healthy volunteers were randomized to olanzapine (highly weight-gain liability), iloperidone (less weight-gain liability), or placebo treatment for 28 days under double-blind conditions. We hypothesized that antipsychotics induce weight gain primarily through increased caloric intake, which causes secondary dyslipidemia and insulin resistance. Subjects were phenotyped pre- and post-treatment for body weight, adiposity by dual energy X-ray absorptiometry, energy expenditure by indirect calorimetry, food intake, oral glucose tolerance, plasma lipids, glucose, insulin, and other hormones. We found significantly increased food intake and body weight but no change in energy expenditure in olanzapine-treated subjects, with associated trends towards lipid abnormalities and insulin resistance the extent of which were presumably limited by the duration of treatment. Iloperidone treatment led to modest non-significant and placebo no weightgain, lipid increases and alterations in insulin metabolism. We conclude that second generation antipsychotic drugs, as represented by olanzapine, produce their weight and metabolic effects, predominantly, by increasing food intake which leads to weight gain that in turn induces metabolic consequences, but also through other direct effects on lipid and glucose metabolism independant of food intake and weight gain.

Topics: Adolescent; Adult; Antipsychotic Agents; Blood Glucose; Body Weight; Double-Blind Method; Dyslipidemias; Eating; Energy Metabolism; Female; Glucose Tolerance Test; Healthy Volunteers; Humans; Insulin; Insulin Resistance; Isoxazoles; Lipids; Male; Obesity; Olanzapine; Piperidines; Weight Gain; Young Adult

The aim of this study was to determine whether weight changes at week 2 or other factors predicted weight gain at week 6 for schizophrenia patients receiving olanzapine. This study was the secondary analysis of a six-week trial for 94 patients receiving olanzapine (5 mg/d) plus trifluoperazine (5 mg/d), or olanzapine (10 mg/d) alone. Patients were included in analysis only if they had completed the 6-week trial (per protocol analysis). Weight gain was defined as a 7% or greater increase of the patient's baseline weight. The receiver operating characteristic curve was employed to determine the optimal cutoff points of statistically significant predictors. Eleven of the 67 patients completing the 6-week trial were classified as weight gainers. Weight change at week 2 was the statistically significant predictor for ultimate weight gain at week 6. A weight change of 1.0 kg at week 2 appeared to be the optimal cutoff point, with a sensitivity of 0.92, a specificity of 0.75, and an AUC of 0.85. Using weight change at week 2 to predict weight gain at week 6 is favorable in terms of both specificity and sensitivity. Weight change of 1.0 kg or more at 2 weeks is a reliable predictor.

Topics: Adult; Antipsychotic Agents; Body Weight; Double-Blind Method; Female; Humans; Male; Middle Aged; Olanzapine; Predictive Value of Tests; Schizophrenia; Weight Gain

ALKS 3831 is composed of a flexible dose of olanzapine and a fixed dose of 10-mg samidorphan (a novel opioid system modulator), designed to provide the established antipsychotic efficacy of olanzapine and to mitigate olanzapine-induced weight gain. To support clinical development of ALKS 3831, we conducted a multicenter, randomized, open-label, Phase I study to obtain steady-state exposure for olanzapine and samidorphan and short-term safety at the intended therapeutic dose range of ALKS 3831 10/10 (10-mg olanzapine/10-mg samidorphan) to ALKS 3831 20/10 (20-mg olanzapine/10-mg samidorphan) in subjects with schizophrenia.. After a 1-week olanzapine lead-in period, 42 subjects (14 women) with schizophrenia were randomly assigned (1:1) to receive ALKS 3831 10/10 or ALKS 3831 20/10 bilayer oral tablets once daily for 14 days. Plasma concentrations of olanzapine and samidorphan were quantified by using an LC-MS/MS method. Pharmacokinetic parameters were calculated according to noncompartmental analysis. Safety was monitored throughout the study.. After a 1-week olanzapine lead-in phase with titration of olanzapine dose up to 15 mg/d, the steady-state concentration of olanzapine was reached in 3-4 days and that of samidorphan was reached in 5 days after initiation of once-daily oral administration of ALKS 3831 10/10 or ALKS 3831 20/10. At steady state, exposure to olanzapine increased dose proportionally from 10 mg (ALKS 3831 10/10) to 20 mg (ALKS 3831 20/10), and exposure to samidorphan was similar between the 2 ALKS 3831 dose groups, indicating that different dose levels of olanzapine in ALKS 3831 had no impact on the pharmacokinetic profile of samidorphan. ALKS 3831 was well tolerated, and no safety concerns unique to ALKS 3831 compared with olanzapine monotherapy were identified.. In the present study, samidorphan exposure was not affected by different dose levels of olanzapine in ALKS 3831. In addition, olanzapine exposure as a component of ALKS 3831 was comparable with previously published data for olanzapine monotherapy. The present data indicate that combining olanzapine with samidorphan does not affect the pharmacokinetic profile of either drug and support continued clinical evaluation of ALKS 3831. ClinicalTrials.gov identifier: NCT02804568.

Topics: Administration, Oral; Adult; Antipsychotic Agents; Chromatography, Liquid; Drug Combinations; Female; Humans; Male; Middle Aged; Naltrexone; Olanzapine; Schizophrenia; Tandem Mass Spectrometry; Weight Gain

Weight gain during treatment with antipsychotics is a prominent side-effect, especially with some second-generation antipsychotics, such as olanzapine and clozapine, and pharmacological treatments which ameliorate this side-effect are important to investigate. Decreases in histaminergic transmission in the brain induced by antipsychotics may be one of the mechanisms contributing to weight gain. Since betahistine is a histaminergic agonist, it may potentially counteract the weight gain effects of antipsychotics.. We conducted a double-blind placebo-controlled study to evaluate the effects of 12 weeks of treatment with betahistine (N = 29) or placebo (N = 22) in adolescents and adults on anthropomorphically measured weight-related parameters, appetite, and fasting glucose-lipid and leptin levels in 51 patients treated with first and/or second-generation antipsychotics who had gained weight during treatment or had high body-mass-index (BMI). Psychopathology and side-effects were also assessed with relevant scales.. In a sub-group of patients being treated with olanzapine or clozapine (n = 26), betahistine was significantly (P < .05) better than placebo in preventing increases in weight (3.1 kg less weight gain than placebo), BMI, and waist circumference. Betahistine did not decrease weight or BMI in patients treated with other antipsychotics. There was also no effect of betahistine on preventing weight or BMI gain in the total combined sample of all subjects. Betahistine did not significantly improve appetite or glucose-lipid measures in either subgroup. There were no significant differences in side-effects or psychopathology changes in the betahistine- vs. placebo-treated patients.. These results suggest that betahistine may potentially be a useful adjunctive drug for decreasing weight gain in patients treated with antipsychotics that are potent histamine antagonists, such as olanzapine or clozapine, but may not be useful for this purpose in patients on other antipsychotic medications. The results justify larger placebo-controlled studies to further confirm these effects before specific recommendations can be made for routine use.

Topics: Adolescent; Adult; Antipsychotic Agents; Betahistine; Body Mass Index; Body Weight; Child; Clozapine; Double-Blind Method; Female; Histamine Agonists; Humans; Male; Olanzapine; Schizophrenia; Treatment Outcome; Weight Gain; Young Adult

We aimed to evaluate melatonin effectiveness in weight gain reduction following olanzapine use for 11-17-year-old bipolar disorder patients.. Seventy-seven adolescent outpatients, subsequent to their initial diagnosis of bipolar I disorder by a psychiatrist, entered this study. After assessing inclusion and exclusion criteria, 48 patients consented to participate. Twenty-four patients were allocated to receive olanzapine, lithium carbonate, and melatonin, and 24 patients were allocated to receive olanzapine, lithium carbonate, and placebo by simple randomization. The Young Mania Rating Scale (YMRS) was performed at baseline. Before treatment and after 6 and 12 weeks of treatment, weight, height, and body mass index (BMI) were measured. Analysis of variance (ANOVA) with repeated measure and t-test were used to analyze data.. Nineteen patients in each group finished the study and their data were entered for analysis. Mean rise in BMI in the melatonin group compared with placebo (2.45 vs. 3.25 respectively) was marginally significant (t = 1.936; df = 36; p = 0.061). ANOVA with repeated measure also showed a marginally significant difference (F = 3.74; df = 1; p = 0.061) between groups and across time in regard to BMI. Mean body weight rise in the melatonin group compared with the placebo group (5.8 kg vs. 8.2 kg respectively) was marginally significant (t = 1.923; df = 28; p = 0.065). ANOVA with repeated measure also showed a marginally significant difference (F = 3.73; df = 1.1; p = 0.056) between groups and across time for body weight.. Coadministration of melatonin with olanzapine and lithium carbonate in adolescents with bipolar disorder could reduce the sharp weight gain side effect of these drugs to near significance.

Topics: Adolescent; Antimanic Agents; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Body Weight; Child; Double-Blind Method; Humans; Lithium Carbonate; Male; Melatonin; Olanzapine; Psychiatric Status Rating Scales; Time Factors; Weight Gain

Asenapine is a new second-generation antipsychotic that is understudied in borderline personality disorder (BPD). Only one study investigating the use of the drug in this indication (an open-label pilot study) has been conducted to date.. The present open-label, randomized, controlled trial aimed to evaluate the efficacy and tolerability of asenapine in comparison with olanzapine, the most broadly studied antipsychotic in BPD.. A total of 51 outpatients aged between 18 and 50 years with a diagnosis of BPD based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria were assigned for 12 weeks to asenapine (5-10 mg/day) or olanzapine (5-10 mg/day). Participants were assessed at baseline and after 12 weeks with the following instruments: the Clinical Global Impression Scale, Severity item (CGI-S), Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A), Social Occupational Functioning Assessment Scale (SOFAS), Borderline Personality Disorder Severity Index (BPDSI), Barratt Impulsiveness Scale, version 11 (BIS-11), Modified Overt Aggression Scale (MOAS), Self-Harm Inventory (SHI), and Dosage Record and Treatment Emergent Symptom Scale (DOTES). Analysis of variance repeated measures was performed. Intention-to-treat analysis with last observation carried forward was conducted.. There were 11 drop-outs (21.57%): six patients taking asenapine and five patients receiving olanzapine. Two patients who received asenapine stopped the drug, one due to oral hypoesthesia and the other due to moderate anxiety. Two patients receiving olanzapine discontinued the treatment because of significant weight gain (≥3 kg). The remaining seven drop-outs resulted from the lack of compliance with the trial prescription. Forty out of the 51 patients (78%) completed the trial: 19 patients received asenapine, while 21 patients received olanzapine. We found a significant within-subject effect (trial duration) for all rating scales, except from the HAM-D, the MOAS, and two items of the BPDSI, namely, "identity disturbance" and "parasuicidal behaviors." A significant effect between subjects was found for the two items of the BPDSI "affective instability" and "dissociation/paranoid ideation." Asenapine was found superior to olanzapine in reducing the affective instability score (P = 0.001), whereas olanzapine was found superior to asenapine in reducing dissociation/paranoid ideation (P = 0.012). However, the study was found to be underpowered to detect a difference between the drugs on the dissociation/paranoid ideation item of the BPDSI. Two patients receiving asenapine experienced akathisia and another two restlessness/anxiety, while three patients receiving olanzapine reported somnolence and two fatigue.. Asenapine and olanzapine were demonstrated to have a similar efficacy. While asenapine was found to be more efficacious than olanzapine in treating affective instability, olanzapine was superior to asenapine in treating paranoid ideation and dissociation. However, the study was underpowered to detect a difference between groups on the dissociation/paranoid ideation item. Both medications were well tolerated, with asenapine being related to a higher frequency of oral hypoesthesia and akathisia, and olanzapine being prone to induce weight gain. The open-label study design, lack of a placebo group, and small sample size constitute major limitations of this trial. Our findings need to be replicated in further studies. Clinical Trials Registry code: ACTRN12614000551695.

Topics: Adolescent; Adult; Akathisia, Drug-Induced; Antipsychotic Agents; Benzodiazepines; Borderline Personality Disorder; Dibenzocycloheptenes; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Hypesthesia; Male; Middle Aged; Olanzapine; Psychiatric Status Rating Scales; Severity of Illness Index; Treatment Outcome; Weight Gain; Young Adult

This study compares the efficacy and tolerability of olanzapine versus risperidone among patients with schizophrenia who are established in outpatient psychiatric care and entering supported employment. A multicenter, randomized, double-blind trial was conducted among 107 outpatients with schizophrenia, who were cross-titrated to flexible dose risperidone or olanzapine over 2 weeks. Clinical endpoints included time to hospitalization and persistence on assigned medication. Weight, laboratory tests, psychopathology, neurologic side effects, social adjustment and role functioning were assessed at 3-6 month intervals. Data were analyzed first by randomized treatment, and then reassessed controlling for prior medication treatment. The proportion of patients on assigned medication at 18 months was 30.9% for risperidone and 37.3% for olanzapine. Mean doses were 6.4 ± 3.2 mg daily for risperidone, and 17.0 ± 5.0 mg daily for olanzapine. The groups did not differ significantly in time to medication discontinuation, first hospitalization or first employment. There were few differences in psychopathology, laboratory, or neurological assessments between groups at 18 months. Patients randomized to olanzapine gained modestly more weight. Controlling for pre-randomization medication suggested improvement in some aspects of psychopathology from switching medications; however, switching from olanzapine to risperidone was associated with more hospitalizations. Risperidone and olanzapine have similar efficacy and tolerability in patients with schizophrenia who are participating in supported employment. Randomization to olanzapine was associated with more weight gain, but randomization from olanzapine to risperidone appeared to be associated with a greater likelihood of hospitalization. Careful monitoring of metabolic effects and participation in supported employment may have contributed to minimal weight gain and metabolic effects.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Double-Blind Method; Employment, Supported; Female; Humans; Male; Middle Aged; Olanzapine; Outcome Assessment, Health Care; Risperidone; Schizophrenia; Weight Gain

Evaluate the efficacy and safety of asenapine 2.5 mg twice daily (bid; n=97) or 5 mg bid (n=113) versus placebo (n=101) in adults with acute exacerbation of schizophrenia.. Adults with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) schizophrenia diagnosis were randomized to asenapine 2.5 mg bid, 5 mg bid, placebo, or olanzapine 15 mg once daily. The primary objective was to test superiority of asenapine versus placebo as measured by the change from baseline to day 42 in the Positive and Negative Syndrome Scale (PANSS) total score. The key safety objective was to evaluate weight change in asenapine versus olanzapine at day 42.. The primary efficacy endpoint was met; the difference in least squares mean change from baseline to day 42 in PANSS total score between asenapine 5 mg bid and placebo was -5.5 points (unadjusted 95% CI: -10.1, -1.0; multiplicity adjusted P=0.0356). Neither asenapine 2.5 mg bid nor olanzapine 15mg were superior to placebo. Both asenapine groups demonstrated significantly less weight gain than olanzapine at day 42. Significantly higher incidences of oral hypoesthesia and dysgeusia (combined) for asenapine 2.5 mg bid (5.2% vs 0.0%; P=0.0217) and 5 mg bid (7.1% vs 0.0%; P=0.0033) were observed versus placebo. There were no significant differences between asenapine and placebo for insomnia, extrapyramidal symptoms, akathisia, dizziness, or combination of somnolence/sedation/hypersomnia.. This study supports previous efficacy and safety findings of asenapine; asenapine 5 mg bid is the lowest effective dose in adults with schizophrenia. Asenapine was associated with significantly less weight gain than olanzapine at day 42.

Topics: Adult; Akathisia, Drug-Induced; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Dibenzocycloheptenes; Disease Progression; Disorders of Excessive Somnolence; Dizziness; Double-Blind Method; Dysgeusia; Europe; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Hypesthesia; Least-Squares Analysis; Male; Mouth Diseases; Olanzapine; Schizophrenia; Schizophrenic Psychology; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Weight Gain

Ziprasidone (ZIP) is often used with olanzapine (OLZ) in 'switch' and combination therapy but empirical evidence to support these strategies is limited.. This study was therefore designed to compare the efficacy and tolerability of switching from OLZ to ZIP, the combination of both medications, and OLZ and ZIP monotherapy, in patients with schizophrenia spectrum disorders (SSD).. In this 12 week open-label, assessor-blinded randomized trial, 148 patients with SSD who had not used antipsychotics for at least 3 months were assigned to ZIP (n = 49) or OLZ monotherapy (n = 31); OLZ for 4 weeks then a switch to ZIP (OLZ/ZIP, n = 35); or combination therapy (OLZ + ZIP, n = 33). The severity of psychosis and abnormal involuntary movements was evaluated at baseline, 1, 2, 4, 8, and 12 weeks using standard instruments. Baseline-to-endpoint changes in weight gain and metabolic measures were compared.. The efficacy of both OLZ/ZIP and OLZ + ZIP was comparable OLZ monotherapy and better than ZIP monotherapy in reducing overall psychotic and negative symptoms at most 8 and 12 week measurement points. Changes in weight gain, glucose, and lipid measures did not differ between OLZ/ZIP and OLZ + ZIP, but were markedly higher following OLZ monotherapy. The OLZ + ZIP group had the lowest overall incidence of adverse events and extrapyramidal symptoms of all the treatment regimens.. We conclude that combining ZIP and OLZ at the outset of treatment is superior to switching from OLZ to ZIP in terms of improving psychotic symptoms and limiting movement side effects without increasing the risk of metabolic syndrome.

Topics: Administration, Oral; Adult; Antipsychotic Agents; Benzodiazepines; Drug Substitution; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Humans; Male; Metabolic Syndrome; Olanzapine; Piperazines; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Severity of Illness Index; Single-Blind Method; Thiazoles; Treatment Outcome; Weight Gain

Weight gain has long been recognized as a side-effect of atypical antipsychotic drugs. Numerous new approaches have been tried for prevention of weight gain, the H2 blockers being one of them. The study was conducted with the aim to evaluate the efficacy of ranitidine in olanzapine-induced weight gain at two fixed doses of 150 and 300 mg day. Seventy-five inpatients with an ICD-10-DCR diagnosis of schizophrenia as their first episode were randomized into three groups of 25 patients each, receiving 150 mg day. All patients were comparable with respect to their weight and BMI at baseline. When a change in the weight and BMI was assessed at 4 and 8 weeks from baseline, no significant difference was observed between the three groups.. Ranitidine at doses of 150 and 300 mg day

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Dose-Response Relationship, Drug; Female; Histamine H2 Antagonists; Humans; Male; Middle Aged; Olanzapine; Ranitidine; Schizophrenia; Weight Gain; Young Adult

Atypical antipsychotic adjunctive therapy to lithium or valproate is effective in treating acute mania. Although continuation of atypical antipsychotic adjunctive therapy after mania remission reduces relapse of mood episodes, the optimal duration is unknown. As many atypical antipsychotics cause weight gain and metabolic syndrome, they should not be continued unless the benefits outweigh the risks. This 52-week double-blind placebo-controlled trial recruited patients with bipolar I disorder (n=159) who recently remitted from a manic episode during treatment with risperidone or olanzapine adjunctive therapy to lithium or valproate. Patients were randomized to one of three conditions: discontinuation of risperidone or olanzapine and substitution with placebo at (i) entry ('0-weeks' group) or (ii) at 24 weeks after entry ('24-weeks' group) or (iii) continuation of risperidone or olanzapine for the full duration of the study ('52-weeks' group). The primary outcome measure was time to relapse of any mood episode. Compared with the 0-weeks group, the time to any mood episode was significantly longer in the 24-weeks group (hazard ratio (HR) 0.53; 95% confidence interval (CI): 0.33, 0.86) and nearly so in the 52-weeks group (HR: 0.63; 95% CI: 0.39, 1.02). The relapse rate was similar in the 52-weeks group compared with the 24-weeks group (HR: 1.18; 95% CI: 0.71, 1.99); however, sub-group analysis showed discordant results between the two antipsychotics (HR: 0.48, 95% CI: 0.17; 1.32 olanzapine patients; HR: 1.85, 95% CI: 1.00, 3.41 risperidone patients). Average weight gain was 3.2 kg in the 52-weeks group compared with a weight loss of 0.2 kg in the 0-weeks and 0.1 kg in the 24-weeks groups. These findings suggest that risperidone or olanzapine adjunctive therapy for 24 weeks is beneficial but continuation of risperidone beyond this period does not reduce the risk of relapse. Whether continuation of olanzapine beyond this period reduces relapse risk remains unclear but the potential benefit needs to be weighed against an increased risk of weight gain.

Topics: Adult; Antimanic Agents; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Combined Modality Therapy; Double-Blind Method; Female; Humans; Lithium; Male; Olanzapine; Risperidone; Time Factors; Weight Gain

Second generation antipsychotics, like olanzapine (OLZ), have become the first line drug treatment for patients with schizophrenia. However, OLZ treatment is often associated with body weight (BW) gain and metabolic derangements. Therefore, the search for prospective markers for OLZ's negative side effects as well as adjunctive treatments to inhibit these has been of major interest. The aim of this study was to investigate in healthy male volunteers (age: 36 ± 11 years; BW: 84 ± 12 kg; BMI=25.5 ± 2.5) whether adjunctive topiramate (TPM) administration opposes OLZ-induced weight gain over the course of 14 days treatment. In addition, we investigated behavioral, endocrine and metabolic characteristics as underlying and potentially predictive factors for weight regulation and/or metabolic derangements associated with OLZ and TPM treatment. While adjunctive TPM indeed reduced OLZ-induced weight gain (P<0.05, Mann-Whitney U), behavioral/metabolic/endocrine characteristics of OLZ treatment were not affected by TPM. Using multiple regression analysis, BW gain was the key factor explaining metabolic disturbances (e.g., plasma insulin- LDL interaction: P<0.01, R(2)=.320), and cumulative food intake during treatment was the best denominator of BW gain (P<0.01, R(2)=.534). Neither TPM treatment, nor its circulating levels, contributed to variation observed in ΔBW. In a second multiple regression analysis, we observed that a low baseline thyrotropin profile (TSHAUC) before the start of drug treatment was associated with an increase in ΔBW over the course of drug treatment (P<0.05, R(2)=.195). Adding TSHAUC as covariate revealed that adjunctive TPM treatment did attenuate OLZ induced BW gain (P<0.05, ANCOVA). Further exploration of the circulating thyroid hormones revealed that individuals with a low plasma TSH profile were also those that were most sensitive to adjunctive TPM treatment blocking OLZ-induced ΔBW gain. Others have shown that OLZ-induced BW gain is associated with improvement in brief psychiatric rating scores (BPRS); adjunctive TPM treatment may be a solution specifically for those subjects susceptible to OLZ-induced rapid weight gain who-on a therapeutic level-benefit most of OLZ treatment.

Topics: Adult; Anti-Obesity Agents; Antipsychotic Agents; Benzodiazepines; Down-Regulation; Drug Antagonism; Fructose; Healthy Volunteers; Humans; Male; Middle Aged; Olanzapine; Overweight; Prognosis; Thyrotropin; Topiramate; Weight Gain; Young Adult

Olanzapine's efficacy in schizophrenia is attributed to antagonism of dopamine and serotonin receptors. Olanzapine is also a potent histamine-H1 antagonist that results in weight gain and somnolence. Betahistine is a centrally acting histamine-H1 agonist, and therefore may reduce olanzapine's effect on histamine receptors in the brain. Olanzapine's high affinity for the histamine-H1 receptor warrants the use of high doses of betahistine. Forty-eight healthy women were recruited and randomized to receive either betahistine 144 mg/day or matching placebo for 4 weeks. Due to the high dose of betahistine, olanzapine was started only on the second week and titrated up to 10 mg/day, and co-administration continued for an additional 2 weeks. Only nominal differences in adverse events were noted between the treatment groups. Betahistine caused a 37% reduction in mean weight gain (1.24 kg in the betahistine arm vs. 1.93 kg in the placebo arm; p=.049) and 60% reduction in the mean increase in daytime Epworth sleepiness scores (1.82 units in the betahistine group vs. 3.57 units in the placebo group; p=.042). The present study suggests that betahistine-olanzapine co-administration, in healthy female subjects, yields an acceptable safety profile with mitigation of weight gain and somnolence. This should be further tested in a patient cohort.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Betahistine; Brain; Double-Blind Method; Female; Histamine Agonists; Humans; Olanzapine; Receptors, Histamine H1; Sleep Initiation and Maintenance Disorders; Weight Gain

This 24-week pilot study assessed the efficacy, tolerability, and safety of adjunctive metformin versus placebo for the prevention of olanzapine-associated weight gain in community-dwelling adult patients with schizophrenia, schizoaffective disorder, bipolar disorder, or major depression with psychotic features.. In a double-blind study, 25 patients were randomly assigned to receive 24 weeks of either olanzapine plus metformin or olanzapine plus placebo. Metformin extended release was titrated to 2000 mg daily as tolerated. No other antipsychotics were allowed, whereas psychotropic medications including antidepressants and mood stabilizers were permitted. The primary outcome measures were change in body weight and homeostatic model assessment for insulin resistance from baseline to week 24.. The intent-to-treat population comprised patients who had 1 or more post-baseline visit. Mean change in body weight for the olanzapine plus metformin (O/M) group was 5.5 lb, which was less than the 12.8 lb gain for the olanzapine plus placebo (O/P) group (P < 0.05). Compared with O/P group who gained 7% of their body weight, patients in the O/M group gained 3% (P < 0.037). Body mass index change in the O/M group was 0.85 versus 2.02 in the O/P group (P < 0.045). There was a trend for a greater increase in baseline to end point homeostatic model assessment for insulin resistance and waist circumference in the O/P group versus the O/M group.. In this naturalistic sample of typical US community-dwelling patients, metformin was effective and well tolerated for the prevention of olanzapine-associated weight gain. Adjunctive metformin should be studied in a similar but larger population to determine its role in the prevention of olanzapine-associated weight gain.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Delayed-Action Preparations; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Independent Living; Male; Mental Disorders; Metformin; Middle Aged; Olanzapine; Pilot Projects; Population Surveillance; United States; Weight Gain; Young Adult

Patients with schizophrenia experience higher rates of obesity and related morbidity and mortality than the general population does. Given preclinical studies revealing the role of histamine H1 receptor in human eating behavior, and the potential of olanzapine to block with this system, we hypothesized that histamine H1 receptor agonists may be beneficial in reducing antipsychotic-associated weight gain. In the present study, 36 patients with a diagnosis of schizophrenia or schizoaffective disorder and treated with olanzapine were randomized to betahistine (48 mg/d) or matching placebo for 16 weeks. Study outcomes were change in body weight from baseline and effect on antipsychotic efficacy of olanzapine. The patients in the betahistine group had less weight gain (-1.95 kg) compared with placebo group (5.6 + 5.5 kg vs 6.9 + 5.6 kg, respectively). Positive and Negative Syndrome Scale Questionnaire showed improvement within each group and that subjects treated with betahistine enjoyed an improvement (reduction) by a mean of 35.7 points, higher when compared with placebo subjects who had a reduction of 26.6 points (P = 0.233). An almost equal amount of subjects in both groups experienced adverse effects during the course of this study (87.5% of betahistine vs 85.0% of placebo-treated subjects). Overall, there were no clinically marked differences in safety signals between both groups. A larger study addressing the weaknesses of this pilot study is warranted.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Betahistine; Double-Blind Method; Drug Therapy, Combination; Female; Histamine Agonists; Humans; Internationality; Male; Olanzapine; Pilot Projects; Psychotic Disorders; Schizophrenia; Weight Gain; Young Adult

One of the primary limitations of many psychiatric medications is weight gain, the mechanism of which remains to be fully elucidated. We conducted a 2-week double-blind placebo-controlled study on weight gain with olanzapine, which is frequently but unpredictably associated with this side effect, to address the possible mechanisms of weight gain independent of changes in the psychiatric condition for which it is prescribed. Healthy male volunteers were randomly assigned to olanzapine (5 mg/day for 7 days, then 10 mg/day for 7 days) or a matching placebo. Of the 24 participants, 19 completed the study (olanzapine, n=13; placebo, n=6). Body weight, glucose, triglyceride, total cholesterol, lipid, leptin, insulin, and aldosterone levels, resting metabolic rate, body composition, physical activity, and 24-h dietary intake were assessed. A significant increase in weight as well as triglyceride, insulin, and leptin levels were found in the olanzapine group as a whole. In participants receiving olanzapine who actually gained weight (n=8), lean but not fat mass increased, as did insulin, fasting glucose, total cholesterol, low-density lipoprotein, and non-high-density lipoprotein levels, whereas aldosterone levels decreased. There were no significant metabolic or endocrine changes in participants receiving placebo or in those receiving olanzapine who did not gain weight. Early metabolic changes appear to be independent of accumulation of fat.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Biomarkers; Body Composition; Double-Blind Method; Energy Intake; Energy Metabolism; Healthy Volunteers; Humans; Male; Motor Activity; Olanzapine; Time Factors; Weight Gain; Young Adult

Olanzapine is used for treatment of psychiatric conditions but causes substantial weight gain. This study assessed safety, efficacy, and changes in metabolic cytokines associated with olanzapine administration in patients with cachexia due to advanced cancer.. Patients with cancer-related cachexia were treated with olanzapine (doses ranging from 2.5 to 20 mg daily by mouth). Patients also received anti-neoplastic treatments. Serum samples were collected at baseline and after weeks 1, 2, 4, and 8 for analysis of levels of leptin, growth hormone, ghrelin, and interleukin-6 (IL-6).. Of the 39 participants, 31 were evaluable for weight change (N = 6 excluded for new ascites; N = 2, incomplete body weight of data). Toxicities related to olanzapine were somnolence (n = 1), pancreatitis (n = 1), extrapyramidal symptoms (n = 1), and nausea/vomiting (n = 1) (all grade 2). The recommended dose of Olanzapine is 20 mg PO daily for cancer patients (same as FDA approved dose for psychiatric conditions). Samples from 29 patients were eligible for analysis of serum cytokine levels. Mean values of leptin, ghrelin, and growth hormone did not change on treatment, though IL-6 levels increased, perhaps due to tumor progression. There was no association between changes in cytokines and weight. The mean change in slope of weight loss before versus after therapy was 0.24 (95 % CI, -0.08, 0.56; p = 0.13) indicating a trend, albeit not reaching statistical significance, toward attenuation of weight loss.. Changes in metabolic cytokines and body weight did not correlate. Treatment with olanzapine had only a modest effect in altering the trajectory of weight loss.

Topics: Adult; Aged; Benzodiazepines; Body Weight; Cachexia; Cytokines; Dose-Response Relationship, Drug; Female; Ghrelin; Humans; Interleukin-6; Leptin; Male; Middle Aged; Neoplasms; Olanzapine; Weight Gain; Weight Loss

Data on the long-term metabolic side-effects associated with antipsychotics are scarce. Prospective longitudinal studies in medication-naive patients with a first episode of psychosis are a valuable source of information as they provide an assessment prior to the antipsychotic exposure and minimize the effect of potential confounding factors. The aim of this study was to assess the course of weight gain and the incidence of metabolic abnormalities during the first 3 yr of antipsychotic treatment. Data were collected from a cohort of 170 first-episode psychosis patients. They were randomly assigned to haloperidol (32%); olanzapine (32%) and risperidone (36%). The dose used was flexible. The initial antipsychotic treatment was changed when required, based on clinical response and tolerability. The results showed that the mean weight gain at 3 yr was 12.1 kg (s.d. = 10.7). It appeared to increase rapidly during the first year (85% of the total mean weight gain) and then stabilized gradually over time. Total cholesterol, LDL-cholesterol and triglyceride levels followed a similar trajectory with a significant increase only during the first year. No significant changes were detected in the mean values of glycaemic parameters. Two patients with a family history of diabetes developed diabetes type II. At short-term the factors positively associated with weight gain were lower body mass index, male gender and olanzapine treatment. At long-term, functional status and clinical response were the main predictors. The results of our study indicate that the first year of antipsychotic treatment is a critical period for weight gain and metabolic changes. Identification of weight gain patterns may help to inform studies that aim to prevent or mitigate the metabolic adverse events associated with antipsychotic therapy.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Haloperidol; Humans; Male; Metabolic Diseases; Middle Aged; Olanzapine; Prospective Studies; Psychotic Disorders; Risk Factors; Risperidone; Time Factors; Weight Gain; Young Adult

The primary aim of the present study was to assess the possible associations between dopaminergic, serotonergic, and glutamatergic system-related genes and adverse events after antipsychotic treatment in paranoid schizophrenia patients. The second aim of the study was to compare the intensity of these symptoms between atypical (ziprasidone and olanzapine) and typical (perazine) antipsychotic drugs. One-hundred and ninety-one Polish patients suffering from paranoid schizophrenia were genotyped for polymorphisms of DRD2, DAT1, COMT, MAOA, SERT, 5HT2A, and GRIK3. The patients were randomized to treatment with perazine, olanzapine or ziprasidone monotherapy for 3 months. The intensity of side effects (changes in body weights and extrapyramidal symptoms (EPS)) was measured at baseline and after 12 weeks of antipsychotic treatment. After 3 months of therapy, the weight increase was the greatest in the group treated with olanzapine and the least in the group treated with ziprasidone. None of the examined gene polymorphisms was associated with the body weight changes. Perazine treatment was associated with the significantly highest intensity of EPS. None of the examined polymorphisms was associated with the changes in extrapyramidal adverse events after antipsychotic treatment. The selected polymorphisms are not primarily involved in changes in body weights and EPS related to antipsychotic treatment in paranoid schizophrenia patients.

Topics: Adult; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Catechol O-Methyltransferase; Dopamine Plasma Membrane Transport Proteins; Female; Genotype; GluK3 Kainate Receptor; Humans; Male; Middle Aged; Monoamine Oxidase; Olanzapine; Overweight; Perazine; Piperazines; Polymorphism, Genetic; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Receptors, Kainic Acid; Schizophrenia, Paranoid; Serotonin Plasma Membrane Transport Proteins; Thiazoles; Weight Gain; Young Adult

Glucagon-like peptide 1 receptor (GLP1R) signaling has been shown to have antipsychotic properties in animal models and to impact glucose-dependent insulin release, satiety, memory, and learning in man. Previous work has shown that two coding mutations (rs6923761 and rs1042044) are associated with altered insulin release and cortisol levels. We identified four frequently occurring haplotypes in Caucasians, haplotype 1 through haplotype 4, spanning exons 4-7 and containing the two coding variants. We analyzed response to antipsychotics, defined as predicted change in PANSS-Total (dPANSS) at 18 months, in Caucasian subjects from the Clinical Antipsychotic Trial of Intervention Effectiveness treated with olanzapine (n=139), perphenazine (n=78), quetiapine (n=14), risperidone (n=143), and ziprasidone (n=90). Haplotype trend regression analysis revealed significant associations with dPANSS for olanzapine (best p=0.002), perphenazine (best p=0.01), quetiapine (best p=0.008), risperidone (best p=0.02), and ziprasidone (best p=0.007). We also evaluated genetic models for the two most common haplotypes. Haplotype 1 (uniquely including the rs1042044 [Leu(260)] allele) was associated with better response to olanzapine (p=0.002), and risperidone (p=0.006), and worse response to perphenazine (p=.03), and ziprasidone (p=0.003), with a recessive genetic model providing the best fit. Haplotype 2 (uniquely including the rs6923761 [Ser(168)] allele) was associated with better response to perphenazine (p=0.001) and worse response to olanzapine (p=.02), with a dominant genetic model providing the best fit. However, GLP1R haplotypes were not associated with antipsychotic-induced weight gain. These results link functional genetic variants in GLP1R to antipsychotic response.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Biomarkers, Pharmacological; Dibenzothiazepines; Female; Genotyping Techniques; Glucagon-Like Peptide-1 Receptor; Haplotypes; Humans; Male; Models, Genetic; Olanzapine; Perphenazine; Piperazines; Polymorphism, Single Nucleotide; Quetiapine Fumarate; Receptors, Glucagon; Regression Analysis; Risperidone; Schizophrenia; Thiazoles; Treatment Outcome; Weight Gain; White People

We previously demonstrated that the addition of the selective norepinephrine reuptake inhibitor reboxetine attenuates olanzapine-induced weight gain. Using the same study sample, we also sought to determine whether reboxetine's weight-attenuating effect was accompanied by a beneficial effect on metabolic and endocrine parameters relevant to antipsychotic-induced weight gain and obesity.. Blood samples at baseline and at the end of the 6-week trial were available for 54 participants who participated in previous double-blind, placebo-controlled studies of reboxetine (4 mg BID) addition to olanzapine-treated schizophrenia patients. Fasting glucose, lipid profile, insulin, leptin, cortisol, dehydroepiandrosterone (DHEA), prolactin, and thyroid-stimulating hormone (TSH) were analyzed.. In contrast to the olanzapine/placebo group, the olanzapine/reboxetine group exhibited a reduction in blood triglyceride (p < 0.05) and leptin (p < 0.05) levels, and elevation in cortisol (p < 0.05) and DHEA (p < 0.008) levels. No significant between-group differences were detected in the changes in cholesterol, glucose, insulin, TSH, and prolactin.. Reboxetine addition resulted in meaningful improvement of some metabolic and endocrine measures associated with olanzapine-induced weight gain. The potential role of reboxetine in the prevention of olanzapine-induced weight gain and cardio-metabolic morbidity merits further large-scale, long-term investigation.

Topics: Adrenergic Uptake Inhibitors; Adult; Antipsychotic Agents; Benzodiazepines; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Morpholines; Olanzapine; Reboxetine; Schizophrenia; Weight Gain; Young Adult

Atypical antipsychotic (AAP) medications that have revolutionized the treatment of mental illness have become stigmatized by metabolic side effects, including obesity and diabetes. It remains controversial whether the defects are treatment induced or disease related. Although the mechanisms underlying these metabolic defects are not understood, it is assumed that the initiating pathophysiology is weight gain, secondary to centrally mediated increases in appetite. To determine if the AAPs have detrimental metabolic effects independent of weight gain or psychiatric disease, we administered olanzapine, aripiprazole, or placebo for 9 days to healthy subjects (n = 10, each group) under controlled in-patient conditions while maintaining activity levels. Prior to and after the interventions, we conducted a meal challenge and a euglycemic-hyperinsulinemic clamp to evaluate insulin sensitivity and glucose disposal. We found that olanzapine, an AAP highly associated with weight gain, causes significant elevations in postprandial insulin, glucagon-like peptide 1 (GLP-1), and glucagon coincident with insulin resistance compared with placebo. Aripiprazole, an AAP considered metabolically sparing, induces insulin resistance but has no effect on postprandial hormones. Importantly, the metabolic changes occur in the absence of weight gain, increases in food intake and hunger, or psychiatric disease, suggesting that AAPs exert direct effects on tissues independent of mechanisms regulating eating behavior.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Eating; Female; Humans; Insulin Resistance; Male; Mental Disorders; Olanzapine; Piperazines; Postprandial Period; Quinolones; Weight Gain; Young Adult

In contrast to olanzapine, ziprasidone has been reported to cause minimal or no weight gain. This study aimed to compare the effects of ziprasidone and olanzapine on weight, body composition, appetite, resting energy expenditure, substrate oxidation, and metabolic parameters in adults with schizophrenia or other psychotic disorders.. Twenty adults with schizophrenia or other psychotic disorders were randomized 1:1 to ziprasidone 20-160 mg/day or olanzapine 5-20 mg/day for 12 weeks. The mean doses during the 12-week study period were 109(range: 65-140) mg/day for ziprasidone and 11.6(range: 8.2-15.5) mg/day for olanzapine. Body weight, appetite, body composition, resting energy expenditure, and metabolic parameters were measured before and after drug treatment. Outcome measurements before and after medication were compared, and ziprasidone- and olanzapine-treated patients were compared.. After 12 weeks, olanzapine-treated patients showed significant weight gain, particularly fat gain, with increased low density lipoprotein-cholesterol and decreased high density lipoprotein-cholesterol concentrations. In contrast, ziprasidone-treated patients showed no significant weight gain with increased high density lipoprotein-cholesterol concentration.. Ziprasidone was associated with a lower propensity for weight gain and central fat deposition than olanzapine. Studies in larger patient samples are required to confirm these results.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Appetite; Benzodiazepines; Body Composition; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Energy Metabolism; Female; Humans; Male; Middle Aged; Olanzapine; Pilot Projects; Piperazines; Psychotic Disorders; Schizophrenia; Thiazoles; Weight Gain; Young Adult

The aim of this study was to assess the use of atomoxetine and olanzapine in combination to treat attention-deficit/hyperactivity disorder (ADHD) and comorbid disruptive behaviors in children and adolescents 10-18 years of age.. Eleven subjects ages 10-18 received open-label atomoxetine and olanzapine for a 10 week treatment period. Patients were assessed at baseline, 2 weeks, 4 weeks, 6 weeks, and 10 weeks (posttreatment). ADHD improvement was measured through the ADHD Rating Scale (ADHD-RS) (Investigator and Parent ratings). Aggression was measured through the Modified Overt Aggression Scale (MOAS).. The combined use of atomoxetine and olanzapine resulted in statistically significant improvement in ADHD symptoms and overt aggression from baseline to posttreatment. As evidenced by a 33% reduction in symptoms on the ADHD-RS-I and the MOAS, 73% of patients were considered responders to ADHD treatment, whereas 55% responded to treatment for aggression. Both medications were generally well tolerated. Olanzapine treatment was associated with significant weight gain. Patients gained, on average, 3.9 kg. throughout the treatment period.. These data provide initial evidence that combination use of atomoxetine and olanzapine for the treatment of ADHD and comorbid disruptive behaviors was effective in reducing ADHD symptoms and aggressive behavior in a 10 week treatment period.

Topics: Adolescent; Adrenergic Uptake Inhibitors; Aggression; Antipsychotic Agents; Atomoxetine Hydrochloride; Attention Deficit and Disruptive Behavior Disorders; Attention Deficit Disorder with Hyperactivity; Benzodiazepines; Child; Drug Therapy, Combination; Female; Humans; Male; Olanzapine; Propylamines; Time Factors; Treatment Outcome; Weight Gain

Induced weight gain is a disturbing side effect of Olanzapine that affects the quality of life in psychotic patients. The aim of this study was to assess the efficacy of Ranitidine in attenuating or preventing Olanzapine-induced weight gain. A parallel 2-arm clinical trial was done on 52 patients with schizophrenia, schizoaffective and schizophreniform disorders who received Olanzapine for the first time. All these were first-episode admitted patients. They were randomly allocated to receive either Ranitidine or placebo. The trend of body mass index (BMI) was compared between groups over 16-week course of treatment. Mean weight was 62.3 (SD: 9.6) kg at baseline. Thirty-three subjects (63.5%) had positive family history of obesity. The average BMI increment was 1.1 for Ranitidine group and 2.4 for the placebo group. The multivariate analysis showed this effect to be independent of sex, family history of obesity, and baseline BMI value. The longitudinal modeling after controlling for baseline values failed to show the whole trend slope to be different. Although the slight change in trend's slope puts forward a hypothesis that combined use of Ranitidine and Olanzapine may attenuate the weight gain long run, this needs to be retested in future larger scale long-term studies. This trial is registered with IRCT.ir 201009112181N5.

Topics: Adult; Benzodiazepines; Body Mass Index; Female; Humans; Male; Obesity; Olanzapine; Placebos; Ranitidine; Weight Gain

The purpose of this study was to investigate associations between body weight and illness characteristics, including weight gain and therapeutic efficacy, in adolescents with schizophrenia.. Adolescents ages 13-17 years (n = 107) with American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) schizophrenia enrolled in a 6 week, double-blind, placebo-controlled trial comparing olanzapine and placebo. Therapeutic response was assessed by the Brief Psychiatric Rating Scale for Children (BPRS-C). Secondary outcomes included the Clinical Global Impressions-Severity (CGI-S) scale and Positive and Negative Syndrome Scale (PANSS). Obesity was defined as sex-/age-adjusted body mass index (BMI) ≥ 95th percentile. Linear regression was used to analyze the relationship between weight gain and psychiatric symptom improvement; logistic regression was conducted to identify predictors of baseline obesity.. Weight gain was significantly correlated with greater BPRS-C reduction among olanzapine-treated subjects (r = -0.31, p<0.01), whereas a trend was observed among placebo-treated subjects (r = -0.31, p = 0.08). However, this relationship became nonsignificant when analyses were controlled for duration of olanzapine treatment (p=0.12), and a treatment by weight gain interaction did not emerge in a repeated-measures mixed model analysis that included time in the study (t = 1.27, p = 0.21). Additionally, weight gain ≥ 7% was not significantly associated with response or remission. Among 17 adolescents (16%) with obesity at study entry, obesity was not significantly associated with endpoint BPRS-C illness severity. However, girls (p = 0.03), individuals hospitalized within the past year (p = 0.02), and those with less severe overall (p = 0.03) and negative symptoms (p = 0.003) according to the CGI-S and PANSS negative subscale, respectively, were more likely to be obese at baseline.. Baseline obesity was associated with lower illness severity, which could be mediated by greater treatment adherence, leading to more weight gain. Olanzapine-related weight gain was not independently associated with symptomatic outcome when controlling for treatment duration. Additional studies are needed to extend these findings to other disorders and medications.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Double-Blind Method; Female; Humans; Male; Models, Statistical; Obesity; Olanzapine; Psychiatric Status Rating Scales; Schizophrenia; Sex Characteristics; Treatment Outcome; Weight Gain

The objective of this paper was to investigate the prognostic and predictive value of a small panel of independent and clinically important factors based on symptom improvement, baseline cognitive impairment, and weight change during the early treatment phase.. The study sample was based on a double-blind, 6-month continuation study of ziprasidone and olanzapine (N=94). We developed a parsimonious 6-month GAF prediction function using a logistic regression model, and evaluated its predictive accuracy and performance using bootstrap estimates of c-statistics and error in predicted probability.. At up to 6 months of follow-up, 52 (55%) of all subjects treated with ziprasidone or olanzapine met the responder criterion of ≥50% improvement in GAF. At Week 2 (acute phase), the majority of ziprasidone (75%) and olanzapine (70%) patients showed greater than 25% improvement in the BPRS psychotic symptom subscale score. These early psychotic symptom responders (Week 2) showed significantly greater improvement in global functioning than early non-responders at all time points (Week 6 and Month 6) (all p's<0.05), confirming early response as an indicator of continued responsiveness to treatment over at least 6 months. A multivariate prediction function based on baseline neurocognitive scores and GAF, early reduction of psychotic symptoms at 2 weeks, and percentage of weight change observed at 6 weeks (All p's <0.05), showed statistically acceptable predictive performance (boostrap c-statistics=0.8598).. Our findings suggest that a parsimonious model incorporating a psychotic symptom assessment score, baseline neurocognitive performance, and risk of weight gain can be developed for predicting patients' likelihood of achieving favorable, long-term treatment outcomes.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Cognition; Cognition Disorders; Double-Blind Method; Drug Monitoring; Drug Resistance; Female; Follow-Up Studies; Humans; Male; Middle Aged; Models, Biological; Olanzapine; Patient Dropouts; Piperazines; Prognosis; Psychiatric Status Rating Scales; Schizophrenia; Thiazoles; Weight Gain

Combination treatment with reboxetine, a selective norepinephrine reuptake inhibitor, and betahistine, a histamine H1 receptor agonist/H3 antagonist, was developed to produce complementary action in CNS pathways regulating appetite and body weight. In the present placebo-controlled study, we evaluated whether a reboxetine-betahistine combination attenuates olanzapine-induced weight gain in schizophrenia patients.. Forty-three inpatients with DSM-IV schizophrenic disorder participated in a randomized double-blind study. Reboxetine (4 mg/day) with betahistine (48 mg/day) (N = 29) or placebo (N = 14) was co-administered with olanzapine (10 mg/day) for 6 weeks. Mental status was assessed at baseline and endpoint with relevant rating scales. Intention-to-treat method was used for statistical analysis.. Seven patients in the study group and four in the placebo group discontinued the trial. At the end of the trial, patients in the olanzapine/reboxetine + betahistine group gained significantly less weight than those in the olanzapine/placebo group [2.02 ± 2.37 and 4.77 ± 3.16 kg, respectively; t = 2. 89, degrees of freedom (df) = 41, p = 0.006]. The weight-attenuating effect of this combination was twofold larger than the weight-attenuating effect previously demonstrated with reboxetine alone. Significantly fewer patients in the study group than in the comparison group increased their initial weight by >7 %, the cutoff for clinically significant weight gain [3/29 (10.3 %) and 6/14 (42.9 %), respectively; χ (2) = 6.03, df = 1, p = 0.014]. The reboxetine-betahistine combination was safe and well tolerated.. Reboxetine-betahistine combination produces a clinically meaningful attenuation of olanzapine-induced weight gain. These results justify direct comparison between the reboxetine-betahistine combination and reboxetine alone.

Topics: Adrenergic Uptake Inhibitors; Adult; Antipsychotic Agents; Benzodiazepines; Betahistine; Double-Blind Method; Female; Histamine Agonists; Humans; Male; Middle Aged; Morpholines; Olanzapine; Reboxetine; Schizophrenia; Treatment Outcome; Weight Gain; Young Adult

This 22-week, open-label study, conducted between November 2006 and September 2008 in a community setting, was designed to determine if weight gain during olanzapine treatment can be prevented or mitigated with adjunctive treatment algorithms that include amantadine, metformin, and zonisamide.. Outpatients with schizophrenia or schizoaffective disorder (DSM-IV-TR criteria) were randomly assigned to olanzapine alone (n = 50), olanzapine plus algorithm A (olanzapine + A [amantadine 200 mg/d with possible switches to metformin 1,000-1,500 mg/d and then to zonisamide 100-400 mg/d; n = 76]), or olanzapine plus algorithm B (olanzapine + B [metformin 1,000-1,500 mg/d with possible switches to amantadine 200 mg/d and then to zonisamide 100-400 mg/d; n = 73]). Brief weight management education was provided at baseline. The primary outcome measure was comparison of mean weight gain between olanzapine and pooled olanzapine + A and olanzapine + B results.. Least squares mean ± SE weight gain was 2.76 ± 0.75 kg for olanzapine, 2.40 ± 0.65 kg for olanzapine + A, and 0.65 ± 0.63 kg for olanzapine + B. Mean weight gain during olanzapine treatment did not differ significantly from pooled results for olanzapine + A and olanzapine + B (P = .065). Participants treated with olanzapine + B experienced significantly less mean weight gain than olanzapine-treated participants (P = .036).. Pooled treatment algorithm results were not significantly different from olanzapine monotherapy in mitigating weight gain. However, participants who received treatment with metformin with possible progression to amantadine and then zonisamide had significantly less mean weight gain than participants treated with olanzapine alone. Progression of some participants through the algorithm indicated that a single therapy solution may not be adequate for every patient. Patients treated with olanzapine should receive regular weight monitoring.. clinicaltrials.gov Identifier: NCT00401973.

Topics: Adolescent; Adult; Aged; Algorithms; Amantadine; Antipsychotic Agents; Benzodiazepines; Clinical Protocols; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Isoxazoles; Male; Metformin; Middle Aged; Olanzapine; Psychotic Disorders; Schizophrenia; Weight Gain; Zonisamide

Although some previous studies have compared the 2 medicines, ziprasidone and olanzapine most selected chronic patients as subjects. Therefore, the present study was designed to compare the efficacy and safety of ziprasidone vs. olanzapine in naive first-episode schizophrenia.. 80 patients were randomly assigned to a 6-week treatment either with 80-160 mg/day of ziprasidone or 10-20 mg/day of olanzapine. The primary efficacy measurements were the Positive and Negative Syndrome Scale and Clinical Global Impression-severity scale scores. The second efficacy measurement was the response rate of treatment. Tolerability assessments were also performed.. 79 patients completed the trial. The average dose was 127.5 mg/day with ziprasidone and 19.1 mg/day with olanzapine. No significant differences were found between the 2 groups in primary or secondary efficacy measurements at each visit point (all p>0.05). Body weight significantly increased with olanzapine, and more extrapyramidal symptoms were observed with ziprasidone (all p<0.05). Both medicines were well tolerated, and no serious adverse events were observed.. Ziprasidone was as effective as olanzapine in short-term treatment for first-episode schizophrenia, and both medicines were well tolerated.

Topics: Adult; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Comparative Effectiveness Research; Dose-Response Relationship, Drug; Drug Monitoring; Episode of Care; Female; Humans; Male; Middle Aged; Olanzapine; Piperazines; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Thiazoles; Time Factors; Treatment Outcome; Weight Gain

Weight gain is commonly observed with olanzapine treatment. Zonisamide is an antiepileptic drug associated with weight loss. This study examined the effectiveness of zonisamide in preventing weight gain in 42 patients beginning olanzapine for bipolar disorder or schizophrenia. Each patient had a body mass index of 22 mg/kg or greater and was randomized to taking olanzapine with either zonisamide (n = 20) or placebo (n = 22) for 16 weeks. The primary outcome measure was change in body weight in kilograms from baseline. In the primary analysis using longitudinal regression, patients who received zonisamide had a significantly slower rate of weight gain and increase in body mass index than those who received placebo. The patients treated with zonisamide gained a mean (SD) of 0.9 (3.3) kg, whereas those treated with placebo gained a mean (SD) of 5.0 (5.5) kg; P = 0.01. None of the patients in the zonisamide group, compared with 7 patients (33%) in the placebo group, gained 7% of body weight or greater from baseline (Fisher exact test, P = 0.009). The zonisamide group, however, reported significantly more cognitive impairment as an adverse event than the placebo group (25% vs 0, respectively; P = 0.02). Zonisamide was effective for mitigating weight gain in patients with bipolar disorder or schizophrenia initiating treatment with olanzapine but was associated with cognitive impairment as an adverse event.

Topics: Adult; Anticonvulsants; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Cognition Disorders; Double-Blind Method; Female; Follow-Up Studies; Humans; Isoxazoles; Male; Middle Aged; Olanzapine; Regression Analysis; Schizophrenia; Treatment Outcome; Weight Gain; Young Adult; Zonisamide

Safety and efficacy results, collected in schizophrenia and schizoaffective disorder patients treated for up to nearly 3 years, are presented for asenapine and olanzapine.. Patients completing a 52-week randomized double-blind core study on flexible-dose asenapine (5 or 10 mg BID) or olanzapine (10 or 20 mg QD) could continue treatment until study blind was broken.290 patients on asenapine and 150 on olanzapine continued treatment for variable lengths of time [mean ± SD (range) 311.0 ± 146.1 (10 - 653) d and 327.4 ± 139.6 (15 - 631) d, respectively]. Adverse event (AE) incidence was lower during the extension (asenapine, 62%; olanzapine, 55%) than during the core study (78%, 80%). In both groups, body weight increase and incidence of extrapyramidal AEs were negligible during the extension. Mean PANSS total score changes during first year of treatment were - 37.0 for asenapine and - 35.3 for olanzapine, with further changes of 1.6 for asenapine and - 0.8 for olanzapine at the extension study endpoint.. Clinical stability on asenapine as well as olanzapine was maintained, with few recurrent or newly emerging AEs beyond 1 year of treatment.

Topics: Adult; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Comparative Effectiveness Research; Diagnostic and Statistical Manual of Mental Disorders; Dibenzocycloheptenes; Dose-Response Relationship, Drug; Drug Monitoring; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Longitudinal Studies; Male; Middle Aged; Olanzapine; Pharmacovigilance; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Time; Treatment Outcome; Weight Gain

Olanzapine and other second generation antipsychotics have been associated with weight gain, which may be related to changes in appetite and food intake. However, it is unclear whether changes in appetite in response to treatment with second generation antipsychotics are persistent in patients treated chronically with these medications and the extent to which changes in appetite are related to any continuing weight gain associated with long-term treatment with these drugs. In a randomized 5-month study of the effects of olanzapine and risperidone on metabolic changes in chronic schizophrenic patients, we assessed appetite changes using two scales and correlated appetite changes with weight gain and metabolic changes. There is evidence that the hormone ghrelin is related to appetite stimulation and falls during satiation after meals, and therefore, may be a physiological concomitant indicating appetite changes. We therefore, also measured ghrelin before and after a fatty meal at baseline and after 2 months of drug treatment. Neither olanzapine nor risperidone increased appetite during the 5 months of study drug treatment, and there was a trend for a decrease in appetite over time. Weight only increased slightly during treatment and changes in appetite scores were not correlated with changes in weight or changes in glucose or lipids. Fasting ghrelin did not increase in olanzapine- or risperidone-treated patients, and there were no significant changes in ghrelin responses to a fatty meal between baseline and 2 months of drug treatment, and no differences in response in olanzapine- vs. risperidone-treated patients. Our findings suggest that in chronic schizophrenic patients treated with multiple antipsychotics in the past, olanzapine or risperidone do not induce increases in appetite and appetite changes are not related to any further small drug-induced weight gain in these chronically treated patients. However, it is possible that different relationships may exist between appetite and weight changes induced by the medications in drug naive patients newly started on olanzapine or risperidone.

Topics: Adult; Antipsychotic Agents; Appetite; Benzodiazepines; Body Weight; Female; Ghrelin; Humans; Male; Middle Aged; Olanzapine; Risperidone; Schizophrenia; Weight Gain

To treat acute schizophrenia, a long-acting injectable antipsychotic needs a rapid onset of action and therapeutic profile similar to that of oral agents. The present post-hoc analyses compared results from a randomized, double-blind, placebo-controlled trial of olanzapine long-acting injection (LAI) for acute schizophrenia with those observed in similarly designed trials of oral olanzapine.. Six-week results from the olanzapine LAI study (N = 404) were compared with those of 3 oral studies (study 1: olanzapine vs. haloperidol vs. placebo [N = 335]; study 2: olanzapine vs. haloperidol vs. low-dose olanzapine [N = 431]; study 3: olanzapine vs. placebo vs. low-dose olanzapine [N = 152]). All patients had baseline Brief Psychiatric Rating Scale (BPRS) scores ≥24 (0-6 scale). Six-week effect sizes were calculated. Efficacy onset, pharmacokinetics, discontinuations, weight gain, and extrapyramidal symptoms were also assessed.. At 6 weeks, mean BPRS scores decreased by 14 to 15 points for olanzapine LAI (405 mg/4 weeks, 210 or 300 mg/2 weeks), by 8 to 16 for oral olanzapine (10 ± 2.5 or 15 ± 2.5 mg/day), and by 12 to 13 for haloperidol (15 ± 5 mg/day). For those same dose groups, effect sizes vs. placebo for the BPRS were 0.7 to 0.8 for olanzapine LAI, 0.5 to 0.7 for oral olanzapine, and 0.6 for haloperidol. The first statistically significant separation from placebo on the BPRS occurred at 3 days for the olanzapine LAI groups and at 1 week for oral olanzapine and haloperidol (15 ± 5 mg/day) in oral study 1 although as late as week 6 for the 10-mg/day olanzapine dose in oral study 3. Olanzapine concentrations were similar across studies. Weight gain ≥7% of baseline occurred in up to 35% of olanzapine LAI and oral patients versus up to 12% of haloperidol and placebo patients. Extrapyramidal symptoms were lowest in the olanzapine LAI groups and significantly greater in the haloperidol groups. No post-injection delirium/sedation syndrome events occurred in the olanzapine LAI study.. Patients treated acutely with olanzapine LAI showed a similar pattern of improvement to that seen historically with oral olanzapine. With the exception of injection-related adverse events, the efficacy and tolerability profile of olanzapine LAI is similar to oral olanzapine.. ClinicalTrials.gov ID; URL: http://http//www.clinicaltrials.gov/: NCT00088478; ClinicalStudyResults.org ID; URL: http://www.clinicalstudyresults.org/: 917, 978, 982, and 5984.

Topics: Administration, Oral; Adult; Antipsychotic Agents; Benzodiazepines; Double-Blind Method; Female; Haloperidol; Humans; Injections; Male; Middle Aged; Olanzapine; Schizophrenia; Treatment Outcome; Weight Gain

Although there have been important advances in the treatment of posttraumatic stress disorder (PTSD), many patients fail to respond to first-line pharmacotherapy. Limited evidence suggests that second generation antipsychotics may have a role to play as monotherapy in PTSD.. We undertook a randomized, placebo-controlled study using flexible-dose olanzapine monotherapy for 8 weeks in 28 adult male and female participants (mean age: 40.75 ± 11.59 years) with non-combat related chronic PTSD. Data were analysed with repeated measures analysis of variance, using an intention to treat, last observation carried forward approach.. The olanzapine group (n = 14) demonstrated significantly greater improvement on the Clinician Administered PTSD Scale from baseline to endpoint than the placebo group (n = 14) (F = 5.71, p = 0.018). Olanzapine was generally well tolerated, with no serious adverse events recorded. Substantial weight gain (6-10 kg) was, however, reported in 6/14 participants in the olanzapine group.. To our knowledge, this is the first controlled evidence of the efficacy of olanzapine monotherapy in an exclusively non-combat related chronic PTSD group. Despite the small sample size, these data suggest that olanzapine may have a role in the treatment of PTSD. These findings warrant replication in a larger sample.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Chronic Disease; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Olanzapine; Stress Disorders, Post-Traumatic; Treatment Outcome; Weight Gain

To describe the efficacy, safety and tolerability of lurasidone for the acute treatment of schizophrenia using the metrics number needed to treat (NNT) and number needed to harm (NNH).. Study data were pooled from six Phase II and III, 6-week, randomized, placebo-controlled trials that were conducted to test the efficacy and safety of lurasidone for the acute treatment of schizophrenia. Included were the following interventions: fixed doses of lurasidone 20, 40, 80, 120 and 160 mg/d; haloperidol 10 mg/d; olanzapine 15 mg/d; quetiapine extended-release 600 mg/d; placebo. The following outcomes were assessed: responder rates as defined by a reduction of ≥20, 30, 40 or 50% from baseline on the Positive and Negative Syndrome Scale (PANSS) total score; study completion; discontinuation due to an adverse event (AE); weight gain ≥7% from baseline; incidence of spontaneously reported AEs; incidence of total cholesterol ≥240 mg/dL, low-density lipoprotein cholesterol ≥160 mg/dL, fasting triglycerides ≥200 mg/dL and glucose ≥126 mg/dL at endpoint. NNT for the efficacy outcomes were calculated after excluding one failed study. NNH for the safety/tolerability outcomes were calculated using all six studies. Likelihood of being helped or harmed (LHH) was also calculated to illustrate trade-offs between outcomes of improvement ≥30% on the PANSS vs. incidence of akathisia, nausea, sedation, somnolence and parkinsonism.. NNT vs. placebo for PANSS reductions ≥30% were 6, 6, 7 and 4 for lurasidone doses of 40, 80, 120 and 160 mg/d, respectively, and 4 and 3 for olanzapine 15 mg/d and quetiapine extended-release 600 mg/d, respectively. Lurasidone was not associated with any statistically significant disadvantages over placebo for weight gain or metabolic abnormalities; NNH vs. placebo for weight gain ≥7% from baseline was 4 for olanzapine and 9 for quetiapine extended-release in contrast to a NNH for this outcome ranging from 43 to 150 for lurasidone 40-160 mg/d. The 5 most consistently encountered adverse events attributable to lurasidone were akathisia, nausea, sedation, somnolence and parkinsonism, with NNH vs. placebo for lurasidone 40-120 mg/d ranging from 6 (akathisia with 120 mg/d) to 30 (parkinsonism with 80 mg/d). Lurasidone 160 mg/d appeared better tolerated than doses of 40, 80 or 120 mg/d for akathisia, nausea, sedation or somnolence, with no NNH values for these adverse events for 160 mg/d vs. placebo being statistically significant. LHH was favorable for lurasidone when contrasting PANSS reductions vs. adverse events.. NNT and NNH can help quantify efficacy, safety and tolerability outcomes and place lurasidone into clinical perspective. Advantages for lurasidone include a low propensity for weight gain and metabolic abnormalities. More commonly encountered adverse events include akathisia, nausea, sedation, somnolence and parkinsonism, but NNH values are generally in the double digits, reflecting an overall tolerable profile. Individual patient characteristics, values and preferences will need to be considered when selecting lurasidone over other antipsychotics.

Topics: Adult; Akathisia, Drug-Induced; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Cholesterol; Dibenzothiazepines; Disorders of Excessive Somnolence; Dose-Response Relationship, Drug; Female; Haloperidol; Humans; Isoindoles; Likelihood Functions; Lurasidone Hydrochloride; Male; Medication Adherence; Nausea; Numbers Needed To Treat; Olanzapine; Psychiatric Status Rating Scales; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Research Design; Schizophrenia; Thiazoles; Treatment Outcome; Triglycerides; Weight Gain

Pharmacogenomic analyses of weight gain during treatment with second-generation antipsychotics have resulted in a number of associations with variants in ankyrin repeat and kinase domain containing 1 (ANKK1)/dopamine D2 receptor (DRD2) and serotonin 2C receptor (HTR2C) genes. These studies primarily assessed subjects with schizophrenia who had prior antipsychotic exposure that may have influenced the amount of weight gained from subsequent therapies. We assessed the relationships between single-nucleotide polymorphisms (SNPs) in these genes with weight gain during treatment with olanzapine in a predominantly antipsychotic-naive population.. The association between 5 ANKK1, 54 DRD2, and 11 HTR2C SNPs and weight change during 8 weeks of olanzapine treatment was assessed in 4 pooled studies of 205 white patients with diagnoses other than schizophrenia who were generally likely to have had limited previous antipsychotic exposure.. The A allele of DRD2 rs2440390(A/G) was associated with greater weight gain in the entire study sample (P = .0473). Three HTR2C SNPs in strong linkage disequilibrium, rs6318, rs2497538, and rs1414334, were associated with greater weight gain in women but not in men (P = .0032, .0012, and .0031, respectively). A significant association with weight gain for 2 HTR2C SNPs previously reported associated with weight gain, -759C/T (rs3813929) and -697G/C (rs518147), was not found.. Associations between weight gain and HTR2C and DRD2 variants in whites newly exposed to olanzapine may present opportunities for the individualization of medication selection and development based on differences in adverse events observed across genotype groups.

Topics: Adult; Alleles; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Borderline Personality Disorder; Depressive Disorder, Treatment-Resistant; Female; Genetic Association Studies; Humans; Linkage Disequilibrium; Male; Mental Disorders; Middle Aged; Olanzapine; Pharmacogenetics; Polymorphism, Single Nucleotide; Risperidone; Schizophrenia; Weight Gain

Early response to antipsychotic medication has been shown to accurately predict later response to continued use of the same treatment in patients with chronic schizophrenia. This study examines whether this predictive pattern exists for patients with first-episode psychosis. We used a data-driven threshold for early response of ≥ 26.2% improvement from baseline on the Positive and Negative Syndrome Scale (PANSS(0-6)) Total score to determine whether response at Week 2 of treatment may predict response at Week 12 in a randomized, double-blind trial of olanzapine versus haloperidol for treatment of patients with first-episode psychosis (N=225). Later response was defined as a ≥ 40% and ≥ 50% improvement in PANSS Total(0-6) score and as remission. At Week 2, 43% (97/225) of patients were identified as early responders. At a threshold for later response of ≥ 50% improvement in PANSS(0-6) Total score, early non-response most strongly predicted later non-response, demonstrating high specificity (74%) and high negative predictive value (80%). As had been seen in the treatment of patients with chronic schizophrenia, early non-response was a robust predictor of subsequent non-response in the treatment of patients with first-episode psychosis.

Topics: Adolescent; Adult; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Double-Blind Method; Female; Follow-Up Studies; Haloperidol; Humans; International Cooperation; Male; Mental Disorders; Olanzapine; Predictive Value of Tests; Psychiatric Status Rating Scales; Time Factors; Treatment Outcome; Weight Gain; Young Adult

Anorexia nervosa (AN) is a serious psychiatric illness associated with significant morbidity and mortality. There is little empirical support for specific treatments and new approaches are sorely needed. This two-site study aimed to determine whether olanzapine is superior to placebo in increasing body mass index (BMI) and improving psychological symptoms in out-patients with AN.. A total of 23 individuals with AN were randomly assigned in double-blind fashion to receive olanzapine or placebo for 8 weeks together with medication management sessions that emphasized compliance. Weight, other physical assessments and measures of psychopathology were collected.. End-of-treatment BMI, with initial BMI as a covariate, was significantly greater in the group receiving olanzapine [F(1, 20)=6.64, p=0.018]. Psychological symptoms improved in both groups, but there were no statistically significant group differences. Of the 23 participants, 17 (74%) completed the 8-week trial. Participants tolerated the medication well with sedation being the only frequent side effect and no adverse metabolic effects were noted.. This small study suggests that olanzapine is generally well tolerated by, and may provide more benefit than placebo for out-patients with AN. Further study is indicated to determine whether olanzapine may affect psychological symptoms in addition to BMI.

Topics: Adolescent; Adult; Analysis of Variance; Anorexia Nervosa; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Double-Blind Method; Female; Humans; Male; Middle Aged; New York; Olanzapine; Ontario; Outpatients; Placebos; Psychiatric Status Rating Scales; Treatment Outcome; Weight Gain; Young Adult

The antipsychotic drug, olanzapine, one of the most widely used drugs in clinical medicine, has a high rate of discontinuation due to inefficacy and/or adverse effects. We identified a single nucleotide polymorphism in the drug metabolizing enzyme, cytochrome P450 3A43 (CYP3A43; rs472660), that highly significantly predicted olanzapine clearance in the Clinical Antipsychotic Trials of Intervention Effectiveness trial (P=5.9e(-7)). Moreover, at standard antipsychotic doses, 50% of individuals with the high clearance genotype (AA) have trough blood levels below the therapeutic range. Interestingly, a much higher proportion of African Americans carry the A allele compared with Caucasians (allele frequency 67 vs 14%). After accounting for CYP3A43 genotype, race is no longer a significant predictor of olanzapine clearance. Olanzapine clearance was associated with measures of clinical response. Patients with greater clearance had higher symptom ratings and were more likely to discontinue treatment due to an inadequate response. Our data identify a genetic mechanism for variation in olanzapine response and demonstrate that blood level monitoring of olanzapine treatment is advisable.

Topics: Antipsychotic Agents; Benzodiazepines; Black or African American; Cytochrome P-450 CYP3A; Female; Gene Frequency; Genotype; Glucose; Humans; Linear Models; Lipid Metabolism; Male; Models, Chemical; Olanzapine; Polymorphism, Single Nucleotide; Psychiatric Status Rating Scales; Schizophrenia; Sex Factors; Smoking; Weight Gain; White People

Atypical or second-generation antipsychotics (SGAs) are associated with excessive body weight gain (BWG) and other components of metabolic syndrome. Among all SGAs, clozapine and olanzapine are known to cause the most significant weight gain, followed by risperidone and quetiapine. The genetic variant of tumor necrosis factor α (TNF-α), -308 G>A polymorphism (rs1800629), has been implicated in clozapine-induced BWG in several studies. We hypothesized that TNF-α -308 G>A polymorphism has a general effect on SGA-induced BWG. The present study was conducted to examine the association between TNF-α -308 G>A polymorphism and BWG during treatment for schizophrenia using a variety of second generation antipsychotics (SGAs). A total of 500 patients with schizophrenia treated with clozapine (n=275), olanzapine (n=79) or risperidone (n=146) for an average of 49.9 months were recruited. Subjects with an increase in weight of more than 7% from the baseline before the current SGA treatment to the weight at the survey point were defined as having BWG. The association between TNF-α -308 G>A polymorphism and BWG was studied, and the effect of non-genetic factors such as baseline BMI, SGA treatment duration and SGA type on the association was controlled by logistic regression. The results revealed that there was no significant association between BWG and TNF-α -308 G>A polymorphism (GG/GA/AA or GG/GA+AA) in each separate SGA group or collectively. These findings suggest that TNF-α -308 G>A polymorphism does not play a major role in SGA-induced weight gain.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Genotype; Humans; Male; Middle Aged; Olanzapine; Polymorphism, Single Nucleotide; Prospective Studies; Risperidone; Schizophrenia; Single-Blind Method; Tumor Necrosis Factor-alpha; Weight Gain

Schizophrenia patients have a potential increased risk of metabolic dysregulation during antipsychotic treatments. Our objective was to compare changes in prolactin and metabolic variables (glucose, lipids and weight) as a post-hoc analysis from a six-month, randomised, controlled study of olanzapine (OLZ, n = 171; 10-20 mg/day) or quetiapine (QUE, n = 175; 300-700 mg/day). No statistically significant treatment group differences for baseline to endpoint mean changes in body mass index (P = 0.209) or weight (P = 0.250) were observed. There was a greater incidence of clinically significant weight gain (defined as > or =7% increase from baseline) in OLZ (19.2%) compared to QUE (13.2%)-treated patients (P = 0.181). No statistically significant treatment group differences for lipids and glucose variables, either as mean change from baseline to endpoint or treatment-emergent (TE) categorical changes were found (P > or = 0.05). Incidence rates for TE diabetes were similar between treatment groups 2.5% (n = 4) in the OLZ-treatment group and 1.3% (n = 2) in the QUE-treatment group (P = 0.685). Hyperprolactinaemia was present at baseline in many patients (OLZ 32.9%; QUE 31.4%), but after 2 weeks of treatment prolactin values had reverted to normal for nearly all patients (OLZ 100%; QUE 99.4%). There were no significant treatment differences in any variable between cohorts.

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Body Weight; Dibenzothiazepines; Double-Blind Method; Female; Humans; Lipid Metabolism; Male; Middle Aged; Olanzapine; Prolactin; Psychotic Disorders; Quetiapine Fumarate; Schizophrenia; Schizophrenic Psychology; Weight Gain

Atypical antipsychotics are increasingly drugs of first choice in schizophrenia. Amisulpride, a new atypical antipsychotic, is reported to be effective for both positive and negative symptoms of schizophrenia in Western countries but Indian experience is limited. The aim of the present study was therefore to conduct a trial of amisulpride versus olanzapine in Indian schizophrenia patients.. Eighty adult patients of either sex were randomized to receive standard doses of the two drugs orally, in a single blind manner, for 12 weeks, with follow up at 4 and 8 weeks. Effectiveness was assessed by changes in scores on the Brief Psychiatric Rating Scale (BPRS), Scale for Assessment of Positive Symptoms (SAPS), Scale for Assessment of Negative Symptoms (SANS), and physician-administered Clinical Global Impression (CGI) scale. Tolerability was assessed by treatment-emergent adverse drug reactions (ADRs).. Evaluable were 39 patients on amisulpride and 38 on olanzapine. The groups were comparable at baseline with respect to demographics, illness duration and rating scores. Final BPRS score was lower for olanzapine (33.2 +/- 9.44) than for amisulpride (37.7 +/- 9.67). SAPS and SANS scores and CGI rating improved individually in both arms but remained comparable between groups throughout the study period, but olanzapine reduced SAPS score to a greater extent. ADRs were encountered in 67.5% and 47.5% of patients (p = 0.113) on amisulpride and olanzapine, respectively. Tremor and insomnia were more frequent with amisulpride, while olanzapine caused more weight gain and sedation. No serious ADRs occurred.. Amisulpride, although comparable to olanzapine on some measures, did not match the improvement seen with the latter drug in BPRS and SAPS scores. Despite differences in ADR profiles, overall tolerability was satisfactory for both drugs. In Indian patients, amisulpride should therefore be an alternative to olanzapine to a limited extent, such as when weight gain and sedation are undesirable.

Topics: Adult; Amisulpride; Antipsychotic Agents; Benzodiazepines; Brief Psychiatric Rating Scale; Drug Administration Schedule; Female; Follow-Up Studies; Humans; India; Male; Olanzapine; Schizophrenia; Schizophrenic Psychology; Selective Serotonin Reuptake Inhibitors; Single-Blind Method; Sleep Initiation and Maintenance Disorders; Sulpiride; Treatment Outcome; Tremor; Weight Gain

Atypical antipsychotic medications like olanzapine (OLZ) induce weight gain and increase the risk of diabetes in patients with schizophrenia. The goal of this study was to assess potential mechanisms of OLZ-induced weight gain and accompanying metabolic effects. Healthy, lean, male volunteers received OLZ and placebo (PBO) in a randomized, double-blind, crossover study. In periods 1 and 2, subjects received OLZ (5 mg for 3 days then OLZ 10 mg for 12 days) or matching PBO separated by a minimum 12-day washout. Twenty-four hour food intake (FI), resting energy expenditure (REE), activity level, metabolic markers, and insulin sensitivity (IS) were assessed. In total, 30 subjects were enrolled and 21 completed both periods. Mean age and BMI were 27 years (range: 18-49 years) and 22.6 +/- 2.2 kg/m(2), respectively. Relative to PBO, OLZ resulted in a 2.62 vs. 0.08 kg increase in body weight (P < 0.001) and 18% (P = 0.052 or 345 kcal) increase in FI. Excluding one subject with nausea and dizziness on the day of OLZ FI measurement, the increase in FI was 547 kcal, (P < 0.05). OLZ increased REE relative to PBO (113 kcal/day, P = 0.003). Significant increases in triglycerides, plasminogen activator inhibitor-I (PAI-I), leptin, and tumor necrosis factor-alpha (TNF-alpha) were observed. No significant differences in activity level or IS were observed. This study provides evidence that OLZ pharmacology drives the early increase in weight through increased FI, without evidence of decreased energy expenditure (EE), activity level, or short-term perturbations in IS.

Topics: Adolescent; Adult; Antipsychotic Agents; Basal Metabolism; Benzodiazepines; Biomarkers; Double-Blind Method; Energy Intake; Exercise; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Olanzapine; Plasminogen Activator Inhibitor 1; Reference Values; Triglycerides; Tumor Necrosis Factor-alpha; Weight Gain; Young Adult

Olanzapine associated weight gain (WG) is a major concern in patients with schizophrenia. The purpose of this study was to assess the efficacy of topiramate to prevent olanzapine induced WG in these cases. We also studied various metabolic parameters.. In this 12-week, double-blind, parallel group study, seventy-two drug-naïve, first-episode schizophrenia patients were randomized to receive olanzapine+placebo (olanzapine group) or olanzapine+topiramate (100mg/day) (topiramate group). Weight, body mass index, fasting glucose, insulin, insulin resistance (IR), leptin, lipids and blood pressure were assessed at baseline and at 12 weeks. The patients were clinically evaluated using Positive and Negative Syndrome Scale (PANSS) and were monitored for adverse effects.. Topiramate resulted in a weight loss of 1.27+/-2.28 kg (p<0.01), decrease in leptin (p<0.001), glucose, cholesterol, triglyceride levels and systolic and diastolic blood pressure. In the olanzapine group, there was a significant WG, hyperglycemia, hyperinsulinemia, increased IR, hyperleptinemia, hypercholesterolemia and hypertriglyceridemia (p<0.001).There was a greater clinical improvement (PANSS scores) (p<0.001) in the topiramate group. The adverse effects were well tolerated.. Topiramate could prevent olanzapine induced weight gain and adverse metabolic effects. It also results in a greater clinical improvement when used with olanzapine in schizophrenia.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Blood Pressure; Body Mass Index; Cholesterol; Double-Blind Method; Female; Fructose; Humans; Insulin; Lipids; Male; Metabolic Diseases; Middle Aged; Neuroprotective Agents; Olanzapine; Prospective Studies; Schizophrenia; Topiramate; Weight Gain; Young Adult

To examine the long-term safety and efficacy of three antipsychotics in early-onset schizophrenia spectrum disorders.. Patients (8 to 19 years old) who had improved during an 8-week, randomized, double-blind acute trial of olanzapine, risperidone, or molindone (plus benztropine) were eligible to continue on the same medication for up to 44 additional weeks under double-blind conditions. Adjunctive medications were allowed according to defined algorithms. Standardized symptom, safety, and functional assessments were conducted every 4 weeks.. Of the 116 youths randomized in the acute trial, 54 entered maintenance treatment (molindone, n = 20; olanzapine, n = 13; risperidone, n = 21). Fourteen (26%) completed 44 weeks of treatment. Adverse effects (n = 15), inadequate efficacy (n = 14), or study nonadherence (n = 8) were the most common reasons for discontinuation. The three treatment arms did not significantly differ in symptom decrease or time to discontinuation. Akathisia was more common with molindone and elevated prolactin concentrations more common with risperidone. Although weight gain and metabolic adverse events had occurred more often with olanzapine and risperidone during the acute trial, no significant between-drug differences emerged in most of these parameters during maintenance treatment.. Only 12% of youths with early-onset schizophrenia spectrum disorders continued on their originally randomized treatment at 52 weeks. No agent demonstrated superior efficacy, and all were associated with side effects, including weight gain. Improved treatments are needed for early-onset schizophrenia spectrum disorders. Clinical trial registry information-Treatment of Schizophrenia and Related Disorders in Children and Adolescents; URL: http://www.clinicaltrials.gov, unique identifier: NCT00053703.

Topics: Adolescent; Akathisia, Drug-Induced; Benzodiazepines; Child; Double-Blind Method; Female; Humans; Long-Term Care; Male; Molindone; Olanzapine; Prolactin; Psychiatric Status Rating Scales; Psychotic Disorders; Psychotropic Drugs; Risk Factors; Risperidone; Schizophrenia; Schizophrenic Psychology; Weight Gain; Young Adult

Many antipsychotic medications carry a substantial liability for weight gain, and one mechanism common to all antipsychotics is binding to the dopamine D2 receptor. We therefore examined the relationship between -141C Ins/Del (rs1799732), a functional promoter region polymorphism in DRD2, and antipsychotic-induced weight gain in 58 first episode schizophrenia patients enrolled in a randomized trial of risperidone versus olanzapine. Carriers of the deletion allele (n=29) were compared with Ins/Ins homozygotes (noncarriers, n=29) in a mixed model encompassing 10 weight measurements over 16 weeks. Deletion allele carriers showed significantly more weight gain after 6 weeks of treatment regardless of assigned medication. Although deletion carriers were prescribed higher doses of olanzapine (but not risperidone), dose did not seem to account for the genotype effects on weight gain. Given earlier evidence that deletion carriers show reduced symptom response to medication, additional study of appropriate treatment options for these patients seems warranted.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Drug Administration Schedule; Female; Humans; Male; Olanzapine; Promoter Regions, Genetic; Receptors, Dopamine D2; Risperidone; Schizophrenia; Weight Gain; Young Adult

We conducted exploratory analyses of the data from a multinational, randomised study to identify factors associated with weight change after 16 weeks of treatment with standard olanzapine tablets (SOT) or sublingual orally disintegrating olanzapine (ODO).. One hundred and forty nine outpatients who gained weight during prior SOT therapy were enrolled into the study and treated with ODO (N = 84) or SOT (N = 65). Exploratory analyses were conducted with the subset of compliant patients (ODO: n = 60; SOT: n = 47).. The decrease in the rate of weight gain at the end of study therapy (change from baseline) was greater in the ODO group than the SOT group (-0.59 kg/week vs. -0.38 kg/week, p = 0.0246). Age was negatively associated with weight change (p = 0.0203) in both treatment groups combined: patients gained 0.7 kg less for every 10 years of age. The least squares mean weight gain was lower with ODO than SOT in male patients (0.35 kg vs. 3.04 kg, p = 0.061), but not female patients and in American patients (0.55 kg vs. 6.21 kg, p < 0.0001), but not Canadian or Mexican patients.. Although not conclusive, these data suggest that ODO may be a reasonable treatment option for some patients who gain weight with SOT. Further research is required to confirm these findings.

Topics: Administration, Oral; Adult; Aged; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Body Mass Index; Double-Blind Method; Female; Humans; Male; Middle Aged; Olanzapine; Psychotic Disorders; Sex Distribution; Tablets; Weight Gain; Young Adult

The objective of this study was to determine if early changes in triglycerides and weight may be useful in predicting longer-term changes in weight and other metabolic parameters. Data were from three 24- to 28-week randomized, controlled studies comparing olanzapine to ziprasidone or aripiprazole for treatment of schizophrenia. Analyses were restricted to completers with fasting laboratory data at all protocol specified time points. Analyses were primarily descriptive and included mean changes and categorical outcomes. In all treatment groups, participants who did not experience a 20 mg/dL or greater increase in triglycerides at early time points were unlikely to experience a change of 50 mg/dL or more in triglycerides after 6 months. Negative predictive values were 83% to 95%. However, early change in triglycerides was not useful for predicting later change in glucose, cholesterol, or weight. Similarly, early weight change gave robust negative predictive values for longer-term weight change (≥10 kg), but not for change in glucose or cholesterol. Lack of early elevation in triglyceride concentrations was predictive of later lack of substantial increase in triglycerides in olanzapine-, ziprasidone-, and aripiprazole-treated participants. Lack of early elevation in weight was predictive of later lack of substantial increase in weight in all 3 treatment groups. Early monitoring of triglyceride concentrations and weight may help clinicians assess risk that individuals will experience significant increase in triglycerides or weight gain, allowing assessments of potential risks and benefits earlier in treatment. Clinical monitoring is advised throughout treatment for all patients.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Blood Glucose; Cholesterol; Drug Monitoring; Female; Humans; Male; Middle Aged; Olanzapine; Piperazines; Quinolones; Schizophrenia; Thiazoles; Time Factors; Triglycerides; Weight Gain

The second generation antipsychotics clozapine and olanzapine are known to cause weight gain. However, only clozapine is associated with drug-induced fever. Cytokines have been linked to the induction of both weight gain and drug-induced fever. We investigated these potential side effects of clozapine and olanzapine and studied their differential effects on cytokine secretion. Thirty patients suffering from schizophrenia, schizophreniform disorder or schizoaffective disorder were treated with either clozapine (mean modal dose: 266.7+/-77.9mg) or olanzapine (21.2+/-2.5mg) in a randomized, double-blind, 6-week study. Body mass index (BMI), tympanic temperature, and plasma levels of leptin and cytokines (tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptor 1 and 2 (sTNFR-1/2), soluble interleukin-2 receptors (sIL-2R), interleukin-6) were determined weekly. BMI, leptin and cytokines significantly increased over time, except interleukin-6 and sTNFR-1 in the olanzapine group. All cytokines numerically increased compared to baseline already during the first week of treatment in both groups. Leptin, TNF-alpha, sTNFR-1, sTNFR-2 and sIL-2R levels correlated with the BMI. Five patients who received clozapine (33%) developed drug-induced fever (>/=38 degrees C). In these, interleukin-6 peak levels were significantly (p<0.01) higher than in those patients treated with clozapine who did not develop fever. In conclusion, increase of BMI appears to be related to clozapine's and olanzapine's similar effects on cytokine systems, whilst drug-induced fever appears to be related to clozapine's differential effects on interleukin-6.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clozapine; Cytokines; Double-Blind Method; Female; Fever; Humans; Leptin; Male; Middle Aged; Olanzapine; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Weight Gain

This study examined the main metabolic side effects induced by antipsychotic treatment in a cohort of first episode drug-naïve subjects after the first year of treatment.. A randomized, open-label, prospective clinical trial was conducted. Participants were 164 consecutive subjects included in a first episode program and never treated with antipsychotic medication. Patients were assigned to haloperidol, olanzapine or risperidone. The main outcome measures were changes at 1 year in fasting glucose parameters (glucose, insulin levels and insulin resistance index) and changes in fasting lipid parameters (total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol).. 144 of the total sample were evaluated at 1 year. There was a statistically significant increase in the mean values of insulin levels, insulin resistance index, total cholesterol, LDL-cholesterol and triglycerides. No pathological values in fasting glucose plasma levels were found at baseline and there were no changes after 1 year. Weight gain was positively correlated with changes in insulin levels, insulin resistance index and triglyceride levels. We did not detect statistically significant differences between treatments in any of the parameters evaluated.. Fasting glycaemia and insulin concentrations at baseline do not support the hypothesis that schizophrenia is associated with an underlying abnormality in glucose metabolism. The changes in insulin and lipid parameters at 1 year seem to be related to the magnitude of weight gain. There were no significant differences between haloperidol, olanzapine and risperidone concerning metabolic adverse effects after the first year of treatment.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Female; Follow-Up Studies; Haloperidol; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Olanzapine; Prospective Studies; Risk Factors; Risperidone; Schizophrenia; Spain; Triglycerides; Weight Gain; Young Adult

Weight gain has been associated with many second generation antipsychotics (SGAs). A variety of theories have been put forward as to the etiology of SGA-associated weight gain. Modafinil possesses pharmacologic effects that could influence the weight gain associated with SGAs. The objective of this trial was to determine the effect of modafinil on olanzapine-associated weight gain.. This study was a 3-week, randomized, double-blind, placebo-controlled trial. All subjects received olanzapine titrated to 10 mg/day. Concurrently, subjects were randomized to receive modafinil titrated to 200 mg/day or placebo. Weight and feeding lab assessments were conducted at baseline and endpoint.. Fifty subjects were enrolled in the study with 20 subjects per group completing the trial. The primary outcome variable was change in the body mass index (BMI) over the 3 weeks of the trial. Increases in BMI were observed in both groups. However, analysis of covariance, controlled for baseline BMI, revealed that the olanzapine/placebo group had a greater increase in BMI at end point compared with the olanzapine/modafinil group (.89 +/- .59 vs. .47 +/- .50 kg/m(2), p < .05). When controlled for gender, the comparison showed a significant difference between groups at week 1 but not at weeks 2 or 3.. The results of this trial should not be extrapolated to clinical practice at this time. These data do serve to support further evaluation in a patient population to determine if the weight modifying effect of modafinil can be demonstrated over a longer period of time.

Topics: Adult; Antipsychotic Agents; Benzhydryl Compounds; Benzodiazepines; Body Mass Index; Central Nervous System Stimulants; Female; Humans; Male; Modafinil; Olanzapine; Weight Gain

The extent of weight changes in depressed patients who use atypical antipsychotics (AAP) as augmentation could not be easily predicted due to weight related symptoms of depression and the interaction with antidepressants which have weight reducing effects.. Patients were treated with either antidepressants augmented with AAP for more than 2 weeks (AAP group, n = 100) or only with antidepressants (non-AAP group, n = 172) during the admission between 2002 and 2006, and the differences in weight were analyzed.. Mean weight gains of AAP group were significantly higher than those of non-AAP group (2.98 +/- 1.87 kg vs. 1.70 +/- 1.85 kg, p = 0.001). When stratified by antidepressants, the significant difference between the two groups was shown among the subjects who had taken serotonin reuptake inhibitors (SSRIs), but not mirtazapine and venlafaxine (3.42 +/- 2.01 kg vs. 1.48 +/- 1.79 kg, p < 0.001). Comparing among different combinations in AAP group showed that subjects treated with SSRIs and olanzapine had the greatest weight gain (4.21 +/- 1.90 kg), significantly higher than that of the other subgroups (p < 0.001).. Our findings suggest that AAP used in patients with depression could severely aggravate preexisting weight-related problems of antidepressants use and the possibility that the combined use with specific antidepressants could have a unique effect on weight by drug-drug interactions.

Topics: Adult; Aged; Antidepressive Agents; Antipsychotic Agents; Benzodiazepines; Cyclohexanols; Depressive Disorder, Major; Drug Interactions; Drug Therapy, Combination; Female; Humans; Male; Mianserin; Middle Aged; Mirtazapine; Olanzapine; Selective Serotonin Reuptake Inhibitors; Venlafaxine Hydrochloride; Weight Gain

The second-generation antipsychotic agents clozapine and olanzapine have been associated with weight gain and increased lipid and glucose blood levels. Since some of the neurotransmitters that are impaired in aggressive patients are involved in lipid/glucose metabolism, aggressive patients may represent a subgroup with a differential profile of adverse metabolic reactions to these medications. The goal of this study was to assess the effects of clozapine and olanzapine in comparison to the first-generation agent haloperidol on these metabolic parameters in aggressive patients with schizophrenia.. 110 inpatients with schizophrenia and a history of physical assaults were included in a randomized double-blind 12-week study. Fasting glucose, cholesterol and triglycerides were collected at baseline and at the end of the study. Ninety-three patients provided blood samples at baseline and at least at one point after randomization to clozapine (N=34), olanzapine (N=31) or haloperidol (N=28).. There were significant differences among the three medication groups in weight gain and in increases in blood lipids and glucose. Patients on haloperidol showed no increase on any of these parameters. Patients on olanzapine gained the most weight, but patients on clozapine had the greatest increases in cholesterol, triglyceride, and glucose. An effect of ethnicity was observed, as African-American patients were more likely to develop metabolic abnormalities than other ethnic groups, especially on clozapine.. In this prospective randomized trial, clozapine and olanzapine were associated with weight gain. Clozapine was associated with increases in both lipids and glucose. This effect was most prominent in the African-American patients.

Topics: Adult; Aggression; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Cholesterol; Clozapine; Double-Blind Method; Ethnicity; Female; Haloperidol; Humans; Inpatients; Lipid Metabolism; Male; Middle Aged; Olanzapine; Prospective Studies; Schizophrenia; Weight Gain; Young Adult

The aim of this 6-month observational study was to examine which clinical, eating- and lifestyle-related factors were associated with weight gain in patients initiating or switching to oral olanzapine for the treatment of schizophrenia or bipolar mania. A total of 622 outpatients in four countries (China, Mexico, Romania, Taiwan) were assessed at monthly intervals for up to 6 months. Mixed model repeated-measures analysis, adjusted for baseline weight, was used to identify which factors were associated with weight gain during olanzapine therapy. After 6 months of therapy, the LS mean weight change was +4.1 kg and 43.9% of the patients had significant (> or = 7%) weight gain. Early significant weight gain after 2 months of therapy occurred in 23.4% of the patients and these patients gained significantly more weight overall. Ten factors were associated with weight gain during 6 months of olanzapine therapy in an exploratory multivariate analysis: country, housing conditions, stronger appetite, excessive amount of food needed to feel full, eating until uncomfortably full, thoughts preoccupied with food, meal location, increased meal frequency, evening snack consumption, and a lower amount of vigorous exercise. These results indicate that the influence of environmental, eating- and lifestyle-related factors should be considered when assessing weight gain during olanzapine therapy.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Demography; Diagnostic and Statistical Manual of Mental Disorders; Feeding Behavior; Female; Health Status; Humans; International Cooperation; Life Style; Male; Obesity; Olanzapine; Prospective Studies; Schizophrenia; Severity of Illness Index; Weight Gain

The aim of this study was to test the efficacy and safety of olanzapine + topiramate versus olanzapine monotherapy in the treatment of bipolar disorder (BPD) and treatment-attendant weight gain in children and adolescents.. Subjects (N = 40) were outpatients of both sexes, 6-17 years of age, with a Diagnostic and Statistical Manual of Mental Disorders, 4(th) edition (DSM-IV) diagnosis of BPD (manic, hypomanic, or mixed) and Young Mania Rating Scale (YMRS) total score of >15 treated over 8-week periods in two partially concurrent open-label trials with olanzapine (n = 17) or olanzapine + topiramate (n = 23).. Subjects in both groups experienced a statistically significant reduction in YMRS scores after 8-week, open-label treatment with olanzapine (baseline YMRS = 26.7 +/- 9.5; end-point YMRS = 18.2 +/- 12.5, p = 0.04) and olanzapine +topiramate (baseline YMRS = 31.3 +/- 7.9; end-point YMRS = 20.4 +/- 11.4, p = 0.04). There was no difference in response between the two groups based on YMRS or Clinical Global Impressions-Improvement (CGI-I) scores. Adverse events were few and mild and similar between the two groups, with the exception of weight gain. The weight gain in the olanzapine group was 5.3 +/- 2.1 kg and the weight gain in the olanzapine + topiramate group was statistically significantly lower, 2.6 +/- 3.6 kg.. Augmentation of olanzapine with topiramate resulted in a reduced weight gain over the course of an 8-week, open-label trial when compared with olanzapine treatment alone, but did not lead to greater reduction in symptoms of mania.

Topics: Adolescent; Anticonvulsants; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Child; Drug Therapy, Combination; Female; Fructose; Humans; Male; Olanzapine; Prospective Studies; Psychiatric Status Rating Scales; Topiramate; Weight Gain

Antipsychotic medications are associated with significant weight gain, type 2 diabetes mellitus, dyslipidemia, and increased cardiovascular risk. Suggested mechanisms of weight gain from antipsychotic medication include antagonism of histamine and serotonin receptors, and effects on the hypothalamic-pituitary-adrenal axis. The objective of this study was to determine if mifepristone, a glucocorticoid receptor antagonist, could prevent olanzapine-induced weight gain.. This was a randomized, double-blind trial. Fifty-seven lean, healthy men (body mass index 18-25 kg/m(2)) aged 19-38 years were randomized to olanzapine (7.5 mg) (n=22), olanzapine (7.5 mg) plus mifepristone (600 mg) (n=24), or mifepristone (600 mg) (n=11) daily for 2 weeks in an institutional setting. Subjects were provided food ad libitum to accentuate weight gain. Body weight was measured daily.. The mean change in baseline weight was +3.2+/-0.9 kg in subjects receiving olanzapine versus +2.0+/-1.2 kg in those receiving olanzapine plus mifepristone (P<0.0001). Subjects receiving mifepristone alone had a similar degree of weight gain compared to those receiving olanzapine plus mifepristone. The olanzapine group had significant increases in waist circumference when compared with the olanzapine plus mifepristone group (3.7+/-1.3 cm vs. 2.2+/-1.9 cm, respectively; P=0.006). Fasting insulin and triglycerides increased more in the olanzapine group, although differences were not statistically significant.. Mifepristone was effective in attenuating the increase in weight associated with olanzapine treatment over a 2-week period. Longer-term studies are required to examine the durability and full magnitude of this response.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Body Weights and Measures; Double-Blind Method; Hormone Antagonists; Humans; Insulin; Lipids; Male; Mifepristone; Olanzapine; Weight Gain; Young Adult

The objective of this study was to assess the dose-response relationship of standard and higher doses of olanzapine in a randomized, double-blind, 8-week, fixed-dose study comparing olanzapine 10 (n = 199), 20 (n = 200), and 40 mg/d (n = 200) for patients with schizophrenia or schizoaffective disorder and suboptimal response to current treatment. Patients meeting criteria for antipsychotic treatment resistance were excluded. Dose-response relationship was assessed by linear regression analysis with log-transformed dose (independent variable) and Positive and Negative Syndrome Scale (PANSS) total score (dependent variable). There were no significant dose group differences in patients completing the study (overall, 67.8%). All dose groups showed statistically significant improvement in PANSS total scores from baseline to end point without significant dose-response relationship (P = 0.295). Post hoc analysis of response showed significant interaction between baseline PANSS and dose (P = 0.023), indicating better response at higher doses for patients with higher baseline PANSS. There was a significant dose response for mean change in weight (P = 0.003) with significant difference between the 10- and 40-mg-dose groups (P = 0.002; 1.9 [10 mg/d], 2.3 [20 mg/d], and 3.0 kg [40 mg/d]). There was a significant dose response for change in prolactin (P < 0.001) with a significant difference between each group (-10.5 [10 mg/d], -1.7 [20 mg/d], and 4.9 ng/mL [40 mg/d]; P < or = 0.018). Over 8 weeks, non-treatment-resistant patients with schizophrenia or schizoaffective disorder responded to all 3 doses of olanzapine, without a statistically significant dose-response relationship, suggesting that for many patients with schizophrenia or schizoaffective disorder, particularly those who are mildly or moderately ill, 10 mg/d should be the initial dose of choice.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Olanzapine; Prolactin; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Treatment Outcome; Weight Gain

Olanzapine is an efficacious drug often used as a first-line medication in the treatment for schizophrenia. However, weight gain is a notable adverse drug reaction of this medication in a proportion of patients and a major cause of noncompliance. Several hypotheses, including a contribution from hormonal, physiological and environmental factors, have been postulated. In this study, we aimed to analyze a possible association of genetic polymorphisms at four important candidate genes involved in appetite regulation and antipsychotic-induced metabolic syndrome with olanzapine-induced weight gain.. A total of 154 schizophrenia subjects were recruited in a systematic, 6-week, open-label trial of olanzapine. We investigated the contribution of 14 polymorphisms from four genes, namely, leptin, lipoprotein lipase, tri-acyl-glycerol lipase and citrate lyase using a binary logistic regression analysis towards olanzapine-induced weight gain.. rs 4731426 C/G SNP, a variant in the leptin gene, was moderately associated with median weight gain (Delta weight(m); [p = 0.05; OR: 2.2; 95% CI: 0.99-4.90]) and significantly associated with extreme weight gain (Delta weight(e) [p = 0.019; OR: 11.43; 95% CI: 1.49-87.55]) when average drug dose was included in a regression model. Using in silico analysis, we found that this associated intronic SNP in the leptin gene alters the binding of zinc finger 5, a transcription factor.. The leptin gene may be a promising candidate for olanzapine-induced weight gain. As the associations are modest, replicate studies are warranted. This approach may facilitate rationalized drug regimens.

Topics: Adult; Benzodiazepines; Female; Genetic Linkage; Humans; India; Leptin; Male; Metabolic Networks and Pathways; Middle Aged; Olanzapine; Polymorphism, Genetic; Schizophrenia; Weight Gain

The Child and Adolescent First-Episode Psychosis Study (CAFEPS) is a naturalistic longitudinal study of early-onset first psychotic episodes. This report describes the antipsychotic treatment during the first year and compares the most frequently used agents after 6 months.. Participants were 110 patients, aged 9-17 years, with a first psychotic episode attended consecutively at six different centers. The Positive and Negative Symptom Scale (PANSS), Clinical Global Impressions (CGI), Disability Assessment Schedule (DAS), and Global Assessment of Function (GAF) scales were administered at baseline and at 6 months and the Udvalg for Kliniske Undersøgelser (UKU) Side Effects Rating Scale only at 6 months.. Diagnoses at baseline were 38.2% psychotic disorder not otherwise specified, 39.1% schizophrenia-type disorder, 11.8% depressive disorder with psychotic symptoms, and 10.9% bipolar disorder, manic episode with psychotic symptoms. The most frequently used antipsychotic agents were risperidone (n = 50), quetiapine (n = 18), and olanzapine (n = 16). Patients who were prescribed olanzapine or quetiapine had more negative and general symptoms. Using the baseline score as covariate, no significant differences were found in the reductions on any scale in patients treated with risperidone, quetiapine, or olanzapine for 6 months. Weight increase was greater with olanzapine than with risperidone (p = 0.020) or quetiapine (p = 0.040). More neurological side effects appeared with risperidone than with olanzapine (p = 0.022). All side effects were mild or moderate.. Second-generation antipsychotics, especially risperidone, quetiapine, and olanzapine, are the most used in our context in first psychotic episodes in children and adolescents. These three obtain similar clinical improvement, but differ in their side effects.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Child; Dibenzothiazepines; Female; Follow-Up Studies; Humans; Longitudinal Studies; Male; Olanzapine; Practice Patterns, Physicians'; Psychiatric Status Rating Scales; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Severity of Illness Index; Treatment Outcome; Weight Gain

The primary aim of the study was to evaluate the effectiveness and tolerability of open-label olanzapine on motor and vocal tics in children and adolescents with Tourette syndrome (TS). Secondary aims included assessing the response of TS-associated disruptive behaviors to olanzapine exposure.. Twelve children and adolescents (mean age 11.3 +/- 2.4 years, range 7-14 years) with Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) TS were enrolled in a single-site, 6-week, open-label, prospective, flexible-dose design in outpatients receiving monotherapy with olanzapine. Standardized ratings of tic symptoms, disruptive behaviors, and aggression were obtained, along with adverse events and safety data.. Over the 6-week trial, olanzapine administration was associated with a significant decrease in total tic severity as measured by the Yale Global Tic Severity Scale (30% reduction by week 6; effect size 0.49). A significant majority of subjects were rated as "much improved" or "very much improved" on the Clinical Global Impressions-Improvement Scale (GCI-I) by both clinicians (67%; 8/12) and parents (64%; 7/11). Attention-deficit/hyperactivity disorder (ADHD) symptoms showed significant improvements from baseline for both inattention (33% decrease) and hyperactive/impulsivity (50% decrease) scores (effect sizes 0.44 and 0.43, respectively). Aggression was also decreased as assessed by fewer numbers of aggressive episodes on the Overt Aggression Scale (OAS). Little change in anxiety symptoms was noted. The most widely reported side effects were drowsiness/sedation and weight gain; adverse events were generally well tolerated. Mean weight gain of 4.1 +/- 2.0 kg was observed over the 6-week trial, a mean percent change of 8.4 +/- 4.4 (p < 0.001).. Additional studies of the benefits of olanzapine treatment for tic control as well as the commonly associated co-morbid features of TS are indicated, especially if approaches to predict or minimize weight gain can be determined.

Topics: Adolescent; Aggression; Antipsychotic Agents; Attention Deficit Disorder with Hyperactivity; Benzodiazepines; Child; Female; Humans; Male; Olanzapine; Prospective Studies; Psychiatric Status Rating Scales; Severity of Illness Index; Tourette Syndrome; Treatment Outcome; Weight Gain

To evaluate the efficacy and safety of olanzapine, divalproex, and placebo in a randomized, double-blind trial in mild to moderate mania (DSM-IV-TR criteria).. The study was conducted from October 2004 to December 2006. A total of 521 patients from private practices, hospitals, and university clinics were randomly assigned to olanzapine (5-20 mg/day), divalproex (500-2500 mg/day), or placebo for 3 weeks; those completing continued with a 9-week double-blind extension. Efficacy (mean change in Young Mania Rating Scale [YMRS] total score was the primary outcome) and safety were assessed.. After 3 weeks of treatment, olanzapine-treated (N = 215) and placebo-treated (N = 105) patients significantly differed in YMRS baseline-to-endpoint total score change (p = .034; least squares [LS] mean: -9.4 and -7.4, respectively). Such changes were not significantly different between olanzapine vs. divalproex (N = 201) or divalproex vs. placebo. After 12 weeks of treatment, olanzapine- and divalproex-treated patients significantly differed in YMRS baseline-to-endpoint changes (p = .004; LS mean: -13.3 and -10.7, respectively). Of observed cases, 35.4% (35/99; 3 weeks) to 57.1% (28/49; 12 weeks) had valproate plasma concentrations lower than the recommended valproate therapeutic range, but these patients' YMRS scores were lower than those of patients with valproate concentrations above/within range. Compared with divalproex, after 12 weeks, olanzapine-treated patients had significant increases in weight (p < .001) and in glucose (p < .001), triglyceride (p = .003), cholesterol (p = .024), uric acid (p = .027), and prolactin (p < .001) levels. Divalproex-treated patients had significant decreases in leukocytes (p = .044) and platelets (p < .001) compared with olanzapine after 12 weeks of treatment. The incidence of potentially clinically significant weight gain (>/= 7% from baseline) was higher with olanzapine than with divalproex (3-week: p = .064, 6.4% vs. 2.7%; 12-week: p = .002, 18.8% vs. 8.5%; respectively).. Olanzapine was significantly more efficacious than placebo but not divalproex at 3 weeks and significantly more efficacious than divalproex at 12 weeks. Olanzapine-treated patients had significantly greater increases in weight and in glucose, cholesterol, triglyceride, uric acid, and prolactin levels than divalproex-treated patients.. clinicaltrials.gov Identifier: NCT00094549.

Topics: Adolescent; Adult; Aged; Antimanic Agents; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Least-Squares Analysis; Male; Middle Aged; Olanzapine; Prolactin; Valproic Acid; Weight Gain

Despite the prevalence and clinical significance of borderline personality disorder, its treatment remains understudied.. To evaluate treatment with variably dosed olanzapine in individuals with borderline personality disorder.. In this 12-week randomised, double-blind trial, individuals received olanzapine (2.5-20 mg/day; n=155) or placebo (n=159) (trial registry: NCT00091650). The primary efficacy measure was baseline to end-point change on the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) using last-observation-carried-forward methodology.. Both olanzapine and placebo groups showed significant improvements but did not differ in magnitude at end-point (-6.56 v. -6.25, P=0.661). Response rates (50% reduction in ZAN-BPD) were 64.7% with olanzapine and 53.5% with placebo (P=0.062); however, time to response was significantly shorter for olanzapine (P=0.022). Weight gain was significantly greater (2.86 v. -0.35 kg, P<0.001), with higher incidence of treatment-emergent abnormal high levels of prolactin for the olanzapine group.. Individuals treated with olanzapine and placebo showed significant but not statistically different improvements on overall symptoms of borderline personality disorder. The types of adverse events observed with olanzapine treatment appeared similar to those observed previously in adult populations.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Benzodiazepines; Borderline Personality Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Olanzapine; Psychiatric Status Rating Scales; Treatment Outcome; Weight Gain; Young Adult

This multicenter, double-blind, randomized, controlled study conducted in China examined the efficacy and safety of olanzapine versus lithium in the treatment of patients with bipolar manic/mixed episodes.. Patients with bipolar manic or mixed episode (DSM-IV criteria) and Young Mania Rating Scale (YMRS) score> or =20 at screening received olanzapine (5-20 mg/day, n=69) or lithium carbonate (600-1800 mg/day, n=71) for 4 weeks. The primary outcome was mean change from baseline in Clinical Global Impressions-Bipolar Version Overall Severity of Illness (CGI-BP) score. Secondary efficacy measures included YMRS, Brief Psychiatric Rating Scale (BPRS), and Montgomery-Asberg Depression Rating Scale (MADRS) scores. Safety was also assessed.. A significantly greater mean change was observed in olanzapine versus lithium patients in CGI-BP (Overall Severity) (P=0.009), YMRS (P=0.013), BPRS (P=0.032), and CGI-BP (Severity of Mania) (P=0.012) scores. More olanzapine than lithium patients experienced at least one adverse event possibly related to study drug (P=0.038). More olanzapine patients had a clinically significant weight increase (> or =7% of baseline weight) compared to lithium patients (P=0.009). More olanzapine patients completed the study than lithium patients, although this difference was not statistically significant (olz, 91.3%; lith, 78.9%; P=0.057).. No placebo arm was included; however both treatments have previously been reported to be more effective than placebo.. These results suggest that olanzapine has superior efficacy to lithium in the acute treatment of patients with bipolar mania over a 4-week period. However, adverse events were experienced by a greater number of olanzapine patients than lithium patients.

Topics: Adult; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Bipolar Disorder; Brief Psychiatric Rating Scale; Depressive Disorder; Diagnostic and Statistical Manual of Mental Disorders; Double-Blind Method; Female; Humans; Lithium Carbonate; Male; Obesity; Olanzapine; Psychiatric Status Rating Scales; Severity of Illness Index; Weight Gain

There is little information about weight gain induced by antipsychotics at long-term.. To quantify the weight gain induced by first (haloperidol) and second generation antipsychotics (olanzapine and risperidone) in a cohort of drug-naïve subjects after 1 year of treatment.. This is a prospective, randomized clinical trial, including a representative sample of first episode psychotic incident cases from a population area of 555.000 people. The main outcome measures were changes in body weight and body mass index at 3 months and at 12 months. Both a per protocol analysis and an intention to treat analysis were conducted.. A total of 164 drug-naïve patients were included. At 12 months 144 patients were evaluated. Of them, 66% completed the protocol and 34% needed treatment switch. We found statistically significant differences in weight gain at 3 months: 3.8 kg (+/-4.1) for haloperidol, 5.9 kg (+/-5.1) for risperidone and 8.4 kg (+/-5.0) for olanzapine (F=7.045; p=0.002). After 1 year the difference in weight gain had disappeared: 9.7 kg (+/-5.7) for haloperidol, 8.9 kg (+/-8.8) for risperidone and 10.9 kg (+/-7.2) for olanzapine (F=0.817; p=0.445).. Drug-naïve patients experience an extraordinary weight gain after 1 year of treatment with haloperidol, olanzapine or risperidone. The main difference among these treatments is the pattern of weight gain but not the final amount of weight gain.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Chronic Disease; Cohort Studies; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Haloperidol; Humans; Long-Term Care; Male; Middle Aged; Olanzapine; Risperidone; Spain; Treatment Outcome; Weight Gain

The aim of this study was to evaluate the efficacy of a psychoeducational program (PEP) for weight control in patients who had experienced an increase of body weight during treatment with olanzapine.. Eligible patients were randomised to the PEP (Group 1) or to no intervention (Group 2) and continued on olanzapine. After 12 weeks, the PEP was also started in Group 2 and continued in Group 1, up to week 24. Body weight was measured every month. Other measures included quality of life, and change in plasma glucose and lipids levels.. Patients in Group 1 (n=15) had a mean weight loss of 3.6 kg at week 12 and 4.5 kg at week 24 (p<0.01 at both times, p<0.01 between groups at week 12), while those in Group 2 (n=18) had no changes at week 12 and a significant weight loss at week 24 (-3.6 kg from week 12, p<0.01). Changes of BMI paralleled those of body weight. Quality of life (Q-LES-Q-SF categorisation) and functioning (GAF) significantly improved in the total population at endpoint (p<0.01). No significant changes were observed in fasting glucose and lipid profile, while insulin levels significantly decreased from baseline to endpoint in both groups (p<0.05). HOMA index and hepatic insulin sensitivity improved, too.. Patients with increased BMI during treatment with olanzapine experienced significant weight and BMI loss following a structured psychoeducational program.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Cognitive Behavioral Therapy; Evaluation Studies as Topic; Female; Humans; Male; Mental Disorders; Middle Aged; Obesity; Olanzapine; Psychiatric Status Rating Scales; Time Factors; Weight Gain

To thoroughly investigate the phenomenon of atypical antipsychotic-associated weight gain, a feeding laboratory paradigm was developed that included obtaining plasma levels of the orexigenic peptide ghrelin that is associated with appetite and eating. This study is a randomized, double-blind, parallel group trial comparing the effects of a 2-week exposure to olanzapine, risperidone, or placebo on plasma ghrelin area under the plasma-time curve (AUC) in 28 healthy human subjects. Subjects were randomized to receive olanzapine, risperidone, or placebo and titrated over 4 days to 10 mg/d or 4 mg/d, respectively. The mean dose at end point was 8.6 + 1.8 mg/d for the olanzapine group and 2.8 + 0.8 mg/d for the risperidone group. Weight changes were significantly different between groups at end point (F2,44 = 10.193; P = 0.0001). The olanzapine group demonstrated a significant increase in weight at end point (2.25 + 1.84 kg) compared with placebo (0.13 + 1.05 kg; P = 0.007). Because of the small subject number, the comparisons between olanzapine and risperidone and risperidone and placebo did not reach statistical significance, although olanzapine's mean weight gain was numerically greater than that of risperidone (2.25 + 1.84 kg vs 1.10 + 0.99 kg) and risperidone's mean weight gain was numerically larger than placebo (1.10 + 0.99 kg vs 0.13 + 1.05 kg). The baseline adjusted Bonferroni corrected contrast of end point ghrelin AUC demonstrated a significant difference between groups (F2,24 = 4.40; P = 0.024), and the post hoc analysis revealed a significant decrease in ghrelin AUC for the olanzapine group in comparison with the risperidone group (P = 0.021) but not between risperidone and placebo or olanzapine and placebo. Ghrelin AUC values did not change significantly from baseline to end point in either of the other 2 groups. The difference between groups approached but did not reach significance (F2,23 = 3.299; P = 0.055) when body mass index change was included as a covariate, suggesting that the difference in ghrelin AUC change followed the change in body weight. Sedation associated with both active drugs (P = 0.006) and "stuffy nose" associated with risperidone (P = 0.020) were the only statistically different adverse reactions when compared with placebo. Thus, a human feeding laboratory paradigm using a brief exposure to atypical antipsychotics functions as a method to investigate pharmacologically induced weight gain and its association with changes in t

Topics: Adult; Antipsychotic Agents; Area Under Curve; Benzodiazepines; Double-Blind Method; Feeding Behavior; Female; Ghrelin; Humans; Male; Olanzapine; Risperidone; Weight Gain

Antipsychotic-induced weight gain is one of the most distressing adverse effects being observed in recent times. Most studies have been limited by several confounders.. To evaluate the predictors of antipsychotic-induced weight gain in drug-naive patients with first-episode psychosis treated with olanzapine, risperidone, or haloperidol and compare them with a healthy matched control group.. Newly diagnosed patients with first-episode schizophrenia treated with antipsychotic medication-olanzapine, risperidone, or haloperidol-and matched healthy controls were followed for 6 weeks. Body mass index (BMI), waist circumference, and weight changes and proportions of subjects with more than 7% weight gain were calculated. The predictors of weight gain were explored.. Ninety-nine patients with first-episode schizophrenia and 51 healthy controls were examined. Waist circumference (r = -0.25; P < 0.01) and weight (r = -0.24; P < 0.01) at baseline in addition to the disease process (P < 0.001) as well as antipsychotic use (P < 0.001) were associated with greater increases in weight and BMI. Olanzapine (77%) had greater clinically significant weight gain as compared with risperidone (63%) and haloperidol (22%). Lower BMI at baseline and a diagnosis of undifferentiated schizophrenia were associated with antipsychotic-induced weight gain.. The results confirm clinically significant and substantial weight gain induced by antipsychotic treatment in drug-naive patients with first-episode schizophrenia and identify several risk factors for weight gain such as lower BMI scores, use of olanzapine, and a diagnosis of undifferentiated schizophrenia.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Double-Blind Method; Female; Haloperidol; Humans; Male; Olanzapine; Prognosis; Prospective Studies; Risperidone; Schizophrenia; Weight Gain

Clozapine, despite its side-effect burden, has been considered to be the drug of choice for patients with schizophrenia whose psychotic symptoms fail to respond adequately to other anti-psychotic drugs. There are conflicting data concerning the potential utility of olanzapine in treatment-resistant schizophrenia at doses beyond the 10- to 20-mg/day range that has proven to be effective for most nonrefractory patients with schizophrenia.. The main objective of this study was to compare the efficacy and tolerability of high-dose olanzapine (target dose, 25-45 mg/day) and clozapine (300-900 mg/day) in patients with schizophrenia or schizoaffective disorder who had failed to respond adequately to prior treatment with other antipsychotic drugs.. This 6-month, randomized, double-blind, parallel-group study compared the efficacy and tolerability of olanzapine (mean dose, 34 mg/day; N = 19) or clozapine (mean dose, 564 mg/day; N = 21) in patients with treatment-resistant schizophrenia or schizoaffective disorder, diagnosed according to DSM-IV criteria. Outcome measures included psychopathology, cognitive performance (as assessed with a comprehensive neuropsychological test battery), and tolerability. The study was conducted between May 2000 and December 2003.. Robust and significant (mostly p < .001) improvement in multiple measures of psychopathology, mainly between 6 weeks and 6 months of treatment, was found in both treatment groups, with no significant difference between the 2 treatments except for the Global Assessment of Functioning score, which favored clozapine (p = .01). Improvement in some domains of cognition was significant-and equivalent for both drugs, as well. Nonsignificantly different improvement in Verbal List Learning-Immediate Recall (p < .05), Controlled Word Association Test (p < .05), and Digit Symbol Substitution Test (p < .001) was found. There were no significant differences in extrapyramidal symptoms. Weight gain was significantly (p = .01) greater with olanzapine.. Olanzapine, at higher than customary doses, demonstrated similar efficacy to clozapine in treatment-resistant schizophrenia and schizoaffective disorder in this study. However, the small sample size precludes definitively concluding that the 2 treatments are equivalent, at these doses, in treatment-resistant schizophrenia. The metabolic side effects of olanzapine are a limitation in its use.. ClinicalTrials.gov identifier NCT00179231.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Cognition; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Olanzapine; Prospective Studies; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Serotonin Antagonists; Time Factors; Treatment Outcome; Weight Gain

The purpose of this study was to assess the efficacy of metformin in preventing olanzapine-induced weight gain.. Forty patients with schizophrenia were randomly assigned to treatment for 12 weeks with olanzapine, 15 mg/day, plus metformin, 750 mg/day (N=20), or olanzapine, 15 mg/day, plus placebo (N=20). This investigation was conducted in a double-blind fashion. Planned assessments included body weight, body mass index, proportion of patients who gained more than 7% of their baseline weight at the end of the 12-week treatment, waist circumference, waist-to-hip ratio, fasting glucose and insulin, insulin resistance index, and scores on the Scale for the Assessment of Positive Symptoms (SAPS) and Scale for the Assessment of Negative Symptoms (SANS).. Of the 40 patients who were randomly assigned, 37 (92.5%) completed treatments. The weight, body mass index, waist circumference, and waist-to-hip ratio levels increased less in the olanzapine plus metformin group relative to the olanzapine plus placebo group during the 12-week follow-up period. The insulin and insulin resistance index values of the olanzapine plus placebo group increased significantly at weeks 8 and 12. In contrast, the insulin and insulin resistance index levels of the olanzapine plus metformin group remained unchanged. Significantly fewer patients in the olanzapine plus metformin group relative to patients in the olanzapine plus placebo group increased their baseline weight by more than 7%, which was the cutoff for clinically meaningful weight gain. There was a significant decrease in SAPS and SANS scores within each group from baseline to week 12, with no between-group differences. Metformin was tolerated well by all patients.. Metformin was effective and safe in attenuating olanzapine-induced weight gain and insulin resistance in drug-naive first-episode schizophrenia patients. Patients displayed good adherence to this type of preventive intervention.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Follow-Up Studies; Humans; Hypoglycemic Agents; Metformin; Middle Aged; Obesity; Olanzapine; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Treatment Outcome; Waist-Hip Ratio; Weight Gain

Metformin (850-1700 mg) plus sibutramine (10-20 mg, n=13) or placebo (n=15) was administered for 12 weeks in olanzapine-treated chronic schizophrenia patients. Weight loss was similar in both groups: -2.8+/-3.2 kg vs. -1.4+/-2.6 kg. Except for preventing a triglyceride increase, the drug combination lacked efficacy for metabolic control in this clinical population.

Topics: Adult; Antipsychotic Agents; Appetite Depressants; Benzodiazepines; Body Mass Index; Chronic Disease; Cyclobutanes; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Male; Metabolic Syndrome; Metformin; Middle Aged; Obesity; Olanzapine; Pilot Projects; Placebos; Schizophrenia; Schizophrenic Psychology; Waist-Hip Ratio; Weight Gain; Weight Loss

Weight gain has often been associated with olanzapine treatment, yet little is known about the influence of patient age or cumulative dose on olanzapine-associated weight gain. The first 118 participants in the National Institutes of Mental Health Study of the Pharmacotherapy of Psychotic Depression randomized clinical trial (ClinicalTrials.gov Registration NCT00056472) completing at least 4 weeks of treatment with olanzapine were analyzed to determine the relationship between weight gain, age, and cumulative olanzapine dose. Younger (age 18-59 years) and older (age 60+ years) participants received open-label olanzapine and either sertraline or placebo for up to 12 weeks. Linear mixed effect regression modeling was used to determine the effects of age and cumulative olanzapine dose on weight gain, controlling for potential confounders. Age was observed to have a significant negative association with weight gain (P=0.01), even after controlling for differences in cumulative dose and baseline body mass index. Each 10-year increase in age was associated with a decrease in mean weight gain over 12 weeks of approximately 0.6 kg (95% confidence interval: 0.14-1.05 kg). Cumulative olanzapine dose was also significantly associated with weight gain (P<0.0001). Approximately 60% of completers of the 12-week trial experienced clinically significant weight gain (> or =7% of baseline weight).

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Antidepressive Agents; Benzodiazepines; Canada; Depression; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Olanzapine; Risk Factors; Sertraline; Treatment Outcome; United States; Weight Gain

Weight gain has become one of the most common and concerning side effects of antipsychotic treatment. The mechanisms whereby antipsychotics induce weight gain are not known. It has been suggested that peptides related to food intake and energy balance could play a role in weight gain secondary to antipsychotic therapy. To better understand the pathophysiology of antipsychotic-induced weight gain, we studied the effects of 3 antipsychotic drugs (haloperidol, olanzapine, and risperidone) on peptides involved in energy balance (insulin, ghrelin, leptin, adiponectin, visfatin, and resistin) in a population of drug-naive patients with first episode of psychosis.A significant increase in weight (10.16 kg [SD, 8.30 kg]; P < 0.001), body mass index (3.56 kg/m [SD, 2.89 kg/m]; P < 0.001), and fasting insulin (3.93 muU/mL [SD, 3.93 muU/mL]; P = 0.028), leptin (6.76 ng/mL [SD, 7.21 ng/mL]; P < 0.001), and ghrelin (15.47 fmol/mL [SD, 47.90 fmol/mL]; P = 0.009) plasma levels were observed. The increments in insulin and leptin concentrations were highly correlated with the increment in weight and body mass index and seem to be a consequence of the higher fat stores. The unexpected increase in ghrelin levels might be related with the causal mechanism of weight gain induced by antipsychotics. Finally, the 3 antipsychotics had similar effects in all parameters evaluated.

Topics: Adiponectin; Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Body Composition; Body Mass Index; Dose-Response Relationship, Drug; Energy Metabolism; Female; Ghrelin; Haloperidol; Humans; Insulin; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Olanzapine; Prospective Studies; Psychotic Disorders; Resistin; Risperidone; Schizophrenia; Weight Gain

Topics: Adult; Antipsychotic Agents; Appetite; Benzodiazepines; Blood Glucose; Chronic Disease; Delayed-Action Preparations; Female; Fluphenazine; Humans; Insulin; Insulin Resistance; Male; Olanzapine; Reference Values; Risperidone; Schizophrenia; Weight Gain

We investigated the relationships between L/S promoter (SERTPR) and l/s intron2 (SERTin2) genetic variants of serotonin transporter (SERT) polymorphisms with olanzapine-induced weight gain and treatment response in 94 female schizophrenic patients treated with olanzapine for up to 3 months. Body mass index (BMI) was calculated for each patient prior to olanzapine administration and 3 months afterwards. To assess and evaluate improvement of clinical psychotic symptoms and therapeutic response to the antipsychotic, all patients were rated using the Positive and Negative Syndrome ScaLe (PANSS). Overall, the presence of S SERTPR allelic variant and SS genotype was associated with significantly higher weight gain in subjects who were non-obese at the time of admission. The presence of L SERTPR variant was associated with significantly better treatment response measured with total PANSS and general PANSS subscale, while the presence of l SERTin2 variant determined better treatment response only in several items. No evidence of linkage disequilibrium between the two loci was found in the sample. These findings identify genetic factors associated with oLanzapine-induced weight gain and treatment response in femaLe schizophrenic patients.

Topics: Adolescent; Adult; Aged; Alleles; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Croatia; Female; Genotype; Humans; Linkage Disequilibrium; Middle Aged; Olanzapine; Polymorphism, Genetic; Psychiatric Status Rating Scales; Schizophrenia; Serotonin Plasma Membrane Transport Proteins; Treatment Outcome; Weight Gain

A post-hoc analysis of the data from a randomised clinical trial involving prescription of antipsychotic treatment to never treated first-onset psychotic patients was used to compare the weight change after 6-week olanzapine treatment (standard tablets vs. orally disintegrating formulation).. In the subgroup of 38 patients randomised to olanzapine, standard olanzapine tablets were non-randomly and consecutively prescribed to the first 19 patients, with the orally disintegrating formulation being prescribed to the following 19 patients.. After 6-week treatment with olanzapine, a significant higher increase in weight was noted in those patients on standard tablets (mean weight increase 6.3 +/- 1.9 Kg) as compared to those on orally disintegrating olanzapine (mean weight increase 3.3 +/- 3.2 Kg) (F = 7.7; p = 0.009). BMI increase was also significantly higher in the olanzapine tablet group (mean increase of 2.1 Kg/m(2) as compared with 1.1 Kg/m(2) in the orally disintegrating group) (F = 4.7; p = 0.036). Substantial weight gain (SWG) (> or =7% increase from baseline weight) was noted in 84.2% (n = 16) of the olanzapine tablet patients and in 31.6% (n = 6) of the orally disintegrating olanzapine patients, with the olanzapine tablet group showing a significant increase in the mean percentage of weight gain (F = 4.0; p = 0.014).. Partial sublingual absorption occurring with orally disintegrating olanzapine may bypass gastrointestinal metabolisation and hence lead to differences in metabolite versus parent compound ratios. However, the need arises to replicate the present study with a longer follow-up.

Topics: Administration, Oral; Administration, Sublingual; Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Body Mass Index; Dosage Forms; Female; Humans; Male; Olanzapine; Psychotic Disorders; Schizophrenia, Paranoid; Weight Gain

Atypical antipsychotics induce pre-diabetic symptoms in some but not all patients, characterized most notably by elevated weight. The side effect profiles of the various drugs in the class differ, however, raising the possibility of drug-specific mechanisms for similar side effects. We used physiogenomic analysis, an approach previously employed to study the genetics of drug and diet response, to discover and compare genetic associations with weight profiles observed in patients treated with olanzapine and risperidone as an approach to unraveling contrasting mechanistic features of both drugs. A total of 29 single nucleotide polymorphisms (SNPs) were selected from 13 candidate genes relevant to two potential pharmacological axes of psychotropic-related weight profiles, appetite peptides and peripheral lipid homeostasis. We applied physiogenomic analysis to a cross-section of 67 and 101 patients being treated with olanzapine and risperidone, respectively, and assessed genetic associations with the weight profiles. Weight profiles in patients treated with olanzapine were significantly associated with SNPs in the genes for apolipoprotein E, apolipoprotein A4 and scavenger receptor class B, member 1. Weight profiles in patients treated with risperidone were significantly associated with SNPs in the genes for leptin receptor, neuropeptide Y receptor Y5 and paraoxonase 1. These results are consistent with contrasting mechanisms for the weight profile of patients treated with these drugs. Genes associated with olanzapine weight profiles may be related to peripheral lipid homeostatic axes, whereas those associated with risperidone's may be related to brain appetite peptide regulation. Future physiogenomic studies will include neurotransmitter receptor SNPs and validation in independent samples.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analysis of Variance; Antipsychotic Agents; Apolipoproteins; Appetite Regulation; Aryldialkylphosphatase; Benzodiazepines; Cross-Sectional Studies; Female; Genomics; Humans; Lipid Metabolism; Male; Mental Disorders; Middle Aged; Olanzapine; Polymorphism, Single Nucleotide; Receptors, Cell Surface; Receptors, Leptin; Receptors, Neuropeptide Y; Risperidone; Scavenger Receptors, Class B; Weight Gain

Several studies have demonstrated the effective use of dehydroepiandrosterone (DHEA) in the management of mood, however studies of its use in psychosis remain limited. The aim of this study was to investigate for the first time efficacy of DHEA augmentation with standardized antipsychotic medication (olanzapine) and to explore effects of DHEA augmentation on side-effect profiles including weight gain, glucose tolerance, aggression, quality of life and neurocognitive function. Finally, we aimed to analyze any relationship between plasma levels and clinical response to DHEA administration. Forty patients with chronic schizophrenia stabilized on olanzapine were randomized in double-blind fashion to receive either DHEA (titrated up to 150mg) or placebo augmentation for a period of 12-weeks. Blood samples were collected at baseline, mid-study and study completion. Results indicated improvement of negative symptoms (SANS scale) even when baseline scores were controlled as a covariate. Some improvement in Parkinsonism and akathisia compared to baseline was seen in patients receiving DHEA. No change in psychosis as reflected by the PANSS was noted. Patients receiving DHEA appeared to demonstrate relatively stable glucose levels compared to controls at the end of the study. An improvement in cognitive performance (most notably memory), which did not reach significance due to low sample number, was observed following DHEA administration. Results further suggest preliminary evidence of involvement of the neurosteroid system in schizophrenia pathophysiology, and confirm initial "cautious" findings identifying an agent capable of improving negative symptoms and certain features of extrapyramidal side effects.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Cognition; Dehydroepiandrosterone; Double-Blind Method; Dyskinesia, Drug-Induced; Female; Glucose Tolerance Test; Hormones; Humans; Male; Middle Aged; Neuropsychological Tests; Olanzapine; Psychiatric Status Rating Scales; Quality of Life; Schizophrenia; Schizophrenic Psychology; Weight Gain

Search for safe and effective strategies to diminish weight gain associated with second generation antipsychotics (SGAs) is imperative. In the present study, we sought to replicate our preliminary findings, which indicated that coadministration of the selective norepinephrine reuptake inhibitor reboxetine attenuates olanzapine-induced weight gain.. Fifty-nine patients hospitalized for first-episode DSM-IV schizophrenic disorder participated in this randomized double-blind study. Reboxetine (4 mg/day; 31 patients) or placebo (29 patients) was coadministered with olanzapine (10 mg/day) for 6 weeks. Analysis was by intention-to-treat.. Nine patients in each group prematurely discontinued the trial. Olanzapine/reboxetine-treated patients showed a significantly lower increase in body weight (mean = 3.31 kg, SD = 2.73) than their olanzapine/placebo-treated counterparts (mean = 4.91 kg, SD = 2.45). Significantly fewer olanzapine/reboxetine-treated patients gained at least 7% of their initial weight, the cutoff for clinically significant weight gain (6 [19.4%] of 31 patients vs 13 [46.4%] of 28 patients). Seven (22.6%) olanzapine/reboxetine-treated patients compared to only one patient (3.6%) in the olanzapine/placebo group revealed no weight change or even modest weight loss. Appetite increase was significantly lower in the olanzapine/reboxetine than olanzapine/placebo group and was correlated with attenuation of weight gain. Reboxetine addition was safe and well tolerated.. The results confirm that coadministration of reboxetine promotes a clinically meaningful attenuation of olanzapine-induced weight gain in schizophrenia patients. If substantiated in long-term studies, along with behavioral management and diet counseling, reboxetine may have a clinical utility in controlling SGA-induced weight gain.

Topics: Adrenergic Uptake Inhibitors; Adult; Antipsychotic Agents; Appetite; Benzodiazepines; Body Mass Index; Double-Blind Method; Female; Humans; Male; Middle Aged; Morpholines; Olanzapine; Reboxetine; Schizophrenia; Weight Gain

Olanzapine (OLA) administration has been reported to induce weight gain in experimental animals and humans, through not yet fully defined mechanisms of action. Aim of this study was to determine whether in patients with Anorexia Nervosa (AN) OLA induces weight gain through the modulation of the hunger-satiety regulatory peptides leptin and ghrelin.. Twenty anorexic probands received a 3 months course of cognitive-behavioral psychotherapy and programmed nutritional rehabilitation, combined with OLA PO (2.5 mg for 1 month and 5 mg for 2 months) in ten patients and with placebo PO (PL) in the other 10. Weight, measured as body mass index (BMI), leptin and ghrelin plasma values were monitored before starting the therapy and then monthly for 3 months. Plasma leptin was measured by ELISA, and plasma ghrelin by radioimmunoassay.. BMI increased significantly but not differently in both treatment groups. Leptin and ghrelin secretion did not change during the course of the treatments. No correlations were observed between BMI values and leptin and ghrelin levels.. Our data suggest that the weight gain observed in our OLA-treated patients was not linked to drug administration. Moreover, leptin and ghrelin secretions were not responsible for BMI changes.

Topics: Adult; Anorexia Nervosa; Benzodiazepines; Body Mass Index; Double-Blind Method; Female; Ghrelin; Humans; Leptin; Olanzapine; Peptide Hormones; Placebos; Selective Serotonin Reuptake Inhibitors; Weight Gain

Data from a published double-blind randomized trial comparing olanzapine versus haloperidol in acute mania were used to address the response and tolerability of Latin American patients. Primary efficacy end point was the remission rate (Young Mania Rating Scale score

Topics: Acute Disease; Aged; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Cholesterol; Diagnostic and Statistical Manual of Mental Disorders; Double-Blind Method; Fasting; Female; Haloperidol; Hispanic or Latino; Hospitalization; Humans; Male; Middle Aged; Olanzapine; Remission Induction; Time Factors; Treatment Outcome; Weight Gain; White People

Melkersson proposed leptin dysregulation as a factor in the olanzapine-induced metabolic dysfunction. Their suggestion was based on the absence of the expected positive correlation between serum leptin levels and the BMI, and the loss of the sex-dependent difference in leptin levels, which are higher in women. Although subsequent studies did not confirm that proposal, few of them assessed basal leptin levels and corrected for body fat percentage. Along with these variables, we added a precise definition of participants out of the expected positive correlation in a large sample of schizophrenia patients. Sixty patients (26 women and 34 men) with severe schizophrenia undergoing chronic hospitalization and conventional antipsychotic treatment were switched to olanzapine (10-20 mg/day). We assessed at baseline, and at weeks 8 and 16 of treatment, the percentage of participants with abnormal correlation (out of the 95% confidence interval in the regression line) between leptin levels and the BMI, and the correlation between leptin and insulin, glucose, the insulin resistance index, c-reactive protein (CRP) and treatment response. Leptin levels were higher in women than in men (P<0.01). The positive correlation between leptin levels, BMI and percentage of fat were preserved. After olanzapine, 3.8% of women and 2.9-5.8% of men were out the 95% confidence interval, and the proportion was similar at baseline. Glucose, insulin, the insulin resistance index and the CRP levels significantly increased after olanzapine. The impact of olanzapine on leptin regulation appears discrete and limited to a small number of participants. Additional studies must clarify the features that render them to metabolic dysregulation.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; C-Reactive Protein; Female; Humans; Insulin; Insulin Resistance; Leptin; Linear Models; Male; Middle Aged; Multivariate Analysis; Olanzapine; Schizophrenia; Sex Factors; Weight Gain

This 52-week randomized, double-blind, flexible-dose, multicenter study evaluated the overall effectiveness (as measured by treatment discontinuation rates) of olanzapine, quetiapine, and risperidone in patients early in the course of psychotic illness.. Patients were randomly assigned to treatment with olanzapine (2.5-20 mg/day), quetiapine (100-800 mg/day), or risperidone (0.5-4 mg/day) administered in twice-daily doses. Statistical analyses tested for noninferiority in all-cause treatment discontinuation rates up to 52 weeks (primary outcome measure) based on a prespecified noninferiority margin of 20%.. A total of 400 patients were randomly assigned to treatment with olanzapine (N=133), quetiapine (N=134), or risperidone (N=133). The mean modal prescribed daily doses were 11.7 mg for olanzapine, 506 mg for quetiapine, and 2.4 mg for risperidone. At week 52, all-cause treatment discontinuation rates were 68.4%, 70.9%, and 71.4% for olanzapine, quetiapine, and risperidone, respectively. Reductions in total score on the Positive and Negative Syndrome Scale (PANSS) were similar for the three treatment groups, but reductions in PANSS positive subscale scores were greater in the olanzapine group (at 12 weeks and at 52 weeks or withdrawal from study) and the risperidone group (at 12 weeks). The most common elicited adverse events for olanzapine were drowsiness (53%), weight gain (51%), and insomnia (38%); for quetiapine, drowsiness (58%), increased sleep hours (42%), and weight gain (40%); and for risperidone, drowsiness (50%), menstrual irregularities in women (47%), and weight gain (41%).. Olanzapine, quetiapine, and risperidone demonstrated comparable effectiveness in early-psychosis patients, as indicated by similar rates of all-cause treatment discontinuation.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Dibenzothiazepines; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Olanzapine; Patient Dropouts; Psychiatric Status Rating Scales; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Schizophrenia; Sleep Stages; Sleep Wake Disorders; Treatment Outcome; Weight Gain

In a randomized controlled trial, we compared the efficacy of topiramate versus placebo in women undergoing olanzapine therapy and found that topiramate effectively contributed to weight loss in short-term treatment and had a positive effect on health-related quality of life, the patients' actual state of health, and psychological impairments. The aim of this observational study was to assess whether topiramate has a sustained benefit in long-term treatment of olanzapine-associated weight gain in subjects who had participated in the previous randomized controlled trial comparing topiramate with placebo. The subjects (topiramate group, n = 25; former placebo group, n = 18) were observed in an 18-month open-label study. After unblinding, subjects from the former topiramate group continued treatment with topiramate, whereas subjects from the former placebo group received neither placebo nor topiramate. The subjects were seen every 6 months, weighed, and tested with the SF-36 Health Survey, Scale of Well-Being, and the Adjective Checklist. According to the intent-to-treat principle, the repeated-measures analysis showed a significant interaction for the group-by-time effect for change of weight (P < 0.01) on the Scale of Well-Being (P < 0.01), all scales of the Adjective Checkist (all P < 0.01), and 5 scales (physical functioning, role limitations due to physical health, social functioning, mental health, and vitality) of the SF-36 Health Survey (all P < 0.01). Topiramate was well tolerated and seems to be effective and safe in the long-term treatment of olanzapine-related adiposity in women. Furthermore, positive changes in the patients' state of health, psychological impairments, and health-related quality of life could be also observed.

Topics: Adiposity; Anti-Obesity Agents; Antipsychotic Agents; Benzodiazepines; Female; Follow-Up Studies; Fructose; Humans; Olanzapine; Quality of Life; Topiramate; Weight Gain; Weight Loss

The purpose of this study was to evaluate the efficacy and safety of olanzapine for the treatment of acute manic or mixed episodes associated with bipolar disorder in adolescents.. A 3-week multicenter, parallel, double-blind, randomized placebo-controlled trial was conducted at 24 sites in the United States and two sites in Puerto Rico. The participants were outpatient and inpatient male and female adolescents 13-17 years of age with an acute manic or mixed episode. Subjects received either olanzapine (2.5-20 mg/day [N=107]) or placebo (N=54). The mean change from baseline to endpoint in the Young Mania Rating Scale total score was the primary outcome measure.. The mean baseline-to-endpoint change in the Young Mania Rating Scale total score was significantly greater for patients receiving olanzapine relative to patients receiving placebo, and a greater proportion of olanzapine-treated patients met response and remission criteria (44.8% versus 18.5% and 35.2% versus 11.1%, respectively). The mean baseline-to-endpoint weight change was significantly greater for patients receiving olanzapine relative to patients receiving placebo (3.7 kg versus 0.3 kg), and the incidence of treatment-emergent weight gain > or =7% of baseline was higher for olanzapine-treated patients (41.9% versus 1.9%). The mean baseline-to-endpoint changes in prolactin, fasting glucose, fasting total cholesterol, uric acid, and the hepatic enzymes aspartate transaminase and alanine transaminase were significantly greater in patients treated with olanzapine relative to patients receiving placebo.. Olanzapine was effective in the treatment of bipolar mania in adolescent patients. Patients treated with olanzapine, however, had significantly greater weight gain and increases in the levels of hepatic enzymes, prolactin, fasting glucose, fasting total cholesterol, and uric acid.

Topics: Adolescent; Age Factors; Alanine Transaminase; Antipsychotic Agents; Aspartate Aminotransferases; Benzodiazepines; Bipolar Disorder; Blood Glucose; Cholesterol; Double-Blind Method; Fasting; Female; Humans; Male; Obesity; Olanzapine; Placebos; Prolactin; Psychiatric Status Rating Scales; Treatment Outcome; Uric Acid; Weight Gain

The second generation antipsychotics clozapine and olanzapine frequently induce weight gain. Randomized studies investigating abnormal eating behavior (food craving, binge eating) possibly associated with weight gain are lacking. Thirty patients with schizophrenia, schizophreniform, or schizoaffective disorder were included in this randomized, double-blind, parallel study comparing abnormal eating behavior using a standardized scale, clinical efficacy using the Brief Psychiatric Rating Scale 0-6 and Clinical Global Impression-Severity scale, and tolerability of clozapine and olanzapine. In both treatment groups, the number of patients reporting food craving, binge eating, or both increased over time. The likelihood to experience food craving at any time during drug treatment showed a trend (P = 0.068) to be higher in the olanzapine group (48.9%) compared with the clozapine group (23.3%). The likelihood to experience binge eating at any time during drug treatment was numerically but not statistically significantly higher in the olanzapine group (16.7%) than in the clozapine group (8.9%). In both groups, significant baseline-to-end point improvements of clinical symptoms (Brief Psychiatric Rating Scale 0-6: clozapine, 36.6 +/- 8.8 to 15.9 +/- 13.7; olanzapine, 36.7 +/- 9.9 to 19.1 +/- 13.8) and severity of illness (Clinical Global Impression-Severity scale: clozapine, 4.7 +/- 0.6 to 2.5 +/- 1.5; olanzapine, 4.5 +/- 0.6 to 2.3 +/- 1.2) were observed. These improvements did not differ significantly between groups. Olanzapine was more tolerable than clozapine; adverse events occurred significantly (P < 0.01) less frequently than in the clozapine group. These results suggest that both clozapine and olanzapine can induce food craving and binge eating, however, olanzapine possibly to a greater extent. Findings on clinical efficacy and safety are in accordance with previous reports.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Appetite; Benzodiazepines; Blood Pressure; Body Mass Index; Bulimia; Clozapine; Dizziness; Dose-Response Relationship, Drug; Double-Blind Method; Fatigue; Female; Heart Rate; Humans; Male; Middle Aged; Olanzapine; Psychotic Disorders; Schizophrenia; Sialorrhea; Treatment Outcome; Weight Gain

This study examined the main metabolic side effects induced by antipsychotic treatment in a cohort of first-episode drug-naive subjects.. A randomized, open-label, prospective clinical trial was conducted. Participants were 145 consecutive subjects included in a first-episode psychosis program (PAFIP) from February 2002 to February 2005, experiencing their first episode of psychosis (DSM-IV codes 295, 297, and 298), and never treated with antipsychotic medication. Patients were assigned to haloperidol, olanzapine, or risperidone treatment during 12 weeks. The main outcome measures were changes at 12 weeks in body weight; body mass index; and 12-hours-fasting morning levels of total cholesterol, tri-glycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein cholesterol, glucose, homeostasis model assessment (HOMA) index, and insulin.. At the endpoint, 128 patients were evaluated (88.3%). The mean doses were haloperidol = 4.2 mg/day, olanzapine = 12.7 mg/day, and risperidone = 3.6 mg/day. A significant weight gain was observed with the 3 antipsychotics: haloperidol = 3.8 (SD = 4.9) kg, olanzapine = 7.5 (SD = 5.1) kg, and risperidone = 5.6 (SD = 4.5) kg. Metabolic parameters showed a worsening lipid profile with the 3 treatments (statistically significant increase in total cholesterol and LDL cholesterol levels). Only the olanzapine group showed significant increases in triglyceride levels. After the 12-week study period, there were no significant changes in parameters involving glucose metabolism for any group.. Drug-naive patients experienced an extraordinary weight gain with first- and second-generation antipsychotics after the first 12 weeks of treatment. Significant increases in total cholesterol and LDL cholesterol levels are associated with the 3 treatments. Weight gain and metabolic disturbances induced by antipsychotics may increase the risk of developing cardiovascular disease.

Topics: Adolescent; Adult; Anthropometry; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Cohort Studies; Diabetes Mellitus, Type 2; Diagnostic and Statistical Manual of Mental Disorders; Dyslipidemias; Female; Haloperidol; Humans; Male; Middle Aged; Olanzapine; Prevalence; Prospective Studies; Psychotic Disorders; Risperidone; Severity of Illness Index; Weight Gain

Topics: Anti-Obesity Agents; Benzodiazepines; Drug Administration Schedule; Fructose; Humans; Male; Obesity; Olanzapine; Schizophrenia; Topiramate; Weight Gain

Topics: Adolescent; Antipsychotic Agents; Asperger Syndrome; Benzodiazepines; Child; Female; Humans; Male; Olanzapine; Psychiatric Status Rating Scales; Treatment Outcome; Weight Gain

In a placebo-controlled, double-blind study, the authors investigated the efficacy and safety of olanzapine as monotherapy in relapse prevention in bipolar I disorder.. Patients achieving symptomatic remission from a manic or mixed episode of bipolar I disorder (Young Mania Rating Scale [YMRS] total score < or =12 and 21-item Hamilton Depression Rating Scale [HAM-D] score or =15, HAM-D score > or =15, or hospitalization).. Time to symptomatic relapse into any mood episode was significantly longer among patients receiving olanzapine (a median of 174 days, compared with a median of 22 days in patients receiving placebo). Times to symptomatic relapse into manic, depressive, and mixed episodes were all significantly longer among patients receiving olanzapine than among patients receiving placebo. The relapse rate was significantly lower in the olanzapine group (46.7%) than in the placebo group (80.1%). During olanzapine treatment, the most common emergent event was weight gain; during the open-label phase, patients who received olanzapine gained a mean of 3.1 kg (SD=3.4). In double-blind treatment, placebo patients lost a mean of 2.0 kg (SD=4.4) and patients who continued to take olanzapine gained an additional 1.0 kg (SD=5.2).. Compared to placebo, olanzapine delays relapse into subsequent mood episodes in bipolar I disorder patients who responded to open-label acute treatment with olanzapine for a manic or mixed episode.

Topics: Acute Disease; Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Double-Blind Method; Female; Humans; Male; Obesity; Olanzapine; Placebos; Secondary Prevention; Time Factors; Treatment Outcome; Weight Gain

Weight gain can be an adverse effect of antipsychotics and is an important factor for long-term health and treatment compliance. Many reports have shown that the alpha(2)-adrenergic receptor may be related to eating behaviors or lipolytic activities, both associated with body weight change. We hypothesized that there might be a relationship between the alpha(2a)-adrenergic receptor -1,291 C/G polymorphism and olanzapine-induced weight gain. A group of 62 Korean schizophrenic patients participated in a study; weight and height measurements were obtained prior to starting olanzapine and measured again after long-term treatment. Genotyping for the -1291 C/G polymorphism was performed on all participants. Body weight changes from baseline to endpoint were significantly associated with genotypes (P = 0.028). The frequency of the G allele was significantly higher in subjects who had severe weight gain (defined as a more than 10% weight gain from baseline) compared to subjects who did not have extreme weight gain (less than 10% weight gain from baseline) (X(2) = 6.120, P = 0.013; OR = 2.58, 95% CI = 1.21-5.51). Therefore, the findings from this study support a relationship between the -1291 C/G polymorphism of the alpha(2a)-adrenergic receptor and weight gain in Korean schizophrenic patients receiving olanzapine treatment.

Topics: Adult; Alleles; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Female; Gene Frequency; Genotype; Humans; Korea; Male; Middle Aged; Olanzapine; Polymorphism, Single Nucleotide; Receptors, Adrenergic, alpha-2; Schizophrenia; Treatment Outcome; Weight Gain

To assess whether metformin prevents body weight gain (BWG) and metabolic dysfunction in patients with schizophrenia who are treated with olanzapine.. Forty patients taking olanzapine (10 mg daily) were randomly allocated to a metformin (n = 20; 850 to 1700 mg daily) or placebo (n = 20) group in a 14-week double-blind study. Waist circumference (WC), BWG, body mass index (BMI) fasting glucose, insulin, and lipids were evaluated at baseline and at Weeks 7 and 14 of treatment.. At Week 14, BWG (kg) was similar in the metformin group (5.5 kg) and the placebo group (6.3 kg), P = 0.4. There were no differences between the changes in BMI, WC, glucose, insulin, insulin resistance index (HOMA-IR), and plasma lipid levels observed in the treatment group and the placebo group; however, glucose levels decreased significantly after metformin administration (P = 0.02). The HOMA-IR decreased significantly in both groups, but 3 subjects from the placebo group developed fasting glucose levels greater than 5 mmol/L. After taking metformin, triglyceride levels increased, but the cholesterol profile improved significantly.. Metformin did not prevent olanzapine-induced BWG. While some lipid parameters worsened during placebo, the HOMA-IR improved in both the placebo and the metformin groups. Carbohydrate metabolism impairment was not systematically observed during short-term olanzapine administration.

Topics: Adult; Anthropometry; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypercholesterolemia; Hypoglycemic Agents; Insulin Resistance; Male; Metformin; Middle Aged; Obesity; Olanzapine; Schizophrenia; Weight Gain

The objective of this study is to compare olanzapine with ziprasidone therapy in patients with schizophrenia or schizoaffective disorder and experiencing depressive symptoms.. This randomized, double-blind, 24-week, fixed-dose study compared olanzapine (n = 202) and ziprasidone (n = 192) for patients with schizophrenia or schizoaffective disorder and experiencing prominent depressive symptoms. Outcome measures included change in Calgary Depression Scale for Schizophrenia (CDSS) score from baseline to 8 weeks (primary outcome) and changes in CDSS, Montgomery-Asberg Depression Rating Scales, Positive and Negative Syndrome Scale, and Global Assessment of Functioning (GAF) scores for 24 weeks. Statistical analyses included mixed-effects model repeated measures (primary analysis) and change from baseline to last observation carried forward (LOCF).. At baseline, patients had moderate depressive symptoms (mean Montgomery-Asberg Depression Rating Scales total score, 27.3). For 8 weeks, patients treated with olanzapine or ziprasidone had significant improvements on CDSS. Treatment group differences were not statistically significant (P = 0.493, mixed-effects model repeated measures; P = 0.497, LOCF). For 24 weeks, olanzapine-treated patients showed significantly greater improvements in depressive symptoms (results varied by depression measure and statistical approach) and GAF (P < 0.017, LOCF). A significantly higher proportion of olanzapine-treated patients completed the study (44.6% vs 29.7%; P = 0.003) and remained longer on medication (median, 163 vs 73 days, P < 0.001), compared with ziprasidone-treated patients. Olanzapine-treated patients experienced significantly (P < 0.05) greater increases in triglycerides, HgbA1c, and weight.. For 24 weeks, olanzapine-treated patients had greater and more sustained participation in treatment, during which time significantly greater improvements were observed in depressive symptoms and GAF scores, along with increases in weight and certain metabolic parameters as compared with ziprasidone-treated patients.

Topics: Antipsychotic Agents; Benzodiazepines; Depression; Glycated Hemoglobin; Humans; Olanzapine; Patient Dropouts; Piperazines; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Thiazoles; Treatment Outcome; Triglycerides; United States; Weight Gain

This study assessed the efficacy of olanzapine in delaying or preventing conversion to psychosis and reducing symptoms in people with prodromal symptoms of schizophrenia.. This randomized trial occurred at four North American clinics in the Prevention Through Risk Identification, Management, and Education project. Outpatients received olanzapine (5-15 mg/day, N=31) or placebo (N=29) during a 1-year double-blind treatment period and no treatment during a 1-year follow-up period. Efficacy measures included the conversion-to-psychosis rate and Scale of Prodromal Symptoms scores.. During the treatment year, 16.1% of olanzapine patients and 37.9% of placebo patients experienced a conversion to psychosis, a nearly significant difference. The hazard of conversion among placebo patients was about 2.5 times that among olanzapine-treated patients, which also approached significance. In the follow-up year, the conversion rate did not differ significantly between groups. During treatment, the mean score for prodromal positive symptoms improved more in the olanzapine group than in the placebo group, and the mixed-model repeated-measures least-squares mean score showed significantly greater improvement between weeks 8 and 28 with olanzapine. The olanzapine patients gained significantly more weight (mean=8.79 kg, SD=9.05, versus mean=0.30 kg, SD=4.24).. A significant treatment difference in the conversion-to-psychosis rate was not demonstrated. However, these results may be influenced by low power. The nearly significant differences suggest that olanzapine might reduce the conversion rate and delay onset of psychosis. Olanzapine was efficacious for positive prodromal symptoms but induced weight gain. Further treatment research in this phase of illness is warranted.

Topics: Adolescent; Ambulatory Care; Antipsychotic Agents; Benzodiazepines; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Obesity; Olanzapine; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Treatment Outcome; Weight Gain

To evaluate the efficacy of olanzapine compared with risperidone in negative symptoms, after 1 year of treatment, in schizophrenic outpatients with prominent negative symptoms.. This was a multicenter, randomized, monitored, open-label, parallel, dose-flexible, 1-year study of outpatients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) with prominent negative symptoms (Scale for the Assessment of Negative Symptoms [SANS] summary score > or =10) previously treated with conventional antipsychotics. Patients were randomly assigned to treatment with an initial dose of olanzapine 10 mg/d or more (n = 120) or risperidone 3 mg/d or more (n = 115). The primary efficacy measure was the SANS summary score. Secondary efficacy measures included Scale for the Assessment of Positive Symptoms, Clinical Global Impression of Severity Scale, Calgary Depression Scale, and Social Functioning Scale. The response rate was defined as 30% or more of improvement in the SANS summary score.. The mean dose throughout the study was 12.2 mg/d (+/-5.8 mg/d) for olanzapine and 4.9 mg/d (+/-2.0 mg/d) for risperidone. At 1 year, olanzapine patients showed significantly higher improvement than risperidone patients on the SANS summary (P = 0.015) and on the affective flattening (P = 0.007) and avolition/apathy (P = 0.028) SANS subscales. There were also significant improvements in favor of olanzapine in the Scale for the Assessment of Positive Symptoms summary (P = 0.021), Clinical Global Impression of Severity (P = 0.008), and Social Functioning Scale total (P < 0.001) scores. The response rate was greater (P = 0.001) in the olanzapine cohort (69.2%) than in the risperidone cohort (48.7%). Olanzapine patients reported less extrapyramidal side effects but a higher incidence of clinically important body weight increase than risperidone patients.. Long-term treatment with olanzapine was associated with significantly better improvement in negative symptoms as compared with risperidone-treated schizophrenic outpatients with prominent negative symptoms.

Topics: Adult; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Body Mass Index; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Male; Olanzapine; Outpatients; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Weight Gain

To determine predictors of substantial weight gain (SWG) during treatment of bipolar disorder with olanzapine, data were pooled from 4 long-term randomized, multicenter studies in patients with bipolar mania or mixed mania (N = 948 at initiation of olanzapine). SWG was defined as gaining 5 kg or 7% of initial weight in 30 +/- 2 weeks. Logistic regression estimated odds ratios associated with early weight gain and baseline risk factors for predicting SWG. A classification system to identify patients at risk for SWG was constructed by recursive data partitioning. Baseline characteristics significantly associated with SWG included younger age, nonwhite ethnicity, lower body mass index (BMI), nonrapid cycling, and psychotic features. Weight gain of 2 or more kg in the first 3 weeks of therapy predicted SWG by 30 weeks (sensitivity = 57%; specificity = 71%). A classification system with thresholds for early weight gain, baseline BMI, and ethnicity further improved SWG predictability (sensitivity = 79%; specificity = 70%). In conclusion, patients with bipolar disorder who gained 2 to 3 kg during the first 3 weeks of treatment with olanzapine, SWG was predicted after 30 weeks of treatment. Patients with less pronounced early weight gain might still be at risk for later SWG if they have close to normal BMI (< or =27 kg/m) at treatment initiation.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Body Mass Index; Databases, Factual; Double-Blind Method; Female; Humans; Logistic Models; Male; Odds Ratio; Olanzapine; Predictive Value of Tests; Reproducibility of Results; Weight Gain

Topics: Antipsychotic Agents; Benzodiazepines; Humans; Olanzapine; Risk; Schizophrenia; Time Factors; Weight Gain

To examine the effectiveness of bupropion in reducing bodyweight gained during treatment with olanzapine.. Eight subjects, who received olanzapine for an average duration of 26 months and had gained an average of 13.3 kg bodyweight, participated in a 24-week study in which they received open-label bupropion 150-300 mg/d while continuing olanzapine. The subjects were also provided low-key nutritional counseling. Change in bodyweight was the primary outcome of interest. Changes in fasting blood glucose and lipids were also examined in addition to changes in body composition and bone mineral density.. Seven subjects completed the full 24-week study treatment. In the intent-to-treat sample, mean [SE] bodyweight decreased significantly over time (99.6 [5.9] kg to 96.2 [5.8] kg; F = 4.0; P < 0.001); average weight change for the eight subjects was -3.4 kg. Four of eight subjects lost > or =3% bodyweight. There was a significant reduction in total cholesterol. Weight loss did not have a negative effect on bone mineral density. Side effects were generally mild.. Bupropion combined with a low-key dietary intervention appeared to be beneficial in reducing olanzapine-associated weight gain in some subjects in this open-label study.

Topics: Adult; Aged; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Benzodiazepines; Bupropion; Cholesterol; Diet; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Olanzapine; Prospective Studies; Psychiatric Status Rating Scales; Triglycerides; Waist-Hip Ratio; Weight Gain; Weight Loss

Atypical antipsychotics have been shown to improve disruptive and repetitive behaviors in pervasive developmental disorders (PDDs), but they require assessment of potential side effects. This is the first placebo-controlled trial of olanzapine in the treatment of children and adolescents with PDD. Eleven patients with a diagnosis of either autism, Asperger's syndrome, or PDD not otherwise specified (PDD-NOS) and aged 6-14 years were randomized into an 8-week double-blind, placebo-controlled, parallel treatment study with olanzapine. There was a significant linear trend x group interaction on the Clinical Global Impressions- Improvement (CGI-I) and 50% on olanzapine versus 20% on placebo were responders. Olanzapine was associated with significant weight gain (7.5 +/- 4.8 lbs vs. 1.5 +/- 1.5 lbs on placebo). Olanzapine may be a promising treatment for improving global functioning of PDDs, but the risk of significant weight gain remains a concern. Additional studies are needed to determine the efficacy and safety of olanzapine in the treatment of children with PDD.

Topics: Adolescent; Antipsychotic Agents; Asperger Syndrome; Autistic Disorder; Benzodiazepines; Child; Child Development Disorders, Pervasive; Double-Blind Method; Female; Humans; Male; Olanzapine; Pilot Projects; Treatment Outcome; Weight Gain

To compare the efficacy and safety of amisulpride and olanzapine in subjects with schizophrenia and comorbid depression in a randomised double-blind trial.. Eighty-five adult patients fulfilling DSM-IV criteria for schizophrenia and presenting a depressive episode were randomised to amisulpride (200-600 mg/day) or olanzapine (5-15 mg/day) for 8 weeks. Primary efficacy variables were change in Calgary Depression Scale (CDS) score and Clinical Global Impression (CGI) of Change. Safety was monitored by adverse event reporting and determination of extrapyramidal function and metabolic variables.. The mean change from baseline of CDS score was -6.84 in the amisulpride group and -7.36 in the olanzapine group. 65.9% and 61.5% of subjects, respectively, were considered "much" or "very much" improved. No significant inter-group difference in effect size was observed. The frequency of adverse events was low and emergence of extrapyramidal symptoms was not seen. Four patients in the olanzapine group developed abnormal triglyceride levels. Mean weight gain was 1.45 and 0.5 kg, respectively, in the olanzapine and amisulpride groups.. Amisulpride and olanzapine are effective in patients with schizophrenia and comorbid depression. Tolerance of both drugs was acceptable, although use of olanzapine was associated with a trend toward greater metabolic side-effects .

Topics: Adult; Amisulpride; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Comorbidity; Depressive Disorder; Double-Blind Method; Female; France; Humans; Italy; Male; Olanzapine; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Sulpiride; Time Factors; Treatment Outcome; Triglycerides; Tunisia; Weight Gain

The authors compared 4-month treatment outcomes for olanzapine versus risperidone in patients with first-episode schizophrenia spectrum disorders.. One hundred twelve subjects (70% male; mean age=23.3 years [SD = 5.1]) with first-episode schizophrenia (75%), schizophreniform disorder (17%), or schizoaffective disorder (8%) were randomly assigned to treatment with olanzapine (2.5-20 mg/day) or risperidone (1-6 mg/day).. Response rates did not significantly differ between olanzapine (43.7%, 95% CI=28.8%-58.6%) and risperidone (54.3%, 95% CI=39.9%-68.7%). Among those responding to treatment, more subjects in the olanzapine group (40.9%, 95% CI=16.8%-65.0%) than in the risperidone group (18.9%, 95% CI=0%-39.2%) had subsequent ratings not meeting response criteria. Negative symptom outcomes and measures of parkinsonism and akathisia did not differ between medications. Extrapyramidal symptom severity scores were 1.4 (95% CI=1.2-1.6) with risperidone and 1.2 (95% CI=1.0-1.4) with olanzapine. Significantly more weight gain occurred with olanzapine than with risperidone: the increase in weight at 4 months relative to baseline weight was 17.3% (95% CI=14.2%-20.5%) with olanzapine and 11.3% (95% CI=8.4%-14.3%) with risperidone. Body mass index at baseline and at 4 months was 24.3 (95% CI=22.8-25.7) versus 28.2 (95% CI=26.7-29.7) with olanzapine and 23.9 (95% CI=22.5-25.3) versus 26.7 (95% CI=25.2-28.2) with risperidone.. Clinical outcomes with risperidone were equal to those with olanzapine, and response may be more stable. Olanzapine may have an advantage for motor side effects. Both medications caused substantial rapid weight gain, but weight gain was greater with olanzapine.

Topics: Adult; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Body Mass Index; Female; Follow-Up Studies; Humans; Male; Obesity; Olanzapine; Psychotic Disorders; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Weight Gain

Weight gain is associated with treatment with many psychotropic agents. Nizatidine, H2 receptor antagonist, has been proposed to have weight-reducing effects. This was a 12-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy of nizatidine in reducing/limiting weight gain in patients with schizophrenia who have been under treatment with olanzapine.. Patients receiving olanzapine (2 to 6 months) and weight gain >or= 5% of their body weight during olanzapine treatment were randomly assigned to receive nizatidine 600 mg or placebo for up to 12 weeks. Change in psychopathology was assessed using Brief Psychiatric Rating Scale scores from baseline to endpoint. Safety was assessed using the Safety Assessed Software, assessment of glucose and lipid blood levels, and treatment-emergent adverse events.. Out of 54 patients enrolled in this analysis, 45 completed the protocol. The mean weight change prior randomization was 7.6 kg and 7.3 kg for those randomized to placebo and nizatidine, respectively (p = 0.828). Patients receiving placebo and nizatidine had a mean weight gain of 12.3% (0.7 kg) and 12% (1.1 kg) from baseline to endpoint, respectively (p = 0.9). Patients from both groups experienced a statistically significant decrease on the Brief Psychiatric Rating Scale mean score from baseline to endpoint. Treatment-emergent adverse events were reported by 18.5% and 25.9% on the placebo and nizatidine group, respectively. There were no statistically significant differences in glucose and lipid blood levels from baseline to endpoint and between groups.. The concomitant use of olanzapine with nizatidine was not effective in controlling weight gain in patients who had previously gained weight during treatment with olanzapine when compared to placebo.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Brief Psychiatric Rating Scale; Double-Blind Method; Education, Nursing, Associate; Female; Histamine H2 Antagonists; Humans; Male; Middle Aged; Nizatidine; Obesity; Olanzapine; Placebos; Schizophrenia; Weight Gain

Weight gain is a common adverse effect associated with olanzapine treatment. Another side effect of olanzapine treatment is a significant increase in circulating leptin levels. This preliminary study monitored the changes in leptin levels for 2 weeks after olanzapine treatment had been initiated. The relationship between the changes in circulating leptin levels and alterations in body weight in 9 patients with schizophrenia who received olanzapine was examined. The results showed that olanzapine may cause a surge in circulating leptin levels before weight gain is manifested. Moreover, higher pretreatment circulating leptin levels predicted lower weight gains after olanzapine treatments (r = -0.93; p < 0.05) after controlling for the effect of sex.

Topics: Acute Disease; Adult; Antipsychotic Agents; Benzodiazepines; Female; Humans; Leptin; Male; Olanzapine; Schizophrenia; Sex Factors; Weight Gain

Increased appetite and weight gain are frequently reported in treatment with olanzapine. However, the mechanism behind this appetite gain remains unclear. Ghrelin is a newly discovered appetite-stimulating peptide that has a role in the regulation of feeding behavior. Ghrelin is synthesized principally in the stomach, and the concentration of circulating ghrelin is negatively correlated with leptin and body fat mass. To elucidate the mechanism of appetite and weight gain during olanzapine treatment, we investigated the circulating ghrelin levels.. Seven patients with schizophrenia were examined before and after 6-month administration of olanzapine. The concentrations of circulating ghrelin, leptin, glucose and lipid metabolic parameters were measured.. Body fat percentage (P=0.0121) and serum leptin (P=0.0284) were significantly increased after 6-month administration of olanzapine. Both plasma total ghrelin (P=0.0188) and active ghrelin levels (P=0.0057) were significantly increased. Six of the seven patients reported increased appetite during olanzapine treatment. Other glucose and lipid parameters were not altered significantly.. Although, the leptin level and body fat percentage were significantly increased, the concentration of circulating ghrelin was also significantly increased. Olanzapine may directly act on the secretion of ghrelin and induce appetite, resulting in weight gain.

Topics: Adult; Aged; Antipsychotic Agents; Appetite; Benzodiazepines; Body Composition; Body Mass Index; Body Weight; Female; Ghrelin; Humans; Leptin; Male; Middle Aged; Olanzapine; Peptide Hormones; Radioimmunoassay; Schizophrenia; Weight Gain

Patients with schizophrenia (Sch), schizoaffective, schizophreniform, or bipolar (BP) I disorders [Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)]; not manic or acutely psychotic [Brief Psychiatric Rating Scale (BPRS) total score < or =45]; treated with olanzapine for 1-24 months; and who had gained > or =5% of their initial body weight were examined to determine whether amantadine could attenuate weight gain or promote weight loss. Olanzapine (Olz; 5-20 mg/day) was co-administered with double-blind treatment of 100-300 mg/day amantadine (Olz+Amt, n=60) or placebo (Olz+Plc, n=65). Visit-wise analysis of weight showed that weight change from baseline [last-observation-carried-forward (LOCF)] in the Olz+Amt group was significantly different from the Olz+Plc group at weeks 8 (P=0.042), 12 (P=0.029), and 16 (primary endpoint, mean+/-S.D.: -0.19+/-4.58 versus 1.28+/-4.26 kg, P=0.045). Mean BPRS total score, positive subscale, and anxiety-depression scores improved comparably in both groups, and Montgomery-Asberg Depression Rating Scale (MADRS) total score improved in the Olz+Amt group. Overall, amantadine was safe, was well tolerated, and attenuated weight gain or promoted weight loss in some patients who had gained weight during olanzapine therapy.

Topics: Adolescent; Adult; Aged; Amantadine; Analysis of Variance; Antiparkinson Agents; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Brief Psychiatric Rating Scale; Demography; Dose-Response Relationship, Drug; Double-Blind Method; Drug Interactions; Drug Therapy, Combination; Female; Humans; Male; Mental Disorders; Middle Aged; Olanzapine; Time Factors; Treatment Outcome; Weight Gain

In an open-label study, 13 patients taking depot antipsychotic medication for greater than 3 years were switched to oral olanzapine. The first 3-month experience has been previously reported. We now describe a second 3-month experience and integrate our observations into a cumulative 6-month report. Monthly, we assessed patients using clinical ratings [Positive and Negative Syndrome Scale (PANSS), Global Assessment of Functioning (GAF), Mini-Mental State Exam (MMSE), and Clinical Global Improvement Scale (CGI)] and side effect parameters [Abnormal Involuntary Movement Scale (AIMS), Association for Methodology and Documentation in Psychiatry psychotropic side effect rating scale (AMDP-5), and weights]. Olanzapine patients showed statistically significant improvement (baseline to endpoint sixth month) in GAF (p=0.015), MMSE (p=0.022), CGI improvement, and AIMS (p=0.038). There was no statistically significant change in PANSS, CGI severity, or AMDP-5 overall side effects. Weight gain over 6 months averaged 8.9 lb. All patients completed the study. Compliance was estimated at 90%, and 81% of patients chose to continue on the oral olanzapine. One patient was hospitalized at the conclusion of the study. Our findings suggest that clinicians may consider oral olanzapine as a viable alternative to depot antipsychotic medications, balancing clinical improvement in some clinical measures with lack of improvement in other clinical measures; and balancing improvement in abnormal involuntary movements with weight gain and its sequelae.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Delayed-Action Preparations; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Olanzapine; Patient Acceptance of Health Care; Psychiatric Status Rating Scales; Schizophrenia; Treatment Outcome; Weight Gain

Previous research indicated that women are more vulnerable than men to adverse psychological consequences of weight gain. Other research has suggested that weight gain experienced during antipsychotic therapy may also psychologically impact women more negatively. This study assessed the impact of acute treatment-emergent weight gain on clinical and functional outcomes of patients with schizophrenia by patient gender and antipsychotic treatment (olanzapine or haloperidol).. Data were drawn from the acute phase (first 6-weeks) of a double-blind randomized clinical trial of olanzapine versus haloperidol in the treatment of 1296 men and 700 women with schizophrenia-spectrum disorders. The associations between weight change and change in core schizophrenia symptoms, depressive symptoms, and functional status were examined post-hoc for men and women and for each medication group. Core schizophrenia symptoms (positive and negative) were measured with the Brief Psychiatric Rating Scale (BPRS), depressive symptoms with the BPRS Anxiety/Depression Scale and the Montgomery-Asberg Depression Rating Scale, and functional status with the mental and physical component scores on the Medical Outcome Survey-Short Form 36. Statistical analysis included methods that controlled for treatment duration.. Weight gain during 6-week treatment with olanzapine and haloperidol was significantly associated with improvements in core schizophrenia symptoms, depressive symptoms, mental functioning, and physical functioning for men and women alike. The conditional probability of clinical response (20% reduction in core schizophrenia symptom), given a clinically significant weight gain (at least 7% of baseline weight), showed that about half of the patients who lost weight responded to treatment, whereas three-quarters of the patients who had a clinically significant weight gain responded to treatment. The positive associations between therapeutic response and weight gain were similar for the olanzapine and haloperidol treatment groups. Improved outcomes were, however, more pronounced for the olanzapine-treated patients, and more olanzapine-treated patients gained weight.. The findings of significant relationships between treatment-emergent weight gain and improvements in clinical and functional status at 6-weeks suggest that patients who have greater treatment-emergent weight gain are more likely to benefit from treatment with olanzapine or haloperidol regardless of gender.

Topics: Acute Disease; Adult; Antipsychotic Agents; Benzodiazepines; Double-Blind Method; Female; Haloperidol; Humans; Male; Obesity; Olanzapine; Outcome Assessment, Health Care; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Sex Factors; Treatment Outcome; Weight Gain

Weight gain from atypical antipsychotic use has become a significant problem. Recent reports have liked the -759 polymorphism of the 5HT2C receptor and obesity as well as weight gain from chlorpromazine, risperidone, and clozapine.. To determine associations between weight gain during olanzapine treatment and the -759C/T polymorphism of the 5HT2C receptor gene.. This study included 42 acutely ill patients with schizophrenia (DSM-IV). Weekly assessments included Brief Psychiatric Rating Scale (BPRS), Scale for Assessment of Negative Symptoms (SANS), and weight measurements. Olanzapine was titrated to a fixed dose (7.5-20 mg/day) for 2-6 weeks. A 24 hr plasma level was obtained at the endpoint visit. Genomic DNA was isolated from a whole blood sample and analyzed for the -759C/T polymorphism of the 5HT2C receptor.. A chi-square analysis was conducted comparing the distribution of T and C alleles in subjects grouped as gaining more or less than 5, 7, and 10% of their baseline weight during treatment with olanzapine. A threshold of 10% was found to be significant. The distribution of T alleles was higher in subjects not gaining 10% of more of their body weight compared who did gain significant weight (11/27 (40.7%) vs. 0/15 (100%), chi2 = 11.805, P = 0.0035).. Subjects with a T allele of the 5HT2C receptor -759C/T polymorphism may have a lower incidence of weight gain from olanzapine over a 6 week period compared to those with the C allele. These results need to be replicated.

Topics: Alleles; Antipsychotic Agents; Benzodiazepines; Body Weight; Dose-Response Relationship, Drug; Female; Gene Frequency; Genotype; Humans; Male; Olanzapine; Polymorphism, Single Nucleotide; Receptor, Serotonin, 5-HT2C; Treatment Outcome; Weight Gain

Histamine antagonism has been implicated in antipsychotic drug-induced weight gain. Betahistine, a histamine enhancer with H1 agonistic/H3 antagonistic properties (48 mg t.i.d.), was coadministered with olanzapine (10 mg/day) in three first-episode schizophrenia patients for 6 weeks. Body weight was measured at baseline and weekly thereafter. Clinical rating scales were completed at baseline and at week 6. All participants gained weight (mean weight gain 3.1+/-0.9 kg) and a similar pattern of weight gain was observed: an increase during the first 2 weeks and no additional weight gain (two patients) or minor weight loss (one patient) from weeks 3 to 6. None gained 7% of baseline weight, which is the cut-off for clinically significant weight gain. Betahistine was safe and well tolerated and did not interfere with the antipsychotic effect of olanzapine. Our findings justify a placebo-controlled evaluation of the putative weight-attenuating effect of betahistine in olanzapine-induced weight gain.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Betahistine; Body Mass Index; Body Weight; Histamine Agonists; Histamine Antagonists; Humans; Olanzapine; Receptors, Histamine H3; Schizophrenia; Weight Gain

Weight gain is commonly observed with olanzapine treatment and can increase the risk for obesity, cardiovascular disease, hypertension, and diabetes mellitus. This study examined the effectiveness of sibutramine, an approved weight loss agent, in overweight and obese subjects taking olanzapine for schizophrenia or schizoaffective disorder.. Each subject had a DSM-IV diagnosis of schizophrenia or schizoaffective disorder, had been taking a stable dose of olanzapine for at least 4 months, and had a body mass index of >/=30 kg/m(2) or >/=27 kg/m(2) plus at least one cardiovascular risk factor. In a 12-week double-blind, randomized, placebo-controlled study, 37 subjects received placebo or sibutramine (up to 15 mg/day). For the first 8 weeks all subjects participated in weekly group sessions focused on nutrition and behavioral modification.. The sibutramine and placebo groups had no significant baseline differences on age, gender, education, ethnicity, diagnosis, weight, body mass index, and blood pressure. At week 12 the sibutramine group had significantly greater losses than the placebo group in weight (mean=8.3 lb, SD=2.4, versus mean=1.8 lb, SD=1.6), waist circumference, body mass index, and hemoglobin A(1c). There were no significant differences on most side effects, although the sibutramine group exhibited a mean increase in systolic blood pressure of 2.1 mm Hg (SD=8.5), and anticholinergic side effects and sleep disturbances were at least twice as common in the sibutramine group.. Sibutramine was an effective and well-tolerated adjunct to behavior modification for weight loss in patients with schizophrenia and schizoaffective disorder being treated with olanzapine.

Topics: Adult; Antipsychotic Agents; Appetite Depressants; Behavior Therapy; Benzodiazepines; Combined Modality Therapy; Cyclobutanes; Double-Blind Method; Female; Humans; Male; Obesity; Olanzapine; Placebos; Psychotic Disorders; Schizophrenia; Sleep Wake Disorders; Treatment Outcome; Weight Gain

The aim of this study was to compare the efficacy of topiramate versus a placebo in the treatment of adiposity in women undergoing olanzapine therapy. We also assessed changes health-related quality of life, the patient's actual state of health, and psychologic impairments. The 10-week, random, double-blind, placebo-controlled study included 43 women who had been treated with olanzapine (mean dose 7.8 +/- 3.6 in the topiramate group and 7.2 +/- 3.1 in the placebo group) and had gained weight as a side effect. The subjects were randomly assigned to topiramate (n = 25) or a placebo (n = 18). Primary outcome measures were weight checks and self-reported changes on the scales of the SF-36 Health Survey, Bf-S Scale of Well-Being, and the Adjective Checklist EWL-60-S. Weight loss was observed and was significantly more pronounced in the topiramate-treated group (difference in weight loss between the 2 groups: 5.6 kg, 95% CI = -8.5, -3.0, P < 0.001). In comparison with the placebo group, significant changes on 7 (7/8) scales of SF-36 Health Survey (all P < 0.001), on all 6 scales of the EWL-60-S, and on the Bf-S were observed in the topiramate-treated subjects after 10 weeks. All patients tolerated topiramate well. Topiramate appears to be a safe and effective agent in the treatment of weight gain that occurred during olanzapine treatment. Significantly positive changes in health-related quality of life, the patient's actual state of health, and psychologic impairments were observed.

Topics: Adipose Tissue; Adult; Anti-Obesity Agents; Benzodiazepines; Confidence Intervals; Double-Blind Method; Female; Fructose; Humans; Mental Disorders; Neuropsychological Tests; Olanzapine; Statistics, Nonparametric; Topiramate; Weight Gain; Weight Loss

Olanzapine is the most commonly prescribed atypical antipsychotic medication in Australia. Research reports an average weight gain of between 4.5 and 7 kg in the 3 months following its commencement. Trying to minimize this weight gain in a population with an already high prevalence of obesity, mortality and morbidity is of clinical and social importance. This randomized controlled trial investigated the impact of individual nutrition education provided by a dietitian on weight gain in the 3 and 6 months following the commencement of olanzapine.. Fifty-one individuals (29 females, 22 males) who had started on olanzapine in the previous 3 months (mean length of 27 days +/- 20) were recruited through Peninsula Health Psychiatric Services and were randomly assigned to either the intervention (n = 29) or the control group (n = 22). Individuals in the intervention group received six 1 hour nutrition education sessions over a 3-month period. Weight, waist circumference, body mass index (BMI) and qualitative measures of exercise levels, quality of life, health and body image were collected at baseline at 3 and 6 months.. After 3 months, the control group had gained significantly more weight than the treatment group (6.0 kg vs 2.0 kg, p < or = 0.002). Weight gain of more than 7% of initial weight occurred in 64% of the control group compared to 13% of the treatment group. The control group's BMI increased significantly more than the treatment group's (2 kg/m(2)vs 0.7 kg/m(2), p < or = 0.03). The treatment group reported significantly greater improvements in moderate exercise levels, quality of life, health and body image compared to the controls. At 6 months, the control group continued to show significantly more weight gain since baseline than the treatment group (9.9 kg vs 2.0 kg, p < or = 0.013) and consequently had significantly greater increases in BMI (3.2 kg/m(2)vs 0.8 kg/m(2), p < or = 0.017).. Individual nutritional intervention provided by a dietitian is highly successful at preventing olanzapine-induced weight gain.

Topics: Adult; Benzodiazepines; Bipolar Disorder; Body Image; Body Mass Index; Depressive Disorder, Major; Exercise; Female; Health Status; Humans; Male; Nutritional Physiological Phenomena; Obesity; Olanzapine; Quality of Life; Schizophrenia; Weight Gain

The authors' goal was to compare the efficacy and tolerability of 6 months' treatment with flexible-dose ziprasidone and olanzapine in patients with schizophrenia or schizoaffective disorder.. Brief Psychiatric Rating Scale (BPRS) scores and Clinical Global Impression (CGI) severity scores were obtained for 126 responders to a 6-week acute study of olanzapine and ziprasidone during a blinded 6-month continuation study and optional extension study.. Comparable improvements in BPRS and CGI severity scores were seen with both drugs. Olanzapine produced significant increases from acute-study baseline values in weight and body mass index and within-group increases in total cholesterol, low-density lipoprotein cholesterol, and fasting insulin. Between-group differences were not significant for lipids and insulin. Mean QTc values at endpoint were 407.1 msec (baseline mean=406.0 msec) and 394.4 msec (baseline mean=399.7 msec) for ziprasidone and olanzapine, respectively. No patient had a QTc interval > or =500 msec.. Ziprasidone and olanzapine had comparable long-term efficacy; olanzapine was associated with significant weight gain and metabolic alterations.

Topics: Ambulatory Care; Antipsychotic Agents; Benzodiazepines; Brief Psychiatric Rating Scale; Double-Blind Method; Drug Administration Schedule; Follow-Up Studies; Humans; Obesity; Olanzapine; Piperazines; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Thiazoles; Treatment Outcome; Weight Gain

To thoroughly investigate the phenomenon of atypical antipsychotic associated weight gain, a feeding laboratory paradigm was developed. This study is a randomized, double-blind, parallel group trial comparing the tolerability and effects of a two-week exposure to olanzapine, risperidone or placebo on weight, resting energy expenditure (REE), and eating behaviors in 48 healthy human subjects. Subjects were randomized to receive olanzapine, risperidone, or placebo and titrated over four days to 10 mg/d, or 4 mg/d, respectively. The mean dose at endpoint was 8.75 mg/day for the olanzapine group and 2.88 mg/d risperidone group. Weight changes were significantly different between groups at midpoint (F = 5.477, df = 2, 44, P = .0001). The olanzapine group demonstrated a significant increase in weight at midpoint (1.59 + 1.80 kg, P = .002) and endpoint (2.25 + 1.62 kg, P = .0001) compared to placebo and at endpoint compared to risperidone (1.05 + 1.15 kg, P = .015). Resting energy expenditures corrected for fat free mass did not reveal any differences between groups. Olanzapine subjects demonstrated significantly more dry mouth and sedation versus placebo while risperidone subjects experienced significantly more sedation, dry mouth, dizziness stuffy nose and restlessness than placebo and more dizziness and stuffy nose versus olanzapine subjects. Thus, a human feeding lab paradigm utilizing a brief exposure to atypical antipsychotics functions as a method to investigate pharmacologically induced weight gain.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Double-Blind Method; Energy Intake; Feeding Behavior; Female; Humans; Hunger; Male; Middle Aged; Olanzapine; Risperidone; Satiety Response; Weight Gain

The relative effectiveness of second-generation (atypical) antipsychotic drugs as compared with that of older agents has been incompletely addressed, though newer agents are currently used far more commonly. We compared a first-generation antipsychotic, perphenazine, with several newer drugs in a double-blind study.. A total of 1493 patients with schizophrenia were recruited at 57 U.S. sites and randomly assigned to receive olanzapine (7.5 to 30 mg per day), perphenazine (8 to 32 mg per day), quetiapine (200 to 800 mg per day), or risperidone (1.5 to 6.0 mg per day) for up to 18 months. Ziprasidone (40 to 160 mg per day) was included after its approval by the Food and Drug Administration. The primary aim was to delineate differences in the overall effectiveness of these five treatments.. Overall, 74 percent of patients discontinued the study medication before 18 months (1061 of the 1432 patients who received at least one dose): 64 percent of those assigned to olanzapine, 75 percent of those assigned to perphenazine, 82 percent of those assigned to quetiapine, 74 percent of those assigned to risperidone, and 79 percent of those assigned to ziprasidone. The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine (P<0.001) or risperidone (P=0.002) group, but not in the perphenazine (P=0.021) or ziprasidone (P=0.028) group. The times to discontinuation because of intolerable side effects were similar among the groups, but the rates differed (P=0.04); olanzapine was associated with more discontinuation for weight gain or metabolic effects, and perphenazine was associated with more discontinuation for extrapyramidal effects.. The majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or for other reasons. Olanzapine was the most effective in terms of the rates of discontinuation, and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine, risperidone, and ziprasidone. Olanzapine was associated with greater weight gain and increases in measures of glucose and lipid metabolism.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Chronic Disease; Dibenzothiazepines; Double-Blind Method; Female; Humans; Lipids; Male; Olanzapine; Patient Compliance; Perphenazine; Piperazines; Proportional Hazards Models; Quetiapine Fumarate; Risperidone; Schizophrenia; Thiazoles; Treatment Outcome; Weight Gain

Substantial weight gain is common with many atypical antipsychotics.. To evaluate the extent, time course and predictors of weight gain and its effect on study retention among people with first-episode psychosis treated with olanzapine or haloperidol.. Survival analysis assessed time to potentially clinically significant weight gain (> or =7%) and the effect of weight gain on study retention. Weight gain during the 2-year study was summarised using last-observation-carried-forward (LOCF), observed cases and study completion approaches.. After 2 years of treatment, LOCF mean weight gain was 10.2 kg (s.d.=10.1) for olanzapine (n=131) and 4.0 kg (s.d.=7.3) for haloperidol (n=132); observed cases mean weight gain was 15.4 kg (s.d.=10.0) for olanzapine and 7.5 kg (s.d.=9.2) for haloperidol. Change in body mass index was significantly predicted only by treatment group (P < 0.0001).. Olanzapine was associated with significantly greater weight gain than haloperidol, with both leading to greater weight gain than previously described.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Cholesterol; Double-Blind Method; Female; Haloperidol; Humans; Male; Olanzapine; Patient Dropouts; Schizophrenia; Time Factors; Treatment Outcome; Weight Gain

Patients with major depressive disorder (MDD) treated with olanzapine in combination with fluoxetine (OFC) demonstrate robust improvement in their depressive symptoms. Treatment with olanzapine may impact a patient's weight; thus, long-term weight gain and potential predictors (e.g., age and gender) and correlates (e.g., cholesterol and glucose levels) of weight gain were investigated in OFC-treated patients with MDD.. Outpatients who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnostic criteria for MDD were included (N = 549) in the current analyses of this 76-week, open-label study (February 2000 to July 2002). Maximum, endpoint, and potentially clinically significant (PCS; > or = 7% increase from baseline) weight gain; time to PCS weight gain; and predictors and correlates of weight change were assessed. Patients were treated once daily with oral olanzapine (6, 12, or 18 mg) plus fluoxetine (25, 50, or 75 mg) capsules. Statistical significance for all tests was based upon p < or = .05.. Mean baseline-to-endpoint weight change was 5.6 +/- 6.6 kg (12.3 +/- 14.6 lb). Weight gain plateaued by 52 weeks. Fifty-six percent of patients met criteria for PCS weight gain by 76 weeks, and the median time to PCS weight gain was 16 weeks. Low baseline body mass index (BMI), female gender, younger age, and increased fluoxetine dose were predictors of weight gain; olanzapine dose was not. Patients with early (< or = 6 weeks) rapid PCS weight gain were 4.6 times more likely to gain substantial (> or = 15%) weight long-term (weeks 7-76). Changes to endpoint in total cholesterol and systolic blood pressure values were positively correlated with weight change.. Long-term (76 weeks) OFC treatment may lead to a large percentage (56%) of patients meeting criteria for PCS weight gain (> or = 7%). The risk of weight gain may be significantly increased for OFC-treated patients who have a low BMI or who are female, younger, or taking high-dose fluoxetine. It is important that prescribers balance the risk of weight gain with the benefit of treatment for individual patients with depression.

Topics: Adult; Ambulatory Care; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Depressive Disorder, Major; Diabetes Mellitus; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluoxetine; Follow-Up Studies; Humans; Male; Obesity; Olanzapine; Regression Analysis; Risk Factors; Selective Serotonin Reuptake Inhibitors; Time Factors; Treatment Outcome; Weight Gain

Atypical antipsychotics are increasingly used in clinical practice in the management of borderline personality disorder (BPD), and a small but growing body of literature supports their efficacy. Here, we report the results of a double-blind, placebo-controlled study of olanzapine as a treatment for BPD.. Forty BPD patients (25 female, 15 male) were randomly assigned in equal numbers to olanzapine and placebo. Diagnoses were made using the Structured Clinical Interview for DSM-IV Axis II Personality Disorders and the Mini-International Neuropsychiatric Interview. Patients with schizophrenia, bipolar disorder, or current major depression were excluded. Olanzapine dosage was flexible, and the dose range was 2.5 to 20 mg/day, with most patients receiving 5 to 10 mg/day. No concomitant psychotropic medications were allowed. Patients were assessed at baseline and at 2, 4, 8, and 12 weeks. The primary outcome was change in the total score for the 9 BPD criteria on a 1-to-7 Likert scale, the Clinical Global Impressions scale modified for borderline personality disorder (CGI-BPD), using an analysis of covariance model including baseline score as covariate. Data were collected from July 2000 to April 2002.. Olanzapine was found to be significantly (p <.05) superior to placebo on the CGI-BPD at endpoint, with separation occurring as early as 4 weeks. Similar results were found for the single-item Clinical Global Impressions scale. Weight gain was significantly (p =.027) greater in the olanzapine group.. This study supports the efficacy of olanzapine for symptoms of BPD in a mixed sample of women and men. Further studies with olanzapine and other atypical antipsychotics are needed.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Borderline Personality Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Olanzapine; Placebos; Treatment Outcome; Weight Gain

To examine the impact of smoking status on antipsychotic-associated weight gain.. In two double-blind studies, 552 adult and elderly patients with schizophrenia or schizoaffective disorder were randomly assigned to risperidone or olanzapine treatment for 8 weeks. Smoking status at baseline was recorded together with other background characteristics.. In both adult and elderly patients, olanzapine-treated smokers and nonsmokers gained weight at a similar rate, whereas risperidone-treated smokers gained less weight than did nonsmokers. Olanzapine was associated with significantly greater weight gain than was risperidone across all measures in both adult and elderly patients.. These findings support a quantitatively or qualitatively different effect of risperidone and olanzapine on the metabolic changes underlying antipsychotic-associated weight gain. Mechanisms responsible for olanzapine's effect on weight appear to counteract smokers' physiologic bias toward weight loss, an effect not seen among risperidone-treated patients.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Double-Blind Method; Female; Humans; Male; Middle Aged; Olanzapine; Psychotic Disorders; Risperidone; Schizophrenia; Smoking; Weight Gain

Olanzapine treatment is associated with substantial weight gain. In this double-blind placebo-controlled study we evaluated whether the H2 antagonist famotidine may prevent/attenuate olanzapine-induced weight gain. Fourteen first-episode DSM-IV schizophrenia patients were randomly allocated to receive either famotidine (40 mg/day, n=7) or placebo (n=7) in addition to olanzapine (10 mg/day) for 6 weeks. All patients completed the trial. Patients in both groups showed a similar increase in body weight (olanzapine/famotidine: 4.8 (3.2) kg and olanzapine/placebo: 4.9 (1.6) kg, respectively; a between-group difference of 0.14 (1.3) kg). Four of seven (57.1%) patients in the olanzapine/famotidine group and three of seven (42.9%) in the olanzapine/placebo group gained at least 7% of their initial body weight, a cut-off for clinically significant weight gain. Famotidine addition was safe and well tolerated and did not interfere with olanzapine's therapeutic effect. In conclusion, famotidine (40 mg/day for 6 weeks) is not effective in preventing/attenuating weight gain in olanzapine-treated first-episode schizophrenia patients.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Double-Blind Method; Drug Interactions; Famotidine; Female; Histamine H2 Antagonists; Humans; Male; Olanzapine; Pilot Projects; Psychiatric Status Rating Scales; Schizophrenia; Time Factors; Weight Gain

The aim of this study was to assess the prevalence of weight gain during long-term treatment with olanzapine under routine conditions. Weight changes in a sample of 27 outpatients with schizophrenic or schizoaffective disorder were assessed over a mean duration of treatment of 22 months (6-42 months). Treatment with olanzapine was started anew or switched from a conventional antipsychotic drug. Eighteen (66.7%) patients gained more than 7% of their initial body weight. Mean weight gain was 9.2 kg over the study period for the first year 7.7 kg, and only 1.7 kg in the second year. Due to some patients losing weight in the second year, the latter finding obscures the fact that more than 50% of patients gained considerable weight also during the second year (4.8 kg). Weight gain per month was significantly higher in patients with lower body mass index, yet the highest weight gain was found in the most obese patient. Weight gain under olanzapine is a serious concern, and should be monitored closely and countered by active measures.

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Olanzapine; Psychotic Disorders; Schizophrenia; Weight Gain

The aim of this study was to examine the effects of olanzapine on aggressive behaviour and tic severity in children with Tourette's Syndrome (TS).. Ten (10) subjects (aged 7-13 years) with a primary diagnosis of TS and a history of aggressive behaviour were treated in a single-blind, 2-week placebo run-in, 8-week treatment phase trial. The starting dose of olanzapine was 1.25-2.5 mg/day and was titrated at biweekly intervals, as tolerated. The mean dosage at the end of the trial was 14.5 mg/day.. All 10 subjects completed the study. Olanzapine produced clinically and statistically significant reductions of aggression and tic severity from baseline to trial completion, as measured by the Achenbach Child Behavior Checklist (CBCL) and Yale Global Tic Severity Scale (YGTSS). Weight gain during the treatment period was the most common adverse effect (range 2-20 lbs: group mean 12.0 lbs +/- 5.71). No other significant adverse effects were observed during the 10-week trial.. The results of this trial confirm clinical observations that olanzapine may be an effective treatment for aggression and tics in children with Tourette's syndrome. Olanzapine was generally well tolerated, although significant weight gain was observed throughout the trial.

Topics: Adolescent; Affect; Aggression; Antipsychotic Agents; Anxiety; Basal Ganglia Diseases; Benzodiazepines; Child; Family; Female; Humans; Male; Obsessive-Compulsive Disorder; Olanzapine; Pilot Projects; Prospective Studies; Psychiatric Status Rating Scales; Single-Blind Method; Social Behavior; Surveys and Questionnaires; Tics; Tourette Syndrome; Weight Gain

Limited randomized, controlled trial data exist on possible differences between atypical antipsychotics in efficacy, overall tolerability, and important indices of health status. The authors compared the efficacy and tolerability of ziprasidone and olanzapine in the treatment of acutely ill inpatients with schizophrenia or schizoaffective disorder.. In this 6-week, multicenter, double-blind, parallel-design, flexible-dose trial, patients were randomly assigned to receive ziprasidone (N=136) or olanzapine (N=133). Primary efficacy measures were improvement in Brief Psychiatric Rating Scale and Clinical Global Impression (CGI) severity scale scores; secondary measures were scores on the CGI improvement scale, Positive and Negative Syndrome Scale, and Calgary Depression Scale for Schizophrenia. Tolerability assessments included fasting lipid profiles, fasting glucose and insulin measurements, electrocardiography, and monitoring of vital signs and body weight.. The overall mean daily doses were 129.9 mg (SD=27.3) for ziprasidone and 11.3 mg (SD=2.8) for olanzapine. Both antipsychotics were efficacious in improving symptoms and global illness severity. The two treatment groups did not differ significantly in primary or secondary efficacy measures at endpoint or in by-visit analysis. Both agents were well tolerated. Body weight, total cholesterol, triglycerides, and low-density lipoprotein cholesterol significantly increased with olanzapine but not with ziprasidone; all between-group comparisons of these variables were significant and favored ziprasidone. Olanzapine, but not ziprasidone, was associated with significant increases in fasting insulin level. No patient in either group exhibited a corrected QT interval >/=500 msec.. During 6 weeks' treatment, ziprasidone and olanzapine demonstrated comparable antipsychotic efficacy. Differences favoring ziprasidone were observed in metabolic parameters.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Lorazepam; Male; Metabolic Syndrome; Middle Aged; Olanzapine; Piperazines; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Thiazoles; Treatment Outcome; Weight Gain

Recent reports raise the possibility that olanzapine can assist weight gain and improve behavioral symptoms during refeeding in anorexia nervosa.. Seventeen DSM-IV anorexia nervosa subjects hospitalized between May 1999 and October 2000 were enrolled in open-label treatment with olanzapine for up to 6 weeks. Baseline weight and symptoms were compared to patients' status at the end of treatment.. Olanzapine administration was associated with a significant reduction in depression, anxiety, and core eating disorder symptoms, and a significant increase in weight. A comparison with our historical data suggests that subjects in this study had a significantly greater decrease in depression.. These data lend support to the possibility that olanzapine may be useful in treating anorexia nervosa. However, a controlled trial is necessary to demonstrate that olanzapine is efficacious.

Topics: Adult; Anorexia Nervosa; Antipsychotic Agents; Behavioral Symptoms; Benzodiazepines; Female; Humans; Olanzapine; Treatment Outcome; Weight Gain

Frequency of adverse reactions (ARs) related with antipsychotics usage is high. Along with clinical implications, economic impact might be important. The purpose of this study was to model the economic consequences of ARs related with ziprasidone, olanzapine, risperidone, and haloperidol in Spain, by means of a cost-effectiveness model developed using a Markov modeling approach. The model simulated treatment of a cohort of 1000 schizophrenics for 12 months, initiating treatment with one of four antipsychotic drugs; haloperidol, risperidone, olanzapine and ziprasidone. Conditional probabilities of developing any of four adverse events were calculated. Treatment was modified (decrease dose, switch medication) according to incidence of ARs and physician judgments, obtained from a local cross-sectional study and clinical trials previously published. The analysis was conducted in year 2002 from a third party payer perspective. Results are shown as annual cost per month with psychotic symptoms controlled and included univariate sensitivity analysis. The therapeutic strategy starting with ziprasidone showed the lower costs and the greater number of months with symptoms controlled in most scenarios evaluated versus the other options considered, although the differences were weak: 9.6, 9.3, 9.5 and 9.5 controlled months per patient in base scenario, with annual cost per patient per month with symptoms controlled of 1035 Euros, 1084 Euros, 1087 Euros and 1090 Euros for ziprasidone, haloperidol, risperidone and olanzapine, respectively. Results were robust to one-way sensitivity analysis. Despite the unlike drug prices of antipsychotics, a considerable economic impact due to adverse reactions was seen in our setting. These results should be taken into account by health decision makers and clinicians in the management of patients with schizophrenia.

Topics: Antipsychotic Agents; Benzodiazepines; Cost-Benefit Analysis; Dyskinesia, Drug-Induced; Follow-Up Studies; Haloperidol; Hospitalization; Humans; Mental Disorders; Models, Econometric; Olanzapine; Outpatients; Patient Compliance; Piperazines; Psychiatric Status Rating Scales; Retrospective Studies; Risperidone; Sensitivity and Specificity; Spain; Survival Analysis; Thiazoles; Treatment Outcome; Weight Gain

Weight gain is a side effect of therapy with many atypical antipsychotics and may have important clinical repercussions with respect to long-term health and treatment compliance. The primary objective of this double-blind study was to compare the safety and tolerability of aripiprazole and olanzapine in patients with schizophrenia as evidenced by the percentage of patients exhibiting significant weight gain.. This was a 26-week, multicenter, randomized, double-blind, active-controlled trial in patients with DSM-IV schizophrenia who were in acute relapse and required hospitalization. Significant weight gain was defined as a > or = 7% increase in body weight from baseline. Body weight, Positive and Negative Syndrome Scale, and Clinical Global Impressions-Improvement scale (CGI-I) assessments were performed at baseline and at regular intervals during the study. The study period was from April 2000 through June 2001.. 317 patients were randomly assigned to aripiprazole (N = 156) or olanzapine (N = 161). Compared with those treated with aripiprazole, a greater proportion of patients treated with olanzapine exhibited clinically significant weight gain during the trial. By week 26, 37% of olanzapine-treated patients had experienced significant weight gain compared with 14% of aripiprazole-treated patients (p < .001). Statistically significant differences in mean weight change were observed between treatments beginning at week 1 and sustained throughout the study. At week 26, there was a mean weight loss of 1.37 kg (3.04 lb) with aripiprazole compared with a mean increase of 4.23 kg (9.40 lb) with olanzapine among patients who remained on therapy (p < .001). Changes in fasting plasma levels of total cholesterol, high-density lipoprotein cholesterol, and triglycerides were significantly different in the 2 treatment groups, with worsening of the lipid profile among patients treated with olanzapine. There was a consistent and sustained improvement in symptoms in patients who remained on therapy with either olanzapine or aripiprazole as assessed by CGI-I scores and responder rates throughout the study.. Olanzapine had a greater impact on patients' weight than aripiprazole. Significant differences in favor of aripiprazole were also observed in the effects of therapy on plasma lipid profile. Both treatment groups achieved comparable clinically meaningful improvements on efficacy measures. The observed effects on weight and lipids indicate a potentially lower metabolic and cardiovascular risk in patients treated with aripiprazole compared with those treated with olanzapine.

Topics: Acute Disease; Adult; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Double-Blind Method; Female; Humans; Hyperlipidemias; Incidence; Lipids; Male; Obesity; Olanzapine; Piperazines; Psychiatric Status Rating Scales; Quinolones; Schizophrenia; Schizophrenic Psychology; Secondary Prevention; Treatment Outcome; Weight Gain

Body weight increase during long-term treatment with olanzapine in schizophrenia patients is well documented, but weight gain and its association with other medical measures are less well evaluated in bipolar disorder patients.. We analyzed data from a 3-week, randomized, placebo-controlled trial of olanzapine for acute mania in DSM-IV bipolar I patients, followed by open continuation treatment with olanzapine up to a year. We examined factors associated with increased body mass index (BMI), including ratings of clinical change and selected physiologic measures.. Among 113 subjects treated with olanzapine for a mean +/- SD of 28.6 +/- 19.9 weeks, BMI increased from a baseline mean of 28.8 +/- 6.2 kg/m(2), by 7.9 +/- 10.8% (p < .001), into the obese range (31.0 +/- 6.1 kg/m(2)). Initial BMI change (first 3 weeks of drug exposure) predicted final BMI increases (Spearman rank correlation r(s) = 0.32, p < .001). History of longer illness (p = .006) and lifetime substance abuse (p = .02) were associated with below-median BMI increases. BMI increased much more among 40 subjects achieving symptomatic recovery than in the 73 who did not (by 11.9 +/- 13.2% vs. 5.3 +/- 7.7%; p = .004), with correspondingly longer olanzapine exposure (44.7 +/- 11.8 vs. 19.7 +/- 17.7 weeks; p < .001) at similar doses. On average, serum cholesterol increased 4.8 times more (17.5% vs. 3.6%) and endpoint cholesterol levels were newly 240 mg/dL or greater 3.6 (95% CI = 1.5 to 8.0) times more frequently in subjects with above-median BMI gain, who also experienced significantly larger increases in systolic and diastolic blood pressure, pulse rates, and nonfasting serum glucose than low-BMI-gain subjects.. Weight gain associated with long-term olanzapine treatment for mania was common, substantial, time-dependent, predicted by initial increases, and temporally associated with significant changes in cardiovascular and metabolic measures in bipolar I patients with prolonged illness and already-high basal BMI. An association of weight gain with favorable clinical response probably reflects longer olanzapine treatment.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Blood Glucose; Blood Pressure; Body Mass Index; Cholesterol; Diagnostic and Statistical Manual of Mental Disorders; Female; Humans; Longitudinal Studies; Male; Obesity; Olanzapine; Psychiatric Status Rating Scales; Pulse; Treatment Outcome; Weight Gain

The association of hyperglycemia and hypercholesterolemia with use of atypical antipsychotics has been documented in case reports and uncontrolled studies. The authors' goal was to assess the effects of clozapine, olanzapine, risperidone, and haloperidol on glucose and cholesterol levels in hospitalized patients with schizophrenia or schizoaffective disorder during a randomized double-blind 14-week trial.. One hundred fifty-seven patients with schizophrenia or schizoaffective disorder who were inpatients at four hospitals were originally included in the study. The 14-week trial consisted of an 8-week fixed-dose period and a 6-week variable-dose period. Planned assessments included fasting glucose and cholesterol, which were collected at baseline and at the end of the 8-week period and the following 6-week period.. One hundred eight of the 157 patients provided blood samples at baseline and at least at one point after random assignment to clozapine, olanzapine, risperidone, or haloperidol during the treatment trial. Seven of these patients had diabetes; their glucose levels were >125 mg/dl at baseline. Data from 101 patients were used for statistical analyses. During the initial 8-week period there was an overall significant increase in mean glucose levels. There were significant increases in glucose levels at the end of the 8-week fixed-dose period for patients given clozapine (N=27) and those given haloperidol (N=25). The olanzapine group showed a significant increase of glucose levels at the end of the 6-week variable-dose period (N=22). Fourteen of the 101 patients developed abnormal glucose levels (>125 mg/dl) during the trial (six with clozapine, four with olanzapine, three with risperidone, and one with haloperidol). Cholesterol levels were increased at the end of the 8-week fixed-dose period for the patients given clozapine (N=27) and those given olanzapine (N=26); cholesterol levels were also increased at the end of the 6-week variable-dose period for patients given olanzapine (N=22).. In this prospective randomized trial, clozapine, olanzapine, and haloperidol were associated with an increase of plasma glucose level, and clozapine and olanzapine were associated with an increase in cholesterol levels. The mean changes in glucose and cholesterol levels remained within clinically normal ranges, but approximately 14% of the patients developed abnormally high glucose levels during the course of their participation in the study.

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Cholesterol; Clozapine; Double-Blind Method; Drug Administration Schedule; Female; Haloperidol; Hospitalization; Humans; Hypercholesterolemia; Hyperglycemia; Male; Middle Aged; Olanzapine; Pirenzepine; Prospective Studies; Psychotic Disorders; Risperidone; Schizophrenia; Weight Gain

Since increased norepinephrine availability may account for the weight-reducing effect of appetite suppressants, the authors hypothesized that the addition of the selective norepinephrine reuptake inhibitor reboxetine may prevent or attenuate olanzapine-induced weight gain.. Twenty-six patients hospitalized for first-episode DSM-IV schizophrenic disorder participated in the study. In addition to 6 weeks of treatment with olanzapine, 10 mg/day, patients were randomly allocated in a double-blind design to receive either reboxetine, 4 mg/day, (N=13) or placebo (N=13).. Ten patients in each group completed the 6-week trial. Patients given olanzapine and reboxetine demonstrated a significantly lower increase in body weight (mean=2.5 kg, SD=2.7) than those given olanzapine and placebo (mean=5.5 kg, SD=3.1). Significantly fewer patients in the olanzapine/reboxetine group (N=2 of 10) than in the olanzapine/placebo group (N=7 of 10) gained at least 7% of their initial weight, the cutoff for clinically significant weight gain. The addition of reboxetine to olanzapine treatment was safe and well tolerated by the patients. A between-group difference in the reduction of Hamilton depression scale scores was seen that favored the olanzapine/reboxetine group (mean difference=-3.1, SD=1.25).. The selective norepinephrine reuptake inhibitor reboxetine may reduce olanzapine-induced weight gain in schizophrenia patients, and activation of the adrenergic system may attenuate weight gain induced by atypical antipsychotic agents.

Topics: Adrenergic Uptake Inhibitors; Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Double-Blind Method; Female; Hospitalization; Humans; Male; Middle Aged; Morpholines; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Reboxetine; Schizophrenia; Treatment Outcome; Weight Gain

Significant weight gain is a side effect associated with olanzapine treatment in some patients. We investigated the efficacy of high-dose fluoxetine as a weight-reducing agent for patients who develop early weight gain with olanzapine treatment. Patients that gained >/=3% of their baseline weight in the initial 8 weeks of olanzapine treatment (n=31) were randomized to double-blind treatment with placebo or fluoxetine (60 mg/day). Clinical, weight, and weight-related measures were assessed. Fluoxetine failed to demonstrate weight-reducing effects (fluoxetine group: baseline mean 80.5 kg, SD=19.1, last mean=83.5 kg, SD=19.8; placebo group: baseline mean=77.1 kg, SD=12.1, last mean=78.8 kg, SD=10.6; F=1.3; df=1, 18; p=0.3). There were no differential effects in psychopathology, extrapyramidal side effects or weight-related measures between the placebo and fluoxetine groups. Serotonin reuptake inhibitors are probably not a practical option to counteract weight gain induced by atypical antipsychotics. Atypical-induced weight gain may result from mechanisms other than 5HT reuptake blockade.

Topics: Adolescent; Adult; Analysis of Variance; Benzodiazepines; Double-Blind Method; Female; Fluoxetine; Humans; Male; Middle Aged; Olanzapine; Outpatients; Pirenzepine; Prospective Studies; Schizophrenia; Weight Gain

Weight gain is associated with treatment with olanzapine and other psychotropic agents. Nizatidine, a histamine H-2 receptor antagonist, has been proposed to have weight-reducing effects. This double-blind trial evaluated the efficacy of nizatidine in limiting weight gain in patients with schizophrenia and related disorders who were treated with olanzapine for up to 16 weeks. After an initial screening period, 175 patients were randomized to receive olanzapine (5-20 mg) with either placebo or nizatidine (150 mg b.i.d. or 300 mg b.i.d.). Significantly less weight gain was observed on average at weeks 3 and 4 with olanzapine+nizatidine 300 mg b.i.d. (P<0.05) compared to olanzapine+placebo, but the difference was not statistically significant at 16 weeks. Nizatidine was well-tolerated and did not adversely affect clinical outcomes. Nizatidine 300 mg b.i.d. may have an early transient effect in limiting the weight gain, but this potential early effect appeared to be diminished or eliminated by 16 weeks.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Benzodiazepines; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Nizatidine; Olanzapine; Pirenzepine; Schizophrenia; Weight Gain

The aim of the present study was to investigate the effect of adjunctive olanzapine in patients with obsessive-compulsive disorder (OCD) refractory to paroxetine. Twenty-one patients unresponsive to treatment with paroxetine, administered for at least 12 weeks at the dose of 60 mg/day, participated to a 12-week open-label, add-on trial with olanzapine (10 mg/day). The psychopathological state was evaluated by the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and by Clinical Global Impression (CGI). Three patients did not complete the 12-week adjunctive treatment with olanzapine. In the 18 completers, the mean Y-BOCS score decreased significantly from 27.1+/-4.0 at baseline to 20.1+/-3.9 at final evaluation (P<.001). Seven patients (38.9%) were rated as responders at final evaluation. Steady-state plasma concentrations of paroxetine were not modified during olanzapine coadministration. The drug combination was generally well tolerated and initial sedation and weight gain were the most frequent unwanted effects. Our findings confirm the results of previous studies and indicate that the addition of olanzapine to ongoing treatment with serotonin reuptake inhibitors (SRI) may be beneficial in some patients unresponsive to SRI monotherapy.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Drug Resistance; Female; Humans; Male; Middle Aged; Obsessive-Compulsive Disorder; Olanzapine; Paroxetine; Pirenzepine; Psychiatric Status Rating Scales; Selective Serotonin Reuptake Inhibitors; Treatment Outcome; Weight Gain

Novel antipsychotics impart substantial weight gain. Persons with bipolar disorder are frequently treated with these and other agents known to impart substantial weight gain. We sought to describe the influence of adjunctive risperidone and olanzapine on body weight, body mass index (BMI, kg/m2) and serum leptin levels over a prospective observation period of 6 months. Throughout the 6-month investigation, significant increases from baseline to end point in weight were noted with both agents; with significantly greater weight gain with olanzapine (t(10) = 2.761, P = 0.023; t(9) = 4.783, P = 0.001). Leptin levels were highly correlated with increases in weight and were significantly elevated from baseline at 4 months (r = 0.658, P < 0.05). Significant increases in weight and body mass index were apparent at 3 months (P < 0.05). The temporal association between weight increase and leptin changes does not support the notion that leptin is a primary promoter of antipsychotic-induced weight gain; however, a secondary perpetuating role cannot be ruled out.

Topics: Adolescent; Adult; Antimanic Agents; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Body Mass Index; Female; Humans; Leptin; Lithium; Male; Middle Aged; Olanzapine; Pirenzepine; Risperidone; Valproic Acid; Weight Gain

A pilot study was conducted to evaluate the effect of nizatidine on olanzapine-associated weight gain (OAWG) in ten patients with schizophrenia and schizophreniform disorder in Korea. Psychometric ratings with positive and negative syndrome scale (PANSS) and brief psychiatric rating scale (BPRS) were measured at baseline, week 4 and week 8; as were weight and body mass index (BMI). A combination of nizatidine for 8 weeks resulted in significant reversal of weight gain without worsening the psychopathology (weight: 3.5% and BMI: 3.7%). In line with studies of Western populations, an add-on therapy of nizatidine could be an effective option for the control of weight gain in olanzapine-treated patients in Korea. Our findings call for further evaluation of the effect of this drug on OAWG, with randomized placebo-controlled studies, in Asian populations.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Female; Histamine H2 Antagonists; Humans; Male; Nizatidine; Obesity; Olanzapine; Pilot Projects; Pirenzepine; Psychiatric Status Rating Scales; Psychometrics; Schizophrenia; Weight Gain

It has been reported that nizatidine may reduce the weight gain in schizophrenic patients receiving olanzapine treatment. Previous studies have demonstrated a relation between olanzapine-induced weight gain and serum leptin levels. Therefore, in the present study, it was planned to investigate the efficacy of nizatidine on the treatment of olanzapine-induced weight gain, and if available, whether leptin levels were associated with reductions in weight gain. Of the patients with schizophrenia on olanzapine treatment, 59 who gave informed consent entered a 3 month open-label screening period. Of them, 35 patients (59%) showed weight gain in excess of 2.5 kg. These patients were randomly divided into two groups; olanzapine plus nizatidine (group I) and olanzapine plus placebo (group II) for an 8-week double-blind phase. The patients were evaluated at the baseline and at week 8 with respect to the positive and negative syndrome scale, body mass index, weight and serum leptin levels. In the open-label period, olanzapine led to a considerable marked increase in weight and in serum leptin levels. There was no statistically significant difference between the groups with respect to weight at the beginning of the 8-week double-blind treatment period. Throughout the 8 week double-blind period, in group I, the weight decreased by 4.5 +/- 2.2 kg ( p<0.05). In contrast, weight increased in group II by a mean of 2.3 +/- 0.9 kg ( p>0.05). The leptin levels decreased by 4.4 +/- 2.3 ng/ml in group I ( p<0.01), and increased by 1.8 +/- 0.6 ng/ml in group II ( p>0.05). These changes were accompanied by changes in the leptin levels in both groups I and II. It is concluded that leptin seems to be strongly associated with olanzapine-induced weight gain and that nizatidine treatment may reduce the weight gain and the correlated leptin levels in patients with schizophrenia on olanzapine treatment.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Double-Blind Method; Female; Histamine H2 Antagonists; Humans; Leptin; Male; Nizatidine; Obesity; Olanzapine; Pirenzepine; Schizophrenia; Treatment Outcome; Weight Gain

Weight gain is an important side effect of antipsychotic (AP) treatment. Weight is regulated by multiple systems, including leptin, neuropeptide Y (NPY) and gonadal steroids. The aim was to investigate whether AP-induced weight gain was related to leptin and NPY abnormalities and whether these were associated with a disruption of gonadal steroid production.. Twenty two female patients with schizophrenia receiving standard AP treatment were studied over a 3-month period. Plasma leptin, NPY, gonadal steroids and their regulators were measured along with weight and BMI.. Weight, leptin and testosterone levels increased over time. There were significant relationships between a change in oestrogen levels and both a change in NPY levels and a change in BMI. Change in BMI, weight and leptin all correlated strongly with a change in the testosterone/luteinizing hormone ratio.. AP treatment results in increase in weight over time and this increase is accompanied by increased leptin levels. AP-induced weight gain is also associated with disruption of the hypothalamic-pituitary-gonadal axis. Altered regulation of NPY, either through abnormal leptin control or serotonin blockade, is a possible explanation for the effects of AP medication on both weight and gonadal steroid levels.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Female; Gonadal Steroid Hormones; Humans; Leptin; Middle Aged; Neuropeptide Y; Olanzapine; Pirenzepine; Radioimmunoassay; Risperidone; Schizophrenia; Time Factors; Weight Gain

To assess the effect of an educational intervention on antipsychotic-induced weight gain among patients with schizophrenia.. Quasi-experimental. Seventy patients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder entered this 6-month study condicted in the United States. All participants began receiving olanzapine treatment when they entered the study. The patients were then randomly assigned to an intervention group or a standard care group. Over the next 4-months, the intervention group participated in weekly psychoeducation classes focused on nutrition, exercise, and living a healthy lifestyle. Patients were followed for an additional 2 months to assess weight change.. A statistically significant difference in weight change between the two groups was observed post-treatment and at endpoint. At endpoint, the mean weight change of the intervention group was -.06 pounds, while the mean weight change in the standard care group was 9.57 pounds. In both groups, men gained significantly more weight than did women.. The results indicate that a structured educational intervention might have a positive effect on antipsychotic-induced weight gain among patients with schizophrenia.

Topics: Adult; Antipsychotic Agents; Attitude to Health; Benzodiazepines; Body Mass Index; Female; Health Knowledge, Attitudes, Practice; Humans; Life Style; Male; Middle Aged; Nurse's Role; Nursing Evaluation Research; Nutritional Sciences; Obesity; Olanzapine; Patient Education as Topic; Pirenzepine; Program Evaluation; Schizophrenia; Self-Help Groups; Weight Gain

To determine the response of children with childhood-onset schizophrenia to a 1-year prospective, open-label trial of olanzapine.. Twenty children (age range 6-15 years) with childhood-onset Diagnostic and Statistical Manual of Mental Disorders (fourth edition) schizophrenia participated. The treating clinician was free to vary or discontinue dosing and use additional medications. Symptoms were assessed by the Brief Psychiatric Rating Scale-Child version (BPRS-C), Scale for the Assessment of Positive Symptoms, and Scale for the Assessment of Negative Symptoms. Extrapyramidal symptoms, akathisia, temperature, and weight were monitored.. BPRS-C subscales of thought disturbance and psychomotor excitation, and the Scale for the Assessment of Positive Symptoms demonstrated significant decreases by 6 weeks of treatment; BPRS-C anxiety and the Scale for the Assessment of Negative Symptoms (SANS) showed significant improvement after 1 year of treatment. Seventy-four percent of subjects were considered treatment responders, with a greater than 20% reduction in total BPRS-C score and overall impairment of mild or better. Weight gain (body mass index) was above that expected for normal development in every child. No child developed neuroleptic-related dyskinesias. Seventy-four percent (n = 14) of patients completed this 1-year, open-label trial. Of the 5 subjects who discontinued, weight gain was noted as the reason for 4 subjects.. Olanzapine appears useful in the treatment of childhood-onset schizophrenia, although there may be a delayed onset of benefit for anxiety and negative symptoms. Weight gain is problematic, but the emergence of dyskinesias may be rare. Additional controlled trials are indicated.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Child; Drug Resistance; Female; Humans; Male; Olanzapine; Pirenzepine; Prospective Studies; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia, Childhood; Schizophrenic Psychology; Weight Gain

The primary goal of the study was to determine if olanzapine is effective in producing weight gain in patients with anorexia nervosa.. Twenty patients with anorexia nervosa (restricting or binge/purge subtype) without schizophrenia, schizoaffective disorder, or bipolar disorder enrolled in an open label study of olanzapine 10 mg. Patients attended weekly drug monitoring sessions and weekly group medication adherence sessions that provided psychoeducation.. Eighteen patients received the drug and 14 patients completed the 10-week study. The four drop-outs had gained a mean of 3.25 lb at their last visit. Of the 14 patients who completed the study, 10 gained an average of 8.75 lb and 3 of these patients attained their ideal body weight. The remaining four patients who completed the study lost a mean of 2.25 lb.. These findings are promising with clinically significant weight gain in an outpatient setting during a brief 10-week period.

Topics: Adolescent; Adult; Anorexia Nervosa; Benzodiazepines; Female; Humans; Male; Middle Aged; Olanzapine; Patient Compliance; Patient Education as Topic; Pirenzepine; Selective Serotonin Reuptake Inhibitors; Severity of Illness Index; Weight Gain

The authors studied weight gain mechanisms and energy balance in patients treated with olanzapine.. The body mass index of male schizophrenic adolescent inpatients treated with olanzapine (N=10) and of 10 matched patients treated with haloperidol (N=10) were measured at baseline and after 4 weeks of treatment. For the patients treated with olanzapine, caloric intake, resting energy expenditure, and physical activity (determined through accelerometry and heart rate monitoring) were assessed at baseline and after 4 weeks of treatment.. Body mass index significantly increased in those treated with olanzapine but not in those given haloperidol. The increase in body mass index was due to an increase in caloric intake without change in diet composition. Olanzapine had no significant effect on resting energy expenditure. Daily energy expenditure was very low before and after treatment.. Olanzapine-induced weight gain is associated with a general increase in caloric intake.

Topics: Adolescent; Age Factors; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Eating; Energy Intake; Energy Metabolism; Haloperidol; Hospitalization; Humans; Male; Obesity; Olanzapine; Physical Exertion; Pilot Projects; Pirenzepine; Schizophrenia; Weight Gain

Since olanzapine-induced weight gain may be attributable to the antagonistic activity of olanzapine at the serotonin-2C receptor, the authors hypothesized that it might be attenuated by addition of the selective serotonin reuptake inhibitor fluoxetine.. First-episode hospitalized schizophrenia patients (N=30) were randomly assigned in an 8-week double-blind study of olanzapine, 10 mg/day, coadministered with either fluoxetine, 20 mg/day (N=15), or placebo (N=15).. The group receiving olanzapine plus fluoxetine showed significantly less improvement in positive and disorganized symptom dimensions than the group receiving olanzapine plus placebo. The two groups demonstrated similar and substantial gradual weight gains.. These results suggest that fluoxetine coadministration is clinically ineffective and cannot attenuate olanzapine-induced weight gain.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Double-Blind Method; Drug Therapy, Combination; Female; Fluoxetine; Hospitalization; Humans; Male; Obesity; Olanzapine; Pirenzepine; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Selective Serotonin Reuptake Inhibitors; Treatment Outcome; Weight Gain

The goal of this study was to evaluate the effect of olanzapine or risperidone treatment on beta-cell function in healthy volunteers. Subjects were randomly assigned to single-blind therapy with olanzapine (10 mg/d; n = 17), risperidone (4 mg/d; n = 13), or placebo (n = 18) for 15-17 d. Insulin secretion was quantitatively assessed at baseline and the end of the study period using the hyperglycemic clamp. Weight increased significantly (P < 0.01) in the olanzapine (2.8 +/- 1.7 kg) and risperidone (3.1 +/- 2.1 kg) treatment groups. An increase ( approximately 25%) in the insulin response to hyperglycemia and a decrease ( approximately 18%) in the insulin sensitivity index were observed after treatment with olanzapine and risperidone. The change in insulin response was correlated (r = 0.5576; P = 0.019) with a change in body mass index. When the impact of weight change was accounted for by multivariate regression analyses, no significant change in insulin response or insulin sensitivity was detected after treatment with olanzapine or risperidone. We found no evidence that treatment of healthy volunteers with olanzapine or risperidone decreased the insulin secretory response to a prolonged hyperglycemic challenge. The results of this study do not support the hypothesis that olanzapine or risperidone directly impair pancreatic beta-cell function.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Female; Glucose Clamp Technique; Humans; Hyperglycemia; Insulin; Insulin Secretion; Male; Middle Aged; Olanzapine; Pirenzepine; Reference Values; Risperidone; Single-Blind Method; Weight Gain

Weight change and the weight-related health factors of nonfasting serum glucose, serum cholesterol, and diastolic blood pressure levels were analyzed in patients with DSM-III-R schizophrenia and related disorders who received treatment with olanzapine for up to 3 years, and comparisons were made to patients treated with haloperidol. Baseline body mass index (BBMI; kg/m2) and dose (mg/day) were investigated as predictors of long-term weight change experienced during olanzapine treatment.. This analysis retrospectively examined 573 patients receiving olanzapine and 103 patients receiving haloperidol for 39 weeks or more from a study of 1,996 patients randomly assigned 2:1 to either olanzapine, 5 to 20 mg/day, or haloperidol, 5 to 20 mg/day. After 6 weeks of acute therapy, patients continued for 1 year or more with either double-blind or open-label olanzapine therapy or double-blind haloperidol therapy.. Mean weight gain for olanzapine-treated patients observed for a median of 2.54 years trended toward a plateau after the first 39 weeks of treatment with a last-observation-carried-forward mean weight change of 6.26 kg (13.8 lb) and a median of 5.90 kg (13.0 lb). This was significantly higher than that for haloperidol-treated patients, whose mean weight gain was 0.69 kg (1.5 lb) after 1.15 years (p < .001). Patients with higher BBMI (> 27.6) gained significantly less weight during treatment with olanzapine than their lighter counterparts (BBMI < 27.6) (p < .001). The effect of olanzapine dose on weight was not significant (p > or = . 183). Median serum glucose at endpoint was not significantly associated (p = .096) with weight change for olanzapine. Median serum cholesterol and diastolic blood pressure for olanzapine-treated patients at endpoint showed a relationship with weight change that was statistically (p < or = .001) but not clinically significant. The difference in incidence of elevated serum glucose, cholesterol, or diastolic blood pressure between olanzapine and haloperidol therapy groups was not different (p > .05).. Mean weight gain during olanzapine treatment trended toward a plateau after the initial 39 weeks of treatment with no further significant gain out to 3 years. Higher BBMI was predictive of a lower long-term weight gain, while dose was not a significant predictor of greater longer term weight change. The relationship between weight change and glucose was not statistically significant. The association between weight change and changes in cholesterol as well as changes in diastolic blood pressure was statistically significant but not considered clinically relevant based on the ranges observed.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; Cholesterol; Diastole; Double-Blind Method; Drug Administration Schedule; Female; Haloperidol; Humans; Longitudinal Studies; Male; Olanzapine; Pirenzepine; Psychotic Disorders; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Weight Gain

Patients treated with olanzapine may gain weight, especially in the first months of therapy. Amantadine (100-300 mg/day) was started in 12 patients having a mean weight gain of 7.3 kg during olanzapine treatment. The patients' weight stabilised and over 3-6 months they lost an average of 3.5 kg. No clinical deterioration occurred and no adverse effects were reported. These observations merit confirmation in randomised, controlled trials.

Topics: Adult; Amantadine; Antipsychotic Agents; Benzodiazepines; Dopamine Agents; Female; Humans; Male; Olanzapine; Pirenzepine; Psychotic Disorders; Weight Gain

The safety and efficacy of risperidone and olanzapine were compared in a double-blind trial that used doses widely accepted in clinical practice.. Subjects (N=377) who met DSM-IV criteria for schizophrenia or schizoaffective disorder were randomly assigned to receive 2-6 mg/day of risperidone (mean modal dose=4.8 mg/day) or 5-20 mg/day of olanzapine (mean modal dose=12.4 mg/day) for 8 weeks.. The two study groups were similar at baseline except that the olanzapine group was slightly younger than the risperidone group. Seventy-five percent of the participants completed the trial, with no between-treatment differences in the proportion of dropouts. Similar proportions of the risperidone and olanzapine groups reported extrapyramidal symptoms (24% and 20%, respectively). Severity of extrapyramidal symptoms was low in both groups, with no between-group differences. Total Positive and Negative Syndrome Scale scores and scores on the five Positive and Negative Syndrome Scale factors were improved in both groups at week 8 (subjects who completed the study) and endpoint (all subjects, including dropouts). There were overall between-treatment differences in efficacy. Comparison of individual factors found no significant differences at endpoint; at week 8, however, improvements on Positive and Negative Syndrome Scale factors for positive symptoms and anxiety/depression were greater with risperidone than olanzapine. An increase in body weight of > or =7% was seen in 27% of olanzapine participants and 12% of risperidone participants.. Both treatments were well tolerated and efficacious. The frequency and severity of extrapyramidal symptoms were similar in the two treatment groups. Greater reductions in severity of positive and affective symptoms were seen with risperidone than with olanzapine treatment among study completers. There was no measure on which olanzapine was superior. Greater weight gain was associated with olanzapine than with risperidone treatment.

Topics: Adult; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Psychotic Disorders; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Weight Gain

Clinical factors predicting weight change in patients with schizophrenia and related disorders during acute treatment with the antipsychotic drugs olanzapine, risperidone, and haloperidol were sought through retrospective analyses.. Six-week body-weight data from 2 trials, study 1 comparing olanzapine and haloperidol (N = 1,369) and study 2 olanzapine and risperidone (N = 268), were analyzed. Effects of 8 clinically relevant covariates--therapy, clinical outcome (Brief Psychiatric Rating Scale), baseline body mass index (BBMI), increased appetite, age, gender, race, and dose--on weight were compared.. In study 1, olanzapine (vs. haloperidol) therapy, better clinical outcome, lower BBMI, and nonwhite race significantly affected weight gain. Effects of increased appetite and male gender on weight gain were significant for olanzapine but not for haloperidol. In study 2, better clinical outcome, lower BBMI, and younger age significantly affected weight gain. Increased appetite was more frequent during olanzapine treatment than during haloperidol, but not significantly different from risperidone. Significant differences in effect on weight change were found between olanzapine and haloperidol but not between olanzapine and risperidone. No evidence was found that lower antipsychotic drug doses were associated with lower weight gain.. This report identifies predictive factors of acute weight change in patients with schizophrenia. Similar factors across antipsychotic drugs in predicting greater weight gain included better clinical outcome, low BBMI, and nonwhite race. Factors differing between conventional (haloperidol) and atypical (olanzapine) agents included increased appetite and gender. Choice of atypical antipsychotic drug (olanzapine vs. risperidone) was of minor importance with regard to influence on acute weight gain.

Topics: Adult; Age Factors; Antipsychotic Agents; Appetite; Benzodiazepines; Body Mass Index; Body Weight; Brief Psychiatric Rating Scale; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Haloperidol; Humans; Male; Olanzapine; Pirenzepine; Racial Groups; Retrospective Studies; Risk Factors; Risperidone; Schizophrenia; Sex Factors; Treatment Outcome; Weight Gain

Olanzapine has demonstrated efficacy in the treatment of acute mania in 2 double-blind, placebo-controlled trials. We describe the results of the open-label extension from one of these trials.. In a 3-week, double-blind study of patients with DSM-IV bipolar I disorder, olanzapine was superior to placebo for the treatment of acute manic symptoms. Of the 139 patients who entered the double-blind phase of the 3-week study, 113 patients continued into the 49-week open-label extension. Efficacy measurements including the Young Mania Rating Scale (YMRS), the 21-item Hamilton Rating Scale for Depression (HAM-D-21), the Clinical Global Impressions scale-Bipolar Version, and the Positive and Negative Syndrome Scale and safety measurements including the Simpson-Angus scale, the Barnes Akathisia Scale, and the Abnormal Involuntary Movement Scale were completed throughout. The analysis considered all treatment results, starting with the first olanzapine dose. Adjunctive lithium and fluoxetine were allowed during the open-label extension.. The mean length of olanzapine treatment was 6.6 months, with a mean modal dose of 13.9 mg/day. A significant mean improvement in the YMRS total score, baseline to endpoint (-18.01, p < .001), was observed. During treatment, 88.3% of patients experienced a remission of manic symptoms (YMRS total score < or =12), and only 25.5% subsequently relapsed (YMRS total score > or = 15). Significant improvement in HAM-D-21 scores was observed (p < .001). Forty-one percent of patients were maintained on olanzapine monotherapy. The most common treatment-emergent adverse events reported were somnolence (46.0%), depression (38.9%), and weight gain (36.3%).. During up to 1 year of olanzapine therapy, either as monotherapy or in combination with lithium and/or fluoxetine, patients with bipolar disorder demonstrated significant improvement in mania and depression symptoms with a favorable safety profile. Further double-blind, controlled studies are needed to confirm these results.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Depressive Disorder; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluoxetine; Humans; Lithium; Male; Middle Aged; Olanzapine; Pirenzepine; Placebos; Psychiatric Status Rating Scales; Severity of Illness Index; Sleep; Treatment Outcome; Weight Gain

This first clinical study of olanzapine in Japanese patients with schizophrenia was conducted to investigate the efficacy and safety of olanzapine. Eighty-one patients were included in the analysis set. Mean modal dose for those patients were 9.4 +/- 3.6 mg/day. For the primary efficacy measure (Final Global Improvement Rating score), 14.8% of patients had remarkable improvement, 59.3% of patients had moderate improvement or better, and 86.4% of patients had slight improvement or better. Results from the Brief Psychiatric Rating Scale showed improvement from baseline in all clusters including positive psychotic symptoms (thought disturbance) but also against negative symptoms (anergia). The most commonly reported treatment-emergent signs and symptoms with > or =10% incidence, were insomnia, weight increase, excitement, sleepiness, and anxiety. There was a low incidence of extrapyramidal treatment-emergent signs and symptoms, and events reported were tremor (6.2%), muscle rigidity (3.7%), and akathisia (2.5%). The most commonly reported treatment-emergent laboratory changes, with > or = 20% of incidence, were prolactin elevations (24.3%) followed by increases in triglycerides (20.4%). However, mean prolactin values tended to be normalized during the study. This study result suggests that olanzapine is an "atypical" antipsychotic.

Topics: Adult; Akathisia, Drug-Induced; Antipsychotic Agents; Anxiety; Benzodiazepines; Female; Humans; Japan; Male; Muscle Rigidity; Olanzapine; Pirenzepine; Prolactin; Psychiatric Status Rating Scales; Psychomotor Agitation; Schizophrenia; Sleep Wake Disorders; Treatment Outcome; Tremor; Triglycerides; Weight Gain

The goal of this study was to explore the pathophysiology of weight gain during treatment with olanzapine for schizophrenia.. The authors used a prospective, controlled, open study comparing body weight, body mass index, and related biological measures in mentally and physically healthy volunteers and olanzapine-treated patients with schizophrenia. Weight, eating behavior, leptin serum levels, body mass index, and body composition were assessed over an 8-week observation period.. A significant increase in body weight, leptin serum levels, and percentage of body fat was seen in patients treated with olanzapine, but the drug-free comparison group did not show any significant changes. The weight gain during antipsychotic treatment with olanzapine was mainly attributable to an increase in body fat; patients' lean body mass did not change.. In addition to the original finding that an increase in body fat is mainly responsible for olanzapine-induced weight gain, these findings confirm results obtained in other studies showing increases in body weight and serum leptin levels during treatment with second-generation antipsychotics.

Topics: Adipose Tissue; Adult; Antipsychotic Agents; Benzodiazepines; Body Composition; Body Mass Index; Feeding Behavior; Female; Humans; Leptin; Male; Olanzapine; Pirenzepine; Prospective Studies; Schizophrenia; Weight Gain

The aim of this study was to estimate the long-term effectiveness of olanzapine as adjunctive therapy in patients with bipolar disorder who exhibited an inadequate response to mood stabilizers. Twenty-three Research Diagnostic Criteria (RDC) patients with bipolar I and II were assessed by means of the Schedule for Affective Disorders and Schizophrenia and entered if they gave their consent to participate. All of them had experienced frequent relapses, residual subsyndromal symptoms, and inadequate responses to other drugs, such as lithium, valproate, or carbamazepine. While maintaining other drugs, they all received open-label, increasing doses of olanzapine, until achieving clinical response. Other drugs were maintained. The patients were assessed several consecutive times from baseline to the endpoint with the Clinical Global Impressions (CGI) scale for use in bipolar illness. Records of recurrences, hospitalizations, and side effects were also collected. The last-observation-carried-forward analysis showed that there was a significant reduction of CGI scores after the introduction of olanzapine, either in manic symptoms (p = 0.0015), depressive symptoms (p = 0.0063), or global symptoms (p = 0.0003). The most frequent adverse events were somnolence (17%) and weight gain (13%). The mean dose of olanzapine at the end of the 43-week follow-up was 8.1 mg/day. Olanzapine may be a useful medication for the long-term adjunctive treatment of patients with bipolar disorder who exhibit a poor response to mood stabilizers, such as lithium, valproate, or carbamazepine. These results suggest mood-stablizing properties of olanzapine.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Disorders of Excessive Somnolence; Dose-Response Relationship, Drug; Drug Resistance; Drug Therapy, Combination; Female; Hospitalization; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Recurrence; Time Factors; Treatment Outcome; Weight Gain

The goal of this study was to assess the effectiveness and tolerability of olanzapine in the treatment of acute mania in children and adolescents.. This was an 8-week, open-label, prospective study of olanzapine monotherapy (dose range 2.5-20 mg/day) involving 23 bipolar youths (manic, mixed, or hypomanic; 5-14 years old). Weekly assessments were made using the Young Mania Rating Scale (YMRS), Clinical Global Impressions Severity Scale (CGI-S), Brief Psychiatric Rating Scale, and Children's Depression Rating Scale. Adverse events were assessed through self-reports, vital sign and weight monitoring, laboratory analytes, and extrapyramidal symptom rating scales (Barnes Akathisia Scale, Simpson-Angus Scale, and Abnormal Involuntary Movement Scale).. Twenty-two of the 23 youths (96%) completed the study. Olanzapine treatment was associated with significant improvement in mean YMRS score (-19.0 +/- 9.2, p < 0.001). Using predefined criteria for improvement of > or = 30% decline in the YMRS and a CGI-S Mania score of < or = 3 at endpoint, the overall response rate was 61%. Overall, olanzapine was well tolerated, and extrapyramidal symptom measures were not significantly different from baseline. Body weight increased significantly over the study (5.0 +/- 2.3 kg, p < 0.001).. Open-label olanzapine treatment was efficacious and well tolerated in the treatment of acute mania in youths with bipolar disorder. Future placebo-controlled, double-blind studies are warranted.

Topics: Abdominal Pain; Adolescent; Antipsychotic Agents; Appetite; Benzodiazepines; Bipolar Disorder; Brief Psychiatric Rating Scale; Child; Child, Preschool; Disorders of Excessive Somnolence; Female; Humans; Male; Olanzapine; Patient Compliance; Pirenzepine; Prospective Studies; Severity of Illness Index; Time Factors; Weight Gain

Adding the atypical neuroleptic risperidone to a serotonin reuptake inhibitor (SRI) has benefited patients with treatment-refractory obsessive-compulsive disorder (OCD). Since olanzapine and risperidone have similar serotonergic and dopaminergic receptor binding profiles, we tested the hypothesis that olanzapine augmentation would be beneficial in treatment-unresponsive OCD.. For this 8-week trial, we recruited 10 adult OCD patients (DSM-IV criteria) unresponsive to fluoxetine (> or =60 mg/day) for > or =10 weeks, which was continued throughout the trial. Other psychotropic medications were discontinued. Subjects had OCD for > or =1 year, a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score of > or =18, and no organic, psychotic, or other primary Axis I disorder. Two weeks after olanzapine, 2.5 mg/day, was added, and in the absence of responder status (Y-BOCS score decrease > or =25%) and limiting side effects, we increased the dose to 5 mg/day, and after 2 more weeks, to 10 mg/day for 4 weeks.. The subjects had failed a mean of 3.3 SRI trials (range, 1-5) and had a mean +/- SD baseline Y-BOCS score of 29.0 +/- 4.9. Nine patients completed the trial. The subjects' mean +/- SD endpoint Y-BOCS score was 24.4 +/- 8.0 (a 16% decrease). The 3 responders' Y-BOCS scores dropped 68%, 30%, and 29%, but only 1 patient was rated "much improved." He maintained this improvement during a 6-month follow-up period taking olanzapine, 5 mg/day. Improvement in OCD was independent of improvement in mood symptoms. Six patients (60%) experienced significant weight gain.. Olanzapine augmentation may benefit treatment-unresponsive OCD. Double-blind, placebo-controlled trials are warranted along with trials comparing risperidone and olanzapine augmentation.

Topics: Adult; Benzodiazepines; Drug Administration Schedule; Drug Therapy, Combination; Fluoxetine; Humans; Male; Middle Aged; Obsessive-Compulsive Disorder; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Risperidone; Selective Serotonin Reuptake Inhibitors; Treatment Outcome; Weight Gain; Xerostomia

We compared the efficacy and safety of olanzapine vs placebo for the treatment of acute bipolar mania.. Four-week, randomized, double-blind, parallel study. A total of 115 patients with a DSM-IV diagnosis of bipolar disorder, manic or mixed, were randomized to olanzapine, 5 to 20 mg/d (n = 55), or placebo (n = 60). The primary efficacy measure was the Young-Mania Rating Scale (Y-MRS) total score. Response and euthymia were defined, a priori, as at least a 50% improvement from baseline to end point and as a score of no less than 12 at end point in the Y-MRS total score, respectively. Safety was assessed using adverse events, Extrapyramidal Symptom (EPS) rating scales, laboratory values, electrocardiograms, vital signs, and weight change.. Olanzapine-treated patients demonstrated a statistically significant greater mean (+/- SD) improvement in Y-MRS total score than placebo-treated patients (-14.8 +/- 12.5 and -8.1 +/- 12.7, respectively; P<.001), which was evident at the first postbaseline observation 1 week after randomization and was maintained throughout the study (last observation carried forward). Olanzapine-treated patients demonstrated a higher rate of response (65% vs 43%, respectively; P =.02) and euthymia (61% vs 36%, respectively; P =. 01) than placebo-treated patients. There were no statistically significant differences in EPSs between groups. However, olanzapine-treated patients had a statistically significant greater mean (+/- SD) weight gain than placebo-treated patients (2.1 +/- 2.8 vs 0.45 +/- 2.3 kg, respectively) and also experienced more treatment-emergent somnolence (21 patients [38.2%] vs 5 [8.3% ], respectively).. Olanzapine demonstrated greater efficacy than placebo in the treatment of acute bipolar mania and was generally well tolerated.

Topics: Acute Disease; Adolescent; Adult; Aged; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Placebos; Psychiatric Status Rating Scales; Severity of Illness Index; Sleep Wake Disorders; Treatment Outcome; Weight Gain

This open-label clinical study was conducted for patients with schizophrenia in order to investigate the efficacy, safety and optimal dose of olanzapine. One hundred and fifty-six of the 159 enrolled patients were included in the analysis set. For the primary efficacy measure, the Final Global Improvement Rating (FGIR) score, 15.4% of patients had remarkable improvement, 58.3% of patients had moderate improvement or more, 79.5% of patients had slight improvement or more, and 10.3% of patients had increase in disease symptomatology (worsening). Results from the Brief Psychiatric Rating Scale (BPRS) in all individual items were improved from baseline. Olanzapine was effective not only against positive psychotic symptoms but also against negative symptoms. This was consistent with results from the Positive and Negative Syndrome Scale (PANSS). For the majority of patients, a dose range of 7.5-10.0mg/day, as a lower bound on the minimally effective dose, was suggested by the results of the dose to first response based on improvement in Global Improvement Rating (GIR) analyses. The ratio of olanzapine dose to equivalent haloperidol dose was estimated at 1.2 :1. The most commonly reported treatment-emergent signs and symptoms (TESS) occurring at a frequency of 10% or more were insomnia, weight increase, excitement, sleepiness, anxiety, malaise and dull headaches. There was a low incidence of extrapyramidal treatment-emergent signs and symptoms; the most commonly reported were akathisia (6.4%), tremor (5.8%) and muscle rigidity (2.6%).

Topics: Adolescent; Adult; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Brief Psychiatric Rating Scale; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Schizophrenia; Treatment Outcome; Weight Gain

We performed a retrospective analysis of 122 clinical records of 92 male patients with DSM-III-R schizophrenia to examine the relative weight gain liabilities of clozapine, risperidone, olanzapine, and sertindole compared with haloperidol. We hypothesized that the unique pharmacodynamic profiles of these agents would contribute to different amounts and patterns of weight gain.. Data were analyzed to determine differences in weight gain during treatment among patients receiving 5 different drug treatments (clozapine [N = 20], olanzapine [N = 13], risperidone [N = 38], haloperidol [N = 43], and sertindole [N = 8]). Measures of maximal weight gain, final weight, and duration to maximal weight gain were calculated.. Repeated measures analyses of variance controlling for age, treatment duration, and initial weight revealed statistically significant differences between groups on all 3 measures. Clozapine and olanzapine had the greatest maximal weight gain liability (F = 4.13, df = 4,23; p = .01). Weight gain with clozapine, but not olanzapine or risperidone, appears to persist (as reflected by final weight) despite behavioral interventions (e.g., nutritional consultation, suggested exercise regimen; F = 5.69, df = 4,23; p = .003). Clozapine- and olanzapine-treated subjects appeared to gain weight over a prolonged period of time, whereas risperidone-and sertindole-treated subjects had a more limited period of weight gain (F = 2.95, df = 4,25; p = .04).. Clozapine and olanzapine caused the most weight gain, risperidone was intermediate, and sertindole had less associated weight gain than haloperidol. The relative receptor affinities of the novel antipsychotics for histamine H1 appear to be the most robust correlate of these clinical findings.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Double-Blind Method; Haloperidol; Humans; Imidazoles; Indoles; Male; Obesity; Olanzapine; Pirenzepine; Placebos; Retrospective Studies; Risperidone; Schizophrenia; Weight Gain

Previous studies have suggested that clozapine is associated with increases in both weight and serum triglyceride (but not cholesterol) levels. Because of the pharmacologic similarities between clozapine and olanzapine, we decided to evaluate if olanzapine use was associated with an increase in triglycerides.. Twenty-five inpatients (21 men, 4 women) were treated with olanzapine, and their outcomes were tracked prospectively in a medication utilization evaluation study.. After 12 weeks on a mean +/- SD dose of 13.8+/-4.4 mg/day, weight increased a mean of 12 lb (5.4 kg; from 190+/-37 lb [85.5+/-16.7 kg] to 202+/-30 lb [90.9+/-13.5 kg]), while fasting triglycerides increased a mean of 60 mg/dL (from 162+/-121 mg/dL to 222+/-135 mg/dL). Both increases were significant at p < .05. Fasting total cholesterol did not increase. The triglyceride increase was even larger when we excluded 8 patients who received various interventions to lower lipid levels (e.g., pravastatin, low-fat diet) during the olanzapine trial. There was a strong association between weight change and triglyceride change (p < .02); after controlling for weight, analysis of covariance showed no independent increase in triglycerides.. These results suggest olanzapine has significant effects on weight and serum triglyceride levels. Clinical implications are discussed.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Dose-Response Relationship, Drug; Female; Hospitalization; Humans; Hypertriglyceridemia; Male; Olanzapine; Pirenzepine; Psychotic Disorders; Schizophrenia; Triglycerides; Weight Gain

Topics: Antipsychotic Agents; Benzodiazepines; Constipation; Costs and Cost Analysis; Dizziness; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy; Humans; Hypotension, Orthostatic; Olanzapine; Pirenzepine; Schizophrenia; Sleep; Weight Gain

Periodontitis is a highly prevalent disease in psychiatric patients, including those undergoing symptomatic treatment with second-generation antipsychotics. Some of these drugs, such as clozapine (CLO) and olanzapine (OLA), have prominent metabolic effects such as weight gain, hyperglycemia, and dyslipidemia, which are risk factors for periodontitis. In addition to the metabolic effects, there are reports of changes in salivary flow, gingival bleeding, and caries. In this context, we aimed to evaluate if the metabolic effects of OLA and CLO alter periodontal parameters in an animal model of periodontitis without the environmental and psychosocial biases inherent to human diseases.. In the first set of experiments, male and female adult Wistar rats received oral administration of CLO, OLA, or vehicle for 45 days. They were evaluated for body mass composition and weight gain, blood glucose parameters (fasting and glucose tolerance and insulin resistance tests), and lipid profile (HDL, total cholesterol, and triglycerides). In a second set of experiments, the same measurements were performed in female rats exposed to the antipsychotics for 45 days and ligature-induced periodontitis on the 30th day of treatment. Macroscopic measurements of exposed roots, microtomography in the furcation region of the first molar, and histological evaluation of the region between the first and second molars were evaluated to assess bone loss. Additionally, gingival measurements of myeloperoxidase activity and pro-inflammatory cytokine TNF-α were made.. Only females exposed to OLA had more significant weight gain than controls. They also exhibited differences in glucose metabolism. Ligature-induced periodontitis produced intense bone retraction without changing the density of the remaining structures. The bone loss was even higher in rats with periodontitis treated with OLA or CLO and was accompanied by a local increase in TNF-α caused by CLO. These animals, however, did not exhibit the same metabolic impairments observed for animals without periodontitis.. The use of clozapine and olanzapine may be a risk factor for periodontal disease, independent of systemic metabolic alterations.

Topics: Adult; Animals; Antipsychotic Agents; Bone Diseases, Metabolic; Clozapine; Female; Humans; Male; Olanzapine; Periodontitis; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha; Weight Gain

In contrast to what is seen clinically, male mice are resistant to antipsychotic-induced obesity. This is problematic as preclinical studies examining mechanisms of antipsychotic-induced metabolic dysfunction might be relevant to only half the population. This study sought to determine whether housing mice at thermoneutrality and under conditions of preexisting obesity, steps that have not been previously considered, would uncover a greater obesogenic effect of the antipsychotic olanzapine (OLZ).. C57BL6/J mice were fed a low- or high-fat diet (HFD) for 4 weeks and then switched to a control HFD or an HFD supplemented with OLZ for 6 weeks.. Irrespective of obesity, OLZ treatment attenuated weight gain and increased energy expenditure in male mice. In females, OLZ increased food intake and potentiated weight gain in mice with preexisting obesity.. Despite taking steps to increase clinical translatability, this study did not unmask an obesogenic effect of OLZ in male mice. Interestingly, prior studies in female mice could have been underestimating the metabolic consequences of OLZ by not considering the importance of preexisting obesity. Uncovering the mechanisms conferring resistance to weight gain in males may provide clues for approaches to counter the metabolic side effects of antipsychotics clinically.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Female; Housing; Male; Mice; Obesity; Olanzapine; Weight Gain

Olanzapine is widely used as a treatment for schizophrenia and other psychiatric disorders. Its metabolic side effects, including weight gain and hyperglycemia, are a clinical problem; however, their full mechanism is not yet clearly understood. Recently, it was reported that the accumulation of oxidative stress in the hypothalamus may cause obesity and diabetes mellitus. Epidemiologically, metabolic side effects are known to be more likely to occur in women. In the present study, we investigated and tested the hypothesis that olanzapine induces oxidative stress in the hypothalamus and induces metabolic side effects. We also examined its association with sex differences. Olanzapine was administered intraperitoneally to male and female C57BL/6 mice, and the expression levels of oxidative stress-responsible genes in the hypothalamus and cerebral cortex were measured by qRT-PCR. In addition, olanzapine was administered intraperitoneally to C57BL/6 and Nrf2 KO mice, and the expression level of total glutathione was measured. Gene expressions induced by the Keap1-Nrf2-regulated system showed different responses to olanzapine for each gene. Under the conditions of this experiment, cystine-glutamate transporter was decreased although heme oxygenase-1 and γ-glutamylcysteine synthetase were increased. It was also clear that these responses were not hypothalamus-specific. Long-term feeding with olanzapine suppressed weight gain in males but not females. No glucose intolerance was observed at 13 weeks of administration. Furthermore, deaths occurred only in females. In conclusion, this study failed to provide evidence that olanzapine induces oxidative stress in a hypothalamic-specific manner. Instead, sex differences were observed in response to long-term and high-dose olanzapine administration, suggesting that individual susceptibility to olanzapine toxicity occurred in female mice.

Topics: Animals; Antipsychotic Agents; Female; Kelch-Like ECH-Associated Protein 1; Male; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Olanzapine; Sex Characteristics; Weight Gain

This study aimed to assess weight changes following antipsychotic treatment in first-episode schizophrenia (FES) patients and make a comparison of aripiprazole, risperidone and olanzapine. Predictors for long-term clinically relevant weight gain (CRW, ≥7%) were examined.. We carried out a second analysis of data from the Chinese First-Episode Schizophrenia Trial. Repeated measures general linear model (GLM) statistics were used to compare body weight at each follow-up point (month of 1, 2, 3, 6, 9and 12). Logistic regression models were constructed to evaluate possible predictors for CRW.. Body weight increased with an average rate of 0.93 % per month, with the fastest growth rate occurring in first 3 months. CRW was observed in 79 % of patients. Participants from olanzapine group showed significantly higher weight gain than risperidone group and aripiprozole group. Repeated measures GLM revealed a significant main effect of time (p < 0.001) and asignificant time*group interaction was revealed (p < 0.001), while the between-subject group effect was not statistically significant (p = 0.272). Multivariate logistic regressionmodel showed that with smaller baseline BMI (OR = 1.33, p < 0.001), with a family history of mental disorder (OR = 5.08, p = 0.004), receiving olanzapine (OR = 2.35, p = 0.001), and CRW at first-month (OR = 4.29, p = 0.032) were independent predictors for first-year CRW.. Antipsychotics are associated with a clinically significant weight gain in FES patients, which occurs mostly in first 3 months. Aripiprazole might not be an ideal choice in terms of long-term metabolic side-effects. Early and close metabolic monitoring should accompany antipsychotic prescription.

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Body Weight; Humans; Olanzapine; Risperidone; Schizophrenia; Weight Gain

Olanzapine (OLA), a widely used second-generation antipsychotic (SGA), causes weight gain and metabolic alterations when administered orally to patients. Recently, we demonstrated that, contrarily to the oral treatment which induces weight gain, OLA administered via intraperitoneal (i.p.) in male mice resulted in body weight loss. This protection was due to an increase in energy expenditure (EE) through a mechanism involving the modulation of hypothalamic AMPK activation by higher OLA levels reaching this brain region compared to those of the oral treatment. Since clinical studies have shown hepatic steatosis upon chronic treatment with OLA, herein we further investigated the role of the hypothalamus-liver interactome upon OLA administration in wild-type (WT) and protein tyrosine phosphatase 1B knockout (PTP1B-KO) mice, a preclinical model protected against metabolic syndrome. WT and PTP1B-KO male mice were fed an OLA-supplemented diet or treated via i.p. Mechanistically, we found that OLA i.p. treatment induces mild oxidative stress and inflammation in the hypothalamus in a JNK1-independent and dependent manner, respectively, without features of cell dead. Hypothalamic JNK activation up-regulated lipogenic gene expression in the liver though the vagus nerve. This effect concurred with an unexpected metabolic rewiring in the liver in which ATP depletion resulted in increased AMPK/ACC phosphorylation. This starvation-like signature prevented steatosis. By contrast, intrahepatic lipid accumulation was observed in WT mice treated orally with OLA; this effect being absent in PTP1B-KO mice. We also demonstrated an additional benefit of PTP1B inhibition against hypothalamic JNK activation, oxidative stress and inflammation induced by chronic OLA i.p. treatment, thereby preventing hepatic lipogenesis. The protection conferred by PTP1B deficiency against hepatic steatosis in the oral OLA treatment or against oxidative stress and neuroinflammation in the i.p. treatment strongly suggests that targeting PTP1B might be also a therapeutic strategy to prevent metabolic comorbidities in patients under OLA treatment in a personalized manner.

Topics: AMP-Activated Protein Kinases; Animals; Fatty Acid Synthases; Fatty Liver; Hypothalamus; Inflammation; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Olanzapine; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Signal Transduction; Weight Gain

Olanzapine is one of the most effective medicines available for stabilizing schizophrenia spectrum disorders. However, it has been reported to show the greatest propensity for inducing body weight gain and producing metabolic side effects, which cause a great burden in patients with psychiatric disorders. Since the gut microbiota has a profound impact on the initiation and development of metabolic diseases, we conducted a longitudinal study to explore its role in olanzapine-induced obesity and metabolic abnormalities. Female Sprague-Dawley rats were treated with different doses of olanzapine, and metabolic and inflammatory markers were measured. Olanzapine significantly induced body weight gain (up to a 2.1-fold change), which was accompanied by hepatic inflammation and increased plasma triglyceride levels (up to a 2.9-fold change), as well as gut microbiota dysbiosis. Subsequently, fuzzy c-means clustering was used to characterize three clusters of longitudinal trajectories for microbial fluctuations: (i) genera continuing to increase, (ii) genera continuing to decrease, and (iii) genera temporarily changing. Among them,

Topics: Animals; Dysbiosis; Female; Gastrointestinal Microbiome; Longitudinal Studies; Obesity; Olanzapine; Rats; Rats, Sprague-Dawley; Weight Gain

Advances have been made in recent years in using opioid receptor antagonists as an adjunct therapy to psychotropic medication to reduce debilitating weight gain and metabolic adverse effects associated with in particular second generation antipsychotics. However, it is unknown whether second generation antipsychotics produce a change in opioid receptor expression in the brain. The present study investigated early changes in opioid receptor expression in the female rat hypothalamus, a master controller of hunger and metabolic regulation, after acute treatment with olanzapine, a commonly used second generation antipsychotic. Using quantitative spatial in situ hybridization and receptor autoradiography, expression levels of the three opioid receptors; kappa, mu and delta, were determined at mRNA and protein level, respectively, in the five hypothalamic areas: paraventricular nucleus, arcuate nucleus, ventromedial nucleus, dorsomedial nucleus and lateral hypothalamus. After 48 h of olanzapine treatment at clinically relevant plasma concentration weight gain and food intake changes, and increased plasma glucose were observed in female rats. Olanzapine treatment also led to a significant increase in mu opioid receptor availability in the arcuate nucleus, which contains both satiety and hunger controlling neurons. No other areas showed any opioid receptor expressional changes with olanzapine treatment on neither at mRNA nor protein level. Technical difficulties made it impossible to analyze mRNA levels in the lateral hypothalamus and overall binding of delta opioid receptors. Thus, the present study provided insights in to how olanzapine at clinically relevant plasma levels already at an early stage modulated the opioid system in the hypothalamus.

Topics: Animals; Antipsychotic Agents; Feeding Behavior; Female; Hypothalamus; Olanzapine; Rats; Receptors, Opioid; Receptors, Opioid, mu; RNA, Messenger; Weight Gain

Pseudotumor cerebri or idiopathic intracranial hypertension (IIH) secondary to psychotropic drugs is a very rare occurrence. Lithium is typically the culprit agent. Here, authors report on an interesting case of an adolescent with early-onset schizophrenia that develops a reversible IIH putatively related to olanzapine-induced weight gain. This is followed by discussion of purported pharmacodynamic mechanisms and brief review of literature. Clinicians should be cognizant to this serious complication given the propensity of the majority of atypical antipsychotics to induce significant weight gain especially in younger population.

Topics: Adolescent; Antipsychotic Agents; Humans; Olanzapine; Pseudotumor Cerebri; Psychotic Disorders; Weight Gain

Antipsychotic medications are used in the management of schizophrenia and a growing number of off-label conditions. While effective at reducing psychoses, these drugs possess noted metabolic side effects including weight gain, liver lipid accumulation and disturbances in glucose and lipid metabolism. To counter the side effects of antipsychotics standard of care has typically included metformin. Unfortunately, metformin does not protect against antipsychotic induced metabolic disturbances in all patients and thus additional treatment approaches are needed. One potential candidate could be salsalate, the prodrug of salicylate, which acts synergistically with metformin to improve indices of glucose and lipid metabolism in obese mice. The purpose of the current investigation was to compare the effects of salsalate, metformin and a combination of both drugs, on weight gain and indices of metabolic health in female mice treated with the antipsychotic, olanzapine. Herein we demonstrate that salsalate was equally as effective as metformin in protecting against olanzapine induced weight gain and liver lipid accumulation with no additional benefit of combining both drugs. Conversely, metformin treatment, either alone or in combination with salsalate, improved indices of glucose metabolism and increased energy expenditure in olanzapine treated mice. Collectively, our findings provide evidence that dual therapy with both metformin and salsalate could be an efficacious approach with which to dampen the metabolic consequences of antipsychotic medications.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Female; Glucose; Humans; Lipids; Metformin; Mice; Olanzapine; Salicylates; Weight Gain

Olanzapine is one of the most commonly used antipsychotic drugs; however, its metabolic disorders are the main obstacle in the clinic. Olanzapine is a potent antagonist of the M3 acetylcholine muscarinic receptor (M3R), while the downregulated hepatic M3R-AMPKα signalling pathway is involved in metabolic disorders.. This study investigated the effects of chronic co-treatment with cevimeline (an agonist of M3Rs) in attenuating olanzapine-induced metabolic disorders and the underlying mechanisms.. Forty-eight adult female Sprague-Dawley rats were treated orally with olanzapine (2 mg/kg, 3 times/day (t.i.d.)) and/or cevimeline (9 mg/kg, t.i.d.), or control (vehicle) for 9 weeks.. Cevimeline co-treatment significantly attenuated olanzapine-induced body weight gain and glucolipid metabolic disorders. Importantly, cevimeline co-treatment attenuated olanzapine-induced upregulation of M3Rs, while the co-treatment improved olanzapine-induced downregulation of AMPKα in the liver. Cevimeline co-treatment attenuated olanzapine-induced dyslipidaemia by modulating the hepatic M3R-AMPKα downstream pathways. Cevimeline co-treatment also improved lower activated AKT-GSK3β signalling to reverse impairment of glucose metabolism and insulin resistance caused by chronic olanzapine treatment.. These results not only support the important role of M3R antagonism and its related AMPKα and downstream pathways in antipsychotic-induced metabolic disorders but also indicate that these pathways might be promising targets for pharmacological intervention to control these side effects caused by antipsychotic therapy.

Topics: AMP-Activated Protein Kinases; Animals; Antipsychotic Agents; Female; Liver; Metabolic Diseases; Muscarinic Agonists; Olanzapine; Quinuclidines; Rats; Rats, Sprague-Dawley; Receptor, Muscarinic M3; Signal Transduction; Thiophenes; Weight Gain

Cyperus rotundus L. is used to treat multiple clinical conditions like inflammation, diarrhea, pyrosis, and metabolic disorders including diabetes and obesity. The present study aimed to predict the interaction of reported bioactives from Cyperus rotundus against obesity via network pharmacology and to evaluate the efficacy of hydroalcoholic extract of Cyperus rotundus against the olanzapine-induced weight gain and metabolic disturbances in experimental animals. Reported phytochemicals of Cyperus rotundus were retrieved from the open-source database(s) and published literature and their targets were predicted using SwissTargetPrediction, enriched in STRING, and bioactives-proteins-pathways network was constructed using Cytoscape. Further, the hydroalcoholic extract of Cyperus rotundus (100, 200, and 400 mg/kg/day, p.o.) was co-administered with olanzapine (2 mg/kg, i.p.) for 21 days in Sprague Dawley rats. During treatment, body weight and food intake were recorded; after the successful completion of 21 days of treatment, animals were fasted to perform oral glucose and insulin tolerance tests. Further, the animals were euthanized; blood and abdominal fat were collected for lipid profiling and histopathological examination respectively. Herein, network pharmacology predicted neuroactive ligand-receptor interaction as a primarily modulated pathway and protein tyrosine phosphatase 1b as a majorly triggered protein via the combined action of bioactives. Further, Cyperus rotundus significantly reversed weight gain, cumulative food intake, ameliorated the lipid and glucose metabolism, and promoted energy expenditure.

Topics: Animals; Cyperus; Olanzapine; Plant Extracts; Rats; Rats, Sprague-Dawley; Weight Gain

Children are prescribed second-generation antipsychotic (SGA) medications, such as olanzapine (OLZ) for FDA-approved and "off-label" indications. The long-term impact of early-life SGA medication exposure is unclear. Olanzapine and other SGA medications are known to cause excessive weight gain in young and adult patients, suggesting the possibility of long-term complications associated with the use of these drugs, such as obesity, diabetes, and heart disease. Further, the weight gain effects of OLZ have previously been shown to depend on the presence of gut bacteria and treatment with OLZ, which shifts gut bacteria toward an "obesogenic" profile. The purpose of the current study was to evaluate changes in gut bacteria in adult mice following early life treatment with OLZ and being fed either a high-fat diet or a high-fat diet supplemented with fish oil, which has previously been shown to counteract gut dysbiosis, weight gain, and inflammation produced by a high-fat diet. Female and male C57Bl/6J mice were fed a high fat diet without (HF) or with the supplementation of fish oil (HF-FO) and treated with OLZ from postnatal day (PND) 37-65 resulting in four groups of mice: mice fed a HF diet and treated with OLZ (HF-OLZ), mice fed a HF diet and treated with vehicle (HF), mice fed a HF-FO diet and treated with OLZ (HF-FO-OLZ), and mice fed a HF-FO diet and treated with vehicle (HF-FO). Following euthanasia at approximately 164 days of age, we determined changes in gut bacteria populations and serum LPS binding protein, an established marker of gut inflammation and dysbiosis. Our results showed that male HF-FO and HF-FO-OLZ mice had lower body weights, at sacrifice, compared to the HF group, with a comparable body weight across groups in female mice. HF-FO and HF-FO-OLZ male groups also exhibited lower serum LPS binding protein levels compared to the HF group, with no differences across groups in female mice. Gut microbiota profiles were also different among the four groups; the Bacteroidetes-to-Firmicutes (B/F) ratio had the lowest value of 0.51 in the HF group compared to 0.6 in HF-OLZ, 0.9 in HF-FO, and 1.1 in HF-FO-OLZ, with no differences in female mice. In conclusion, FO reduced dietary obesity and its associated inflammation and increased the B/F ratio in male mice but did not benefit the female mice. Although the weight lowering effects of OLZ were unexpected, FO effects persisted in the presence of olanzapine, demonstrating its potential protective eff

Topics: Animals; Body Weight; Diet, High-Fat; Dietary Supplements; Female; Fish Oils; Gastrointestinal Microbiome; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Olanzapine; Sex Characteristics; Weight Gain

Metabolic abnormalities have been associated with olanzapine treatment. We assessed if olanzapine has dose-dependent effects on metabolic parameters with changes for weight, blood pressure, lipid and glucose profiles being modelled using linear mixed-effects models. The risk of metabolic abnormalities including early weight gain (EWG) (≥5% during first month) was assessed using mixed-effects logistic regression models. In 392 olanzapine-treated patients (median age 38.0 years, interquartile range [IQR] = 26.0-53.3, median dose 10.0 mg/day, IQR = 5.0-10.0 for a median follow-up duration of 40.0 days, IQR = 20.7-112.2), weight gain was not associated with olanzapine dose (p = 0.61) although it was larger for doses versus ≤10 mg/day (2.54 ± 5.55 vs. 1.61 ± 4.51% respectively, p = 0.01). Treatment duration and co-prescription of >2 antipsychotics, antidepressants, benzodiazepines and/or antihypertensive agents were associated with larger weight gain (p < 0.05). Lower doses were associated with increase in total and HDL cholesterol and systolic and diastolic blood pressure (p < 0.05), whereas higher doses were associated with glucose increases (p = 0.01). Patients receiving >10 mg/day were at higher EWG risk (odds risk: 2.15, 1.57-2.97). EWG might be prominent in high-dose olanzapine-treated patients with treatment duration and co-prescription of other medications being weight gain moderators. The lack of major dose-dependent patterns for weight gain emphasizes that olanzapine-treated patients are at weight gain risk regardless of the dose.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Humans; Olanzapine; Prospective Studies; Weight Gain

Olanzapine is a commonly used drug in the treatment of schizophrenia, but its clinical application has been restricted by metabolic-related side effects. In order to mitigate the weight gain side effects caused by olanzapine, other drugs with different targets were selected for combined use and evaluated in animal models of schizophrenia. SEP-363856 is a novel psychotropic agent which is under phase III clinical trials for schizophrenia treatment. The aim of the research was to evaluate whether co-administration of olanzapine and SEP-363856 exerts synergistic anti-schizophrenic effects in the apomorphine (APO)-induced climbing test, the MK-801-induced hyperactivity test, and the Morris water maze test, and therefore reduces the weight gain side effects induced by olanzapine. Through isobolographic analysis, the results showed a synergistic interaction in the climbing test; the experimental ED30 (3 mg/kg) was significantly smaller (p < 0.05) than the theoretical ED30 (5 mg/kg). Additionally, such potentiating effects appeared additive in the MK-801 challenge experiment. Co-treatment with an effective dose of olanzapine and a low dose of SEP-363856 reversed MK-801-induced cognitive impairment symptoms in mice. Moreover, combination treatment with olanzapine and SEP-363856 controls sustained weight gain in mice with chronic exposure to olanzapine. These results support further clinical trials to test the effectiveness of co-treatment of olanzapine and SEP-363856 for controlling symptoms and weight gain in patients with schizophrenia during antipsychotic treatments.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Dizocilpine Maleate; Humans; Mice; Olanzapine; Pyrans; Schizophrenia; Weight Gain

Antipsychotics (APs) can cause weight gain. Little is known about changes in weight when APs are combined with other psychotropics. This study examines the weight change in patients undergoing long-term treatment with APs or with AP combined with other psychotropics.. Patients with non-affective psychotic disorder from the GROUP study were divided into three groups: AP medication group (APm) (n = 100), AP in combination with other psychotropics (APc) (n = 73), and medication-free (Meds-free) (n = 100). Weight change was examined at inclusion and after three years using a paired-sample t-test. An Independent-sample t-test was performed to evaluate weight change among patients taking clozapine, olanzapine, and quetiapine and individuals not taking these medications. Linear regression was performed to evaluate the association between covariates and weight.. Patients in the APm group [mean = 1.800 kg, t(99)=2.849, 95% CI(0.546, 3.054), p = 0.005] and the APc group [mean = 1.877 kg, t(72)=2.688, 95% CI(0.485, 3.268), p = 0.009] showed significant weight gain. Patients taking clozapine, olanzapine or quetiapine showed significant weight gain compared to those not taking these medications [mean difference=1.707 kg, t(271)= 2.061, 95% CI(0.077, 3.337), p = 0.040)].. Patients receiving APs and APs with other psychotropics gain weight during long-term treatment. It is possible that weight gain is mainly driven by APs.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Humans; Longitudinal Studies; Olanzapine; Psychotic Disorders; Psychotropic Drugs; Quetiapine Fumarate; Risperidone; Weight Gain

Weight gain is the one of the most important factors which increases global burden of psychiatric disorder. Second-generation antipsychotics, olanzapine (Olz) and valproic acid (Vpa) in particular, are held responsible for weight gain. However, it is still uncertain how these drugs cause this. Thus, the rats selected for the experiment were randomly divided into 3 groups. The 1st group received only 0.5 ml saline solution intraperitoneally (n = 20, control group); the second group was given 200 mg / kg Vpa intraperitoneally (n = 20, Vpa group) and 2 mg / kg Olz was given intraperitoneally to the 3rd group (n = 20, Olz group) between 8 and 10 am for 30 days. We examined serum leptin, adiponectin, resistin, TNF-α, IL-6, ghrelin level and, the amount of ghrelin secreting cells in the stomach and growth hormone secretagogue receptor-1a (GHSR-1a, ghrelin receptor) expression in the hypothalamus. The hypothalamic GHS-1a receptor index was significantly higher in the Olz group compared with the control group and Vpa group (p = 0.036 and p = 0.016 respectively). Ghrelin immune positive cell index in stomach was statistically significantly lower in the Vpa group compared with the control and Olz groups (p = 0.028 and p = 0.013 respectively) There was no difference between the groups in terms of serum leptin, resistin, IL-6 and ghrelin levels. In the Vpa group, a statistically significant increase was found in serum adiponectin level compared with both the control group and the Olz group (p = 0009 and p = 0024 respectively) and, significant decrease was found in serum TNF-α level compared to Olz group (p = 0007). In conclusion, we found that the main cause of weight gain in Olz use was the increase in the number of hypothalamic ghrelin receptors. Investigating the mechanism by which Olz increases the number of ghrelin receptors may help to develop effective treatment strategies in preventing obesity in psychiatric patients.

Topics: Adiponectin; Animals; Ghrelin; Hypothalamus; Interleukin-6; Leptin; Olanzapine; Rats; Receptors, Ghrelin; Resistin; Tumor Necrosis Factor-alpha; Valproic Acid; Weight Gain

Second-generation antipsychotic (SGA) medications can produce abnormal weight gain and metabolic dysfunction in children, but little is known about the post-treatment consequences of adolescent SGA exposure.. The objective of this study was to determine the long-term, post-treatment effects of adolescent olanzapine exposure on weight and metabolic function and whether dietary fish oil (FO) modulated any observed effects of olanzapine.. Male and female mice were fed a high-fat, high-sugar (HF-HS) diet or an HF-HS diet supplemented with fish oil (HF-HS-FO) and were treated with olanzapine or vehicle for 29 days beginning on postnatal day 37.. In male mice, adolescent olanzapine treatment suppressed weight gain during and after treatment and improved metabolic function in adulthood; dietary fish oil reduced weight gain, increased expression of fatty acid oxidation genes, and decreased expression of genes associated with fatty acid synthesis and inflammation. In contrast, few effects were observed in female mice.. The current results suggest that adolescent olanzapine exposure can produce long-term alterations in weight and metabolic function in male mice and that dietary fish oil can reduce adverse effects of lifelong consumption of an HF-HS diet. Because expected adverse effects of adolescent olanzapine treatment were not observed, the potential beneficial effects of dietary fish oil for SGA-induced weight gain and metabolic dysfunction could not be evaluated.

Topics: Animals; Antipsychotic Agents; Diet, High-Fat; Dietary Supplements; Fatty Acids; Female; Fish Oils; Male; Mice; Mice, Inbred C57BL; Olanzapine; Sugars; Weight Gain

Olanzapine (OLZ) is one of the most effective antipsychotic agents, however, its clinical utility has been limited by weight gain. Samidorphan (SAM) is a μ-opioid receptor antagonist and it can reduce the weight gain associated with OLZ. A combination of OLZ and SAM (OLZ/SAM) has been developed to provide the antipsychotic efficacy of OLZ, while mitigating OLZ-associated weight gain.. A comprehensive literature search was conducted in PubMed. Key search terms included SAM and weight gain associated with OLZ. The pharmacological action, clinical efficacy, and safety of SAM were reviewed.. OLZ can lead to weight gain. SAM is a new drug that acts as an opioid receptor antagonist that can decrease weight gain. SAM mitigates OLZ-associated weight gain while preserving the antipsychotic efficacy of OLZ. Clinical trials have confirmed that OLZ/SAM significantly improved psychotic symptoms, and resulted in significantly less weight gain than OLZ. OLZ/SAM was well tolerated. Therefore, it is a potential new treatment option for schizophrenia.

Topics: Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Humans; Naltrexone; Narcotic Antagonists; Olanzapine; Schizophrenia; Weight Gain

Second-generation antipsychotics (SGAs) are a mainstay therapy for schizophrenia. SGA-treated patients present higher risk for weight gain, dyslipidemia and hyperglycemia. Herein, we evaluated the effects of olanzapine (OLA), widely prescribed SGA, in mice focusing on changes in body weight and energy balance. We further explored OLA effects in protein tyrosine phosphatase-1B deficient (PTP1B-KO) mice, a preclinical model of leptin hypersensitivity protected against obesity.. Wild-type (WT) and PTP1B-KO mice were fed an OLA-supplemented diet (5 mg/kg/day, 7 months) or treated with OLA via intraperitoneal (i.p.) injection or by oral gavage (10 mg/kg/day, 8 weeks). Readouts of the crosstalk between hypothalamus and brown or subcutaneous white adipose tissue (BAT and iWAT, respectively) were assessed. The effects of intrahypothalamic administration of OLA with adenoviruses expressing constitutive active AMPKα1 in mice were also analyzed.. Both WT and PTP1B-KO mice receiving OLA-supplemented diet presented hyperphagia, but weight gain was enhanced only in WT mice. Unexpectedly, all mice receiving OLA via i.p. lost weight without changes in food intake, but with increased energy expenditure (EE). In these mice, reduced hypothalamic AMPK phosphorylation concurred with elevations in UCP-1 and temperature in BAT. These effects were also found by intrahypothalamic OLA injection and were abolished by constitutive activation of AMPK in the hypothalamus. Additionally, OLA i.p. treatment was associated with enhanced Tyrosine Hydroxylase (TH)-positive innervation and less sympathetic neuron-associated macrophages in iWAT. Both central and i.p. OLA injections increased UCP-1 and TH in iWAT, an effect also prevented by hypothalamic AMPK activation. By contrast, in mice fed an OLA-supplemented diet, BAT thermogenesis was only enhanced in those lacking PTP1B. Our results shed light for the first time that a threshold of OLA levels reaching the hypothalamus is required to activate the hypothalamus BAT/iWAT axis and, therefore, avoid weight gain.. Our results have unraveled an unexpected metabolic rewiring controlled by hypothalamic AMPK that avoids weight gain in male mice treated i.p. with OLA by activating BAT thermogenesis and iWAT browning and a potential benefit of PTP1B inhibition against OLA-induced weight gain upon oral treatment.

Topics: Adipose Tissue, Brown; AMP-Activated Protein Kinases; Animals; Body Weight; Energy Metabolism; Hypothalamus; Male; Mice; Olanzapine; Phosphorylation; Thermogenesis; Weight Gain

Antipsychotic-induced obesity affects millions of people and is a serious health condition worldwide. Olanzapine is the most widely prescribed antipsychotic agent with high obesogenic potential. However, the exact mechanism by which it causes its metabolic dysregulation remains poorly understood. In this study, we investigated the effect of agmatine in olanzapine-induced metabolic derangements in Female Sprague-Dawley rats. Repeated olanzapine administration for 28 days increased body weight while treatment with agmatine from days 15 to 28 prevented the body weight gain induced by olanzapine without any alteration in food intake. Repeated agmatine treatment decreased the elevated feeding efficiency and adiposity index, as well as improved dysregulated lipid metabolism induced by olanzapine. Increased activity of fatty acid synthase (FAS) and decreased expression of carnitine palmitoyl transferase-1 (CPT-1) were detected in chronic olanzapine-treated rats. Although agmatine treatment did not alter FAS activity, it increased CPT-1 activity. It is possible that the inhibitory effect of agmatine on weight gain and adiposity might be associated with increased mitochondrial fatty acid oxidation and energy expenditure in olanzapine-treated rats. We suggest that agmatine can be explored for the prevention of obesity complications associated with chronic antipsychotic treatment.

Topics: Agmatine; Animals; Antipsychotic Agents; Benzodiazepines; Body Weight; Eating; Female; Obesity; Olanzapine; Rats; Rats, Sprague-Dawley; Weight Gain

The present work was designed to investigate whether fenofibrate could ameliorate olanzapine deleterious effect on insulin resistance via its effect on fibroblast growth factor-21 (FGF-21)-adiponectin axis without affecting olanzapine antipsychotic effect in postweaning socially isolated reared female rats. Treatment with olanzapine (6 mg/kg, intraperitoneally) or fenofibrate (100 mg/kg, orally) have been started 5 weeks after isolation, then behavioral tests, hippocampal content of neurotransmitters, and brain-derived neurotrophic factor (BDNF) were assessed. Moreover, insulin resistance, lipid profile, FGF-21, adiponectin, inflammatory, and oxidative stress markers of adipose tissue were assessed. Treatment of isolated-reared animals with olanzapine, or fenofibrate significantly ameliorated the behavioral and biochemical changes induced by postweaning social isolation. Co-treatment showed additive effects in improving hippocampal BDNF level. Besides, fenofibrate reduced the elevation in weight gain, adiposity index, insulin resistance, lipid profile, and FGF-21 level induced by olanzapine treatment. Also, fenofibrate increased adiponectin level which was reduced upon olanzapine treatment. Moreover, fenofibrate improved both adipose tissue oxidative stress and inflammatory markers elevation as a result of olanzapine treatment. Fenofibrate could ameliorate olanzapine-induced insulin resistance without affecting its central effect in isolated reared rats via its action on FGF-21-adiponectin axis.

Topics: Adiponectin; Adipose Tissue; Animals; Antipsychotic Agents; Female; Fenofibrate; Fibroblast Growth Factors; Hypolipidemic Agents; Insulin Resistance; Olanzapine; Oxidative Stress; Rats; Rats, Sprague-Dawley; Weight Gain

Vitamin D deficiency is associated with poor mental health and dysmetabolism. Several metabolic abnormalities are associated with psychotic diseases, which can be compounded by atypical antipsychotics that induce weight gain and insulin resistance. These side-effects may be affected by vitamin D levels. The gut microbiota and endocannabinoidome (eCBome) are significant regulators of both metabolism and mental health, but their role in the development of atypical antipsychotic drug metabolic side-effects and their interaction with vitamin D status is unknown. We studied the effects of different combinations of vitamin D levels and atypical antipsychotic drug (olanzapine) exposure on whole-body metabolism and the eCBome-gut microbiota axis in female C57BL/6J mice under a high fat/high sucrose (HFHS) diet in an attempt to identify a link between the latter and the different metabolic outputs induced by the treatments. Olanzapine exerted a protective effect against diet-induced obesity and insulin resistance, largely independent of dietary vitamin D status. These changes were concomitant with olanzapine-mediated decreases in

Topics: Aldo-Keto Reductases; Amidohydrolases; Animals; Antipsychotic Agents; Diet, High-Fat; Dietary Sucrose; Endocannabinoids; Ethanolamines; Female; Gastrointestinal Microbiome; Gene Expression Regulation; Lipid Metabolism; Mice; Mice, Inbred C57BL; Monoacylglycerol Lipases; Monoglycerides; Obesity; Olanzapine; Phosphoric Diester Hydrolases; TRPV Cation Channels; Vitamin D; Weight Gain

The present study aimed to investigate the possible effects of metformin on the olanzapine-induced insulin resistance in rats.. Rats were randomly divided into three groups: the control (Control) group, the olanzapine (Ola) group and the olanzapine + metformin (Ola + Met) group. Rats in the Ola group received olanzapine (8 mg/kg/day) intraperitoneally while rats in the Ola + Met group received olanzapine (8 mg/kg/day) intraperitoneally and metformin (300 mg/kg/day) orally for 8 weeks. Rats in the Control group received vehicle accordingly. Body weight and fasting blood glucose were recorded routinely. Inflammatory cytokines TNF-α, IL-6 and IL-1β and IL-10 were measured by ELISA. The gene expression of macrophages markers was examined by qPCR. The epididymal white adipose tissue, liver and skeletal muscle were also isolated for immunohistochemical analysis.. Olanzapine significantly induced body weight gain and insulin resistance compared to the control, which was markedly alleviated by metformin. Pro-inflammatory cytokines TNF-α, IL-6 and IL-1β were upregulated while the anti-inflammatory cytokine IL-10 was downregulated by olanzapine in plasma and epididymal white adipose tissue compared to the control, but not the liver and skeletal muscle. However, metformin co-administration significantly decreased the levels of TNF-α, IL-6 and IL-1β while increased the level of IL-10 in epididymal white adipose tissue compared to olanzapine-treated rats. Moreover, olanzapine treatment markedly increased the expression of the CD68 and the M1 macrophage markers while decreased the expression of the M2 macrophage markers in epididymal white adipose tissue in rats compared to the control. However, metformin co-treatment ameliorated the effects of olanzapine.. Our results suggest that metformin alleviated olanzapine-induced insulin resistance possibly by suppressing the inflammatory responses mediated by macrophage infiltration and polarization in epididymal white adipose tissue.

Topics: Adipose Tissue; Animals; Anti-Inflammatory Agents; Blood Glucose; Cytokines; Disease Models, Animal; Epididymis; Hypoglycemic Agents; Inflammation; Inflammation Mediators; Insulin; Insulin Resistance; Macrophages; Male; Metformin; Olanzapine; Phenotype; Rats, Sprague-Dawley; Signal Transduction; Weight Gain

The role of Olanzapine therapeutic drug monitoring is controversial. The present study explores the associations of Olanzapine plasma concentrations with clinical response and metabolic side effects in first episode psychosis (FEP) after 2 months of treatment.. Forty-seven patients were included. Improvement in clinical symptomatology was assessed using the PANSS. Metabolic assessment included weight, blood pressure, waist circumference, blood glucose, total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides.. The Olanzapine plasma concentrations after 2 months of treatment were positively correlated with weight gain (r = 0.49, p = 0.003), and a concentration > 23.28 ng/mL was identified as a positive predictor of weight gain (≥ 7%). The Olanzapine concentration to dose (C/D) ratio was positively correlated with the percentage of improvement in the total PANSS (r = 0.46, p = 0.004), and a C/D ratio > 2.12 was identified as a positive predictor of a good response (percentage of improvement > 30%) after 2 months of treatment. We also identified several factors that could alter Olanzapine pharmacokinetics: gender (p = 0.03), diagnosis (p = 0.05), smoking habit (p = 0.05), and co-medications such as valproic acid (p = 0.05) and anxiolytics (p = 0.01).. In conclusion, our results suggest that therapeutic drug monitoring of Olanzapine could be helpful to evaluate therapeutic efficacy and metabolic dysfunction in FEP patients treated with Olanzapine.

Topics: Adult; Antipsychotic Agents; Blood Glucose; Blood Pressure; Drug Monitoring; Female; Humans; Male; Middle Aged; Olanzapine; Psychotic Disorders; Smoking; Treatment Outcome; Weight Gain

Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist that prevents metabolic side effects of the antipsychotic drugs (APDs) olanzapine and clozapine through unknown mechanisms.. This study aimed to investigate the effect of chronic APD and liraglutide co-treatment on key neural and peripheral metabolic signals, and acute liraglutide co-treatment on clozapine-induced hyperglycaemia.. In study 1, rats were administered olanzapine (2 mg/kg), clozapine (12 mg/kg), liraglutide (0.2 mg/kg), olanzapine + liraglutide co-treatment, clozapine + liraglutide co-treatment or vehicle for six weeks. Feeding efficiency was examined weekly. Examination of brain tissue (dorsal vagal complex (DVC) and mediobasal hypothalamus (MBH)), plasma metabolic hormones and peripheral (liver and kidney) cellular metabolism and oxidative stress was conducted. In study 2, rats were administered a single dose of clozapine (12 mg/kg), liraglutide (0.4 mg/kg), clozapine + liraglutide co-treatment or vehicle. Glucose tolerance and plasma hormone levels were assessed.. Liraglutide co-treatment prevented the time-dependent increase in feeding efficiency caused by olanzapine, which plateaued by six weeks. There was no effect of chronic treatment on melanocortinergic, GABAergic, glutamatergic or endocannabionoid markers in the MBH or DVC. Peripheral hormones and cellular metabolic markers were unaltered by chronic APD treatment. Acute liraglutide co-treatment was unable to prevent clozapine-induced hyperglycaemia, but it did alter catecholamine levels.. The unexpected lack of change to central and peripheral markers following chronic treatment, despite the presence of weight gain, may reflect adaptive mechanisms. Further studies examining alterations across different time points are required to continue to elucidate the mechanisms underlying the benefits of liraglutide on APD-induced metabolic side effects.

Topics: Animals; Antipsychotic Agents; Clozapine; Female; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Hypoglycemic Agents; Liraglutide; Olanzapine; Rats; Rats, Sprague-Dawley; Weight Gain

Atypical antipsychotics such as risperidone cause drug-induced metabolic syndrome. However, the underlying mechanisms remain largely unknown. Here, we report a new mouse model that reliably reproduces risperidone-induced weight gain, adiposity, and glucose intolerance. We found that risperidone treatment acutely altered energy balance in C57BL/6 mice and that hyperphagia accounted for most of the weight gain. Transcriptomic analyses in the hypothalamus of risperidone-fed mice revealed that risperidone treatment reduced the expression of Mc4r. Furthermore, Mc4r in Sim1 neurons was necessary for risperidone-induced hyperphagia and weight gain. Moreover, we found that the same pathway underlies the obesogenic effect of olanzapine-another commonly prescribed antipsychotic drug. Remarkably, whole-cell patch-clamp recording demonstrated that risperidone acutely inhibited the activity of hypothalamic Mc4r neurons via the opening of a postsynaptic potassium conductance. Finally, we showed that treatment with setmelanotide, an MC4R-specific agonist, mitigated hyperphagia and obesity in both risperidone- and olanzapine-fed mice.

Topics: alpha-MSH; Animals; Antipsychotic Agents; Female; Hyperphagia; Hypothalamus; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Models, Animal; Neurons; Obesity; Olanzapine; Potassium; Receptor, Melanocortin, Type 4; Risperidone; Synaptic Potentials; Transcriptome; Weight Gain

Previous studies have demonstrated that patients with schizophrenia (SZ) have greater rate of metabolic disorder as compared with the control population, which likely be the consequence of use of atypical antipsychotics. Olanzapine is a widely used antipsychotic, which increases the weight of SZ patients. However, the underlying mechanism remains poorly understood. Here we report the metabolomics-based understanding of the weight gain induced by olanzapine. 57 first-episode drug-naïve patients (FEDN) were recruited, of whom 27 patients completed a 4-week clinical trial. We then profiled the metabolomes of their plasma with the LC-MS-based nontargeted metabolomics approach at the baseline and after olanzapine monotherapy for 4 weeks. We observed that the plasma of the olanzapine-treated patient had significantly higher lysophosphatidylcholine (LysoPC), lysophosphatidylethanolamine (LysoPE) and lower carnitine as compared with that of the baseline plasma samples. Moreover, regression analyses indicated that the change of LysoPC(14:0) level was an independent contributor to the olanzapine-induced weight gain. Our study suggests that the metabolomics-based approach may facilitate the identification of biomarkers associated with the metabolic disorder causing by antipsychotic in schizophrenia patients.

Topics: Antipsychotic Agents; Benzodiazepines; Female; Humans; Metabolomics; Olanzapine; Pharmaceutical Preparations; Schizophrenia; Weight Gain

Although antipsychotics, such as olanzapine, are effective in the management of psychiatric conditions, some patients experience excessive antipsychotic-induced weight gain (AIWG). To illuminate pathways underlying AIWG, we compared baseline blood gene expression profiles in two cohorts of mice that were either prone (AIWG-P) or resistant (AIWG-R) to weight gain in response to olanzapine treatment for two weeks. We found that transcripts elevated in AIWG-P mice relative to AIWG-R are enriched for high-confidence transcriptional targets of numerous inflammatory and immunomodulatory signaling nodes. Moreover, these nodes are themselves enriched for genes whose disruption in mice is associated with reduced body fat mass and slow postnatal weight gain. In addition, we identified gene expression profiles in common between our mouse AIWG-P gene set and an existing human AIWG-P gene set whose regulation by immunomodulatory transcription factors is highly conserved between species. Finally, we identified striking convergence between mouse AIWG-P transcriptional regulatory networks and those associated with body weight and body mass index in humans. We propose that immunomodulatory transcriptional networks drive AIWG, and that these networks have broader conserved roles in whole body-metabolism.

Topics: Animals; Antipsychotic Agents; Gene Regulatory Networks; Humans; Mice; Olanzapine; Schizophrenia; Weight Gain

Schizophrenia (Sz) patients, especially treated with atypical antipsychotics, are at high risk of the development of metabolic syndrome that increases morbidity and mortality and impairs compliance with treatment. Mechanism of the high association of metabolic syndrome with the use of atypical antipsychotics is not clear. Literature and our data suggest that chronic inflammation- or stress-induced dysregulation of the peripheral down-stream kynurenine (Kyn) metabolism, shared by both Sz and metabolic syndrome, contributes to the development of metabolic syndrome in Sz patients treated with atypical antipsychotics. Correction of dysregulation of the peripheral down-stream metabolism of Kyn would prevent/treat metabolic syndrome. This is a pre-clinical trial of the effect of benserazide (BRZ), an inhibitor of the key enzymes of Kyn metabolism, on olanzapine-induced mouse model of metabolic syndrome. Olanzapine is one of the most effective atypical antipsychotics but has high potential to induce metabolic syndrome. Olanzapine (4 mg/kg, p.o) and/or BRZ (100 mg/day, p.o.) were administered to 6-week-old C57Bl/6 female mice, 5 days/week, for 10 weeks. The study was approved by the Tufts Medical Center Institutional Animal Care and Use Committee. BRZ attenuated olanzapine-induced excessive weight gain, impairment of glucose tolerance, and elevation of plasma cholesterol and triglycerides. Present results suggest that peripheral down-stream Kyn metabolism is a new target for prevention/treatment of olanzapine-induced metabolic syndrome. BRZ has a high translational potential as medication already approved for human use.

Topics: Animals; Antipsychotic Agents; Benserazide; Dyslipidemias; Female; Insulin Resistance; Kynurenine; Metabolic Syndrome; Mice, Inbred C57BL; Obesity; Olanzapine; Weight Gain

Olanzapine is an atypical antipsychotic indicated for the treatment of schizophrenia and, either as monotherapy or as an adjunct to lithium or valproate, for bipolar I disorder. Multiple daily doses of olanzapine do not affect the pharmacokinetics of lithium or valproate; therefore, concomitant olanzapine administration does not require dosage adjustment of lithium or valproate. ALKS 3831, a combination of olanzapine and the opioid receptor antagonist samidorphan (OLZ/SAM), is currently under development to provide the established antipsychotic efficacy of olanzapine while mitigating olanzapine-induced weight gain. Olanzapine is recognized as one of the most efficacious antipsychotics; however, the benefits of olanzapine are offset by its propensity to cause significant weight gain, which may lead to long-term metabolic sequelae. This study evaluated the effects of multiple daily doses of OLZ/SAM on the pharmacokinetics of lithium or valproate in healthy subjects.. This was an open-label, single-sequence, two-cohort study (ALKS3831-B101) conducted at a single center in the USA. Thirty-four healthy adult subjects were assigned (1:1) to receive lithium carbonate 300-mg tablets (cohort 1) or divalproex sodium 500-mg tablets (cohort 2), once every 12 h on days 1-7. Once-daily oral doses of OLZ/SAM (olanzapine 10 mg/samidorphan 10 mg) bilayer tablets were administered on days 8-18. Subjects resumed every 12-h doses of lithium or valproate concomitantly with the once-daily oral doses of OLZ/SAM on days 12-18. Plasma concentrations of lithium and valproic acid (valproate) were quantified in blood samples collected prior to and up to 12 h after lithium or valproate dose administration on days 7 and 18. Pharmacokinetic parameters of lithium and valproate, including maximum plasma concentration and area under the plasma concentration-time curve over a 12-h dosing interval, were calculated. The ratio of geometric means of maximum plasma concentration and area under the plasma concentration-time curve over a 12-h dosing interval in the presence and absence of OLZ/SAM, and its two-sided 90% confidence intervals, were derived from a mixed-effects model. Adverse events were monitored throughout the study.. The 90% confidence intervals for the ratios of geometric means, in the presence vs. absence of OLZ/SAM, were within the equivalence interval of 80-125% for both maximum plasma concentration and area under the plasma concentration-time curve over a 12-h dosing interval of lithium and of valproate. The safety profiles of lithium or valproate co-administered with OLZ/SAM were consistent with what has been previously reported for lithium or valproate. The safety profile of OLZ/SAM was consistent with that observed in previous clinical studies with OLZ/SAM.. Consistent with previously reported findings on olanzapine, administration of multiple doses of OLZ/SAM did not have a clinically significant effect on the pharmacokinetics of lithium or valproate. Co-administration of OLZ/SAM and lithium or valproate was generally well tolerated; the safety profile of OLZ/SAM was consistent with that observed in previous clinical studies.

Topics: Adult; Antipsychotic Agents; Cohort Studies; Drug Combinations; Drug Interactions; Female; Humans; Lithium Carbonate; Male; Naltrexone; Narcotic Antagonists; Olanzapine; Valproic Acid; Weight Gain; Young Adult

Antipsychotics are often prescribed for long-term periods, however, most evidence of their impact on body weight comes from short-term clinical trials. Particularly, impact associated with dosage has been barely studied.. The aim of this study was to describe the short- and long-term change in body weight of people initiated on high or low doses of the three most commonly prescribed second-generation antipsychotics.. Retrospective cohorts of individuals with a diagnosed psychotic disorder observed from 2005 to 2015 in the UK primary care. The exposure was the first prescription of olanzapine, quetiapine or risperidone. The main outcome was change in body weight four years before and four years after initiation of antipsychotic treatment, stratified on sex and 'low' or 'high' dose.. In total, 22,306 women and 16,559 men were observed. Olanzapine treatment was associated with the highest change in weight, with higher doses resulting in more weight gain. After 4 years, given a high dose of olanzapine (> 5 mg), women gained on average +6.1 kg; whereas given a low dose (⩽ 5 mg), they gained +4.4 kg. During the first six weeks of olanzapine treatment, they gained on average +3.2 kg on high dose and +1.9 kg on low dose. The trends were similar for men. Individuals prescribed risperidone and quetiapine experienced less weight gain in both the short- and long-term.. Olanzapine treatment was associated with the highest increase in weight. Higher doses were associated with more weight gain. Doctors should prescribe the lowest effective dose to balance mental-health benefits, weight gain and other adverse effects.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Antipsychotic Agents; Body Weight; Cohort Studies; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Olanzapine; Quetiapine Fumarate; Retrospective Studies; Risperidone; Time Factors; Weight Gain; Young Adult

Topics: Antipsychotic Agents; Genomics; Human Genome Project; Humans; Mental Disorders; Obesity; Olanzapine; Psychiatry; Weight Gain

Second generation antipsychotics, particularly olanzapine, induce severe obesity, which is associated with their antagonistic effect on the histamine H1 receptor (H1R). We have previously demonstrated that oral administration of olanzapine increases the concentration of neuropeptide Y (NPY) in the hypothalamus of rats, accompanied by hyperphagia and weight gain. However, it is unclear if the increased NPY after olanzapine administration is due to its direct effect on hypothalamic neurons and its H1R antagonistic property. In the present study, we showed that with an inverted U-shape dose-response curve, olanzapine increased NPY expression in the NPY-GFP hypothalamic neurons; however, this was not the case in the hypothalamic neurons of H1R knockout mice. Olanzapine inhibited the interaction of H1R and GHSR1a (ghrelin receptor) in the primary mouse hypothalamic neurons and NPY-GFP neurons examined by confocal fluorescence resonance energy transfer (FRET) technology. Furthermore, an H1R agonist, FMPH inhibited olanzapine activation of GHSR1a downstream signaling pAMPK and transcription factors of NPY (pFOXO1 and pCREB) in the hypothalamic NPY-GFP cell. However, an olanzapine analogue (E-Olan) with lower affinity to H1R presented negligible enhancement of pCREB within the nucleus of NPY neurons. These findings suggest that the H1R antagonist property of olanzapine inhibits the interaction of H1R and GHSR1a, activates GHSR1a downstream signaling pAMPK-FOXO1/pCREB and increases hypothalamic NPY: this could be one of the important molecular mechanisms of H1R antagonism of olanzapine-induced obesity in antipsychotic management of psychiatric disorders.

Topics: AMP-Activated Protein Kinases; Animals; Antipsychotic Agents; Dose-Response Relationship, Drug; Histamine H1 Antagonists; Hypothalamus; Mice; Mice, Knockout; Neurons; Neuropeptide Y; Olanzapine; Receptors, Ghrelin; Receptors, Histamine H1; Signal Transduction; Weight Gain

Olanzapine has been used for the treatment of schizophrenia and other mental disorders. However, it is associated with serious weight gain and other metabolic side-effects. The antagonistic affinity of olanzapine to muscarinic M3 receptors has been evidenced as one of the main contributors for its weight gain and other metabolic side-effects. Therefore, this study investigated whether the co-treatment of cevimeline (a M3 receptor agonist) could prevent the metabolic side-effects associated with olanzapine medication. Female Sprague Dawley rats were treated orally with olanzapine (2 mg/kg, t.i.d.) and/or cevimeline at 3 dosages (3, 6, 9 mg/kg, t.i.d.), or vehicle for two weeks. Weight gain and food/water intake were measured throughout the drug treatment period. Intraperitoneal glucose tolerance tests and open field tests were conducted. Olanzapine-treated rats demonstrated significantly elevated body weight gain, food intake, feeding efficiency, total white fat mass, liver mass, and plasma triglyceride levels, which could be partly reversed by the co-treatment with cevimeline in a dosage-dependent manner. In general, the body weight gain can only be reversed by the co-treatment of 9 mg/kg cevimeline. The cevimeline co-treatment decreased plasma triglyceride and glucose levels compared with olanzapine only treatment. The results suggested a dosage-dependent effect of cevimeline in ameliorating olanzapine-induced weight gain and metabolic side-effects, which supports further clinical trials using cevimeline to control weight gain and metabolic side-effects caused by antipsychotic medications.

Topics: Adipose Tissue; Adiposity; Animals; Behavior, Animal; Blood Glucose; Dose-Response Relationship, Drug; Drug Interactions; Eating; Female; Locomotion; Metabolic Syndrome; Olanzapine; Open Field Test; Quinuclidines; Rats; Rats, Sprague-Dawley; Receptor, Muscarinic M3; Thiophenes; Treatment Outcome; Triglycerides; Weight Gain

While both men and women gain weight as a side effect of antipsychotic (AP) treatment, studies in mice have found only female mice are susceptible to weight gain. Therefore, to we set out to identify a strain of male mice that gain significant weight in response to APs which could better model AP-induced weight gain observed in humans. These studies determined that male Balb/c mice developed late onset olanzapine-induced weight gain. Patients often take APs for many years and thus understanding AP-mediated changes in food intake, energy expenditure and body weight regulation is particularly important.

Topics: Animals; Antipsychotic Agents; Body Weight; Energy Metabolism; Female; Humans; Male; Mice; Olanzapine; Weight Gain

Prescription of second-generation antipsychotic drugs (SGAs) to childhood/adolescent has exponentially increased in recent years, which was associated with the greater risk of significant weight gain and dyslipidemia. Statin is considered a potential preventive and treatment approach for reducing SGA-induced weight gain and dyslipidemia in schizophrenia patients. However, the effect of statin treatment in children and adolescents with SGA-induced dyslipidemia is not clearly demonstrated.. To investigate the efficacy of statin interventions for reversing SGA-induced dyslipidemia, young Sprague Dawley rats were treated orally with either olanzapine (1.0 mg/kg, t.i.d.), simvastatin (3.0 mg/kg, t.i.d.), olanzapine plus simvastatin (O + S), or vehicle (control) for 5 weeks.. Olanzapine treatment increased weight gain, food intake and feeding efficiency compared to the control, while O + S co-treatment significantly reversed body weight gain but without significant effects on food intake. Moreover, olanzapine treatment induced a slight but significant reduction in body temperature, with a decrease in locomotor activity. Fasting plasma glucose, triglycerides (TG), and total cholesterol (TC) levels were markedly elevated in the olanzapine-only group, whereas O + S co-treatment significantly ameliorated these changes. Pronounced activation of lipogenic gene expression in the liver and down-regulated expression of uncoupling protein-1 (UCP1) and peroxisome-proliferator-activated receptor-γ co-activator-1α (PGC-1α) in brown adipose tissue (BAT) was observed in the olanzapine-only group. Interestingly, these protein changes could be reversed by co-treatment with O + B.. Simvastatin is effective in ameliorating TC and TG elevated by olanzapine. Modulation of BAT activity by statins could be a partial mechanism in reducing metabolic side effects caused by SGAs in child and adolescent patients.

Topics: Adipose Tissue, Brown; Animals; Antipsychotic Agents; Blood Glucose; Body Temperature; Cholesterol; Dyslipidemias; Eating; Female; Hypolipidemic Agents; Liver; Locomotion; Olanzapine; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Rats, Sprague-Dawley; Simvastatin; Triglycerides; Uncoupling Protein 1; Weight Gain

Accompanied with profound efficacy, atypical antipsychotics (AAPs) contribute to metabolic adverse effects with few effective strategies to attenuate. Serotonin 5-HT2C receptor (HTR2C) plays a critical role in hyperphagia and weight gain induced by AAPs, and expression of phosphatase tensin homolog (PTEN) in the hypothalamus also affects feeding behavior and weight change. Moreover, PTEN has a physical crosstalk between PTEN and a region in the third intracellular loop (3L4F) of the HTR2C. Tat-3L4F has the property to disrupt crosstalk between PTEN and HTR2C. This is the first study to our knowledge to investigate the effect of Tat-3L4F on olanzapine-induced metabolic abnormalities and PTEN/ phosphatidylinositol 3-kinase/protein kinase B expression in the hypothalamus in rats.. The effects of Tat-3L4F were investigated through measuring body weight, food intake, and blood glucose. In addition, PTEN/phosphatidylinositol 3-kinase/protein kinase B level in the hypothalamus was detected by immunofluorescence assay and western blot. Metabolites in the liver tissue were detected by liquid chromatography-mass spectrometry and analyzed by multivariate analyses and pairwise comparison.. Our results showed that hyperphagia and weight gain were evident in the olanzapine alone-fed rats but was attenuated after Tat-3L4F treatment. In addition, oral glucose tolerance test indicated blood glucose at 120 minutes was higher in the olanzapine alone-treated group than in groups treated with vehicle and olanzapine + Tat-3L4F (10 μmol kg-1 per day). Furthermore, compared with olanzapine alone treatment, treatment with Tat-3L4F (10 μmol kg-1 per day) significantly inhibited PTEN expression in the hypothalamus. The olanzapine alone-treated group had the highest bile acid level, followed by the olanzapine with Tat-3L4F (1 μmol kg-1) group, olanzapine with Tat-3L4F (10 μmol kg-1) group, and vehicle group.. Our present results reveal that Tat-3L4F is a potential pharmacological strategy for suppressing hyperphagia and weight gain induced by olanzapine, which acts through disrupting crosstalk between HTR2C and PTEN as a result of PTEN downregulation in the hypothalamus.

Topics: Animals; Antipsychotic Agents; Appetite Depressants; Blood Glucose; Feeding Behavior; Female; Hypothalamus; Olanzapine; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2C; Recombinant Fusion Proteins; Signal Transduction; Weight Gain

Antipsychotic drugs (AP) are used to treat a multitude of psychiatric conditions including schizophrenia and bipolar disorder. However, APs also have metabolic side effects including increased food intake and body weight, but the underlying mechanisms remain unknown. We previously reported that minocycline (MINO) co-treatment abrogates olanzapine (OLZ)-induced hyperphagia and weight gain in mice. Using this model, we investigated the changes in the pharmacometabolome in the plasma and hypothalamus associated with OLZ-induced hyperphagia and weight gain. Female C57BL/6 mice were divided into groups and fed either i) control, CON (45% fat diet) ii) CON + MINO, iii) OLZ (45% fat diet with OLZ), iv) OLZ + MINO. We identified one hypothalamic metabolite indoxylsulfuric acid and 389 plasma metabolites (including 19 known metabolites) that were specifically associated with AP-induced hyperphagia and weight gain in mice. We found that plasma citrulline, tricosenoic acid, docosadienoic acid and palmitoleic acid were increased while serine, asparagine and arachidonic acid and its derivatives were decreased in response to OLZ. These changes were specifically blocked by co-treatment with MINO. These pharmacometabolomic profiles associated with AP-induced hyperphagia and weight gain provide candidate biomarkers and mechanistic insights related to the metabolic side effects of these widely used drugs.

Topics: Animals; Anti-Bacterial Agents; Antipsychotic Agents; Eating; Female; Hyperphagia; Hypothalamus; Metabolome; Mice; Mice, Inbred C57BL; Minocycline; Olanzapine; Weight Gain

Topics: Antipsychotic Agents; Humans; Naltrexone; Olanzapine; Schizophrenia; Weight Gain

Mining the data contained within Electronic Health Records (EHRs) can potentially generate a greater understanding of medication effects in the real world, complementing what we know from Randomised control trials (RCTs). We Propose a text mining approach to detect adverse events and medication episodes from the clinical text to enhance our understanding of adverse effects related to Clozapine, the most effective antipsychotic drug for the management of treatment-resistant schizophrenia, but underutilised due to concerns over its side effects.. We used data from de-identified EHRs of three mental health trusts in the UK (>50 million documents, over 500,000 patients, 2835 of which were prescribed Clozapine). We explored the prevalence of 33 adverse effects by age, gender, ethnicity, smoking status and admission type three months before and after the patients started Clozapine treatment. Where possible, we compared the prevalence of adverse effects with those reported in the Side Effects Resource (SIDER).. Sedation, fatigue, agitation, dizziness, hypersalivation, weight gain, tachycardia, headache, constipation and confusion were amongst the highest recorded Clozapine adverse effect in the three months following the start of treatment. Higher percentages of all adverse effects were found in the first month of Clozapine therapy. Using a significance level of (p< 0.05) our chi-square tests show a significant association between most of the ADRs and smoking status and hospital admission, and some in gender, ethnicity and age groups in all trusts hospitals. Later we combined the data from the three trusts hospitals to estimate the average effect of ADRs in each monthly interval. In gender and ethnicity, the results show significant association in 7 out of 33 ADRs, smoking status shows significant association in 21 out of 33 ADRs and hospital admission shows the significant association in 30 out of 33 ADRs.. A better understanding of how drugs work in the real world can complement clinical trials.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Databases, Factual; Female; Hospitals, Psychiatric; Humans; Infant; Male; Middle Aged; Olanzapine; Piperazines; Risperidone; Schizophrenia; Thiazoles; Weight Gain

Antipsychotic (AP) medications are the first line of treatment for schizophrenia. However, most conferr a risk of antipsychotic-induced weight gain (AIWG). The objective of this investigation was to conduct a genome-wide association study (GWAS) of AIWG, followed by comprehensive, post-GWAS approaches.. We investigated n = 201 schizophrenia or schizoaffective disorder patients of European and African American ancestry who were treated primarily with clozapine or olanzapine. We conducted a genome-wide association analysis for AIWG, defined primarily as a percentage of weight change from baseline.. When examining Europeans (n = 147), we noticed an association between rs62097526 (β = 0.39, p = 3.59 × 10-6, CADD = 2.213) variant, located downstream of the CIDEA gene, which is considered a risk factor for AIWG. In the entire sample, we observed a significant association between rs1525085 (β = 0.411, p = 3.15 × 10-9) variant of the DGKB gene and AIWG. The association was nominally significant in Europeans (β = 0.271, p = 0.002) and African Americans (β = 0.579, p = 5.73 × 10-5) with the same risk allele. Our top genes (p < 5 × 10-5) were enriched in the GWAS catalog for the risk of obesity and interacted with the known risk factors for obesity (G6PD) and diabetes (IRS1). In addition, these genes are targeted by miRNAs related to schizophrenia (mir-34a) and obesity (mir-19b). However, our polygenic risk score analyses did not provide support for major genetic overlap between obesity and the risk of AIWG.. In summary, we propose that the CIDEA and DGKB genes are risk factors for AIWG in transethnic populations. Additionally, our evidence suggests that the G6PD and IRS1 gene-related pathways might be involved in AIWG.

Topics: Adolescent; Adult; Antipsychotic Agents; Black or African American; Chronic Disease; Clozapine; Diacylglycerol Kinase; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Male; Middle Aged; Multifactorial Inheritance; Obesity; Olanzapine; Psychotic Disorders; Schizophrenia; Weight Gain; White People; Young Adult

To elucidate the protective effect of berberine on olanzapine induced-metabolic syndrome.. This prospective experimental study involved thirty Sprague-Dawley male rats which were divided into three groups. Group A (n=10): Rats treated with distilled water, Group B (n=10): Rats treated with olanzapine, Group C (n=10): Rats treated with olanzapine plus berberine. The duration of the study was 8 weeks, baseline and follow up data were evaluated. Fasting blood glucose(FBG) total cholesterol (TC), triglyceride (TG) and high-density lipoprotein (HDL), Low density lipoprotein (LDL), atherogenic index of plasma (AI), fasting serum insulin level, insulin resistance, β- cell function and insulin sensitivity were evaluated.SPSS 20.. Olanzepine led to significant deterioration in gluco-metabolic profile compared with control P<0.01. Olanzapine plus berberine improved body weight, FBG, FSI, HOMA-IR and QUICKI compared with olanzapine P=0.0001.. Berberine attenuates olanzapine induced-metabolic via amelioration of gluco-lipid disturbances.

Topics: Animals; Berberine; Biomarkers; Insulin Resistance; Male; Metabolic Syndrome; Olanzapine; Prospective Studies; Rats; Rats, Sprague-Dawley; Weight Gain

Topics: Adult; Antipsychotic Agents; Ghrelin; Humans; Meta-Analysis as Topic; Olanzapine; Psychotic Disorders; Weight Gain

Atypical antipsychotics, such as olanzapine, are commonly prescribed to patients with schizophrenic symptoms and other psychiatric disorders. However, weight gain and metabolic disturbance cause adverse effects, impair patient compliance and limit clinical utility. Thus, a better understanding of treatment-acquired adverse effects and identification of targets for therapeutic intervention are believed to offer more clinical benefits for patients with schizophrenia. Beyond its nutritional effects, studies have indicated that supplementation of chromium brings about beneficial outcomes against numerous metabolic disorders. In this study, we investigated whether olanzapine-induced weight gain and metabolic disturbance involved chromium dynamic mobilization in a female Sprague-Dawley rat model, and whether a dietary supplement of chromium improved olanzapine-acquired adverse effects. Olanzapine medicated rats experienced weight gain and adiposity, as well as the development of hyperglycemia, hyperinsulinemia, insulin resistance, hyperlipidemia, and inflammation. The olanzapine-induced metabolic disturbance was accompanied by a decrease in hepatic Akt and AMP-activated Protein Kinase (AMPK) actions, as well as an increase in serum interleukin-6 (IL-6), along with tissue chromium depletion. A daily intake of chromium supplements increased tissue chromium levels and thermogenic uncoupling protein-1 (UCP-1) expression in white adipose tissues, as well as improved both post-olanzapine weight gain and metabolic disturbance. Our findings suggest that olanzapine medicated rats showed a disturbance of tissue chromium homeostasis by inducing tissue depletion and urinary excretion. This loss may be an alternative mechanism responsible for olanzapine-induced weight gain and metabolic disturbance.

Topics: Adipose Tissue, White; Adiposity; Administration, Oral; AMP-Activated Protein Kinases; Animals; Antipsychotic Agents; Chlorides; Chromium Compounds; Female; Gene Expression Regulation; Hyperglycemia; Hyperinsulinism; Hyperlipidemias; Inflammation; Insulin Resistance; Interleukin-6; Liver; Muscle, Skeletal; Olanzapine; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Signal Transduction; Uncoupling Protein 1; Weight Gain

The intestinal microbiome is emerging as a novel therapeutic target owing to the wide range of potential health benefits that could result by manipulating the microbiota composition through relatively simple interventions. Ingestion of the prebiotic Bimuno™ galacto-oligosaccharide (B-GOS

Topics: Animals; Brain; Female; Histone Deacetylase Inhibitors; Histone Deacetylases; Olanzapine; Prebiotics; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Sodium Acetate; Weight Gain

Antipsychotic drugs can negatively affect the metabolic status of patients, with olanzapine as one of the most potent drugs. While patients are often medicated for long time periods, experiments in rats typically run for 1 to 12 weeks, showing olanzapine-related weight gain and increased plasma lipid levels, with transcriptional upregulation of lipogenic genes in liver and adipose tissue. It remains unknown whether metabolic status will deteriorate with time.. To examine long-term metabolic effects, we administered intramuscular long-acting injections of olanzapine (100 mg/kg BW) or control substance to female rats for up to 13 months.. Exposure to olanzapine long-acting injections led to rapid weight gain, which was sustained throughout the experiment. At 1, 6, and 13 months, plasma lipid levels were measured in separate cohorts of rats, displaying no increase. Hepatic transcription of lipid-related genes was transiently upregulated at 1 month. Glucose and insulin tolerance tests indicated insulin resistance in olanzapine-treated rats after 12 months.. Our data show that the continuous increase in body weight in response to long-term olanzapine exposure was accompanied by surprisingly few concomitant changes in plasma lipids and lipogenic gene expression, suggesting that adaptive mechanisms are involved to reduce long-term metabolic adverse effects of this antipsychotic agent in rats.

Topics: Adipose Tissue; Animals; Animals, Outbred Strains; Antipsychotic Agents; Blood Glucose; Female; Glucose Tolerance Test; Injections, Intramuscular; Insulin; Insulin Resistance; Lipids; Liver; Olanzapine; Random Allocation; Rats, Sprague-Dawley; Time Factors; Weight Gain

Despite benefits, atypical antipsychotics produce troublesome metabolic adverse effects particularly hyperphagia, weight gain, dyslipidemia, hyperglycemia and insulin resistance which further develop metabolic and cardiac complications. The animal models studied for antipsychotic-induced weight gain only focused on metabolic alteration in antipsychotics treated animals but none has considered psychosis as a predisposing factor which mimics the clinical condition. The present study was aimed to rule out the impact of pharmacologically induced psychosis-like phenotype on metabolic alterations induced by antipsychotics. Female BALB/c mice (weighing 18-23 g) exhibiting schizophrenia-like behavior after 5 days of MK-801 treatment (0.1 mg/kg, i.p.) were administered olanzapine (3 and 6 mg/kg, per oral) and risperidone (2 and 4 mg/kg, per oral) for six weeks. Acute as well as chronic treatment with olanzapine and risperidone treatment significantly reduced locomotion, increased feed intake and body weight in a time-dependent manner, which confirms the face validity of the animal model. Olanzapine (6 mg/kg) treatment significantly altered glucose and lipid homeostasis which was further accompanied by elevated levels of proinflammatory cytokines, ghrelin and leptin. These metabolic and biochemical alterations have demonstrated construct validity. Further, no significant difference was observed in the metabolic parameters in control and schizophrenic mice treated with olanzapine which confers that antipsychotic-induced metabolic alterations are independent of psychosis. Our study concluded that six-week olanzapine (6 mg/kg) treatment in control mice induced most of the clinically relevant physiological, biochemical and metabolic alterations (clinically relevant), that is independent of pharmacologically-induced psychosis.

Topics: Animals; Antipsychotic Agents; Body Weight; Female; Ghrelin; Hyperglycemia; Leptin; Mice; Mice, Inbred BALB C; Olanzapine; Psychotic Disorders; Risperidone; Schizophrenia; Weight Gain

Olanzapine, regarded as one of the most efficacious antipsychotic medications for the treatment of schizophrenia, is associated with a high risk of weight gain and metabolic dysfunction. ALKS 3831, a clinical candidate for treatment of schizophrenia, is a combination of olanzapine and samidorphan, an opioid receptor antagonist. The addition of samidorphan is intended to mitigate weight gain and the metabolic dysregulation associated with the use of olanzapine.. Non-clinical studies were conducted to assess the metabolic effects of olanzapine and samidorphan alone and in combination at clinically relevant exposure levels.. Chronic olanzapine administration in male and female rats shifted body composition by increasing adipose mass, which was accompanied by an increase in the rate of weight gain in female rats. Co-administration of samidorphan normalized body composition in both sexes and attenuated weight gain in female rats. In hyperinsulinemic euglycemic clamp experiments conducted prior to measurable changes in weight and/or body composition, olanzapine decreased hepatic insulin sensitivity and glucose uptake in muscle while increasing uptake in adipose tissue. Samidorphan appeared to normalize glucose utilization in both tissues, but did not restore hepatic insulin sensitivity. In subsequent studies, samidorphan normalized olanzapine-induced decreases in whole-body glucose clearance following bolus insulin administration. Results from experiments in female monkeys paralleled the effects in rats.. Olanzapine administration increased weight gain and adiposity, both of which were attenuated by samidorphan. Furthermore, the combination of olanzapine and samidorphan prevented olanzapine-induced insulin insensitivity. Collectively, these data indicate that samidorphan mitigates several metabolic abnormalities associated with olanzapine in both the presence and the absence of weight gain.

Topics: Adipose Tissue; Animals; Antipsychotic Agents; Drug Combinations; Female; Glucose Metabolism Disorders; Macaca fascicularis; Male; Naltrexone; Narcotic Antagonists; Olanzapine; Rats; Rats, Sprague-Dawley; Sex Factors; Weight Gain

Antipsychotic drugs (APDs), olanzapine and clozapine, do not effectively address the cognitive symptoms of schizophrenia and can cause serious metabolic side-effects. Liraglutide is a synthetic glucagon-like peptide-1 (GLP-1) receptor agonist with anti-obesity and neuroprotective properties. The aim of this study was to examine whether liraglutide prevents weight gain/hyperglycaemia side-effects and cognitive deficits when co-administered from the commencement of olanzapine and clozapine treatment.. Rats were administered olanzapine (2 mg/kg, three times daily (t.i.d.)), clozapine (12 mg/kg, t.i.d.), liraglutide (0.2 mg/kg, twice daily (b.i.d.)), olanzapine + liraglutide co-treatment, clozapine + liraglutide co-treatment or vehicle (Control) ( n = 12/group, 6 weeks). Recognition and working memory were examined using Novel Object Recognition (NOR) and T-Maze tests. Body weight, food intake, adiposity, locomotor activity and glucose tolerance were examined.. Liraglutide co-treatment prevented olanzapine- and clozapine-induced reductions in the NOR test discrimination ratio ( p < 0.001). Olanzapine, but not clozapine, reduced correct entries in the T-Maze test ( p < 0.05 versus Control) while liraglutide prevented this deficit. Liraglutide reduced olanzapine-induced weight gain and adiposity. Olanzapine significantly decreased voluntary locomotor activity and liraglutide co-treatment partially reversed this effect. Liraglutide improved clozapine-induced glucose intolerance.. Liraglutide co-treatment improved aspects of cognition, prevented obesity side-effects of olanzapine, and the hyperglycaemia caused by clozapine, when administered from the start of APD treatment. The results demonstrate a potential treatment for individuals at a high risk of experiencing adverse effects of APDs.

Topics: Adiposity; Animals; Body Weight; Clozapine; Eating; Glucose Tolerance Test; Hypoglycemic Agents; Liraglutide; Locomotion; Male; Maze Learning; Memory, Short-Term; Olanzapine; Rats; Recognition, Psychology; Weight Gain

Although olanzapine is highly efficacious and most widely used second generation antipsychotic drug, the success of treatment has been hampered by its propensity to induce weight gain. While the underlying neuronal mechanisms are unclear, their elucidation may help to target alternative pathways regulating energy balance. The present study was undertaken to define the role of cocaine- and amphetamine-regulated transcript (CART), a well-known anorexic peptide, in olanzapine-induced hyperphagia and body weight gain in female rats. Olanzapine was administered daily by intraperitoneal route, alone or in combination with CART (intracerebroventricular) for a period of two weeks. Immediately after drug administrations, preweighed food was offered to the animals at the commencement of the dark phase. The food intake and body weight were measured daily just prior to next injection. Furthermore, the brains of olanzapine-treated rats were processed for the immunohistochemical analysis of CART-containing elements in the hypothalamus. Treatment with olanzapine (0.5 mg/kg) for the duration of 14 days produced a significant increase in food intake and body weight as compared to control. However, concomitant administration of CART (0.5 µg) attenuated the olanzapine-induced hyperphagia and weight gain. Olanzapine administration resulted in a significant reduction in CART immunoreactivity in the hypothalamic arcuate, paraventricular, dorsomedial and ventromedial nuclei. We suggest that decreased CART contents in the hypothalamus may be causally linked with the hyperphagia and weight gain induced by olanzapine.

Topics: Animals; Antipsychotic Agents; Body Weight; Eating; Feeding Behavior; Female; Hyperphagia; Hypothalamus; Neuropeptides; Olanzapine; Rats, Sprague-Dawley; Weight Gain

Antipsychotic-related weight gain is a common clinically relevant side effect when treating psychotic disorders in pediatric populations, yet few predictors and no moderators of antipsychotic-related weight gain are known.. The Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS) study randomized 119 youths (age 8-19 years) with schizophrenia or schizoaffective disorder to 8 weeks of antipsychotic treatment with molindone, risperidone, or olanzapine and assessed treatment response and side effects. In this secondary analysis, we used multivariable linear regression and receiver operating characteristic analysis to investigate predictors and moderators of weight change and percent weight change from baseline to week 8.. Treatment assignment was the most discriminant predictor of weight change [F(2, 66) = 17.00, p < 0.001] and percent weight change [F(2, 66) = 16.85, p < 0.001]. Mean weight gain was 0.74 (standard deviation ±3.51) kg for molindone, 4.13 ± 3.79 kg for risperidone, and 7.29 ± 3.44 kg for olanzapine. After adjusting for treatment assignment, lower pretreatment hemoglobin A1C (HgbA1C) predicted more weight gain [F(1, 55) = 4.71, p = 0.03]. Diagnosis (schizoaffective vs. schizophrenia) moderated weight change [F(2, 63) = 6.02, p = 0.004] and percent weight change [F(2, 63) = 5.26, p = 0.008] such that schizoaffective diagnosis predicted larger weight gain for youths in the risperidone treatment arm. Age, sex, family income, baseline weight, and symptoms neither predicted nor moderated weight change or percent weight change.. We identified prognostic subgroups and novel risk factors for antipsychotic-related weight gain. We confirmed that antipsychotic choice is extremely important for predicting future weight gain. We also found that younger age did not predict greater weight gain, in contrast to prior studies. Our findings require replication in an independent sample because we did not adjust for multiple comparisons to minimize false negatives. ClinicalTrials.gov Identifier: NCT00053703.

Topics: Adolescent; Antipsychotic Agents; Female; Humans; Male; Olanzapine; Psychiatric Status Rating Scales; Risk Factors; Risperidone; Schizophrenia; Weight Gain

Follow-up studies of weight gain related to antipsychotic treatment beyond a year are limited in number. We compared weight change in the three most commonly prescribed antipsychotics in a representative UK General Practice database.. We conducted a cohort study in United Kingdom primary care records of people newly prescribed olanzapine, quetiapine or risperidone. The primary outcome was weight in each six month period for two years after treatment initiation. Weight changes were compared using linear regression, adjusted for age, baseline weight and diagnosis.. N = 6338 people received olanzapine, 12,984 quetiapine and 6556 risperidone. Baseline weight was lowest for men treated with olanzapine (80.8 kg versus 83.5 kg quetiapine, 82.0 kg risperidone) and women treated with olanzapine (67.7 kg versus 71.5 kg quetiapine 68.4 kg risperidone. Weight gain occurred during treatment with all three drugs. Compared with risperidone mean weight gain was higher with olanzapine (adjusted co-efficient +1.24 kg (95% confidence interval: 0.69-1.79 kg per six months) for men and +0.77 kg (95% confidence interval: 0.29-1.24 kg) for women). Weight gain with quetiapine was lower in unadjusted models compared with risperidone, but this difference was not significant after adjustment.. Olanzapine is more commonly prescribed to people with lower weight. However, after accounting for baseline weight, age, sex and diagnosis, olanzapine is still associated with greater weight gain over two years than risperidone or quetiapine. Baseline weight does not ameliorate the risks of weight gain associated with antipsychotic medication. Weight gain should be assertively discussed and managed for people prescribed antipsychotics, especially olanzapine.

Topics: Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Body Weight; Cohort Studies; Databases, Factual; Female; Follow-Up Studies; Humans; Linear Models; Male; Middle Aged; Olanzapine; Primary Health Care; Quetiapine Fumarate; Retrospective Studies; Risperidone; Sex Factors; United Kingdom; Weight Gain

A positive correlation between antipsychotic-induced weight gain (AIWG) and the antagonist effect of antipsychotic drugs at the histamine H1 receptor (HRH1) as well as the agonist effect at the histamine H3 receptor (HRH3) in the brain has been consistently demonstrated. We investigated the potential impact of single-nucleotide polymorphisms (SNPs) in HRH1 and HRH3 genes on AIWG.. We analysed 40 tagSNPs in HRH1 (n = 34) and HRH3 (n = 6) in schizophrenia/schizoaffective disorder patients (n = 193) primarily treated with clozapine or olanzapine for up to 14 weeks. Linear regression was used to evaluate the association between SNPs and AIWG, with baseline weight and treatment duration as covariates.. In HRH1, a nominal association of rs7639145 with AIWG was observed in patients of European ancestry treated with either clozapine or olanzapine (P. The current study suggests that SNPs in HRH1 and HRH3 may not have a major role in AIWG.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Male; Olanzapine; Polymorphism, Single Nucleotide; Psychotic Disorders; Receptors, Histamine H1; Receptors, Histamine H3; Schizophrenia; Weight Gain

Weight gain is an important side effect of most atypical antipsychotic drugs such as olanzapine. Moreover, although many animal models with metabolic side effects have been well defined, the interaction with other pathways has to be considered. The endocannabinoid system and the CB1 receptor (CB1R) are among the most promising central and peripheral targets involved in weight and energy balance. In this study we developed a rat model based 15-days treatment with olanzapine that shows weight gain and an alteration of the blood parameters involved in the regulation of energy balance and glucose metabolism. Consequently, we analysed whether, and by which mechanism, a co-treatment with the novel CB1R neutral antagonist NESS06SM, could attenuate the adverse metabolic effects of olanzapine compared to the reference CB1R inverse agonist rimonabant. Our results showed alterations of the cannabinoid markers in the nucleus accumbens and of orexigenic/anorexigenic markers in the hypothalamus of female rats treated with olanzapine. These molecular modifications could explain the excessive food intake and the resulting weight gain. Moreover, we confirmed that a co-treatment with CB1R antagonist/inverse agonist compounds decreased food intake and weight increment and restored all blood parameters, without altering the positive effects of olanzapine on behaviour. Furthermore, rimonabant and NESS06SM restored the metabolic enzymes in the liver and fat tissue altered by olanzapine. Therefore, CB1 receptor antagonist/inverse agonist compounds could be good candidate agents for the treatment of weight gain induced by olanzapine.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Benzoxepins; Body Weight; Drug Therapy, Combination; Eating; Female; Olanzapine; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Treatment Outcome; Weight Gain

The present paper discusses the design, characterization and in vivo evaluation of glyceryl monostearate nanoparticles of Olanzapine, an atypical antipsychotic drug for acute schizophrenia treatment, during which hospitalization is mandatory and adverse effects are at its peak. The solid lipid nanoparticulate system was obtained by emulsification-ultra sonication technique wherein three factors such as solid lipid content, concentration of surfactant and drug: solid lipid ratio were selected at three different levels in order to study their influence on significant characteristic responses such as particle size, encapsulation efficiency and drug content. A Box Behnken design with 17 runs involving whole factors at three levels was employed for the study. The optimized formulation was further coated with Polysorbate 80 in order to enhance its brain targeting potential through endocytosis transport process via blood brain barrier. The designed formulations were pre-clinically tested successfully in Wistar rat model for in vivo antipsychotic efficacy (apomorphine induced psychosis) and adverse effects (weight gain study for 28days). The results obtained indicated that solid lipid nanoparticles had very narrow size distribution (151.29±3.36nm) with very high encapsulation efficiency (74.51±1.75%). Morphological studies by SEM have shown that solid lipid nanoparticles were spherical in shape with smooth surface. Olanzapine-loaded nanoparticles prepared from solid lipid, extended the release of drug for 48h, as found by the in vitro release studies. The formulations also exhibited high redispersibility after freeze-drying and stability study results demonstrated good stability, with no significant change for a period of 6months. In vivo evaluation and adverse effects studies of Olanzapine-loaded nanoparticulate systems in animal model have demonstrated an improved therapeutic efficacy than pure Olanzapine. The antipsychotic effect of drug loaded nanoparticulate systems was maintained for 48h as compared to 8h antipsychotic action of pure Olanzapine solution. The weight gain studies for 28days demonstrated a significant inhibition in weight gain for Olanzapine-loaded nanoparticulate systems as compared to the pure Olanzapine. The present research findings indicate that OLN-loaded nanoparticulate systems may be highly promising for effective delivery of Olanzapine with better efficacy and minimum adverse effects.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Delayed-Action Preparations; Drug Carriers; Drug Compounding; Drug Liberation; Drug Stability; Female; Glycerides; Nanoparticles; Olanzapine; Polysorbates; Rats, Wistar; Schizophrenia; Surface-Active Agents; Weight Gain

Chronic treatment with second-generation antipsychotic drugs (SGAs) has been associated with an increased risk of metabolic syndrome. To evaluate the longitudinal changes in glucose-lipid homeostasis after SGA use, we studied the time-dependent effects of olanzapine (OLZ) (3 mg/kg, b.i.d.) or clozapine (CLZ) (20 mg/kg, b.i.d.) treatment on metabolic profiles for 9 weeks in rats. Although only OLZ significantly increased body weight in rats, both OLZ and CLZ elevated blood lipid levels. Chronic OLZ treatment induced significant weight gain leading to a higher fasting insulin level and impaired glucose tolerance, whereas CLZ lowered fasting insulin levels and impaired glucose tolerance independent of weight gain. Treatment with both drugs deranged AKT/GSK phosphorylation and up-regulated muscarinic M3 receptors in the rats' livers. Consistent with an elevation in lipid levels, both OLZ and CLZ significantly increased the protein levels of nuclear sterol regulatory element-binding proteins (SREBPs) in the liver, which was associated with improvement in hepatic histamine H1R. However, enhanced carbohydrate response element binding protein (ChREBP) signalling was observed in only CLZ-treated rats. These results suggest that SGA-induced glucose-lipid metabolic disturbances could be independent of weight gain, possibly through activation of SREBP/ChREBP in the liver.

Topics: Adipose Tissue, White; Animals; Antipsychotic Agents; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Blood Glucose; Clozapine; Disease Models, Animal; Glucose; Glucose Metabolism Disorders; Humans; Lipid Metabolism; Lipid Metabolism Disorders; Liver; Metabolic Networks and Pathways; Olanzapine; Rats; Sterol Regulatory Element Binding Proteins; Weight Gain

Antipsychotic Induced Weight Gain (AIWG) is a common and severe side effect of many antipsychotic medications. Mitochondria play a vital role for whole-body energy homeostasis and there is increasing evidence that antipsychotics modulate mitochondrial function. This study aimed to examine the role of variants in nuclear-encoded mitochondrial genes and the mitochondrial DNA (mtDNA) in conferring risk for AIWG. We selected 168 European-Caucasian individuals from the CATIE sample based upon meeting criteria of multiple weight measures while taking selected antipsychotics (risperidone, quetiapine or olanzapine). We tested the association of 670 nuclear-encoded mitochondrial genes with weight change (%) using MAGMA software. Thirty of these genes showed nominally significant P-values (<0.05). We were able to replicate the association of three genes, CLPB, PARL, and ACAD10, with weight change (%) in an independent prospectively assessed AIWG sample. We analyzed mtDNA variants in a subset of 74 of these individuals using next-generation sequencing. No common or rare mtDNA variants were found to be significantly associated with weight change (%) in our sample. Additionally, analysis of mitochondrial haplogroups showed no association with weight change (%). In conclusion, our findings suggest nuclear-encoded mitochondrial genes play a role in AIWG. Replication in larger sample is required to validate our initial report of mtDNA variants in AIWG.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; DNA, Mitochondrial; Female; Genes, Mitochondrial; Genome-Wide Association Study; Humans; Male; Olanzapine; Pharmacogenomic Testing; Pharmacogenomic Variants; Prospective Studies; Quetiapine Fumarate; Risk Factors; Risperidone; Weight Gain; White People

Atypical antipsychotics such as olanzapine often induce excessive weight gain and type 2 diabetes. However, the mechanisms underlying these drug-induced metabolic perturbations remain poorly understood. Here, we used an experimental model that reproduces olanzapine-induced hyperphagia and obesity in female C57BL/6 mice. We found that olanzapine treatment acutely increased food intake, impaired glucose tolerance, and altered physical activity and energy expenditure in mice. Furthermore, olanzapine-induced hyperphagia and weight gain were blunted in mice lacking the serotonin 2C receptor (HTR2C). Finally, we showed that treatment with the HTR2C-specific agonist lorcaserin suppressed olanzapine-induced hyperphagia and weight gain. Lorcaserin treatment also improved glucose tolerance in olanzapine-fed mice. Collectively, our studies suggest that olanzapine exerts some of its untoward metabolic effects via antagonism of HTR2C.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Body Composition; Body Weight; Diabetes Mellitus, Type 2; Female; Glucose; Glucose Tolerance Test; Hyperphagia; Male; Mice; Mice, Inbred C57BL; Olanzapine; Receptor, Serotonin, 5-HT2C; Serotonin Antagonists; Weight Gain

Antipsychotic treatment, particularly olanzapine and clozapine, induces severe obesity. The Histamine H1 receptor is considered to be an important contributor to olanzapine-induced obesity, however how olanzapine modulates the histaminergic system is not sufficiently understood. This study examined the effect of olanzapine on key molecules of the histaminergic system, including histidine decarboxylase (HDC), H1 receptor (H1R) and H3 receptor (H3R), in the brain at different stages of olanzapine-induced obesity. During short-term treatment (8-day), olanzapine increased hypothalamic HDC mRNA expression and H1R binding in the arcuate nucleus (Arc) and ventromedial hypothalamus (VMH), without changing H3R binding density. HDC mRNA and Arc H1R binding were positively correlated with increased food intake, feeding efficiency and weight gain. When the treatment was extended to 16 and 36 days, H1R binding was increased not only in the hypothalamic Arc and VMH but also in the brainstem dorsal vagal complex (DVC). The H1R bindings in the Arc, VMH and DVC were positively correlated with weight gain induced by olanzapine treatment. However, the expression of HDC and H3R mRNA was not increased. These results suggest that olanzapine time-dependently modulates histamine neurotransmission, which suggested the different neuronal mechanisms underlying different stages of weight gain development. Treatment targeting the H1R may be effective for both short- and long-term olanzapine-induced weight gain.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Brain Stem; Female; Histidine Decarboxylase; Hypothalamus; Obesity; Olanzapine; Rats; Rats, Sprague-Dawley; Receptors, Histamine H1; Receptors, Histamine H3; RNA, Messenger; Weight Gain

Topics: Antipsychotic Agents; Clozapine; Humans; Liraglutide; Obesity; Olanzapine; Overweight; Prediabetic State; Schizophrenia; Weight Gain

Olanzapine is an orexigenic antipsychotic drug associated with serious metabolic adverse effects in humans. Development of valid rodent models for antipsychotic-induced metabolic adverse effects is hampered by the fact that such effects occur in females only. Estradiol is a predominant female hormone that regulates energy balance. We hypothesized that the female-specific hyperphagia and weight gain induced by olanzapine in the rat are dependent on the presence of estrogens.. Female sham-operated or ovariectomized rats were treated with a single injection of olanzapine depot formulation. Food intake, body weight, plasma lipids, lipogenic gene expression, energy expenditure, and thermogenic markers including brown adipose tissue uncoupling protein 1 protein levels were measured. Olanzapine was also administered to ovariectomized rats receiving estradiol replacement via the subcutaneous (peripheral) or intracerebroventricular route.. Orexigenic effects of olanzapine were lost in ovariectomized female rats. Ovariectomized rats treated with olanzapine had less pronounced weight gain than expected from their food intake. Accordingly, brown adipose tissue temperature and protein levels of uncoupling protein 1 were elevated. Replacement in ovariectomized rats with either peripherally or centrally administered estradiol reduced food intake and body weight. Cotreatment with olanzapine blocked the anorexigenic effect of peripheral, but not central estradiol.. Our results indicate that the ovarian hormone estradiol plays an important role in olanzapine-induced hyperphagia in female rats and pinpoint the complex effects of olanzapine on the balance between energy intake and thermogenesis.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Body Weight; Eating; Energy Intake; Estradiol; Female; Gene Expression Regulation; Injections, Intraventricular; Lipids; Olanzapine; Ovariectomy; Ovary; Rats; Rats, Sprague-Dawley; Uncoupling Protein 1; Weight Gain

There is little information about the pharmacological treatment of avoidant and restrictive food intake disorder (ARFID), a challenging feeding disorder associated with marked impairment and developmental arrest. This brief clinical report seeks to fill this gap.. A retrospective chart review of nine patients with ARFID treated in an eating disorder (ED) program (residential, partial hospital, and intensive outpatient levels of care) with adjunctive olanzapine was undertaken.. The mean initial and final olanzapine doses were 0.9 + 0.63 mg/day and 2.8 + 1.47 mg/day, respectively. There was a statistically significant difference in weight gain pre- versus post-olanzapine treatment (3.3 ± 7.3 lbs vs. 13.1 ± 7.9 lbs [2.99 ± 6.62 lb SI vs. 11.88 ± 7.17 lb SI], paired t-test (p < 0.04, t = -2.48). Clinically, adjunctive olanzapine was helpful for not only weight gain but also reduction of associated anxious, depressive, and cognitive symptoms. Clinical Global Impressions scale scores indicated marked improvement in patients receiving adjunctive olanzapine.. These cases illustrate that judicious use of low-dose olanzapine, when used as an adjunct to other treatment modalities, may facilitate eating, weight gain, and the reduction of anxious, depressive, and cognitive symptoms in ARFID patients. Future randomized, placebo-controlled studies in ARFID are warranted.

Topics: Adolescent; Anorexia Nervosa; Antipsychotic Agents; Appetite Regulation; Benzodiazepines; Child; Combined Modality Therapy; Feeding and Eating Disorders; Female; Humans; Male; Olanzapine; Retrospective Studies; Weight Gain

To analyze weight gain, metabolic hormones, and homocysteine (Hcys) levels in children and adolescents on antipsychotics (AP) during a year-long follow-up. 117 patients, AP-naïve or quasi-naïve (less than 30 days on AP), were included. Weight, body mass index (BMI), BMI z-score (z-BMI), and levels of leptin, insulin, insulin resistance (HOMA-IR), adiponectin, ghrelin, thyroid stimulating hormone (TSH), free thyroxine (FT4), and Hcys were measured at baseline, and at 3, 6, and 12 months, while patients remained on the same AP. Patients (mean age: 14.4 ± 3 years; 64.1 % male) were on risperidone (N = 84), olanzapine (N = 20) or quetiapine (N = 13) from baseline up to 1-year follow-up and significantly increased weight (5.8 ± 4.3 kg at 3-month, 8.1 ± 6.1 kg at 6-month, and 11.6 ± 7.0 kg at 1 year), BMI, and z-BMI. Leptin levels significantly increased from baseline to 3 and 6 months, as did TSH levels from baseline to 3 months, while FT4 levels decreased from baseline to 3 and 6 months. Patients with BMI >85th percentile at baseline (N = 16) significantly increased weight, BMI, and z-BMI, more than patients with normal BMI over time. Higher baseline levels of insulin, HOMA-IR, and leptin were associated with increased weight/BMI during follow-up, while higher baseline levels of FT4, adiponectin, and ghrelin were associated with lower weight/BMI during follow-up. All AP were associated with increased weight and BMI/z-BMI in all of the assessments; however, at 1-year assessment, this increase was significantly higher for patients on quetiapine. Both higher baseline levels of insulin, HOMA-IR, and leptin, as well as being overweight/obese at baseline were associated with increased weight/BMI during 1-year follow-up in children and adolescents on AP. Awareness of weight-related parameters in this population may help inform decisions regarding AP prescriptions.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Body Weight; Child; Child, Preschool; Female; Follow-Up Studies; Ghrelin; Homocysteine; Humans; Insulin; Leptin; Male; Obesity; Olanzapine; Prospective Studies; Risperidone; Time Factors; Treatment Outcome; Weight Gain

Major depressive disorder (MDD) is a debilitating psychiatric illness with a high cost burden. This analysis evaluates the cost-effectiveness of adjunctive brexpiprazole versus comparator branded adjunctive treatment for MDD and background antidepressant therapy (ADT) alone from a US payer perspective.. An economic model was developed to assess the cost-effectiveness of brexpiprazole versus comparator adjunctive treatment and ADT alone on total direct medical costs using a 6-week cycle time frame for a total of 48 weeks, with treatment response and remission as primary outcomes. The model consisted of 3 parts, 1 to represent the acute treatment phase and 2 to represent the maintenance stage.. In the base-case analysis, brexpiprazole as reference treatment resulted in cost per additional responder ranging from $19,442-$48,745 and cost per additional remitter ranging from $27,196-$71,839 versus comparator treatments over 48 weeks. Sensitivity analyses showed treatment with brexpiprazole was more costly, but more clinically effective in all probabilistic simulations.. This representation of disease natural history over 48 weeks may not account for all possible health states. Resource utilization on treatment was estimated using the resource use data from previous trials, and may overestimate medical costs compared to the real-world setting. Treatment comparators were limited to branded therapies, and head-to-head studies were not available to obtain data inputs.. Compared to other branded adjunctive therapies, brexpiprazole increases response and remission at 6 weeks; medical care cost savings were observed with the use of brexpiprazole. These findings may assist clinicians and formulary decision makers when selecting treatment for MDD.

Topics: Adolescent; Adult; Aged; Akathisia, Drug-Induced; Antidepressive Agents; Antipsychotic Agents; Benzodiazepines; Cost-Benefit Analysis; Depressive Disorder, Major; Disorders of Excessive Somnolence; Drug Costs; Drug Therapy, Combination; Fatigue; Female; Health Care Costs; Humans; Male; Middle Aged; Models, Economic; Olanzapine; Patient Selection; Quetiapine Fumarate; Quinolones; Serotonin Agents; Thiophenes; Weight Gain; Young Adult

Antipsychotic-induced weight gain (AIWG) is a common side effect of treatment with antipsychotics such as clozapine and olanzapine. The orexin gene and its receptors are expressed in the hypothalamus and have been associated with maintenance of energy homeostasis. In this study, we have analysed tagging single nucleotide polymorphisms (SNPs) in orexin receptors 1 and 2 (HCRTR1 and HCRTR2) for association with AIWG.. Schizophrenia or schizoaffective disorder subjects (n = 218), treated mostly with clozapine and olanzapine for up to 14 weeks, were included. Replication was conducted in a subset of CATIE samples (n = 122) treated with either olanzapine or risperidone for up to 190 days. Association between SNPs and AIWG was assessed using analysis of covariance (ANCOVA) with baseline weight and duration of treatment as covariates.. Several SNPs in HCRTR2 were nominally associated with AIWG in patients of European ancestry treated with either clozapine or olanzapine (P<0.05). In the replication analysis two SNPs rs3134701 (P = 0.043) and rs12662510 (P = 0.012) were nominally associated with AIWG. None of the SNPs in HCRTR1 were associated with AIWG.. This study provides preliminary evidence supporting the role of HCRTR2 in AIWG. However, these results need to be confirmed in large study samples.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Genetic Association Studies; Humans; Male; Middle Aged; Olanzapine; Orexin Receptors; Polymorphism, Single Nucleotide; Risperidone; Schizophrenia; United States; Weight Gain; White People; Young Adult

Olanzapine-induced weight gain is associated with atherosclerosis, hypertension, dyslipidemia, and diabetes. We synthesized a novel antipsychotic drug (PGW5) possessing an olanzapine moiety linked to sarcosine, a glycine transporter 1 inhibitor. In this study, we compared the metabolic effects of PGW5 and olanzapine in a female rat model of weight gain. Female rats were treated daily with oral olanzapine (4 mg/kg), PGW5 (25 mg/kg), or vehicle for 16 days. Behavioral tests were conducted on days 12-14. Biochemical analyses were performed at the end of the treatment. A significant increase in body weight was observed in the olanzapine-treated group, while the PGW5 group did not differ from the controls. The open field test showed hypo-locomotion in the olanzapine-treated animals as compared to PGW5 and control groups. A significant increase in hypothalamic protein expression of the neuropeptide Y5 receptor and a decrease in pro-opiomelanocortin messenger ribonucleic acid (mRNA) levels were detected following PGW5 treatment, but not after olanzapine administration. PGW5 appears to possess minor metabolic effects compared with the parent compound olanzapine. The differential modulation of brain peptides associated with appetite regulation is possibly involved in the attenuation of metabolic effects by PGW5.

Topics: Alanine; Animals; Antipsychotic Agents; Benzodiazepines; Female; Hypothalamus; Olanzapine; Rats; Rats, Wistar; Receptors, Neuropeptide Y; Sarcosine; Weight Gain

Olanzapine (OLZ) treatment is associated with a high risk of weight gain, and may cause abnormalities in glycolipid metabolism. Therefore, the underlying mechanism of OLZ-related weight gain is needed to clarify but not yet been adequately determined. In recent years, adipocytokines such as leptin, adiponectin, and tumor necrosis factor (TNF)-α, which play important roles in energy homeostasis, have been suggested as biomarkers of weight gain. Here, we determined if baseline plasma concentrations of leptin, adiponectin, and TNF-α predict weight gain following OLZ treatment.. We recruited 31 schizophrenia outpatients (12 men and 19 women, 28.8 ± 10.2 years old) that were unmedicated or on another antipsychotic monotherapy medication. Baseline body mass index (BMI) and plasma levels of leptin, adiponectin, and TNF-α were obtained. All patients started or were switched to OLZ monotherapy for a maximum of 1 year. BMI was also obtained at the endpoint.. Mean BMI change following OLZ treatment was 2.1 ± 2.7 kg/m2. BMI change from baseline to endpoint negatively-correlated with baseline leptin levels in female patients (r = -0.514, P = 0.024), but not male patients. Baseline adiponectin or TNF-α levels were not correlated with BMI change.. Baseline plasma leptin can have an effect on subsequent weight gain following OLZ treatment in female patients with schizophrenia.

Topics: Adiponectin; Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Female; Humans; Leptin; Male; Olanzapine; Schizophrenia; Tumor Necrosis Factor-alpha; Weight Gain; Young Adult

Topics: Administration, Oral; Agouti-Related Protein; Animals; Benzodiazepines; Dopamine Antagonists; Eating; Gene Expression; Hypothalamus; Leptin; Male; Nerve Tissue Proteins; Neuropeptide Y; Olanzapine; Pro-Opiomelanocortin; Random Allocation; Rats, Wistar; RNA, Messenger; Serotonin Antagonists; Weight Gain

Metabolic adverse effects of atypical antipsychotics (AAP) contribute significantly to increased risk of cardiovascular morbidity and mortality in patients suffering from schizophrenia. Extensive preclinical research has addressed this issue over the past years, though mechanisms underlying these adverse effects of AAP are still not understood completely. Recently, attention is drawn towards the role of adipose tissue metabolism and neurohormonal regulations.. The aim of this study was to evaluate the time-dependent effects of olanzapine depot administration at clinically relevant dosing on the regulation of energy homeostasis, glucose and lipid metabolism, gastrointestinal and adipose tissue-derived hormones involved in energy balance regulations in female Sprague-Dawley rats. The study lasted 8 weeks and the markers were assayed at day 8, 15, 29, 43 and 57.. The results indicate that in the absence of hyperphagia, olanzapine chronic exposure induced weight gain from the beginning of the study. In the later time-point, increased adiposity was also observed. In the initial phase of the study, lipid profile was altered by an early increase in triglyceride level and highly elevated leptin level was observed. Clear bi-phasic time-dependent effect of olanzapine on leptin serum concentration was demonstrated. Olanzapine treatment did not lead to changes in serum levels of ghrelin, FGF-21 and pro-inflammatory markers IL-1a, IL-6 and TNF-α at any time-point of the study.. This study provides data suggesting early alteration in adipose tissue endocrine function as a factor involved in mechanisms underlying metabolic adverse effects of antipsychotics.

Topics: Adipose Tissue; Animals; Antipsychotic Agents; Benzodiazepines; Drug-Related Side Effects and Adverse Reactions; Female; Leptin; Olanzapine; Rats; Rats, Sprague-Dawley; Triglycerides; Weight Gain

Topics: Adult; Amygdala; Antipsychotic Agents; Appetite; Arachidonic Acids; Benzodiazepines; Biomarkers; Endocannabinoids; Female; Humans; Magnetic Resonance Imaging; Male; Olanzapine; Polyunsaturated Alkamides; Schizophrenia; Treatment Outcome; Weight Gain; Young Adult

Second-generation antipsychotics (SGAP) and mood stabilizers (MS) are prescribed widely for the treatment of bipolar disorder, but they are associated with the risk of relevant side-effects, among which is weight gain. The identification of genes that predispose to weight gain would represent a useful tool to evaluate the risk-benefit ratio of treatment.. This study investigated the genetic factors associated with weight gain in bipolar patients treated with SGAP, MS and their combinations (n=486). Single-nucleotide polymorphisms belonging to 16 candidate genes supported by the literature were investigated in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) genome-wide dataset. Linear regression models were constructed including age, sex, initial weight and prescription of SGAP at high risk for inducing weight gain (olanzapine or clozapine) as covariates. Genes harbouring single-nucleotide polymorphisms associated with phenotypes were investigated by a pathway analysis.. No association was found between phenotypes and individual polymorphisms or pathways after multiple-test correction. HTR2C, LEP, FTO and TBC1D1 represented the top genes for weight gain during treatment with a SGAP and/or MS. A genome-wide signal (FTO rs9930506) associated previously with obesity was associated with psychotropic-induced weight gain. The genes that influenced both SGAP and MS weight gain were FTO, TBC1D1, MTHFR and HRH1. ADCY9, ADCY5 and PRKAG2 were interesting candidate genes that emerged from the pathway analysis.. This study was the first to compare the genes involved in SGAP-induced and MS-induced weight gain. Individual genes probably play a limited role in psychotropic-induced weight gain; further studies should focus on the extension from known candidate genes to wider groups of molecular pathways.

Topics: Adipose Tissue; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Clozapine; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Homeostasis; Humans; Male; Olanzapine; Polymorphism, Single Nucleotide; Psychotropic Drugs; Weight Gain

The ataxin-2 binding protein 1 (A2BP1) gene is reported to be one of the susceptibility genes in schizophrenia, autism, and obesity. The aim of this study was to explore the association of A2BP1 gene polymorphisms with antipsychotic induced weight gain (AIWG) in Chinese Han population. Three hundred and twenty-eight patients with schizophrenia were followed-up for an 8-week period of treatment with olanzapine. The fasting weights of 328 patients were measured before and after the 8-week course of treatment. Four single nucleotide polymorphisms (SNPs: rs8048076, rs1478697, rs10500331, and rs4786847) of the A2BP1 gene were genotyped by polymerase chain reaction (PCR). We analyzed putative association of A2BP1 polymorphisms with AIWG of olanzapine using linear regression analysis and found that SNP rs1478697 was significantly associated with AIWG caused by olanzapine (p=0.0012; Bonferroni corrected p=0.0048). The association was replicated in another independent sample including 208 first-episode and drug-naïve patients presenting with schizophrenia after a 4-week treatment with olanzapine (p=0.0092; Bonferroni corrected p=0.0368; meta p=5.33×10(-5)). To explore the biological plausibility of A2BP1 in the pathogenesis of AIWG, we made expression analyses and eQTL analyses; these analyses showed that A2BP1 was highly expressed in whole brain tissues using the HBT database, and that rs1478697 has an expression quantitative trait locus effect in human cerebellar cortex tissues using the BRAINEAC database (p=2.50E-04). In conclusion, the rs1478697 in A2BP1 may be associated with AIWG induced by 8-week treatment with olanzapine.

Topics: Adolescent; Adult; Antipsychotic Agents; Asian People; Benzodiazepines; Brain; China; Cohort Studies; Female; Gene Expression; Genetic Predisposition to Disease; Humans; Male; Olanzapine; Polymorphism, Single Nucleotide; Quantitative Trait Loci; RNA Splicing Factors; RNA-Binding Proteins; Schizophrenia; Tissue Distribution; Weight Gain; Young Adult

To study correlations between parameters of lipid metabolism and ECG in patients with schizophrenia in light of therapy with atypical antipsychotics.. We examined 42 patients with paranoid schizophrenia. All patients received atypical neuroleptics - seroquel, zyprexa, and rispolept. A group of controls included 25 healthy people.. There was a significant increase (p=0.0002) in body mass (in average by 1.5 kg) in 88% patients. A significant increase in the concentration of serum triglycerides was identified as well. The concentration of VLDL in the patients with schizophrenia was 2 times higher compared to controls. After treatment, VLDL concentration increased even more considerably An increase in atherogenic index (AI) was up to 3.1 in patients with schizophrenia compared to 2.2 in controls. After treatment, Al increased up to 4 that demonstrated the high risk of development of atherosclerosis. A significant increase in QT interval in the ECG and heart rate (p=0.03) was revealed only in patients receiving rispolept. In patients receiving zyprexa and seroquel only heart rate was increased.. The antipsychotics studied increase the risk of development of cardiovascular pathology.. Цель исследования - изучение сопряженности показателей липидного обмена и ЭКГ у больных шизофренией в процессе терапии антипсихотическими препаратами. Материал и методы. Обследованы 42 пациента, страдающих параноидной шизофренией. Все пациенты лечились атипичными нейролептиками - рисперидоном, оланзапином и кветиапином. Группу контроля составили 25 здоровых. Результаты и заключение. Было отмечено увеличение массы тела у 88% больных в среднем на 1,5 кг (р=0,0002). Было выявлено также под влиянием терапии достоверное увеличение концентрации триглицеридов в сыворотке крови. Концентрация ЛПОНП у больных шизофренией достоверно выше, чем у здоровых в 2 раза, после терапии происходило еще более выраженное увеличение их концентрации; кроме того, у больных шизофренией имело место увеличение индекса атерогенности (ИА) до 3,1 в сравнении со здоровыми - 2,2. После терапии ИА увеличивается до 4, что свидетельствует о высоком риске развития атеросклероза. На ЭКГ отмечалось увеличение интервала QT и ЧСС (р=0,03) только у больных, принимающих рисперидон. У больных, лечившихся оланзапином и кветиапином, достоверно была увеличена только ЧСС. Сделан вывод, что лечение атипичными нейролептиками увеличивает риск развития сердечно-сосудистой патологии.

Topics: Adult; Antipsychotic Agents; Atherosclerosis; Benzodiazepines; Dibenzothiazepines; Electrocardiography; Female; Humans; Lipid Metabolism; Lipoproteins, VLDL; Male; Middle Aged; Olanzapine; Quetiapine Fumarate; Risperidone; Schizophrenia, Paranoid; Weight Gain; Young Adult

Second-generation antipsychotics including olanzapine are associated with weight gain, dyslipidemia and other metabolic disorders. Both animal and clinical studies have shown that co-treatment with betahistine (a histamine H1 receptor agonist/H3 receptor antagonist) is effective in controlling olanzapine-induced weight gain. In the present study, we investigate whether co-treatment with betahistine is able to prevent dyslipidemia induced by chronic olanzapine treatment and the underlying mechanisms. Female rats were orally administered with olanzapine (1 mg/kg, t.i.d.) for 3.5 consecutive weeks and then a 2.5-week drug withdrawal. Then, rats were divided into 4 groups for 5 weeks treatment: (1) vehicle, (2) olanzapine-only (1 mg/kg, t.i.d.), (3) betahistine-only (9.6 mg/kg, t.i.d.), and (4) olanzapine and betahistine (O+B) co-treatment. After completing treatment, hepatic mRNA expression was measured by qRT-PCR, while the protein levels were detected by western blot. In our study, olanzapine-only treatment significantly increased triglyceride accumulation and non-esterified fatty acids (NEFA), and upregulated mRNA expression of sterol regulatory element binding protein 1 (SREBP-1) and its target genes, while these alterations were ameliorated by O+B co-treatment. Hepatic AMP-activated protein kinase α (AMPKα) was activated in the O+B co-treatment group, with a significant reduction in nuclear SREBP-1 protein expression but an increased expression of peroxisome proliferator-activated receptor-α (PPARα) and its-responsive molecule(CPT1A), compared with olanzapine-only treatment. In addition, olanzapine significantly increased hepatic histamine H1 receptors, while O+B co-treatment significantly reversed them to normal levels. This study provided the first evidence that betahistine could act on hepatic H1 receptors via modulation of AMPKα-SREBP-1 and PPARα-dependent pathways to ameliorate olanzapine-induced dyslipidemia in rats.

Topics: AMP-Activated Protein Kinases; Animals; Antipsychotic Agents; Benzodiazepines; Betahistine; Dyslipidemias; Female; Liver; Olanzapine; PPAR alpha; Rats; Rats, Sprague-Dawley; Receptors, Histamine H1; Sterol Regulatory Element Binding Protein 1; Weight Gain

Several antipsychotics have well-known adverse metabolic effects. Studies uncovering molecular mechanisms of such drugs in patients are challenging due to high dropout rates, previous use of antipsychotics and restricted availability of biological samples. Rat experiments, where previously unexposed animals are treated with antipsychotics, allow for direct comparison of different drugs, but have been hampered by the short half-life of antipsychotics in rodents. The use of long-acting formulations of antipsychotics could significantly increase the value of rodent models in the molecular characterization of therapeutic and adverse effects of these agents. However, as long-acting formulations have rarely been used in rodents, there is a need to characterize the basic metabolic phenotype of different antipsychotics. Using long-acting olanzapine injections as a positive control, the metabolic effects of intramuscular long-acting risperidone in female rats were investigated for the first time. Like olanzapine, risperidone induced rapid, significant hyperphagia and weight gain, with concomitant increase in several plasma lipid species. Both drugs also induced weight-independent upregulation of several genes encoding enzymes involved in lipogenesis, but this activation was not confirmed at the protein level. Our findings shed light on the role of drug administration, drug dose and nutritional status in the development of rodent models for adverse metabolic effects of antipsychotic agents.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Body Weight; Female; Half-Life; Olanzapine; Rats; Rats, Sprague-Dawley; Risperidone; Weight Gain

Rats are used as animal models in the study of antipsychotic-induced metabolic adverse effects, with oral drug administration yielding hyperphagia, weight gain and, in some cases, lipogenic effects. However, the rapid half-life of these drugs in rats, in combination with development of drug tolerance after a few weeks of treatment, has limited the validity of the model. In order to prevent fluctuating drug serum concentrations seen with daily repeated administrations, we injected female rats with a single intramuscular dose of long-acting olanzapine formulation. The olanzapine depot injection yielded plasma olanzapine concentrations in the range of those achieved in patients, and induced changes in metabolic parameters similar to those previously observed with oral administration, including increased food intake, weight gain and elevated plasma triglycerides. Moreover, the sensitivity to olanzapine was maintained beyond the 2-3 wk of weight gain observed with oral administration. In a separate olanzapine depot experiment, we aimed to clarify the role of hypothalamic AMP-activated protein kinase (AMPK) in olanzapine-induced weight gain, which has been subject to debate. Adenovirus-mediated inhibition of AMPK was performed in the arcuate (ARC) or the ventromedial hypothalamic (VMH) nuclei in female rats, with subsequent injection of olanzapine depot solution. Inhibition of AMPK in the ARC, but not in the VMH, attenuated the weight-inducing effect of olanzapine, suggesting an important role for ARC-specific AMPK activation in mediating the orexigenic potential of olanzapine. Taken together, olanzapine depot formulation provides an improved mode of drug administration, preventing fluctuating plasma concentrations, reducing handling stress and opening up possibilities to perform complex mechanistic studies.

Topics: Adipose Tissue; AMP-Activated Protein Kinases; Animals; Antipsychotic Agents; Arcuate Nucleus of Hypothalamus; Benzodiazepines; Delayed-Action Preparations; Disease Models, Animal; Eating; Female; Gene Expression; Gene Knockdown Techniques; Liver; Metabolic Diseases; Olanzapine; Rats; Triglycerides; Ventromedial Hypothalamic Nucleus; Weight Gain

Mitochondria are the main source of energy for neurons and have a role in many vital neuronal functions. Mitochondrial dysfunction has been described in schizophrenia, and antipsychotics such as clozapine and olanzapine have been associated with differences in gene expression in mitochondria. We investigated the hypothesis that nuclear-encoded mitochondrial genes, particularly those involved in oxidative phosphorylation or involved in oxidative stress, mitochondrial biogenesis, inflammation, and apoptosis, would be associated with antipsychotic-induced weight gain (AIWG). In total, we selected 28 genes and analyzed 60 SNPs (50 are functional), in 283 schizophrenia subjects, treated with atypical medications for up to 14 weeks. Association between AIWG (as measured by the % of weight gain from baseline) and SNP genotypes were tested using linear regression with treatment duration, baseline body weight, and medication type as covariates. We observed a significant association between rs6435326 in the NDUFS1 gene and AIWG in the subset of European patients (N=150, Pcorrected=0.02). The haplotype carrying the risk alleles of rs6435326 and two other SNPs (rs1053517 and rs1801318) in NDUFS1 was also nominally associated with percentage of weight gain (T-C-G vs A-T-A, P=0.005). In addition, stepwise linear regression was performed to select important variables predictive of the outcome, and a gene-gene interaction analysis was carried out. We observed a significant interaction between the TT risk genotype of rs6435326 in NDUFS1 and AG genotype of rs3762883 in COX18 (Pcorrected=0.001). A permutation-based test of all 60 SNPs jointly showed significant association with weight gain (P=0.02). Finally, our replication study of rs6435326, rs1053517 and rs1801318 in NDUFS1 using samples from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) showed that rs1801318 was significantly associated with AIWG (N=200, Pcorrected=0.04), and the three SNPs were collectively associated with AIWG (P=0.04). In conclusion, our findings suggest an association between NDUFS1 and AIWG in schizophrenia subjects. To the best of our knowledge, this is the first study to explore genetic variation in the mitochondrial genes in the context of AIWG.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Weight; Clozapine; Female; Genes, Mitochondrial; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Linkage Disequilibrium; Male; Membrane Proteins; Mitochondrial Proteins; Models, Biological; NADH Dehydrogenase; Olanzapine; Polymorphism, Single Nucleotide; Risk; Schizophrenia; Time Factors; Weight Gain

Bipolar disorder (BPD) is prevalent and is associated with a significant economic burden. Asenapine, the first tetracyclic antipsychotic approved in Canada for the treatment of BPD, has shown a comparable efficacy profile to other atypical antipsychotics. In addition, it is associated with a favourable metabolic profile and minimal weight gain potential. This study aimed to assess the economic impact of asenapine compared to olanzapine in the treatment of BPD in Canada.. A decision tree combined with a Markov model was constructed to assess the cost-utility of asenapine compared with olanzapine. The decision tree takes into account the occurrence of extrapyramidal symptoms (EPS), the probability of switching to a different antipsychotic, and the probability of gaining weight. The Markov model takes into account long-term metabolic complications including diabetes, hypertension, coronary heart diseases (CHDs), and stroke. Analyses were conducted from both a Canadian Ministry of Health (MoH) and a societal perspective over a five-year time horizon with yearly cycles.. In the treatment of BPD, asenapine is a dominant strategy over olanzapine from both a MoH and a societal perspective. In fact, asenapine is associated with lower costs and more quality-adjusted life years (QALYs). Results of the probabilistic sensitivity analysis indicated that asenapine remains a dominant strategy in 99.2% of the simulations, in both a MoH and a societal perspective, and this result is robust to the many deterministic sensitivity analyses performed.. This economic evaluation demonstrates that asenapine is a cost-effective strategy compared to olanzapine in the treatment of BPD in Canada.

Topics: Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Canada; Cost-Benefit Analysis; Dibenzocycloheptenes; Heterocyclic Compounds, 4 or More Rings; Humans; Olanzapine; Quality-Adjusted Life Years; Weight Gain

Excessive weight gain is a major metabolic side effect of second-generation antipsychotics (SGAs) in the treatment of schizophrenia. Ghrelin is an orexigenic hormone secreted mainly from the stomach, which can induce weight gain and hyperphagia through regulating neuropeptides at the hypothalamus. Accumulating evidence implicates a relationship between ghrelin signalling and SGA-induced hyperphagia and weight gain. We report that olanzapine (a SGA with high weight gain liability) potently and time-dependently up-regulate ghrelin and ghrelin signalling, leading to hyperphagia and weight gain in female Sprague-Dawley rats, an action reversed by i.c.v. injection of a ghrelin receptor (GHS-R1a) antagonist. These findings indicate a crucial role of ghrelin signalling in hyperphagia induced by olanzapine, supporting the notion that GHS-R1a antagonist may be useful for pharmacological treatment of SGA-induced weight gain resulted from hyperphagia.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Central Nervous System Agents; Eating; Female; Ghrelin; Hyperphagia; Hypothalamus; Neuropeptides; Olanzapine; Oligopeptides; Rats; Rats, Sprague-Dawley; Receptors, Ghrelin; RNA, Messenger; Signal Transduction; Time Factors; Transcription Factors; Up-Regulation; Weight Gain

GLP-1 plays a key role in glucose metabolism and influences antipsychotic-induced weight gain (AIWG). Our study is the first to investigate the encoding gene, GCG, and the GLP-1 receptor gene, GLP1R, and association with AIWG.. In 216 schizophrenic patients treated with antipsychotics for up to 14 weeks, we investigated four GCG and 33 GLP1R polymorphisms. Statistical analyses were conducted using SPSS, Haploview 4.2, UNPHASED 3.1.4 and the R-package mbmdr.. We observed association of rs13429709 near GCG with AIWG (p(corr) = 0.044) in patients of European ancestry receiving olanzapine or clozapine (n = 87). We also found significant gene-gene interaction between rs13429709 and rs2268639 in GLP1R. Only nonsignificant trends were observed for GLP1R polymorphisms with AIWG.. We found significant association of rs13429709 with AIWG. Although there was no significant finding for GLP1R, the observed trends and interaction suggest this to be an interesting gene for further examination.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Genetic Association Studies; Genotype; Glucagon-Like Peptide-1 Receptor; Humans; Male; Olanzapine; Polymorphism, Single Nucleotide; Receptors, Glucagon; Schizophrenia; Weight Gain; White People

Although second-generation antipsychotics induce severe weight gain and obesity, there is a lack of detailed knowledge about the progressive development of antipsychotic-induced obesity. This study examined the hypothalamic histamine H1 receptor and AMP-activated protein kinase (H1R-AMPK) signaling at three distinctive stages of olanzapine-induced weight gain (day 1-12: early acceleration, day 13-28: middle new equilibrium, and day 29-36: late heavy weight maintenance). At the early acceleration stage, the rats were hyperphagic with an underlying mechanism of olanzapine-increased H1R mRNA expression and AMPK phosphorylation (pAMPK), in which pAMPK levels positively correlated with H1R mRNA expression and food intake. At the middle stage, when the rats were no longer hyperphagic, the changes in H1R-AMPK signaling vanished. At the late stage, olanzapine increased H1R mRNA expression but decreased pAMPK which were positively and negatively correlated with weight gain, respectively. These data suggest a time-dependent change of H1R-AMPK signaling, where olanzapine activates AMPK by blocking the H1Rs and causing hyperphagia in the acute phase. The chronic blockade of H1R may contribute to the late stage of olanzapine-induced heavy weight maintenance. However, pAMPK was no longer elevated and actually decreased. This indicates that AMPK acts as an energy sensor and negatively responds to the positive energy balance induced by olanzapine. Furthermore, we showed that an H1R agonist, 2-(3-trifluoromethylphenyl) histamine, can significantly inhibit olanzapine-induced hyperphagia and AMPK activation in the mediobasal hypothalamus in a dose dependent manner. Therefore, lowering H1R-AMPK signaling is an effective treatment for the olanzapine-induced hyperphagia associated with the development of obesity.

Topics: Adenylate Kinase; Animals; Antipsychotic Agents; Benzodiazepines; Female; Hyperphagia; Olanzapine; Phosphorylation; Rats; Rats, Sprague-Dawley; Receptors, Histamine H1; Signal Transduction; Time Factors; Weight Gain

Olanzapine is a first line medication for the treatment of schizophrenia, but it is also one of the atypical antipsychotics carrying the highest risk of weight gain. Metformin was reported to produce significant attenuation of antipsychotic-induced weight gain in patients, while the study of preventing olanzapine-induced weight gain in an animal model is absent. Berberine, an herbal alkaloid, was shown in our previous studies to prevent fat accumulation in vitro and in vivo. Utilizing a well-replicated rat model of olanzapine-induced weight gain, here we demonstrated that two weeks of metformin or berberine treatment significantly prevented the olanzapine-induced weight gain and white fat accumulation. Neither metformin nor berberine treatment demonstrated a significant inhibition of olanzapine-increased food intake. But interestingly, a significant loss of brown adipose tissue caused by olanzapine treatment was prevented by the addition of metformin or berberine. Our gene expression analysis also demonstrated that the weight gain prevention efficacy of metformin or berberine treatment was associated with changes in the expression of multiple key genes controlling energy expenditure. This study not only demonstrates a significant preventive efficacy of metformin and berberine treatment on olanzapine-induced weight gain in rats, but also suggests a potential mechanism of action for preventing olanzapine-reduced energy expenditure.

Topics: Adipose Tissue, White; Animals; Antipyretics; Benzodiazepines; Berberine; Eating; Female; Ion Channels; Metformin; Mitochondrial Proteins; Olanzapine; Organ Size; Rats; Rats, Sprague-Dawley; Transcriptome; Uncoupling Protein 1; Weight Gain

Around one-third of patients with bipolar I disorder (BD-I) experience mixed episodes, characterized by both mania and depression, which tend to be more difficult and costly to treat. Atypical antipsychotics are recommended for the treatment of mixed episodes, although evidence of their efficacy, tolerability, and cost in these patients is limited. This study evaluates, from a UK National Health Service perspective, the cost-effectiveness of asenapine vs olanzapine in BD-I patients with mixed episodes.. Cost-effectiveness was assessed using a Markov model. Efficacy was informed by a post-hoc analysis of two short-term clinical trials, with response measured as a composite Young Mania Rating Score and Montgomery-Åsberg Depression Rating Scale end-point. Probabilities of discontinuation and relapse to manic, mixed, and depressive episodes were sourced from published meta-analyses. Direct costs (2012-2013 values) included drug acquisition, monitoring, and resource use related to bipolar disorder as well as selected adverse events. Benefits were measured as quality-adjusted life years (QALYs).. For treating mixed episodes, asenapine generated 0.0187 more QALYs for an additional cost of £24 compared to olanzapine over a 5-year period, corresponding to a £1302 incremental cost-effectiveness ratio. The higher acquisition cost of asenapine was roughly offset by the healthcare savings conferred through its greater efficacy in treating these patients. The model shows that benefits were driven by earlier response to asenapine during acute treatment and were maintained during longer-term follow-up. RESULTS were sensitive to changes in key parameters including short and longer-term efficacy, unit cost, and utilities, but conclusions remained relatively robust.. RESULTS suggest that asenapine is a cost-effective alternative to olanzapine in mixed episode BD-I patients, and may have specific advantages in this population, potentially leading to healthcare sector savings and improved outcomes. Limitations of the analysis stem from gaps in clinical and economic evidence for these patients and should be addressed by future clinical trials.

Topics: Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Clinical Trials as Topic; Cost-Benefit Analysis; Dibenzocycloheptenes; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Male; Markov Chains; Models, Economic; Olanzapine; Quality-Adjusted Life Years; State Medicine; United Kingdom; Weight Gain

Alpha-lipoic acid (ALA) was shown to suppress atypical antipsychotic drug (AAPD)-induced weight gain. However, its mode of action has remained unidentified.. We aimed to identify mechanisms underlying anti-obesity effects of ALA in mice treated with olanzapine.. We compared body weight and food intake among vehicle-, olanzapine-, and olanzapine plus ALA-treated mice, and measured hypothalamic AMP-activated protein kinase (AMPK) activity by detecting levels of Thr(172) and Ser(485/491) phosphorylation, which indicate activation and inhibition of AMPK, respectively.. Body weights were increased by olanzapine in parallel with increased levels of Thr(172) phosphorylation of hypothalamic AMPK. Initially increased rate of weight gain was diminished as Thr(172) phosphorylation levels were decreased to control levels after 10 days of olanzapine treatment. ALA successfully not only prevented olanzapine-induced weight gain but also induced additional weight loss even relative to control levels throughout the treatment period. During the initial stage, ALA's action was indicated by both suppression of olanzapine-induced Thr(172) phosphorylation and an increase in Ser(485/491) phosphorylation levels. However, in the later stage when no more increases in Thr(172) phosphorylation and weight gain by olanzapine were observed, ALA's action was only indicated by increased levels of Ser(485/491) phosphorylation.. Our data suggest that anti-obesity effects of ALA may be related to modulation of both Ser(485/491) phosphorylation and Thr(172) phosphorylation of hypothalamic AMPK, while olanzapine-induced weight gain may be only associated with increase in Thr(172) phosphorylation. This might be an important mechanistic clue for the future development of anti-obesity drugs beyond control of AAPD-induced weight gain.

Topics: AMP-Activated Protein Kinases; Animals; Anti-Obesity Agents; Antipsychotic Agents; Benzodiazepines; Body Weight; Eating; Female; Hypothalamus; Mice; Obesity; Olanzapine; Phosphorylation; Serine; Thioctic Acid; Weight Gain; Weight Loss

Antipsychotics are effective in treating schizophrenia symptoms. However, the use of clozapine and olanzapine in particular are associated with significant weight gain. Mouse and human studies suggest that the protein kinase cAMP-dependent regulatory type II beta (PRKAR2B) gene may be involved in energy metabolism, and there is evidence that it is associated with clozapine's effects on triglyceride levels. We aimed at assessing PRKAR2B's role in antipsychotic-induced weight gain in schizophrenia patients.. DNA samples from adult schizophrenia or schizoaffective disorder patients of mixed ancestry were genotyped, and weight gain was assessed. We analyzed 16 tag single-nucleotide polymorphisms across the PRKAR2B gene in a Caucasian subset treated either with clozapine or olanzapine (N = 99). Linear regression based on an additive model was performed with the inclusion of relevant covariates.. Normalized per cent weight change was analyzed, revealing that patients with the minor allele at rs9656135 had a mean weight increase of 4.1%, whereas patients without this allele had an increase of 3.4%. This association is not significant after correcting for multiple testing.. Because of limited power, PRKAR2B's role in antipsychotic-induced weight gain is unclear, but biological evidence suggests that PRKAR2B may be involved. Further research in larger sample sizes is warranted.

Topics: Adolescent; Adult; Aged; Alleles; Antipsychotic Agents; Benzodiazepines; Clozapine; Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; Female; Genetic Predisposition to Disease; Genotyping Techniques; Humans; Linkage Disequilibrium; Male; Middle Aged; Olanzapine; Polymorphism, Single Nucleotide; Psychotic Disorders; Schizophrenia; Weight Gain; White People; Young Adult

This study attempted to evaluate the effect of a calorie-restricted diet on weight change in short-term acute care psychiatric patients receiving atypical antipsychotic medication. A descriptive correlational design utilizing chart review and a convenience sample of 100 participants was used. Fifty charts of patients hospitalized prior to the implementation of the calorie-restricted diet for those receiving atypical antipsychotic agents were compared to 50 charts of patients who received the diet. Weight changes in the two groups were compared relative to age, gender, length of time taking the medication, and the type of medication. The Mann-Whitney U test, Spearman's rank-correlation coefficient, and the two-way analysis of variance were used to conduct the analyses. The calorie-restricted diet was not significantly associated with a reduction in weight gain in participants who received any of the atypical antipsychotic agents except for olanzapine; therefore, findings indicate that the calorie-restricted diet may only be effective for patients receiving olanzapine.

Topics: Adult; Age Factors; Antipsychotic Agents; Benzodiazepines; Caloric Restriction; Education, Nursing, Continuing; Female; Humans; Male; Mental Disorders; Obesity; Olanzapine; Risperidone; Sex Factors; Time Factors; Weight Gain

Antipsychotics frequently cause changes in glucose metabolism followed by development of weight gain and/or diabetes. Recent findings from our group indicated an influence of glucose-related genes on this serious side effect. With this study, we aimed to extend previous research and performed a comprehensive study on the peroxisome proliferator-activated receptor gamma (PPARG) and the adiponectin (ADIPOQ) genes. In 216 schizophrenic patients receiving antipsychotics for up to 14 weeks, we investigated single-nucleotide polymorphisms in or near PPARG (N=24) and ADIPOQ (N=18). Statistical analysis was done using ANCOVA in SPSS. Haplotype analysis was performed in UNPHASED 3.1.4 and Haploview 4.2. None of the PPARG or ADIPOQ variants showed significant association with antipsychotic-induced weight gain in our combined sample or in a refined subsample of patients of European ancestry treated with clozapine or olanzapine after correction for multiple testing. Similarly, no haplotype association could withstand multiple test correction. Although we could not find a significant influence of ADIPOQ and PPARG on antipsychotic-induced weight gain, our comprehensive examination of these two genes contributes to understanding the biology of this serious side effect. More research on glucose metabolism genes is warranted to elucidate their role in metabolic changes during antipsychotic treatment.

Topics: Adiponectin; Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Haplotypes; Humans; Male; Middle Aged; Olanzapine; Overweight; Polymorphism, Single Nucleotide; PPAR gamma; Psychotic Disorders; Weight Gain; White People; Young Adult

Antipsychotic efficacy biomarkers have the potential to improve outcomes in psychotic patients. This study examined the effect of SULT4A1-1 haplotype status (rs2285162 [A]-rs2285167 [G]) on olanzapine response.. We evaluated 87 olanzapine treated subjects from Phases 1, 1B and 2 of the CATIE trial for the impact of SULT4A1-1 status on change in Positive and Negative Syndrome Scale (PANSS) total score using two models of response. We also examined weight change.. SULT4A1-1-positive status correlated with superior olanzapine response in Phase 1 (p = 0.004 for model 1 and p = 0.001 for model 2) and Phases 1B/2 (p = 0.05 for model 1 and p = 0.007 for model 2). SULT4A1-1-positive subjects gained significantly less weight per month on olanzapine, 0.15 lbs, than did SULT4A1-1-negative subjects, 2.27 lbs (p = 0.04).. This study provides a second replication of superior olanzapine response in SULT4A1-1-positive subjects compared with SULT4A1-1-negative subjects. SULT4A1-1-positive subjects treated with olanzapine also gained less weight than SULT4A1-1-negative subjects.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clinical Trials as Topic; Female; Humans; Male; Middle Aged; Olanzapine; Pharmacogenetics; Sulfotransferases; Weight Gain

Olanzapine is widely used to treat schizophrenia and other disorders, but causes adverse obesity and other metabolic side-effects. Both animal and clinical studies have shown that co-treatment with betahistine (a histaminergic H1 receptor agonist and H3 receptor antagonist) is effective for ameliorating olanzapine-induced weight gain/obesity. To reveal the mechanisms underlying these effects, this study investigated the effects of co-treatment of olanzapine and betahistine (O+B) on expressions of histaminergic H1 receptor (H1R), AMP-activated protein kinase (AMPK), neuropeptide Y (NPY), and proopiomelanocortin (POMC) in the hypothalamus associated with reducing olanzapine-induced weight gain. Olanzapine significantly upregulated the mRNA and protein expressions of H1R, while O+B co-treatment significantly downregulated the H1R levels, compared to the olanzapine-only treatment group. The NPY mRNA expression was significantly enhanced by olanzapine, but it was significantly reversed by O+B co-treatment. The hypothalamic H1R expression was positively correlated with total food intake, and NPY expression. Olanzapine also increased AMPKα activation measured by the AMPKα phosphorylation (pAMPKα)/AMPKα ratio compared with controls, whereas O+B co-treatment decreased the pAMPKα/AMPKα ratio, compared with olanzapine only treatment. The pAMPKα/AMPKα ratio was positively correlated with total food intake and H1R expression. Although olanzapine administration decreased the POMC mRNA level, this level was not affected by O+B co-treatment. Therefore, these results suggested that co-treatment with betahistine may reverse olanzapine-induced body weight gain via the H1R-NPY and H1R-pAMPKα pathways.

Topics: Adenylate Kinase; Adiposity; Animals; Antipsychotic Agents; Benzodiazepines; Betahistine; Eating; Female; Histamine; Histamine Agonists; Neuropeptide Y; Olanzapine; Rats; Rats, Sprague-Dawley; Signal Transduction; Weight Gain

Olanzapine is the one of first line antipsychotic drug for schizophrenia and other serious mental illness. However, it is associated with troublesome metabolic side-effects, particularly body weight gain and obesity. The antagonistic affinity to histamine H1 receptors (H1R) of antipsychotic drugs has been identified as one of the main contributors to weight gain/obesity side-effects. Our previous study showed that a short term (2 weeks) combination treatment of betahistine (an H1R agonist and H3R antagonist) and olanzapine (O+B) reduced (-45%) body weight gain induced by olanzapine in drug-naïve rats. A key issue is that clinical patients suffering with schizophrenia, bipolar disease and other mental disorders often face chronic, even life-time, antipsychotic treatment, in which they have often had previous antipsychotic exposure. Therefore, we investigated the effects of chronic O+B co-treatment in controlling body weight in female rats with chronic and repeated exposure of olanzapine. The results showed that co-administration of olanzapine (3 mg/kg, t.i.d.) and betahistine (9.6 mg/kg, t.i.d.) significantly reduced (-51.4%) weight gain induced by olanzapine. Co-treatment of O+B also led to a decrease in feeding efficiency, liver and fat mass. Consistently, the olanzapine-only treatment increased hypothalamic H1R protein levels, as well as hypothalamic pAMPKα, AMPKα and NPY protein levels, while reducing the hypothalamic POMC, and UCP1 and PGC-1α protein levels in brown adipose tissue (BAT). The olanzapine induced changes in hypothalamic H1R, pAMPKα, BAT UCP1 and PGC-1α could be reversed by co-treatment of O+B. These results supported further clinical trials to test the effectiveness of co-treatment of O+B for controlling weight gain/obesity side-effects in schizophrenia with chronic antipsychotic treatment.

Topics: Adipose Tissue, Brown; Adiposity; Animals; Benzodiazepines; Betahistine; Disease Models, Animal; Feeding Behavior; Female; Hypothalamus; Lipid Droplets; Liver; Olanzapine; Organ Size; Rats, Sprague-Dawley; Weight Gain

Patients with schizophrenia have a higher risk for cardiovascular disease (CVD) than the general population. Research has suggested that autonomic imbalance is a common pathway to increased morbidity and mortality for CVD. Heart rate variability (HRV) analysis is a non-invasive method that assesses autonomic imbalance, and low HRV is correlated with high cardiovascular risk. Olanzapine, a widely used antipsychotic drug, is considered to have good cardiac safety because of not causing significant corrected QT-interval (QTc) prolongation; however, it is still unclear whether olanzapine affects HRV. We recruited 83 patients with schizophrenia who were medication-free for at least 1 month and tested their HRV at the baseline and 4 weeks after treatment with olanzapine. We found that patients who had substantial weight gain (EWG) manifested significantly lower HRV than those who had non-substantial weight gain (NWG) and that HRV decrease was positively correlated to an increase in body mass index (BMI) and weight gain. Our results indicate that olanzapine-induced weight gain may play an important role in its potential cardiovascular risk. Since olanzapine has a very high potential for weight gain compared with other antipsychotics, further research is needed to explore its cardiovascular safety profile, specifically long-term cardiac safety.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Cardiovascular Diseases; China; Female; Heart Rate; Humans; Male; Olanzapine; Risk Factors; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Weight Gain

The second-generation antipsychotic olanzapine is effective in reducing psychotic symptoms but can cause extreme weight gain in human patients. We investigated the role of the gut microbiota in this adverse drug effect using a mouse model. First, we used germ-free C57BL/6J mice to demonstrate that gut bacteria are necessary and sufficient for weight gain caused by oral delivery of olanzapine. Second, we surveyed fecal microbiota before, during, and after treatment and found that olanzapine potentiated a shift towards an "obesogenic" bacterial profile. Finally, we demonstrated that olanzapine has antimicrobial activity in vitro against resident enteric bacterial strains. These results collectively provide strong evidence for a mechanism underlying olanzapine-induced weight gain in mouse and a hypothesis for clinical translation in human patients.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Female; Gastrointestinal Microbiome; Mice; Olanzapine; Weight Gain

To assess the association of second-generation antipsychotics (SGAs) with changes in body mass index (BMI) among adolescents compared with a matched untreated comparison group.. A retrospective cohort study was conducted using an electronic medical record database between January 2004 and July 2009. Adolescents (12-19 years old), newly initiated on SGAs formed the exposure group and untreated adolescents formed the comparison group matched (3:1) to the antipsychotic group based on age, gender, and month of index SGA. Both the exposure and comparison groups were followed for slightly more than a year (395 days). Baseline and follow-up BMI were evaluated for both groups and percentage change from baseline BMI to follow-up BMI was calculated. Multivariate linear regression was conducted to assess the impact of SGAs on percent change in follow-up BMI from baseline controlling for demographic characteristics, baseline medications, comorbidities, and other covariates.. The mean percentage increase in follow-up BMI from baseline for antipsychotic group was significantly higher than the comparison group (p < .01). After adjusting for covariates, adolescents on olanzapine had the highest percentage increase in follow-up BMI from baseline (5.84%, 95% confidence interval [CI], 4.07-7.61) followed by aripiprazole (4.36%; 95% CI, 3.08-5.64), risperidone (3.65%; 95% CI, 2.61-4.68), and quetiapine (1.53%; 95% CI, .53-2.52) compared with the comparison group.. This study further validates a growing concern of increased BMI in adolescents on SGA therapy.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Confidence Intervals; Dibenzothiazepines; Female; Humans; Male; Medical Audit; Olanzapine; Piperazines; Quetiapine Fumarate; Regression Analysis; Retrospective Studies; Risperidone; Thiazoles; United States; Weight Gain

Topics: Adult; Alleles; Antipsychotic Agents; Benzodiazepines; Case-Control Studies; Female; Genetic Predisposition to Disease; Genotype; Humans; Male; Olanzapine; Polymorphism, Genetic; Receptors, Histamine H1; Schizophrenia; Weight Gain; Young Adult

The frequency of severe adverse drug reactions (ADRs) from psychotropic drugs was investigated in hospitalised psychiatric patients in relation to their age. Specifically, the incidence of ADRs in patients up to 60 years was compared to that of patients older than 60 years.. Prescription rates of psychotropic drugs and reports of severe ADRs were collected in psychiatric hospitals in Switzerland between 2001 and 2010. The data stem from the drug surveillance programme AMSP.. A total of 699 patients exhibited severe ADRs: 517 out of 28,282 patients up to 60 years (1.8%); 182 out of 11,446 elderly patients (1.6%, ns). Logistic regression analyses showed a significantly negative relationship between the incidence of ADRs and patients' age in general and in particular for weight gain, extrapyramidal motor system (EPMS) symptoms, increased liver enzymes and galactorrhoea. A significantly negative relationship was observed for age and the dosages of olanzapine, quetiapine, risperidone, valproic acid and lamotrigine. When comparing age groups, frequency of ADRs was lower in general for antipsychotic drugs and anticonvulsants, in particular for valproic acid in the elderly. Weight gain was found to be lower in the elderly for antipsychotic drugs, in particular for olanzapine. For the group of mood-stabilising anticonvulsants (carbamazepine, lamotrigine and valproic acid) the elderly exhibited a lower incidence of reported allergic skin reactions.. The results suggest that for psychiatric inpatients the incidence of common severe ADRs (e.g., weight gain or EPMS symptoms) arising from psychotropic medication decreases with the age of patients.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Age Factors; Aged; Aged, 80 and over; Antimanic Agents; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Carbamazepine; Causality; Dibenzothiazepines; Drug-Related Side Effects and Adverse Reactions; Female; Galactorrhea; Humans; Lamotrigine; Logistic Models; Male; Middle Aged; Neuroleptic Malignant Syndrome; Olanzapine; Quetiapine Fumarate; Risperidone; Severity of Illness Index; Switzerland; Triazines; Valproic Acid; Weight Gain; Young Adult

Atypical antipsychotic drugs such as Olanzapine (Olan) induce weight gain and metabolic changes associated with the development of type 2 diabetes. The mechanisms underlying these undesired side-effects are currently unknown. It has been shown that peripheral injections of Olan activate neurons in the lateral hypothalamus/perifornical area and that a large part of these neurons are orexin (Ox) A-positive. We investigated further the possible involvement of the central Ox system in the metabolic side-effects of Olan by comparing the hyperglycaemic effects of an intragastric (IG) Olan infusion between animals treated intracerebroventricularly (ICV) with an Ox-1 receptor antagonist (SB-408124) or vehicle. As observed in previous studies IG Olan caused an increase in blood glucose, endogenous glucose production and plasma glucagon levels. ICV pre-treatment with the Ox-1 receptor antagonist did not affect the Olan-induced hyperglycaemia or increased plasma glucagon concentrations, but the increased endogenous glucose production was blunted by the ICV SB-408124 treatment. From these results we conclude that the metabolic side-effects of Olan are partly mediated by the hypothalamic Ox system.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Glucose; Hypothalamus; Injections, Intraventricular; Male; Olanzapine; Orexin Receptor Antagonists; Phenylurea Compounds; Rats; Weight Gain

Olanzapine (OLZ), an effective treatment of schizophrenia and other disorders, causes weight gain and metabolic syndrome. Most studies to date have focused on the potential effects of OLZ on the central nervous system's mediation of weight; however, peripheral changes in liver or other key metabolic organs may also play a role in the systemic effects of OLZ. Thus, the purpose of this study was to investigate the effects of OLZ on hepatic metabolism in a mouse model of OLZ exposure. Female C57Bl/6J mice were administered OLZ (8 mg/kg per day) or vehicle subcutaneously by osmotic minipumps for 28 days. Liver and plasma were taken at sacrifice for biochemical analyses and for comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry metabolomics analysis. OLZ increased body weight, fat pad mass, and liver-to-body weight ratio without commensurate increase in food consumption, indicating that OLZ altered energy expenditure. Expression and biochemical analyses indicated that OLZ induced anaerobic glycolysis and caused a pseudo-fasted state, which depleted hepatic glycogen reserves. OLZ caused similar effects in cultured HepG2 cells, as determined by Seahorse analysis. Metabolomic analysis indicated that OLZ increased hepatic concentrations of amino acids that can alter metabolism via the mTOR pathway; indeed, hepatic mTOR signaling was robustly increased by OLZ. Interestingly, OLZ concomitantly activated AMP-activated protein kinase (AMPK) signaling. Taken together, these data suggest that disturbances in glucose and lipid metabolism caused by OLZ in liver may be mediated, at least in part, via simultaneous activation of both catabolic (AMPK) and anabolic (mammalian target of rapamycin) pathways, which yields new insight into the metabolic side effects of this drug.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Eating; Female; Infusion Pumps, Implantable; Lipid Metabolism; Liver; Mice; Mice, Inbred C57BL; Olanzapine; Osmotic Pressure; TOR Serine-Threonine Kinases; Weight Gain

The atypical antipsychotic olanzapine is often associated with serious metabolic side effects including weight gain and increased visceral fat. These adverse events are a considerable clinical problem and the mechanisms underlying them are multifactorial and poorly understood. Growing evidence suggests that the gut microbiota has a key role in energy regulation and disease states such as obesity. Moreover, we recently showed that chronic olanzapine altered the composition of the gut microbiome in the rat. It is thus possible that treatments that alter gut microbiota composition could ameliorate olanzapine-induced weight gain and associated metabolic syndrome. To this end, we investigated the impact of antibiotic-induced alteration of the gut microbiota on the metabolic effects associated with chronic olanzapine treatment in female rats. Animals received vehicle or olanzapine (2 mg kg(-1) per day) for 21 days, intraperitoneal injection, two times daily. Animals were also coadministered vehicle or an antibiotic cocktail consisting of neomycin (250 mg kg(-1) per day), metronidazole (50 mg kg(-1) per day) and polymyxin B (9 mg kg(-1) per day) by oral gavage, daily, beginning 5 days before olanzapine treatment. The antibiotic cocktail drastically altered the microbiota of olanzapine-treated rats, and olanzapine alone was also associated with an altered microbiota. Coadministration of the antibiotic cocktail in olanzapine-treated rats attenuated: body weight gain, uterine fat deposition, macrophage infiltration of adipose tissue, plasma free fatty acid levels, all of which were increased by olanzapine alone. These results suggest that the gut microbiome has a role in the cycle of metabolic dysfunction associated with olanzapine, and could represent a novel therapeutic target for preventing antipsychotic-induced metabolic disease.

Topics: Animals; Anti-Bacterial Agents; Antipsychotic Agents; Benzodiazepines; Fatty Acids, Nonesterified; Female; Intestines; Intra-Abdominal Fat; Macrophages; Metronidazole; Microbiota; Neomycin; Olanzapine; Polymyxin B; Rats; Rats, Sprague-Dawley; Weight Gain

Weight gain and metabolic abnormalities are common side effects of antipsychotic treatment. Retinoids have been suggested as promising substances to suppress obesity. This study has investigated the effects of a retinoid agonist AM-80 on olanzapine-induced weight gain and metabolic changes in rats.. Female Sprague-Dawley rats (7 weeks) were treated with AM-80 (1 mg/kg/day, subcutaneously) and/or olanzapine (4 mg/kg/day, intraperitoneally) for 21 days. Body weight and food/water intake were measured daily. The open field (OFT) and prepulse inhibition (PPI) tests were done on days 18 and 21, respectively. Animals were sacrificed on day 22 to measure weight of adipose tissues and serum levels of adiponectin and leptin levels.. Olanzapine significantly increased body weight, food/water intake and the mass of inguinal adipose tissue (IAT) compared to vehicle-treated rats. AM-80 demonstrated significant inhibition of weight gain. No significant effect of olanzapine or AM-80 was found on behaviors or serum adiponectin/leptin levels.. These findings suggests that AM-80 is a potential therapeutic agent to attenuate weight gain and metabolic side effects associated with olanzapine.

Topics: Adiponectin; Adiposity; Animals; Antipsychotic Agents; Benzoates; Benzodiazepines; Body Weight; Drinking; Eating; Female; Leptin; Motor Activity; Olanzapine; Rats; Retinoids; Sensory Gating; Tetrahydronaphthalenes; Weight Gain

Metabolic abnormalities are serious adverse effects of atypical antipsychotic treatment. This study aims to determine the effects of adjunctive aripiprazole on metabolic profiles among patients receiving treatment with atypical antipsychotics, and to examine whether these effects are different from that of pre-existing atypical antipsychotics. In the 8-week open-label trial, aripiprazole was added to patients who were receiving treatment with atypical antipsychotics and had experienced weight gain or dyslipidemia. The dosage of pre-existing atypical antipsychotics was fixed, while the dosage of aripiprazole ranged from 5 to 20 mg/day during the study period. Metabolic profiles, including body weight, body mass index (BMI), plasma levels of fasting glucose, triglycerides, total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, and adiponectin, were measured at baseline and week 8. As a result, 43 subjects (16 males and 27 females, mean age: 37.8±10.8 years) completed the study. The pre-existing antipsychotics were olanzapine (n=12), risperidone (n=19), quetiapine (n=6) and amisulpiride (n=6). The mean dosage of adjunctive aripiprazole was 9.9±3.2 mg/day. After the aripiprazole-augmented regimen for 8 weeks, patients treated with olanzapine had significant decreases in body weight, BMI and triglyceride levels, and had significant increases in adiponectin levels. For patients treated with other atypical antipsychotics, none of the metabolic parameters significantly changed after administering aripiprazole. In conclusion, aripiprazole-augmented treatment might be beneficial for the metabolic regulation of patients being treated with a stable dose of olanzapine, but not for those treated with other atypical antipsychotics. A long-term, randomized, double-blind controlled design is suggested to confirm these findings.

Topics: Adiponectin; Adult; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Blood Glucose; Body Mass Index; Body Weight; Female; Humans; Lipids; Male; Middle Aged; Obesity; Olanzapine; Piperazines; Prospective Studies; Psychotic Disorders; Quinolones; Weight Gain

Antipsychotic-induced weight gain is a problematic side effect. The mechanism is still not fully understood. Carbohydrate (and possibly other food) cravings have been suggested in literature, but not been systematically investigated.. To investigate the hypothesis that food cravings, especially for carbohydrate, are responsible for olanzapine-induced weight gain.. A case control design was used to measure general and specific food cravings using Food Craving Inventory (White et al., 2002) in three groups: patients with a diagnosis of schizophrenia taking olanzapine (Number = 20) or typical antipsychotics (Number = 20) and in a healthy control group (Number = 20).. No statistically significant differences were found between the three groups in the craving scores. There was a trend in the typical group to show more cravings than other groups.. Our study failed to prove the hypothesis that carbohydrate craving is responsible for olanzapine-induced weight gain. This conclusion is limited by the small number of the subjects included.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Benzodiazepines; Case-Control Studies; Feeding and Eating Disorders; Feeding Behavior; Female; Humans; Male; Middle Aged; Olanzapine; Weight Gain; Young Adult

Significant body weight gain (BWG) is a serious adverse effect of a number of antipsychotic drugs. Previous studies have demonstrated an influence of clozapine, but not haloperidol, on neuropeptide Y (NPY) expression in the hypothalamus. Because NPY is a potent orexigenic peptide stimulating food intake, and genetic variation of the gene has been shown to influence development of obesity, we investigated the impact of NPY polymorphisms on antipsychotic-induced BWG.We analyzed 5 polymorphisms in the NPY gene (rs10551063, rs16147, rs5573, rs5574, and rs16475) in schizophrenia subjects (n = 226), treated mostly with clozapine and olanzapine for up to 14 weeks. Association was tested using analysis of covariance with change (%) from baseline weight as the dependent variable and duration of treatment and baseline body weight as covariates.In patients of European ancestry who received either clozapine or olanzapine, significant genotypic and allelic association of rs16147 with weight change was observed (P(corrected) = 0.012 and 0.018, respectively). Carriers of the C allele gained significantly more weight compared with individuals with TT genotype (CC + CT vs TT; 5.82% ± 5.6% vs 2.25% ± 4.8%; P= 0.001). Similarly, 2 other polymorphisms (rs5573 and rs5574) were also significantly associated with weight change (P(corrected) = 0.018 and 0.03). In addition, we observed a significant gene-gene interaction between the rs16147 in NPY and rs806378 in cannabinoid receptor 1 (P(corrected) = 0.011).Our observation of association of NPY polymorphisms gives further evidence for a genetic influence on antipsychotic-induced BWG and suggests a role of NPY gene in influencing this complex adverse effect.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Black or African American; Chi-Square Distribution; Clozapine; Female; Gene Frequency; Genotype; Germany; Humans; Male; Middle Aged; Neuropeptide Y; New York; Ohio; Olanzapine; Phenotype; Polymorphism, Single Nucleotide; Receptor, Cannabinoid, CB1; Risk Assessment; Risk Factors; Schizophrenia; Weight Gain; White People; Young Adult

The aim was to explore weight and body mass index (BMI) changes by baseline BMI in patients completing three years of monotherapy with various first- and second-generation antipsychotics in a large cohort in a post hoc analysis of three-year observational data. Data were analyzed by antipsychotic and three baseline BMI bands: underweight/normal weight (BMI <25 kg/m²), overweight (25-30 kg/m²) and obese (>30 kg/m²). Baseline BMI was associated with subsequent weight change irrespective of the antipsychotic given. Specifically, a smaller proportion of patients gained ≥7% baseline bodyweight, and a greater proportion of patients lost ≥7% baseline bodyweight with increasing baseline BMI. For olanzapine (the antipsychotic associated with highest mean weight gain in the total drug cohort), the percentage of patients gaining ≥7% baseline weight was 45% (95% CI: 43-48) in the underweight/normal weight BMI cohort and 20% (95% CI: 15-27) in the obese BMI cohort; 7% (95% CI: 6-8) of the underweight/normal cohort and 19% (95% CI: 13-27) of the obese cohort lost ≥7% baseline weight. BMI has an association with the likelihood of weight gain or loss and should be considered in analyses of antipsychotic weight change.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Cohort Studies; Databases, Factual; Female; Global Health; Humans; Longitudinal Studies; Male; Middle Aged; Obesity; Olanzapine; Overweight; Prospective Studies; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Thinness; Weight Gain; Weight Loss

No studies have compared the response to selective serotonin reuptake inhibitors and atypical antipsychotics in anorexia nervosa. This case study examines such a comparison.. This report describes a case of 12-year-old identical twins with anorexia nervosa, one of whom was treated with olanzapine and the other with fluoxetine, while undergoing family therapy.. Twin A treated with fluoxetine went from 75 to 84.4% ideal body weight, while Twin B treated with olanzapine went from 72 to 99.9% ideal body weight over the course of 9 months.. This case supports the need for adequately powered, controlled clinical trials to test the efficacy of olanzapine in adolescents presenting with anorexia nervosa.

Topics: Anorexia Nervosa; Benzodiazepines; Child; Diseases in Twins; Family Therapy; Female; Fluoxetine; Humans; Olanzapine; Selective Serotonin Reuptake Inhibitors; Treatment Outcome; Twins, Monozygotic; Weight Gain

This study aims to investigate whether orexigenic antipsychotic drugs may induce dyslipidemia and glucose disturbances in female rats through direct perturbation of metabolically active peripheral tissues, independent of prior weight gain.. In the current study, we examined whether a single intraperitoneal injection of clozapine or olanzapine induced metabolic disturbances in adult female outbred Sprague-Dawley rats. Serum glucose and lipid parameters were measured during time-course experiments up to 48 h. Real-time quantitative PCR was used to measure specific transcriptional alterations in lipid and carbohydrate metabolism in adipose tissue depots or in the liver.. Our results demonstrated that acute administration of clozapine or olanzapine induced a rapid, robust elevation of free fatty acids and glucose in serum, followed by hepatic accumulation of lipids evident after 12-24 h. These metabolic disturbances were associated with biphasic patterns of gluconeogenic and lipid-related gene expression in the liver and in white adipose tissue depots.. Our results support that clozapine and olanzapine are associated with primary effects on carbohydrate and lipid metabolism associated with transcriptional changes in metabolically active peripheral tissues prior to the development of drug-induced weight gain.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Carbohydrate Metabolism; Clozapine; Fatty Acids, Nonesterified; Female; Lipid Metabolism; Olanzapine; Rats; Rats, Sprague-Dawley; Time Factors; Weight Gain

Metabolic adverse effects such as weight gain and dyslipidaemia represent a major concern in treatment with several antipsychotic drugs, including olanzapine. It remains unclear whether such metabolic side-effects fully depend on appetite-stimulating actions, or whether some dysmetabolic features induced by antipsychotics may arise through direct perturbation of metabolic pathways in relevant peripheral tissues. Recent clinical and preclinical studies indicate that dyslipidaemia could occur independently of weight gain. Using a rat model, we showed that subchronic treatment with olanzapine induces weight gain and increases adipose tissue mass in rats with free access to food. This effect was also observed for aripiprazole, considered metabolically neutral in the clinical setting. In pair-fed rats with limited food access, neither olanzapine nor aripiprazole induced weight gain. Interestingly, olanzapine, but not aripiprazole, induced weight-independent elevation of serum triglycerides, accompanied by up-regulation of several genes involved in lipid biosynthesis, both in liver and in adipose tissues. Our findings support the existence of tissue-specific, weight-independent direct effects of olanzapine on lipid metabolism.

Topics: Adipose Tissue; Animals; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Body Weight; Female; Gene Expression Regulation; Hyperphagia; Lipid Metabolism; Lipogenesis; Olanzapine; Piperazines; Quinolones; Rats; Rats, Sprague-Dawley; Triglycerides; Weight Gain

The second generation antipsychotic drug (SGA) olanzapine has an efficacy to treat schizophrenia, but can cause obesity and type II diabetes mellitus. Cholinergic muscarinic M3 receptors (M3R) are expressed on pancreatic β-cells and in the brain where they influence insulin secretion and may regulate other metabolic hormones via vagal innervation of the gastrointestinal tract. Olanzapine's M3R antagonism is an important risk factor for its diabetogenic liability. However, the effects of olanzapine on central M3Rs are unknown. Rats were treated with 0.25, 0.5, 1.0 or 2.0 mg olanzapine/kg or vehicle (3×/day, 14-days). M3R binding densities in the hypothalamic arcuate (Arc) and ventromedial nuclei (VMH), and dorsal vagal complex (DVC) of the brainstem were investigated using [3H]4-DAMP plus pirenzepine and AF-DX116. M3R binding correlations to body weight, food intake, insulin, ghrelin and cholecystokinin (CCK) were analyzed. Olanzapine increased M3R binding density in the Arc, VMH and DVC, body weight, food intake, circulating plasma ghrelin and CCK levels, and decreased plasma insulin and glucose. M3R negatively correlated to insulin, and positively correlated to ghrelin, CCK, food intake and body weight. Increased M3R density is a compensatory up-regulation in response to olanzapine's M3R antagonism. Olanzapine acts on M3R in regions of the brain that control food intake and insulin secretion. Olanzapine's M3R blockade in the brain may inhibit the acetylcholine pathway for insulin secretion. These findings support a role for M3Rs in the modulation of insulin, ghrelin and CCK via the vagus nerve and provide a mechanism for olanzapine's diabetogenic and weight gain liability.

Topics: Animals; Benzodiazepines; Brain; Cholecystokinin; Eating; Female; Ghrelin; Insulin; Metabolic Networks and Pathways; Olanzapine; Protein Binding; Rats; Rats, Sprague-Dawley; Receptor, Muscarinic M3; Treatment Outcome; Weight Gain

To investigate the influence of a single episode of psychiatric inpatient treatment on metabolic parameters.. A total of 294 consecutive patients of an Upper Austrian psychiatric department were assessed at admission and discharge regarding bodyweight, body mass index (BMI), high density cholesterol (HDL), low density cholesterol (LDL), triglycerides (TG) and fasting glucose (FG), and the TG/HDL ratio.. Patients showed an increase of BMI of 0.35 kg/m² (+ 1.3%) during a mean duration of inpatient stay of 25.8 days. LDL rose by 10.7 mg/dl (+ 8.1%), triglycerides by 23.0 mg/dl (+ 17%), HDL decreased by 4.4 mg/dl (-7.4%). Fasting glucose decreased by 3.6 mg/dl (-3.8%), yet the TG/HDL ratio, as a marker for insulin resistance, increased significantly from 2.86 to 3.58 (+ 25.2%) on average. Patients with psychotic disorders gained about three times more weight than patients with other diagnoses. Negative alterations of serum lipids were to be found in all diagnostic groups but were especially pronounced in patients with psychotic disorders who were treated with second-generation antipsychotics clozapine, olanzapine and quetiapine.. Psychiatric inpatient treatment leads to clinically relevant deterioration of metabolic parameters within a short time, most pronouncedly in patients with psychotic disorders.

Topics: Antipsychotic Agents; Austria; Benzodiazepines; Biomarkers; Body Mass Index; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Clozapine; Dibenzothiazepines; Female; Glucose; Hospitalization; Humans; Insulin Resistance; Length of Stay; Lipid Metabolism; Male; Mental Disorders; Middle Aged; Multivariate Analysis; Olanzapine; Polypharmacy; Prospective Studies; Psychiatric Department, Hospital; Psychotic Disorders; Quetiapine Fumarate; Regression Analysis; Triglycerides; Weight Gain

The purpose of these analyses was to compare the weight and other metabolic changes between adolescents and adults during long-term (at least 24 weeks) olanzapine treatment.. The adult database included 86 studies with 12,425 patients with schizophrenia, schizoaffective disorder, depression, borderline personality disorder, or bipolar I disorder; the adolescent database comprised six studies with 489 patients with schizophrenia, schizoaffective disorder, borderline personality disorder, bipolar I disorder, or prodromal psychosis. Patients who had at least 24 weeks of olanzapine exposure (N=4,280 from adult database and N=179 from adolescent database) were analyzed in this study. Weight data were collected for all patients, fasting glucose and lipids data were collected in some patients. For weight gain, data in 34.5% adults (4,280/12,425) and 36.6% adolescents (179/489) were analyzed while for glucose and lipids, data in 8.4% (1,038/12,425) adults and 24.9% adolescents (122/489) were analyzed. Adult patients were treated with oral (5-20 mg/day) or depot formulations (doses equivalent to oral doses of 5-20 mg/day) of olanzapine and adolescent patients were treated with oral olanzapine (2.5-20 mg/day). The incidences of potentially clinically significant categorical changes in weight and metabolic parameters were calculated with a 95% confidence interval (CI). Nonoverlapping 95% CIs were considered as indicating a statistically significant difference. Weight, lipid, and glucose change comparisons are summarized.. The mean age for adolescents and adults was 15.8 and 38.8, respectively. The percentage of the male population was similar for both adults (58.5%) and adolescents (62.8%). The median duration of the follow-up period was 201 days for adolescent database and 280 days for adult database. The mean weight gain from baseline to endpoint in adolescents was 11.24 kg when compared with 4.81 kg in adults. The 95% CI for adolescents (10.1, 12.4) and adults (4.57, 5.04) are not overlapping, which indicates that the difference between adolescents and adults is statistically significant. The percentage of olanzapine-treated adolescents with ≥ 7% mean weight gain was 89.4% compared with 55.4% in adults (Number need to harm [NNH]=3). Mean changes from baseline to endpoint were also greater for adolescents than for adults in fasting total cholesterol (5.49 mg/dL vs. 2.06 mg/dL), LDL (5.41 mg/dL vs. 0.49 mg/dL), and triglycerides (20.49 mg/dL vs. 16.72 mg/dL), but overlapping 95% CIs were observed for all lipid parameters. Mean changes from baseline to endpoint in fasting glucose values were similar between adolescents and adults (3.13 mg/dL vs. 3.95 mg/dL). However, the incidence of treatment-emergent significant glucose changes was greater in adults. Among olanzapine-treated adults and adolescents, 8.9% and 0.9% experienced a shift from normal to high and 12.5% and 3.3% experienced a shift from normal/impaired glucose tolerance (IGT) to high fasting glucose, respectively. The incidence of IGT to high elevations in glucose was greater in adolescents, but overlapping 95% CI was observed.. The types of metabolic changes during the long-term olanzapine treatment in adolescents were similar to those observed in adults. However, the magnitude of changes in weight and lipid parameters was greater in adolescents. Patients should receive regular monitoring of weight, fasting blood glucose, and lipid profile at the beginning of, and periodically during, treatment with olanzapine.

Topics: Adolescent; Adult; Age Factors; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Databases, Factual; Dose-Response Relationship, Drug; Drug Monitoring; Female; Follow-Up Studies; Humans; Incidence; Lipids; Male; Olanzapine; Time Factors; Weight Gain

Weight gain is a common problem of treatment with atypical antipsychotics. However, the dimension of body weight change differs interindividually, and various genetic factors are considered to be associated with this effect. Peroxisome proliferator-activated receptor gamma (PPARG) Pro12Ala polymorphism and its reported relationship to type 2 diabetes susceptibility and body mass accumulation prompted us to investigate the impact of this single nucleotide polymorphism (SNP) on antipsychotic-induced changes of body weight and body mass index (BMI) in a naturalistic study design.. Included were 138 olanzapine- and 32 clozapine-treated psychiatric inpatients whose demographic data, medical anamnesis, and drug treatment were assessed at admission to hospital and 4 weeks thereafter. The PPARG Pro12Ala SNP was determined with a validated real-time PCR assay.. In contrast to previous investigations, we did not detect significant variations of weight gain among the different PPARG Pro12Ala genotypes.. Our results suggest that the examined polymorphism appears to play a minor or no role in clinical practice concerning antipsychotic drug-induced weight gain.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clozapine; Female; Genetic Association Studies; Humans; Male; Mental Disorders; Middle Aged; Olanzapine; Polymorphism, Single Nucleotide; PPAR gamma; Weight Gain; Young Adult

Second generation antipsychotics (SGAs) are used to treat schizophrenia but can cause serious metabolic side-effects, such as obesity and diabetes. This study examined the effects of low to high doses of olanzapine on appetite/metabolic regulatory signals in the hypothalamus and brainstem to elucidate the mechanisms underlying olanzapine-induced obesity.. Levels of pro-opiomelanocortin (POMC), neuropeptide Y (NPY) and glutamic acid decarboxylase (GAD(65), enzyme for GABA synthesis) mRNA expression, and cannabinoid CB1 receptor (CB1R) binding density (using [(3)H]SR-141716A) were examined in the arcuate nucleus (Arc) and dorsal vagal complex (DVC) of female Sprague Dawley rats following 0.25, 0.5, 1.0 or 2.0 mg/kg olanzapine or vehicle (3×/day, 14-days). Consistent with its weight gain liability, olanzapine significantly decreased anorexigenic POMC and increased orexigenic NPY mRNA expression in a dose-sensitive manner in the Arc. GAD(65) mRNA expression increased and CB1R binding density decreased in the Arc and DVC. Alterations to neurotransmission signals in the brain significantly correlated with body weight and adiposity. The minimum dosage threshold required to induce weight gain in the rat was 0.5 mg/kg olanzapine.. Olanzapine-induced weight gain is associated with reduced appetite-inhibiting POMC and increased NPY. This study also supports a role for the CB1R and GABA in the mechanisms underlying weight gain side-effects, possibly by altering POMC transmission. Metabolic dysfunction can be modelled in the female rat using low, clinically-comparable olanzapine doses when administered in-line with the half-life of the drug.

Topics: Animals; Antipsychotic Agents; Appetite Regulation; Arcuate Nucleus of Hypothalamus; Base Sequence; Benzodiazepines; Cannabinoids; Eating; Female; gamma-Aminobutyric Acid; Gene Expression; Glutamate Decarboxylase; Intra-Abdominal Fat; Models, Biological; Neuropeptide Y; Olanzapine; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; RNA, Messenger; Synaptic Transmission; Weight Gain

This study assessed clinical and functional outcomes following a switch from risperidone to olanzapine in a 1-year naturalistic study of schizophrenia patients in Japan.. We used data from a large 1-year prospective, multicenter, observational non-interventional study of individuals who were initiated on olanzapine for the treatment of schizophrenia in Japan. Current analyses focused on patients who were switched at study entry from risperidone to olanzapine (n = 258). Repeated measures analysis was employed to assess outcomes on validated measures.. At study entry, 45% were inpatients and 55% outpatients. Participants were in their early 40s with mean illness duration of 14 years. Approximately half were male. Most were switched from risperidone to olanzapine due to poor medication efficacy (67.8%) rather than medication intolerability (29.1%). Most patients (67.8%) completed the 1-year study. Patients experienced clinically and statistically significant (P < 0.05) improvements in global symptom severity, positive, negative, depressive, and cognitive symptoms, health-related quality of life, and paid work rates. Most patients (59.2%) demonstrated treatment response to olanzapine and 43.4% experienced symptom remission. Mean weight gain was 2.19 kg, with one-third of patients (33.3%) experiencing clinically significant weight gain (≥7%).. In this 1-year naturalistic study, inpatients and outpatients who were switched from risperidone to olanzapine experienced clinically and statistically significant improvements in their clinical and functional outcomes. One-third of all patients experienced clinically significant weight gain. Current findings highlight the favorable benefit-to-risk profile of switching to olanzapine therapy following treatment failure on risperidone among patients with schizophrenia in Japan.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Drug Resistance; Female; Humans; Income; Japan; Male; Olanzapine; Prospective Studies; Psychiatric Status Rating Scales; Quality of Life; Retreatment; Risperidone; Schizophrenia; Schizophrenic Psychology; Weight Gain

Olanzapine is effective at treating multiple domains of schizophrenia symptoms. However, it induces serious metabolic side effects. Antipsychotic drug's antagonistic affinity to histamine H₁ receptors has been identified as a main contributor for weight gain/obesity side effects. This study therefore investigated whether a combined treatment of betahistine (a H₁ receptor agonist and H₃ receptor antagonist) could reduce the body weight/obesity induced by olanzapine. Female Sprague Dawley rats were treated orally with olanzapine (1 mg/kg, t.i.d.) and/or betahistine (2.67 mg/kg, t.i.d.), or vehicle for two weeks. Rats treated with olanzapine exhibited significant body weight gain and increased food intake. Co-treatment of olanzapine with betahistine significantly prevented (-45%) weight gain and reduced feeding efficiency compared to sole olanzapine treatment. Betahistine treatment alone had no effect on weight gain and food intake. Olanzapine reduced locomotor activity, but not betahistine. These findings demonstrate that olanzapine-induced body weight gain can partially be reduced by co-treatment with betahistine. Betahistine has H₃ receptor antagonistic effects to increase histamine release, which may augment its direct agonistic effects on H₁ receptors. These findings have important implications for clinical trials using betahistine to control antipsychotic-induced obesity side effects.

Topics: Animals; Antipsychotic Agents; Appetite Depressants; Behavior, Animal; Benzodiazepines; Betahistine; Disease Models, Animal; Drug Interactions; Exploratory Behavior; Feeding Behavior; Female; Histamine Agonists; Histamine H3 Antagonists; Hyperphagia; Motor Activity; Olanzapine; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Histamine H1; Weight Gain

There is evidence that some atypical antipsychotics, including olanzapine, can produce unwanted metabolic side effects, weight gain and diabetes. However, neuronal correlates of change related to food information processing have not been investigated with these medications. We studied the effect of a pharmacological manipulation with an antipsychotic known to cause weight gain on metabolites, cognitive tasks and neural correlates related to food regulation. We used functional magnetic resonance imaging in conjunction with a task requiring visual processing of appetitive stimuli in schizophrenic patients and healthy controls before and after 16 weeks of antipsychotic medication with olanzapine. In patients, the psychological and neuronal changes associated following the treatment correlated with appetite control measures and metabolite levels in fasting blood samples. After 16 weeks of olanzapine treatment, the patients gained weight, increased their waist circumference, had fewer positive schizophrenia symptoms, a reduced ghrelin plasma concentration and an increased concentration of triglycerides, insulin and leptin. In premotor area, somatosensory cortices as well as bilaterally in the fusiform gyri, the olanzapine treatment increased the neural activity related to appetitive information in schizophrenic patients to similar levels relative to healthy individuals. However, a higher increase in sensitivity to appetitive stimuli after the treatment was observed in insular cortices, amygdala and cerebellum in schizophrenic patients as compared with healthy controls. Furthermore, these changes in neuronal activity correlated with changes in some metabolites and cognitive measurements related to appetite regulation.

Topics: Adult; Antipsychotic Agents; Appetite; Benzodiazepines; Brain Mapping; Case-Control Studies; Female; Ghrelin; Humans; Insulin; Leptin; Magnetic Resonance Imaging; Male; Neurons; Olanzapine; Schizophrenia; Statistics, Nonparametric; Weight Gain

Blockade of opioidergic neurotransmission contributes to reduction in body weight. However, how such blockade affects body weight gain (BWG) attributed to second generation antipsychotic agents (SGAs) has not yet been established. Here we examined the effects of an opioid receptor antagonist, naltrexone (NTX), on food intake and BWG associated with an SGA, olanzapine (OL). Four groups of Wistar Han IGS rats were treated for 28 days with either OL (2 mg/kg twice daily, intraperitoneal (IP)), a combination of OL (2 mg/kg twice daily, IP) + extended-release NTX (50 mg/kg, one-time, intramuscular (IM)), extended-release NTX (50 mg/kg, one-time, IM) or vehicle and their food intake and body weight were measured daily for the first nine days and every other day thereafter. Food intake and BWG that were increased by OL were decreased by the added NTX while NTX alone had no significant effects on food intake or on BWG. Plasma leptin concentrations were significantly elevated in the three groups receiving pharmacological agents, but did not differ among each other, suggesting that changes in leptin secretion and/or clearance alone would not explain the food intake and the body weight findings. Our results extend prior reports on anorexigenic effects of opioid antagonists by demonstrating that such effects may generalize to food intake increases and BWG arising in the context of OL pharmacotherapy.

Topics: Animals; Antipsychotic Agents; Appetite Depressants; Appetite Regulation; Behavior, Animal; Benzodiazepines; Delayed-Action Preparations; Drug Interactions; Energy Intake; Feeding Behavior; Female; Injections, Intramuscular; Injections, Intraperitoneal; Leptin; Naltrexone; Narcotic Antagonists; Olanzapine; Random Allocation; Rats; Rats, Wistar; Weight Gain

Olanzapine, an atypical antipsychotic drug with affinities for dopamine, serotonin, and histamine binding sites appears to be associated with substantial weight gain and metabolic alterations. The aim of this study was to evaluate weight gain and metabolic alterations in rats treated with olanzapine on a hypercaloric diet.. We used 40 rats divided into 4 groups: Group 1, standard food and water conditions (control); Group 2, standard diet plus olanzapine; Group 3, cafeteria diet (hypercaloric); and Group 4, olanzapine plus cafeteria diet. Olanzapine was administered by gavage at a dose of 3 mg/kg for 9 weeks. RESULTS There were no significant changes in the cholesterol levels in any group. Glucose levels increased in Group 3 by the fourth week. Triglyceride levels were altered in group 2 toward the end of the experiment. Leptin levels decreased in Groups 2 and 4. Complex II activity in the muscles and liver was altered in Group 2 (muscle), and Groups 2, 3, and 4 (liver). Complex IV activity was altered only in the liver in Group 2, without significant alterations within the muscles.. These results suggest that olanzapine is correlated with weight gain and the risks associated with obesity.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Energy Metabolism; Leptin; Male; Olanzapine; Random Allocation; Rats; Rats, Wistar; Weight Gain

We report the optimization of a series of non-steroidal GR antagonists that led to the identification of compound 7. This compound is efficacious when dosed orally in an olanzapine-induced weight gain model in rats.

Topics: Administration, Oral; Animals; Benzodiazepines; Dose-Response Relationship, Drug; Drug Discovery; Models, Animal; Molecular Structure; Olanzapine; Rats; Rats, Sprague-Dawley; Receptors, Glucocorticoid; Structure-Activity Relationship; Thymine; Weight Gain

Psychiatric patients often require chronic treatment with antipsychotic drugs, and while rats are frequently used to study antipsychotic-induced metabolic adverse effects, long-term exposure has only partially mimicked the appetite-stimulating and weight-inducing effects found in the clinical setting. Antipsychotic-induced effects on serum lipids are also inconsistent in rats, but in a recent study we demonstrated that subchronic treatment with the orexigenic antipsychotic olanzapine resulted in weight-independent increase in serum triglycerides and activation of lipogenic gene expression in female rats. In addition, a recent long-term study in male rats showed that chronic treatment with antipsychotic drugs induced dyslipidemic effects, despite the lack of weight gain.. In the current study, we sought to examine long-term effects of antipsychotic drugs on weight gain, lipid levels and lipid composition after twice-daily administration of antipsychotics to female rats, and to investigate potential beneficial effects of the lipid-lowering agent tetradecylthioacetic acid (TTA), a modified fatty acid.. Female rats were exposed to orexigenic antipsychotics (olanzapine or clozapine), metabolically neutral antipsychotics (aripiprazole or ziprasidone), or TTA for 8 weeks. Separate groups received a combination of clozapine and TTA or olanzapine and TTA. The effects of TTA and the combination of olanzapine and TTA after 2 weeks were also investigated.. The antipsychotic-induced weight gain and serum triglyceride increase observed in the subchronic setting was not present after 8 weeks of treatment with antipsychotics, while lipid-lowering effect of TTA was much more pronounced in the chronic than in the subchronic setting, with concomitant upregulation of key oxidative enzymes in the liver. Unexpectedly, TTA potentiated weight gain in rats treated with antipsychotics.. TTA is a promising candidate for prophylactic treatment of antipsychotic-induced dyslipidemic effects, but a more valid long-term rat model for antipsychotic-induced metabolic adverse effects is required.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Antipsychotic Agents; Benzodiazepines; Fasting; Feeding Behavior; Female; Hypolipidemic Agents; Lipid Metabolism; Lipids; Liver; Male; Olanzapine; Rats; Rats, Sprague-Dawley; Sulfides; Time Factors; Transcription, Genetic; Weight Gain

The atypical antipsychotic medication olanzapine is a useful agent in acute and maintenance treatment of schizophrenia and related disorders. It has beneficial effects on both positive and negative symptoms, an early onset of antipsychotic action and a favourable side effect profile. On the other hand, olanzapine has many reports of causing weight gain, glucose metabolism disturbances and lipidosis. We carried out blood tests (leptin, adiponectin, remnant-like lipoprotein cholesterol (RLP-C), total cholesterol, HbA1C, 75-OGTT and etc.) on patients with schizophrenia who had taken olanzapine. As a result, leptin, neutral lipid and RLP-C were significantly correlated by BMI. (The average blood test data and BMI revealed a normal range). Most analysis results of the lipoprotein fraction by a polyacrylamide-gel-electrophoresis method were normal patterns. Furthermore, the serum insulin concentrations from 75 g glucose tolerance (75 g-OGTT) 30 minutes later, in one third of patients receiving olanzapine, registered more than 100 microU/ml. The mechanism of the insulin secretion rise by olannzapine is unknown. Olanzapine may impair glucose tolerance due in part to increased insulin resistance. These findings do not necessarily imply that olanzapine is directly associated with a risk of impairment of weight gain, glucose metabolism disturbances and lipidosis. These results suggest that it is useful to promote diet cure and exercise therapy with patients with high BMI levels.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Female; Humans; Insulin; Lipid Metabolism; Male; Middle Aged; Olanzapine; Schizophrenia; Weight Gain

The relative risk of changes in metabolic parameters during treatment with atypical antipsychotics has not been fully investigated. Baseline-to-endpoint mean and anytime-categorical changes in metabolic parameters were evaluated in Lilly active comparator-controlled clinical trials. Olanzapine-treated patients gained significantly more baseline-to-endpoint weight versus risperidone- (3.3 kg [N = 713; median exposure [ME, days] = 68] versus 1.8 kg [N = 697; ME = 65], p < 0.001), ziprasidone-(2.8 kg [N = 463; ME = 168] versus -1.3 kg [N = 443; ME = 89], p < 0.001), and aripiprazole-treated patients (3.7 kg [N = 273; ME = 104] versus 0.5 kg [N = 275; ME = 187], p < 0.001). Significantly more olanzapine-treated patients gained ≥ 7% of their baseline weight versus risperidone-(30.6% [N = 713; ME = 169] versus 20.2% [N = 697; ME = 140], p < 0.001), ziprasidone-(30.0% [N = 463; ME = 147] versus 6.5% [N = 443; ME = 165], p < 0.001), and aripiprazole-treated patients (40.3% [N = 273; ME = 170] versus 16.4% [N = 275; ME = 154], p < 0.001). Olanzapine-treated patients had significantly greater baseline-to-endpoint changes in fasting triglycerides compared with ziprasidone- (0.24 mmol/L [N = 365; ME = 168] versus -0.24 mmol/L [N = 316; ME = 140], p < 0.001) and aripiprazole-treated patients (0.28 mmol/L [N = 215; ME = 195] versus -0.19 mmol/L [N = 210; ME = 194], p < 0.001). Olanzapine-treated patients had significantly greater baseline-to-endpoint changes in fasting glucose than ziprasidone-(0.25 mmol/L [N = 379; ME = 168] versus -0.04 mmol/L [N = 333; ME = 133], p = 0.016) and aripiprazole-treated patients (0.27 mmol/L [N = 227; ME = 195] versus 0.04 mmol/L [N = 220; ME = 194], p = 0.048). The study concluded that there are changes with varying frequencies and magnitude in some metabolic parameters in patients treated with olanzapine compared with other atypical antipsychotics.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Databases, Factual; Female; Humans; Male; Olanzapine; Risk; Triglycerides; Weight Gain

Body weight gain is one of the most serious side effects associated with clinical use of antipsychotics. However, the mechanisms by which antipsychotics induce body weight gain are unknown, and no reliable animal models of antipsychotics-induced weight gain have been established. The present studies were designed to establish male rat models of weight gain induced by chronic and acute treatment with antipsychotics. Six-week chronic treatment with olanzapine (5, 7.5, and 10mg/kg/day) in male Sprague-Dawley rats fed a daily diet resembling a human macronutrient diet, significantly increased body weight gain and weight of fatty tissues. In contrast, ziprasidone (1.25, 2.5, and 5mg/kg/day) administration caused no observable adverse effects. We then investigated feeding behavior with acute antipsychotic treatment in male rats using an automated food measurement apparatus. Rats were allowed restricted access to normal laboratory chow (4h/day). With acute olanzapine (0.5, 1, and 2mg/kg, i.p.) treatment in the light phase, food intake volume and duration were significantly increased, while treatment with ziprasidone (0.3, 1, and 3mg/kg, i.p.) did not increase food intake volume or meal time duration. Findings from the present studies showed that chronic treatment with olanzapine in male rats induced body weight gain, and acute injection induced hyperphagia, suggesting that hyperphagia may be involved in the weight gain and obesity-inducing properties of chronically administered olanzapine. These animal models may provide useful experimental platforms for analysis of the mechanism of hyperphagia and evaluating the potential risk of novel antipsychotics to induce weight gain in humans.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Disease Models, Animal; Dose-Response Relationship, Drug; Feeding Behavior; Hyperphagia; Male; Olanzapine; Piperazines; Rats; Rats, Sprague-Dawley; Thiazoles; Weight Gain

Second generation antipsychotics are commonly prescribed for the treatment of schizophrenia, however some can induce metabolic dysfunction side-effects such as weight gain, obesity and diabetes. Clinical reports suggest olanzapine alters satiety signals, although findings appear conflicting. Previous animal model studies have utilised a range of olanzapine dosages, however the dosage that better mimics the human scenario of olanzapine-induced weight gain is unclear. Female Sprague-Dawley rats were treated orally, three times daily with olanzapine (0.25mg/kg, 0.5mg/kg, 1.0mg/kg, 2.0mg/kg), self-administered in a sweet cookie dough pellet at eight-hourly intervals) or vehicle (n=12/group) for 14-days. Olanzapine orally self-administered in multiple doses (eight-hourly intervals) may circumvent a drop in plasma drug concentration and ensure the maintenance of a consistently high olanzapine level in the rat. Olanzapine increased body weight (0.5mg/kg, 1.0mg/kg, 2.0mg/kg), food intake (2.0mg/kg) and feeding efficiency (0.5-2.0mg/kg), with no effect on water intake. Subcutaneous inguinal (1.0mg/kg, 2.0mg/kg) and intra-abdominal perirenal fat were increased (2.0mg/kg), but not interscapula brown adipose tissue. Olanzapine increased circulating ghrelin and cholecystokinin, but had no effect on peptide YY((3-36)). Olanzapine decreased insulin (0.25-2.0mg/kg) and locomotor activity in the open field arena (0.5-2.0mg/kg). A low dosage of 0.25mg/kg olanzapine had no effect on most parameters measured. Olanzapine-induced weight gain is associated with hyperphagia, enhanced feeding efficiency and adiposity, decreased locomotor activity and altered satiety signaling. The animal model used in the present study of self-administered oral olanzapine treatment (t.i.d.) at a dosage range of 0.5-2.0mg/kg (but not 0.25mg/kg) mimics aspects of the clinic.

Topics: Adiposity; Analysis of Variance; Animals; Behavior, Animal; Benzodiazepines; Cholecystokinin; Dose-Response Relationship, Drug; Drug Administration Schedule; Eating; Exploratory Behavior; Female; Hormones; Intra-Abdominal Fat; Metabolic Diseases; Olanzapine; Peptide Fragments; Peptide YY; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Self Administration; Statistics as Topic; Weight Gain

The objective of this study was to evaluate weight gain and its potential risk factors among different second generation antipsychotics (SGAs). The study was conducted for Korean inpatients with schizophrenia in a university hospital in Seoul, between Jan 2000 and Dec 2007. Data were collected by reviewing the medical records of the patients, who were prescribed to one of the SGAs among aripiprazole, olanzapine, quetiapine or risperidone. The changes of weight and body mass index (BMI); risk of clinically significant weight gain (>7% gain to initial weight) and their associations with various clinical characteristics of such patients were analyzed. Five hundred and eighty-eight (588) and 294 subjects treated with one of the four SGAs for a duration of 1 month and 2 months were included, respectively. Olanzapine showed significantly greater weight and BMI increase at month 1 (p=0.028 for weight; p=0.019 for BMI) and month 2 (p=0.032 for weight; p=0.029 for BMI) than others. Females showed greater BMI increase change (0.70±0.91 kg/m(2), p=0.008) and were also more likely to experience clinically significant weight gain (odd ratio=1.846, 95% CI=1.098 to 3.105, p=0.021) at month 1. Younger patients (<45 years old) had significantly greater weight and BMI increase at both months 1 and 2. Younger patients also showed greater risk for clinically significant weight gain at month 2 (odd odd ratio=2.567, 95% CI=1.196 to 5.508, p=0.016). Low baseline BMI (<25 kg/m(2)) was associated with greater weight gain at month 1 (1.92±2.29 kg, p<0.001) and month 2 (4.07±3.56 kg, p<0.001) and BMI increase at month 1 and month 2 (p<0.001 for both). Patients with low baseline BMI showed higher risk of clinically significant weight gain at both months 1 and 2 (p<0.001 for both). Olanzapine was shown to have higher metabolic risk than other SGAs in inpatients with schizophrenia. The individual's own clinical characteristics also exerted influence on weight gain effects of SGAs. Younger patients with lower baseline BMI were under greater risk of antipsychotic-induced weight gain. More studies are required to verify the role of gender on weight gain.

Topics: Age Factors; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Body Mass Index; Body Weight; Dibenzothiazepines; Female; Humans; Inpatients; Male; Olanzapine; Piperazines; Quetiapine Fumarate; Quinolones; Retrospective Studies; Risk; Risk Factors; Risperidone; Schizophrenia; Sex Factors; Time Factors; Weight Gain

The present study aimed to explore the association between weight gain and ghrelin among schizophrenic patients under olanzapine treatment. The relationships among weight gain and adiponectin, fasting glucose, and lipid profile were also investigated.. This case-control study recruited 66 schizophrenic patients from the Chung Shan Medical University Hospital in central Taiwan. All of them were undergoing olanzapine monotherapy and were categorized into weight gain (WG) and non-weight gain (NWG) groups. Subjects in the control group (CG) were recruited from a healthy community population based on a health survey (n=119). Multivariate logistic regression was used to explore the association of ghrelin with weight gain.. The 66 schizophrenic patients had a mean age of 36.3±9.6 years, with 50% females. They received olanzapine treatment for a mean period of 8.3±7.5 years. The control group had a mean age of 38.9±9.3 years and 52.9% were females. Comparing fasting serum ghrelin levels, the WG group had the lowest mean value (822.3±253.1 pg/ml) while the control group had the highest mean value (1261.2±1639.7 pg/ml), with a significant difference between the two (p=0.01). In contrast, there was no difference in adiponectin levels among the three groups. The WG and NWG groups had higher diastolic blood pressure than the control group, but systolic blood pressure was the same in all three groups. There was no difference in the total cholesterol level although the WG and NWG groups had higher triglyceride (TG) and glucose levels than the control group.. Weight gain after olanzapine treatment is associated with lower ghrelin level. Olanzapine is linked to elevated diastolic pressure, TG, and glucose, regardless of the weight gain.

Topics: Adiponectin; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Case-Control Studies; Fasting; Female; Ghrelin; Humans; Lipids; Male; Olanzapine; Taiwan; Weight Gain

The use of antipsychotic medication has consistently been associated with serious side effects including weight gain and metabolic abnormalities. Strategies for mitigating these side effects have been tested, yet effective interventions have not been identified. The current study tested whether two recently identified selective glucocorticoid receptor antagonists would prevent weight gain induced by the antipsychotic olanzapine. Female Sprague-Dawley rats fed a normal chow diet were randomized (n=10 per group) to receive one of the following for 18days: vehicle, olanzapine plus vehicle (2.4mg/kg), olanzapine plus CORT 112716 (20mg/kg), olanzapine plus CORT 112716 (60mg/kg), olanzapine plus CORT 113083 (20mg/kg), or olanzapine plus CORT 113083 (60mg/kg). Rats receiving olanzapine plus CORT 112716 (60mg/kg) or olanzapine plus CORT 113083 (60mg/kg) gained significantly less weight than rats receiving only olanzapine. Both glucocorticoid receptor antagonists significantly attenuated the weight gain induced by olanzapine in a dose dependent manner. Differences in weight gain were not attributable to decreased food intake.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Eating; Female; Naphthalenes; Olanzapine; Rats; Rats, Sprague-Dawley; Receptors, Glucocorticoid; Weight Gain

Depression is a disorder held responsible for high morbidity in the overall population. Causes of depression vary, but lifestyle and stress can greatly contribute to its morbidity. Consumption of antidepressants is showing a trend in the economically developed countries. Apart from antidepressants, the treatment of depression can consist of other psychopharmaca. Depending on the severity of a disorder, that is - of psychotic symptoms, antipsychotics can be introduced in the treatment. Among those atypical antipsychotics have an advantage. This paper will illustrate a course of treatment of a female patient, diagnosed with psychotic depression and treated with antipsychotics (i.e. olanzapine, ziprasidone), to which she developed side effects. To each of the antypsychotics the patient developed side effechts, causing in prolonged treatment and affected its course.

Topics: Affective Disorders, Psychotic; Antipsychotic Agents; Benzodiazepines; Depressive Disorder, Major; Dose-Response Relationship, Drug; Drug Eruptions; Drug Substitution; Drug Therapy, Combination; Female; Humans; Middle Aged; Olanzapine; Piperazines; Pruritus; Sulpiride; Thiazoles; Weight Gain

According to current medical opinion chronic mental diseases such as schizophrenia require life-long treatment. The choice of antipsychotics is an important treatment factor, since their side-effects often influence patients' compliance with treatment. Severe side-effects may cause the patients to reject such treatment, the latter being their right. In case a psychiatrist does not agree with the patient's decision to interrupt his antipsychotic treatment regardless its serious side-effects, the former should be persistent in convincing the patient to replace such drug with a more appropriate therapy.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Combined Modality Therapy; Drug Substitution; Female; Humans; Metabolic Syndrome; Olanzapine; Piperazines; Psychotherapy; Schizophrenia; Schizophrenic Psychology; Social Adjustment; Thiazoles; Weight Gain

Children and adolescents are being treated with antipsychotics more often than before, although the risk of adverse events in this age group still remains unclear. Because of increased use of antipsychotics in children and adolescents, their endocrine and metabolic side-effects (weight gain, obesity, and related metabolic deviations) are of particular worrying, especially within pediatric and adolescent population that appears to be at greater risk comparing with adults for antipsychotic-induced metabolic adverse events. In this work we will present the course of treatment of an adolescent girl with psychotic symptoms, within the clinical diagnosis of Organic delusional disorder, who had a considerable weight gain after one year of olanzapine treatment.

Topics: Adolescent; Anticonvulsants; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Cooperative Behavior; Delayed-Action Preparations; Dibenzothiazepines; Drug Substitution; Drug Therapy, Combination; Epilepsy; Female; Follow-Up Studies; Humans; Interdisciplinary Communication; Lamotrigine; Neurocognitive Disorders; Olanzapine; Quetiapine Fumarate; Triazines; Weight Gain

Weight gain is an undesirable side effect of second-generation antipsychotics (SGAs). We performed this study to examine the influence of SGAs on resting energy expenditure (REE) and the relationship of REE to weight gain in adolescent patients.. Antipsychotic-naïve or quasi-naïve (<72 h of exposure to antipsychotics) adolescent patients taking olanzapine, quetiapine, or risperidone in monotherapy were followed up for one year. We performed a prospective study (baseline, 1, 3, 6, and 12 months after treatment) based on anthropometric measurements, bioelectrical impedance analysis, and indirect calorimetry (Deltatrac™ II MBM-200) to measure REE. We also analyzed metabolic and hormonal data and adiponectin concentrations.. Forty-six out of the 54 patients that started treatment attended at least 2 visits, and 16 completed 1 year of follow-up. Patients gained 10.8 ± 6.2 kg (60% in the form of fat mass) and increased their waist circumference by 11.1 ± 5.0 cm after 1 year of treatment. The REE/kg body mass ratio decreased (p = 0.027), and the REE/percentage fat-free mass (FFM) ratio increased (p = 0.007) following the fall in the percentage of FFM during treatment. Weight increase was significantly correlated with the REE/percentage FFM ratio at all the visits (1-3-6-12 months) (r = 0.69, p = 0.004 at 12 months).. SGAs seem to induce a hypometabolic state (reflected as decreased REE/kg body mass and increased REE/percentage FFM). This could explain, at least in part, the changes in weight and body composition observed in these patients.

Topics: Adiponectin; Adolescent; Adolescent Development; Antipsychotic Agents; Basal Metabolism; Benzodiazepines; Biomarkers; Body Composition; Child; Cohort Studies; Dibenzothiazepines; Female; Follow-Up Studies; Humans; Male; Mental Disorders; Olanzapine; Prospective Studies; Quetiapine Fumarate; Risperidone; Waist Circumference; Weight Gain

The atypical antipsychotic drug olanzapine induces weight gain and defects in glucose metabolism in patients. Using a rat model we investigated the effects of acute and long term olanzapine treatment on weight gain, food preference and glucose metabolism. Olanzapine treated rats fed a chow diet grew more slowly than vehicle controls but olanzapine treated animals fed a high fat/sugar diet grew faster than control animals on the same diet. These changes in weight were paralleled by changes in fat mass. Olanzapine also induced a strong preference for a high fat/high sugar diet. Acute exposure to olanzapine rapidly induced severe impairments of glucose tolerance and increased insulin secretion but did not impair insulin tolerance. These results indicate the defect in glucose metabolism induced by acute olanzapine treatment was most likely due to increased hepatic glucose output associated with a reduction in active GLP-1 levels and correspondingly high glucagon levels.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Body Composition; Body Weight; Diet, High-Fat; Food Preferences; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Liver; Male; Obesity; Olanzapine; Rats; Schizophrenia; Weight Gain

Olanzapine is known to be advantageous with respect to outcome and drug compliance in patients with schizophrenia. However, olanzapine has adverse effects, including a higher incidence of weight gain and metabolic disturbances, when compared with those of other antipsychotic agents. The mechanisms underlying these adverse events remain obscure. Female rats were orally administered olanzapine (2 mg/kg) or vehicle once a day for 2 weeks to ascertain if hypothalamic AMP-activated protein kinase (AMPK) mediates olanzapine-induced weight gain and hyperphagia. Body weight and food intake in each rat were evaluated every day and every two days, respectively. After the termination of drug treatment, we measured the protein levels of AMPK and phosphorylated AMPK in the hypothalamus using western blot analyses. Olanzapine significantly increased body weight and food intake. The phosphorylation levels of AMPK were significantly elevated by olanzapine. These results suggest that activation of hypothalamic AMPK may mediate hyperphagia and weight gain induced by chronic treatment with olanzapine.

Topics: AMP-Activated Protein Kinases; Animals; Antipsychotic Agents; Benzodiazepines; Body Weight; Eating; Female; Hyperphagia; Hypothalamus; Olanzapine; Rats; Rats, Sprague-Dawley; Weight Gain

The success of antipsychotic drug treatment in patients with schizophrenia is limited by the propensity of these drugs to induce hyperphagia, weight gain and other metabolic disturbances, particularly evident for olanzapine and clozapine. However, the molecular mechanisms involved in antipsychotic-induced hyperphagia remain unclear. Here, we investigate the effect of olanzapine administration on the regulation of hypothalamic mechanisms controlling food intake, namely neuropeptide expression and AMP-activated protein kinase (AMPK) phosphorylation in rats. Our results show that subchronic exposure to olanzapine upregulates neuropeptide Y (NPY) and agouti related protein (AgRP) and downregulates proopiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC). This effect was evident both in rats fed ad libitum and in pair-fed rats. Of note, despite weight gain and increased expression of orexigenic neuropeptides, subchronic administration of olanzapine decreased AMPK phosphorylation levels. This reduction in AMPK was not observed after acute administration of either olanzapine or clozapine. Overall, our data suggest that olanzapine-induced hyperphagia is mediated through appropriate changes in hypothalamic neuropeptides, and that this effect does not require concomitant AMPK activation. Our data shed new light on the hypothalamic mechanism underlying antipsychotic-induced hyperphagia and weight gain, and provide the basis for alternative targets to control energy balance.

Topics: Agouti-Related Protein; Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Animals; Arcuate Nucleus of Hypothalamus; Benzodiazepines; Clozapine; Feeding Behavior; Female; Gene Expression Regulation; Hyperphagia; Hypothalamus; Injections, Intraventricular; Insulin; Intracellular Signaling Peptides and Proteins; Leptin; Neuropeptide Y; Neuropeptides; Olanzapine; Orexins; Phosphorylation; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Ribonucleotides; Signal Transduction; Weight Gain

Weight gain and metabolic abnormalities are serious side effects associated with the use of several second generation antipsychotics (SGA). The adipose tissue has been considered a direct SGA target involved in the development of these adverse effects. Recent studies, mainly using murine cells, have suggested that SGA increase both adipogenesis of preadipocytes and lipid accumulation in mature adipocytes. However, to date there has been little research comparing the effects of antipsychotics with different propensities to induce weight gain on human in vitro models of white adipose tissue neoformation and metabolism. The present study aimed to investigate the effects of antipsychotics either strongly associated with weight gain, such as the SGA clozapine and olanzapine, or not, such as the SGA ziprasidone and the classical antipsychotic haloperidol, on proliferation and adipocyte differentiation of human adipose-derived stem cells (ADSCs) and lipogenesis in human mature adipocytes. Whereas ziprasidone induced elevated levels of cell death during adipogenesis and could not be investigated further, we observed that clozapine, olanzapine and haloperidol had slight stimulatory effects on the transcriptional program of ADSCs adipogenesis. However, the observed changes in adipocyte-specific genes were not accompanied by a significant increase in triglyceride accumulation within differentiated adipocytes. Our data also showed that these three antipsychotics displayed inhibitory effects on the proliferation rates of undifferentiated ADSCs. Regarding mature adipocyte metabolism, we observed that olanzapine slightly inhibited insulin-stimulated lipogenesis at the highest concentration used, and haloperidol exerted the strongest inhibitory effects on both basal and insulin-stimulated lipogenesis. Taken together, our results suggest that a direct and potent effect of clozapine and olanzapine on adipose tissue biology is not an important mechanism by which these SGA induce metabolic disturbances in humans. On the other hand, the haloperidol-mediated downregulation of the lipogenic capacity of human adipose tissue may be a possible mechanism contributing to its lower propensity to induce serious metabolic side effects.

Topics: Adipocytes; Adipogenesis; Adipose Tissue; Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Haloperidol; Humans; Olanzapine; Piperazines; Thiazoles; Weight Gain

To identify the factors associated with newly prescribed, first-line, second-generation antipsychotics (SgAs) associated with weight gain-olanzapine, risperidone, and quetiapine.. Retrospective medical record review.. Outpatient and inpatient psychiatry services at a tertiary care, academic medical center.. Three hundred forty consecutive adults who had major depressive disorder with psychotic features, bipolar I, bipolar II, bipolar not otherwise specified, or schizoaffective disorder over two time periods (August 30-October 30, 2009, and April 1-May 31, 2010).. Clinical and sociodemographic variables associated with newly prescribed olanzapine, risperidone, and quetiapine were identified by using univariate and multivariate logistic regression. Several clinical factors were individually associated with initiation of these SgAs: mania (odds ratio [OR] 3.6, 95% confidence interval [CI] 1.2-10.8, p=0.02), psychosis (OR 3.3, 95% CI 1.5-6.9, p=0.002), and inpatient treatment (OR 3.8, 95% CI 1.8-7.9, p=0.0005). Prevalent use of lithium (OR 0.3, 95% CI 0.1-0.9, p=0.03) and being married (OR 0.3, 95% CI 0.1-0.8, p=0.02) were inversely associated with new use of an SgA. Mania, psychosis, married status, and lithium use remained independently associated on multivariate analysis. Factors related to metabolic or vascular risk were not associated with SgA initiation.. Psychiatric clinicians were influenced heavily by clinical features related to mental status and acuity when determining whether to prescribe SgAs. However, factors related to vascular risk were not associated. Future observational studies should consider current clinical status as an important factor in determining propensity to receive antipsychotics or other short-term treatments for bipolar and related disorders.

Topics: Academic Medical Centers; Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Depressive Disorder, Major; Dibenzothiazepines; Female; Humans; Logistic Models; Male; Middle Aged; Multivariate Analysis; Olanzapine; Practice Patterns, Physicians'; Psychotic Disorders; Quetiapine Fumarate; Retrospective Studies; Risperidone; Weight Gain

Schizophrenic patients treated with atypical antipsychotics (AAPs) often develop excessive body weight gain, which may lead to further morbidity and poor treatment compliance. This study examined whether genetic variants in the brain-derived neurotrophic factor (BDNF) gene may be associated with body weight change after AAP treatment. The study included 481 schizophrenic patients treated with clozapine (n = 266), olanzapine (n = 79), or risperidone (n = 136) for an average of 49.2 ± 28.2 months. Three common single-nucleotide polymorphisms (SNPs) of the BDNF gene were chosen as tagging SNPs. In single-marker-based analysis, the BDNF rs11030101-T homozygous genotype was found to be associated with significantly increased body weight gain (P = 0.037). The BDNF Val66Met (rs6265) polymorphism was not found to be associated with body weight gain. Haplotype analysis further showed that the rs11030101-T-allele-related haplotype is also associated with increased body weight gain (P = 0.047). Our findings suggest that there is a nominal association with rs11030101 but did not replicate the previously found relationship between the BDNF Val66Met polymorphism and body weight gain during long-term AAP treatment.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Brain-Derived Neurotrophic Factor; Clozapine; Female; Genetic Association Studies; Haplotypes; Humans; Male; Middle Aged; Olanzapine; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Risperidone; Schizophrenia; Weight Gain; Young Adult

Adverse impact of atypical antipsychotic drugs on body weight of adult and juvenile groups has been well-documented both at clinical and preclinical investigations. However, studies on impact of drug on body weight during fetal or neonatal development received little attention. The present study is the first-ever preclinical investigation demonstrating the effect of lactational exposure of olanzapine (4, 8, and 10 mg/kg) and risperidone (1 and 2 mg/kg), two widely prescribed antipsychotics, on body weight of mice neonates. Body weight gain was observed with both the drugs, although a sex-related differential response was noted. In olanzapine-exposed female neonates, the weight gain was more with the highest dose. Male neonates showed a reverse trend, i.e. the highest gain with the lowest dose. Female neonates exposed to risperidone also showed significant, but less gain as compared to their olanzapine-exposed counterparts. Risperidone-exposed male neonates showed little body weight gain. Waist-to-hip ratio and plasma prolactin level were measured to explain the reason behind the body weight gain, but there were deviations with respect to drug and sex. The body weight gain may be the overall manifestations of drug-induced endocrine and metabolic dysregulations.

Topics: Animals; Animals, Newborn; Animals, Suckling; Antipsychotic Agents; Benzodiazepines; Body Weight; Female; Lactation; Male; Mice; Milk; Olanzapine; Prolactin; Risperidone; Sex Characteristics; Waist-Hip Ratio; Weight Gain

Olanzapine is a novel antipsychotic drug known to induce clinically significant weight gain. Although the cause of such weight gain is not fully known, drug-induced changes in appetite and food intake are likely to play a significant role together with other possible mechanisms enhancing weight and/or adiposity. We assessed acute drug effects on 1 hour intake and behavioural expression in female rats. Low doses of olanzapine (0.5 and 1 mg/kg) enhanced acute mash intake. Marked drug effects were seen on a number of behaviours following olanzapine over a range of doses. These effects included dose-related reductions in activity and exploratory behaviours and associated substantial dose-related increases in resting behaviour. Behavioural data were also used to plot drug effects over time, including behavioural satiety sequence (BSS) profiles, to evaluate whether olanzapine's hyperphagic effects might be a consequence of altered satiety development. BSS profiles reflected enhanced eating behaviour at low doses (0.5 and 1 mg/kg) but showed dose-related increases in resting, indicative of drug-induced sedation, which meant that it was impossible to fully discern olanzapine's effects on satiety. Acute olanzapine induces both hyperphagia and sedation, both of which may promote weight gain and adiposity, but which interact competitively.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Benzodiazepines; Dose-Response Relationship, Drug; Energy Intake; Exploratory Behavior; Feeding Behavior; Female; Hyperphagia; Olanzapine; Rats; Rats, Wistar; Satiety Response; Weight Gain

Psychiatric pharmacotherapy with olanzapine is commonplace. We investigated the influence of CYP1A2*1F (-163A, rs762551) and serotonergic polymorphisms on olanzapine serum concentrations and clinical outcome in a naturalistic clinical setting. Included were 124 Caucasian psychiatric inpatients treated with olanzapine for at least 4 weeks with steady-state serum concentrations available for 73 patients. The CYP1A2*1F polymorphism was reported to affect the inducibility of CYP1A2. In our study population, CYP1A2*1F/*1F genotype alone resulted in a 22% reduction of dose-/body weight-normalized olanzapine serum concentrations compared to homo- and heterozygote carriers of CYP1A2*1A (both groups without inducers). This effect was independent of the well-known effect of inducing agents (here tobacco smoke and carbamazepine which led to on average 28% lower concentrations in CYP1A2*1A carriers and 26% lower concentrations in CYP1A2*1F/*1F carriers). Consistently, patients with the CYP1A2*1F/*1F genotype taking inducers had 22% lower concentrations compared to CYP1A2*1A carriers taking inducers. The influence of genotype alone remained significant after Bonferroni's post hoc test. Higher olanzapine concentrations were significantly correlated with better improvement of paranoid and depressive symptoms in patients with schizophrenic disorders (Spearman's r=0.5, P=0.026 and P=0.006, respectively). No relationship between serum concentrations and the side effects (DOTES) score was detected. However, patients with the 5-HTR2A intron 2 (rs7997012) AA genotype suffered from more pronounced side effects compared to carriers of the GA or GG genotype (P=0.018 and P=0.002). Short-term weight gain under olanzapine therapy was significantly lower for 5-HTR2C -759 T-allele carriers (P=0.011). Our data suggest that the CYP1A2*1F/*1F genotype exhibits a significant influence on olanzapine concentrations independent of other inducing factors. Thus, CYP1A2*1F genotyping may be useful for clinical treatment decisions given the fact that olanzapine serum concentrations correlated with treatment response. Side effects and weight gain, however, seem to be more influenced by serotonergic polymorphisms.

Topics: Adult; Aged; Benzodiazepines; Cytochrome P-450 CYP1A2; Depressive Disorder; Female; Genotype; Humans; Male; Mianserin; Middle Aged; Mirtazapine; Olanzapine; Pharmacogenetics; Polymorphism, Genetic; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Schizophrenia; Smoking; Weight Gain

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Female; Olanzapine; Rats; Sex Factors; Weight Gain

Numerous studies have demonstrated an association between bipolar disorder (BD) and obesity. However, these reports are limited by retrospective or cross-sectional designs, and the assessment of patients with lengthy illnesses. Prospective data, and data on weight gain early in the course of BD, are lacking.. We prospectively measured weight gain and laboratory metabolic indices over 12 months in 47 patients with BD receiving maintenance treatment following their first manic episode, and in 24 age- and gender-matched healthy subjects.. Although approximately two-thirds of patients had experienced previous depressive or hypomanic episodes, there was no difference between patients and healthy subjects in mean body mass index or rates of overweight or obesity at recovery from the first mania. Mean weight gain over 12 months was 4.76kg in patients and 1.50kg in healthy subjects (p=0.047). Combined rates of overweight and obesity at 6 months and 12 months exceeded 50% in patients, and were almost double those of healthy subjects. Logistic regression demonstrated that weight gain in the first 6 months was significantly associated with male gender and prescription of olanzapine or risperidone. Patients who were obese at 6 months and/or 12 months had significantly greater mean serum triglyceride levels and fasting glucose levels than non-obese patients.. This was a naturalistic study.. Even in patients with previous depressions and hypomanias, clinically significant weight gain in BD begins following the first manic episode, suggesting that it is primarily related to treatment with mood stabilizers and second-generation antipsychotics. However, the very small number of patients in our sample who were medication-free precludes a meaningful analysis of the degree to which weight gain might be an inherent feature of post-manic BD.

Topics: Adult; Antimanic Agents; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Blood Glucose; Body Mass Index; Cholesterol; Dibenzothiazepines; Female; Follow-Up Studies; Humans; Insulin; Lithium Carbonate; Male; Obesity; Olanzapine; Overweight; Prospective Studies; Quetiapine Fumarate; Risperidone; Triglycerides; Valproic Acid; Weight Gain; Young Adult

The effect of risperidone and olanzapine on beta-cell function and mass was investigated in 90% pancreatectomized and ovariectomized female rats, of which some were treated with estrogen replacement and some were not. Ovariectomized diabetic rats were divided into two groups: one group received daily estrogen replacement (30 mug 17beta-estradiol/kg body weight) and the other group received a vehicle. Each group was further divided into three subgroups and orally given either a placebo, risperidone (0.5 mg/kg body weight), or olanzapine (2 mg/kg body weight) each day in conjunction with a high-fat diet for eight weeks. Ovariectomy reduced serum prolactin levels, while risperidone and estrogen replacement increased them. Olanzapine, not risperidone, increased body weight gain and epididymal fats, and impaired glucose tolerance in ovariectomized diabetic rats, while estrogen replacement improved them. This was related to changes in insulin secretion capacity. Ovariectomized rats had decreased beta-cell mass, due to decreasing beta-cell proliferation, compared with Sham rats, and olanzapine, but not risperidone, caused further reduction. Olanzapine reduced IRS2 protein levels in the islets of ovariectomized rats. Decreased IRS2 attenuated the phosphorylation of Akt and, subsequently, PDX-1 protein levels were lowered in olanzapine-treated rats. Estrogen replacement activated insulin/IGF-1 signaling regardless of treatment. In conclusion, olanzapine, but not risperidone, exacerbated glucose homeostasis partly by attenuating beta-cell function and mass in ovariectomized diabetic rats, while estrogen replacement reversed its negative impact. Further human studies are needed to support the claim that olanzapine should be avoided in the treatment of schizophrenic postmenopausal patients with diabetes.

Topics: Adipose Tissue; Animals; Antipsychotic Agents; Benzodiazepines; Blotting, Western; Cell Separation; Cell Survival; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Estradiol; Estrogen Replacement Therapy; Female; Glucose; Glucose Tolerance Test; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Insulin-Secreting Cells; Olanzapine; Ovariectomy; Pancreatectomy; Prolactin; Rats; Rats, Sprague-Dawley; Risperidone; Weight Gain

Many atypical antipsychotic drugs cause weight gain, but the mechanism of this weight gain is unclear. To dissect the role of the dopamine D2 receptor (D2R), an important receptor in the pharmacology of antipsychotic drugs, we analyzed the effect of olanzapine, risperidone, and ziprasidone on changes in body weight and food intake in male wild-type (WT) and D2R knockout (D2R(-/-)) mice. The oral delivery of atypical antipsychotics, olanzapine (5 and 10mg/kg), risperidone (0.1 and 1.0mg/kg) and ziprasidone (10 and 20mg/kg) in both strains mice for 2 weeks suppressed body weight gain, except for olanzapine treatment in D2R(-/-) mice. Olanzapine treatment suppressed body weight gain and decreased food intake in WT mice, but also reduced fat body mass and locomotor activity, whereas D2R(-/-) mice did not show these changes. Ziprasidone and risperidone treatment produced similar responses in WT and D2R(-/-) mice. These data suggest the involvement of D2R in the effect of olanzapine on metabolic regulation. Further studies are required to explore the implications of D2R activity in antipsychotic-mediated metabolic complications.

Topics: Adipose Tissue; Animals; Antipsychotic Agents; Benzodiazepines; Body Weight; Eating; Male; Mice; Mice, Knockout; Motor Activity; Olanzapine; Piperazines; Receptors, Dopamine D2; Risperidone; Thiazoles; Weight Gain

Topics: Antipsychotic Agents; Benzodiazepines; Humans; Olanzapine; Weight Gain

This is the first study to examine the effect of subchronic olanzapine (OLZ) on energy homeostasis in rats, covering all aspects of energy balance, including energy intake as metabolizable energy, storage, and expenditure. We further analyzed whether, and by which mechanism, the CB1-antagonist AVE1625 might attenuate OLZ-induced body weight gain. For this purpose, we selected juvenile female Hanover Wistar rats that robustly and reproducibly demonstrated weight gain on OLZ treatment, accepting limitations to model the aberrations on lipid and carbohydrate metabolism. Rats received 2 mg/kg OLZ orally twice daily for 12 days. Body weight and body composition were analyzed. Moreover daily food intake, energy expenditure, and substrate oxidation were determined in parallel to motility and body core temperature. OLZ treatment resulted in substantial body weight gain, in which lean and fat mass increased significantly. OLZ-treated rats showed hyperphagia that manifested in increased carbohydrate oxidation and lowered fat oxidation (FO). Energy expenditure was increased, motility decreased, but there was no indication for hypothermia in OLZ-treated rats. Coadministration of OLZ and AVE1625 (10 mg/kg orally once daily) attenuated body weight gain, diminishing the enhanced food intake while maintaining increased energy expenditure and decreased motility. Our data reveal that energy expenditure was enhanced in OLZ-treated rats, an effect not critically influenced by motility. Energy uptake, however, exceeded energy expenditure and led to a positive energy balance, confirming hyperphagia as the major driving factor for OLZ-induced weight gain. Combination of OLZ treatment with the CB1-antagonist AVE1625 attenuated body weight gain in rats.

Topics: Animals; Anti-Obesity Agents; Antipsychotic Agents; Benzodiazepines; Dietary Carbohydrates; Dietary Fats; Energy Intake; Energy Metabolism; Female; Hydrocarbons, Halogenated; Hyperphagia; Obesity; Olanzapine; Oxidation-Reduction; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Sulfonamides; Weight Gain

We investigated whether estrogen replacement modulated energy and glucose metabolic changes induced by olanzapine (OZP) and risperidone (RPD) in 90% pancreatectomized diabetic rats, some of whom had also been ovariectomized (OVX) and some of whom had not (sham).. OVX diabetic rats were subcutaneously injected with estrogen replacement (17beta-estradiol, 30 microg/kg/day) or a vehicle. Each group was divided into 3 subgroups, and each subgroup was orally either given a placebo, RPD (0.5 mg/kg body weight/day) or OZP (2 mg/kg body weight/day) for 8 weeks. Sham rats were also divided into 3 subgroups and given drugs in the same manner as the OVX rats were. All rats were fed high-fat diets.. OZP increased body weight and epididymal fat pads more than the control (vehicle) in sham and OVX rats. Increased body weight in OZP-treated sham and OVX rats was due to the increment in food intake, which was associated with potentiating the phosphorylation of hypothalamic adenosine-monophosphate-activated protein kinase. At euglycemic hyperinsulinemic clamping, OZP decreased glucose infusion rates and increased hepatic glucose output in OVX diabetic rats. In sham rats, OZP increased hepatic glucose output but not as much as in OVX rats. Hepatic insulin signaling and glucose sensing were attenuated in OZP-treated OVX rats, and the attenuation increased hepatic phosphoenolpyruvate carboxykinase expression to induce gluconeogenesis. These negative and harmful effects noted among OZP-treated OVX rats were reversed by estrogen replacement treatment. However, RPD did not alter body weight and peripheral insulin sensitivity in sham and OVX rats.. OZP treatment should be avoided when treating diabetic and schizophrenic women, especially those in their postmenopausal period.

Topics: Adipose Tissue; Animals; Antipsychotic Agents; Benzodiazepines; Diabetes Mellitus, Type 2; Eating; Estradiol; Estrogen Replacement Therapy; Female; Glucose; Insulin Resistance; Liver; Olanzapine; Ovariectomy; Pancreatectomy; Random Allocation; Rats; Rats, Sprague-Dawley; Risperidone; Weight Gain

Topics: Adolescent; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Child; Child, Preschool; Dibenzothiazepines; Humans; Olanzapine; Overweight; Piperazines; Quetiapine Fumarate; Quinolones; Risperidone; Weight Gain

Schizophrenic patients treated with atypical antipsychotics (AAPs) often develop excessive body weight gain (BWG), which may lead to further morbidity and poor treatment compliance. This study examined whether genetic variants in the dopamine receptor D2 (DRD2) gene may be associated with body weight change after AAP treatment.. The study included 479 schizophrenic patients treated with clozapine (n=239), olanzapine (n=70) or risperidone (n=170) for an average of 48.2+/-27.8 months. BWG was defined as an increase of more than 7% of the baseline body weight during AAP treatment. Thirteen common single nucleotide polymorphisms of the DRD2 gene were chosen as tagging single nucleotide polymorphisms.. In single-marker-based analysis, the DRD2 rs4436578-C homozygous genotype was found to be associated with a significantly increased risk of BWG [P=0.001, adjusted odds ratio=3.36 (95% confidence interval=1.62 - 7.00)]. In addition, haplotype analysis further showed that the rs4436578-C-allele-related haplotype was more frequent in those patients with BWG than those without (P=0.01 - 0.00019).. Our findings confirm the importance of genetic factors in body weight change induced by long-term AAP treatment in patients with schizophrenia and indicate a role of DRD2 in body weight regulation during long-term AAP treatment.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Weight; Clozapine; Female; Genes; Genotype; Haplotypes; Humans; Long-Term Care; Male; Middle Aged; Odds Ratio; Olanzapine; Receptors, Dopamine D2; Risperidone; Schizophrenia; Weight Gain

Despite known metabolic effects of second-generation antipsychotics (SGAs) on children and adolescents, comparative effects in youth with different diagnoses remain underreported. We compared differences in metabolic changes three months after starting treatment with SGAs in youth with bipolar disorder and with other psychotic and nonpsychotic disorders.. Weight and metabolic differences among diagnostic groups before and three months after starting treatment with SGAs were compared in a naturalistic cohort of children and adolescents (14.9 +/- 3.0 years) diagnosed with bipolar disorder (n = 31), other psychotic disorders (n = 29), and other nonpsychotic disorders (n = 30), with no (35.6%) or very little (6.6 +/- 9.0 days) previous exposure to antipsychotics. Composite measurements of significant weight gain [weight increase > or = 5% at three months or increase > or = 0.5 in body mass index (BMI) z-score] and 'risk for adverse health outcome' (> or = 95(th) BMI percentile, or > or = 85(th) BMI percentile plus presence of one other obesity-related complication) were included. SGAs (risperidone, olanzapine, and quetiapine) were prescribed in comparable proportion among groups.. Baseline weight and metabolic indices were not significantly different among diagnoses. Three months after starting treatment with SGAs, more than 70% patients had significant weight gain, BMI z-score increased in all diagnostic groups (p < 0.001 for all comparisons), total cholesterol increased in the bipolar (p = 0.02) and psychotic (p = 0.01) disorder groups, low-density lipoprotein cholesterol increased in the bipolar group (p = 0.02), and free T4 decreased in the psychotic disorder group (p = 0.05). More patients with bipolar disorder presented overweight plus > or = 1 obesity-related complication at follow-up.. There are early weight gain and metabolic changes across diagnoses in youth treated with SGAs.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Biomarkers; Bipolar Disorder; Body Mass Index; Child; Cholesterol, LDL; Chromatography, High Pressure Liquid; Dibenzothiazepines; Female; Follow-Up Studies; Humans; Male; Mental Disorders; Obesity; Olanzapine; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Thyroxine; Treatment Outcome; Weight Gain

In our original study based on five monozygotic twin pairs and seven same-sex sib pairs, we previously showed that genetic factors contribute to body weight gain induced by the atypical antipsychotic clozapine. We aim to study this further by including patients treated with the atypical antipsychotics olanzapine or risperidone as well as opposite-sex sib pairs.. Twin and sib pairs were identified by a telephone screening. Measured data on weight and other clinical variables were obtained cross-sectionally and retrospectively from medical records. In seven monozygotic twin pairs and 12 sib pairs (total number of patients treated: n = 38, mean age 29.5 +/- 9.5, range 13.7-54.3 years), the similarity in BMI (kg/m(2)) change under these atypical antipsychotics (atypical Delta BMI) and upon additional inclusion of BMI change under prior antipsychotic medication (total Delta BMI) was explored.. For total Delta BMI we found greater similarity in antipsychotic-induced BMI change in MZ twin pairs than in sib pairs (intrapair difference) with a heritability of h(2) = 0.6, but not for atypical Delta BMI, possibly because of a genetically influenced weight plateau achieved under antipsychotic medication.. The results of the present and our previous report suggest a contribution of genetic factors in antipsychotic-induced weight gain of 60-80%.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Olanzapine; Retrospective Studies; Risperidone; Siblings; Twins, Monozygotic; Weight Gain; Young Adult

Olanzapine is an antipsychotic drug that frequently induces weight gain accompanied by increased fat deposition as a side effect. To investigate how olanzapine affects different aspects of energy balance, we used male rats to determine effects on meal patterns, food preference, locomotor activity and body temperature. In two short-term experiments olanzapine was administered via osmotic minipumps. In the first experiment, we offered rats standard lab chow only. In the second experiment, we offered rats free choice between chow, sucrose and saturated fat. In a third experiment, olanzapine was chronically administered via the drinking water to determine effects on body composition. In each experiment olanzapine decreased locomotor activity and altered meal patterns. Olanzapine caused an increase in average meal size accompanied by reduced meal frequency, without clearly affecting food preference. In the chronic experiment body composition was altered, favoring adipose tissue over lean muscle mass, despite reductions in overall body weight gain. The increase in average meal size implies that the primary effect of olanzapine on feeding is an impairment of the normal satiation process. Furthermore, energy balance is clearly affected by a reduction in locomotor activity. Thus, the effects of olanzapine on adiposity do not depend solely on the presence of hyperphagia.

Topics: Administration, Oral; Animals; Benzodiazepines; Eating; Feeding Behavior; Infusion Pumps, Implantable; Male; Motor Activity; Olanzapine; Rats; Rats, Wistar; Weight Gain

Use of antipsychotic medications has been associated consistently with weight gain and metabolic disturbances, and a subsequent increased risk for diabetes and cardiovascular disease. Two experiments tested whether CORT 108297, a newly identified selective glucocorticoid antagonist could (i) reduce and (ii) prevent olanzapine-induced weight gain in rats. In the first experiment, rats dosed only with olanzapine gained a statistically significant amount of weight. When vehicle was added to their olanzapine dose, they continued to gain weight; when CORT 108297 was added to their regimen, they lost a significant amount of weight. Rats administered CORT 108297 plus olanzapine had significantly less abdominal fat than those who received olanzapine alone. In the second experiment, rats receiving olanzapine plus CORT 108297 gained significantly less weight than rats receiving only olanzapine. Increasing doses of CORT 108297 were associated with less weight gain.

Topics: Animals; Antipsychotic Agents; Aza Compounds; Benzodiazepines; Body Weight; Female; Heterocyclic Compounds, 4 or More Rings; Olanzapine; Rats; Receptors, Glucocorticoid; Weight Gain

Olanzapine is an a-typical antipsychotic drug antagonizing predominantly 5-HT and dopamine, but also histamine, muscarin, and α-adrenergic receptors. In humans, Olanzapine induces weight gain and increases the risk of type 2 diabetes. The underlying mechanisms of Olanzapine-induced weight gain are unclear. To study this we administered Olanzapine (5mg/kg) in female Wistar rats on a medium fat diet for 14 days via a permanent gastric catheter twice a day, just prior to the onset and at the middle of dark phase. Food and water intake, locomotor activity and body temperature were measured. Olanzapine acutely induced hypothermia, markedly decreased locomotor activity and increased body weight during 14 days of treatment. Olanzapine treatment did not result in an alteration of 24h food intake, but diurnal patterns of feeding behavior and body temperature were dramatically changed. We conclude that in female Wistar rats Olanzapine has an acute hypothermic effect, that the effect of Olanzapine on feeding behavior is secondary to the effect on activity, and that Olanzapine-induced weight gain is primarily the result of reduction in locomotor activity.

Topics: Animals; Benzodiazepines; Drug Administration Schedule; Feeding Behavior; Female; Hypothermia; Motor Activity; Olanzapine; Rats; Rats, Wistar; Sucrose; Weight Gain

In comparison with conventional, first-generation antipsychotics (e.g., haloperidol), the administration of atypical antipsychotics (AAPs) has been associated with a higher risk of metabolic derangements, including body weight increase, dysregulation of glucose homeostasis, fat accumulation, and even liability to develop type II diabetes. Since this is a serious clinical problem that may be further exacerbated in overweight schizophrenics, establishing animal models of AAP-induced adverse effects may contribute to clarifying the mechanisms underlying these effects. Here we present three basic protocols by which this problem has been modeled. The three protocols differ in many aspects (routes of administration, extent of the chronic treatment, diets, and dosage regimen), and the pros and cons of each procedure are systematically detailed throughout. It should be noted that several factors (e.g., species, sex, duration, and class of AAPs) could restrict the feasibility of these models, as well as their correspondence to the clinical condition.

Topics: Administration, Oral; Animals; Antipsychotic Agents; Benzodiazepines; Disease Models, Animal; Eating; Female; Infusion Pumps, Implantable; Metabolic Diseases; Mice; Mice, Mutant Strains; Olanzapine; Rats; Rats, Transgenic; Weight Gain

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Controlled Clinical Trials as Topic; Double-Blind Method; Humans; Obesity; Olanzapine; Piperazines; Quinolones; Schizophrenia; Weight Gain

Clinically significant weight gain has been reported during treatment with atypical antipsychotics. It has been suggested that weight changes in patients treated with olanzapine may be associated with increased appetite.. Data were used from adult patients for whom both appetite and weight data were available from 4 prospective, 12- to 24-week clinical trials. Patients' appetites were assessed with Eating Behavior Assessment (EBA, Study 1), Platypus Appetite Rating Scale (PARS, Study 2), Eating Inventory (EI, Study 3), Food Craving Inventory (FCI, Study 3), and Eating Attitude Scale (EAS, Study 4).. In Studies 1 (EBA) and 4 (EAS), patients who reported overall score increases on appetite scales, indicating an increase in appetite, experienced the greatest overall weight gains. However, in Studies 2 (PARS) and 3 (EI, FCI), patients who reported overall score increases on appetite scales did not experience greater weight changes than patients not reporting score increases. Early weight changes (2-4 weeks) were more positively correlated with overall weight changes than early or overall score changes on any utilized appetite assessment scale. No additional information was gained by adding early appetite change to early weight change in correlation to overall weight change.. Early weight changes may be a more useful predictor for long-term weight changes than early score changes on appetite assessment scales.. This report represents secondary analyses of 4 clinical studies. Studies 1, 2, and 3 were registered at http://clinicaltrials.gov/ct2/home, under NCT00190749, NCT00303602, and NCT00401973, respectively. Study 4 predates the registration requirements for observational studies that are not classified as category 1 observational studies.

Topics: Adult; Aged; Antipsychotic Agents; Appetite; Appetite Regulation; Benzodiazepines; Clinical Trials, Phase IV as Topic; Feeding Behavior; Female; Humans; Life Style; Male; Middle Aged; Olanzapine; Probability; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Weight Gain

Atypical antipsychotic-induced weight gain is a significant impediment in the treatment of schizophrenia.. In a putative model of antipsychotic drug-induced weight gain, we investigated the effects of sub-chronic olanzapine on body weight, meal patterns, the expression of genes encoding for hypothalamic feeding-related neuropeptides and the contribution of hyperphagia to olanzapine-induced weight gain in rats.. In experiment 1, female rats received either olanzapine (1 mg/kg, p.o.) or vehicle, twice daily for 7 days, while meal patterns were recorded. At the end of the treatment regimen, we measured the levels of hypothalamic messenger RNAs (mRNAs) encoding neuropeptide-Y (NPY), hypocretin/orexin (HCRT), melanin concentrating hormone and pro-opiomelanocortin. NPY and HCRT mRNA levels were also assessed in a separate cohort of female rats treated acutely with olanzapine (1 mg/kg, p.o.). In experiment 2, we investigated the effect of a pair-feeding paradigm on sub-chronic (1 mg/kg, p.o.) olanzapine-induced weight gain.. In experiment 1, sub-chronic olanzapine increased body weight, food intake and meal size. Hypothalamic neuropeptide mRNA levels were unchanged after both acute and sub-chronic olanzapine treatment. In experiment 2, the restriction of food intake to the level of vehicle-treated controls abolished the sub-chronic olanzapine-induced increase in body weight.. Hyperphagia mediated by drug-induced impairments in satiety (as evidenced by increased meal size) is a key requirement for olanzapine-induced weight gain in this paradigm. However, olanzapine-induced hyperphagia and weight gain may not be mediated via alterations in the expression of the feeding-related hypothalamic neuropeptides examined in this study.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Eating; Female; Hyperphagia; Intracellular Signaling Peptides and Proteins; Neuropeptide Y; Neuropeptides; Olanzapine; Orexins; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; RNA, Messenger; Weight Gain

The administration of antipsychotic drugs to human patients or experimental animals leads to significant weight gain, which is widely presumed to be driven by hyperphagia; however, the contribution from energy expenditure remains unclear. These studies aim to examine the contribution of shifts in energy expenditure, particularly those involving centrally mediated changes in thermogenesis, to the body weight gain associated with the administration of olanzapine to female Sprague Dawley rats. Olanzapine (6 mg/kg/day orally) caused a transient increase in food intake but a maintained increase in body weight. When pair-fed rats were treated with olanzapine, body weight continued to rise compared to vehicle-treated rats, consistent with a reduction in energy expenditure. Brown adipose tissue (BAT) temperature, measured using biotelemetry devices, decreased immediately after the onset of olanzapine treatment and remained depressed, as did physical activity. UCP1 expression in interscapular BAT was reduced following chronic olanzapine treatment. An acute injection of olanzapine was preceded by an injection of a retrograde tracer into the spinal cord to evaluate the nature of the olanzapine-activated neural pathway. Levels of Fos protein in a number of spinally projecting neurons within discrete hypothalamic and brainstem sites were elevated in olanzapine-treated rats. Some of these neurons in the perifornical region of the lateral hypothalamus (LHA) were also Orexin A positive. These data collectively show a significant impact of thermogenesis (and physical activity) on the weight gain associated with olanzapine treatment. The anatomical studies provide an insight into the central neuroanatomical substrate that may subserve the altered thermogenic responses brought about by olanzapine.

Topics: Adipose Tissue, Brown; Animals; Antipsychotic Agents; Benzodiazepines; Body Weight; Energy Intake; Female; Hypothalamus; Medulla Oblongata; Motor Activity; Olanzapine; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Thermogenesis; Weight Gain

To explore the impact of premorbid and baseline body mass indices (BMIs) as well as BMI of patient's parents and associated variables on the prediction of antipsychotic-induced body weight gain.. Retrospective/cross-sectional data of 65 patients receiving clozapine, olanzapine and/or risperidone were assessed according to a systematic categorization of the long-term (7.3+/-9.2 years) weight course and evaluated using descriptive, explorative correlation and regression analyses.. Increased values of parents' BMI (p=0.041) and patients' BMI at premorbid stage (p=0.039) and prior to first antipsychotic treatment (p=0.032) as well as female gender (p=0.012), younger age (p=0.005) and non-smoking (p=0.047) have the most predictive value on body weight gain under antipsychotic treatment including pre-treatment with typical antipsychotics. Weight gain under atypical antipsychotics (pre-treatment excluded) is predicted by an increased premorbid BMI (p=0.019). Conversely, a low BMI prior to first antipsychotic treatment predicts a higher acceleration of BMI change (p=0.008) in vulnerable individuals, but not total BMI change itself. Furthermore, a diagnosis of a schizophrenia spectrum disorder showed a trend towards the prediction of an increased atypical DeltaBMI (p=0.067), possibly due to a longer treatment duration with atypical antipsychotics (p<0.001).. The study indicates increased parents' BMI and patients' premorbid BMI, female gender, younger age and - as a trend - the diagnosis of a schizophrenia spectrum disorder to be predictors for antipsychotic-induced body weight gain involving atypical antipsychotics. Data contribute to the assumption of a strong impact of predispositional factors on weight gain, besides treatment-related factors.

Topics: Adolescent; Adult; Age Factors; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Clozapine; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Olanzapine; Parents; Retrospective Studies; Risk Factors; Risperidone; Sex Factors; Smoking; Time Factors; Weight Gain; Young Adult

This Schizophrenia Outcome Survey compared medical costs, psychopathology and adverse events in outpatients for 2 years following hospitalisation for an acute schizophrenic episode.. Adults stabilised with haloperidol, olanzapine or risperidone entered this observational study or=1 EPS; 69% (p<0.013), 40 and 44%, respectively, had >or=1 sexual problem (NS). Mean weight gain was 0.4 (NS), 2.6 (p<0.05) and 2.6 kg (p<0.05), respectively.. In this naturalistic study, treatment allocation might have introduced a bias in the interpretation of efficiency results, but olanzapine and risperidone caused less EPS than haloperidol during 2 years of outpatient follow-up.

Topics: Adult; Antipsychotic Agents; Basal Ganglia Diseases; Belgium; Benzodiazepines; Brief Psychiatric Rating Scale; Dyskinesia, Drug-Induced; Female; Haloperidol; Health Care Costs; Hospitalization; Humans; Male; Olanzapine; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Weight Gain

Topics: Antipsychotic Agents; Benzodiazepines; Biotransformation; Body Mass Index; Drug Monitoring; Humans; Olanzapine; Weight Gain

This study focuses on exploring the relationship between changes in appetite or eating behaviors and subsequent weight change for adult patients with schizophrenia or bipolar disorder treated with olanzapine and adjunctive potential weight mitigating pharmacotherapy. The aim is not to compare different weight mitigating agents, but to evaluate patients' characteristics and changes in their eating behaviors during treatment. Identification of patient subgroups with different degrees of susceptibility to the effect of weight mitigating agents during olanzapine treatment may aid clinicians in treatment decisions.. Data were obtained from 3 randomized, double-blind, placebo-controlled, 16-week clinical trials. Included were 158 patients with schizophrenia or bipolar disorder and a body mass index (BMI) > or = 25 kg/m2 who had received olanzapine treatment in combination with nizatidine (n = 68), sibutramine (n = 42), or amantadine (n = 48). Individual patients were analyzed for categorical weight loss > or= 2 kg and weight gain > or = 1 kg. Variables that were evaluated as potential predictors of weight outcomes included baseline patient characteristics, factors of the Eating Inventory, individual items of the Eating Behavior Assessment, and the Visual Analog Scale.. Predictors/correlates of weight loss > or = 2 kg included: high baseline BMI, low baseline interest in food, and a decrease from baseline to endpoint in appetite, hunger, or cravings for carbohydrates. Reduced cognitive restraint, increase in hunger, and increased overeating were associated with a higher probability of weight gain > or = 1 kg.. The association between weight gain and lack of cognitive restraint in the presence of increased appetite suggests potential benefit of psychoeducational counseling in conjunction with adjunctive pharmacotherapeutic agents in limiting weight gain during antipsychotic drug therapy.. This analysis was not a clinical trial and did not involve any medical intervention.

Topics: Adult; Amantadine; Appetite; Benzodiazepines; Bipolar Disorder; Cognition Disorders; Cyclobutanes; Drug Therapy, Combination; Feeding Behavior; Female; Humans; Male; Nizatidine; Olanzapine; Randomized Controlled Trials as Topic; Schizophrenia; Weight Gain; Weight Loss

Topics: Antipsychotic Agents; Benzodiazepines; Clothing; Femoral Neuropathy; Humans; Male; Middle Aged; Nerve Compression Syndromes; Obesity; Olanzapine; Weight Gain

Weight gain, a serious problem associated with some antipsychotic drugs, notably olanzapine and clozapine, was suggested to be associated with -759C/T polymorphism of the 5-HT2C receptor gene. This study aimed to examine a potential association of two functional polymorphisms of the promoter region of this gene: -759C/T (rs3813929) and -697G/C (rs518147), with weight gain after 6 weeks of olanzapine monotherapy. It included 107 patients with schizophrenia; among them 36 are first-episode drug-naive patients. Analysis was carried out by PCR-restriction fragment length polymorphism. A protective effect of -759T and -697C alleles was found: significantly less patients with -697C (3/51) and no patient with -759T (0/28) alleles experienced body mass index increase >or=10% (P=0.0006 and 0.002, respectively). The same was true for drug-naive patients possessing any of the variant alleles. There was a significant association of haplotypes with a >or=10% body mass index increase (P=0.001). On the basis of the additional statistical analysis, the more important role of -697C allele was suggested.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Female; Humans; Male; Middle Aged; Olanzapine; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Receptor, Serotonin, 5-HT2C; Weight Gain

Objectives of the study were to evaluate the relationship between olanzapine plasma concentrations and efficacy, prolactin, and weight and to assess effects of smoking, sex, and race on the pharmacokinetic characteristics of oral olanzapine up to 40 mg/d. Patients were randomly allocated to olanzapine 10, 20, or 40 mg/d for 8 weeks. Olanzapine concentrations in 634 samples from 380 patients were analyzed. Mean sample collection time was approximately 15 hours after dose for all groups. Mean olanzapine concentrations were 19.7 +/- 11.4, 37.9 +/- 22.8, and 74.5 +/- 43.7 ng/mL for 10-, 20-, and 40-mg doses, respectively. Olanzapine concentration and Positive and Negative Syndrome Scale improvement were not significantly correlated. Change in both weight and prolactin showed significant dose response. Prolactin concentration was correlated with olanzapine concentration (r = 0.46, P < 0.001). No significant correlation between olanzapine concentration and weight change was observed. Olanzapine concentrations were lower in self-reported smokers (16.5 +/- 9.6, 34.2 +/- 20.8, and 60.9 +/- 34.6 ng/mL) than in self-reported nonsmokers (25.6 +/- 12.3, 43.4 +/- 24.7, and 113.2 +/- 44.0 ng/mL) for 10-, 20-, and 40-mg doses, respectively (P

Topics: Administration, Oral; Adult; Antipsychotic Agents; Benzodiazepines; Black or African American; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Olanzapine; Prolactin; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Schizophrenia; Schizophrenic Psychology; Sex Factors; Smoking; Weight Gain; White People

The antipsychotic drug, olanzapine, often induces weight gain and glucose metabolism disturbances, which may result from feeding pattern abnormalities.. The objectives of the study were to examine the effects of a chronic olanzapine treatment on feeding patterns in the rat and to investigate a potential time-related association between feeding patterns and the appearance of glucose metabolism abnormalities and adiposity.. Male rats were treated with olanzapine (2 mg/kg/day), haloperidol (1 mg/kg/day) or a control solution (drugs mixed with the food). In experiment 1, treatments lasted 26 days and feeding patterns were measured on day 21. In experiment 2, treatments lasted for 46 days, and an oral glucose tolerance test (OGTT) was realised on day 31. At the end of both experiments, plasma parameters and body composition were analysed.. In experiment 1, olanzapine-treated animals showed increased meal number, decreased ingestion rate, meal size and inter-meal interval, and no change in total food intake. Plasma glucose, OGTT and body composition were not altered. In experiment 2, after 31 days of treatment, fasting blood glucose was increased and OGTT indicated an insulin resistance. After 46 days of treatment, hyperglycaemia was aggravated (compared to 31 days), and adiposity was increased in olanzapine-treated animals. In both experiments, the haloperidol-treated rats did not differ from the control ones.. Chronic olanzapine treatment produces changes in feeding patterns, in a way consistent with an increased incentive drive to eat. As a whole, the results raise the hypothesis that long-term alteration of feeding pattern by olanzapine may predispose to disturbances in the regulation of energy metabolism.

Topics: Adiposity; Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Eating; Energy Metabolism; Feeding Behavior; Glucose Tolerance Test; Haloperidol; Male; Olanzapine; Rats; Rats, Sprague-Dawley; Schizophrenic Psychology; Time Factors; Weight Gain

The aim of this study was to compare the outcomes of olanzapine- and valproate-treated patients in an observational study of acute mania with the results of a randomised controlled trial (RCT) assessing the same treatments.. EMBLEM (European Mania in Bipolar Evaluation of Medication) was a 2-year, prospective, observational study of health outcomes associated with the treatment of mania. Severity of mania and depression were assessed at baseline and 6 weeks using the YMRS and the 5-item version of the HAMD, respectively.. 621 patients were analysed (n=107 valproate, n=514 olanzapine). Both groups improved from baseline to 6 weeks in mean YMRS and HAMD-5 total scores, with greater mean improvements in the olanzapine compared with the valproate group. Olanzapine was associated with more weight gain and less gastrointestinal difficulties than valproate.. The EMBLEM results support those of the RCT, which suggest that olanzapine monotherapy seems to be more effective than valproate monotherapy in the treatment of acute mania.

Topics: Adult; Antidepressive Agents; Antimanic Agents; Benzodiazepines; Bipolar Disorder; Female; Gastrointestinal Diseases; Humans; Male; Olanzapine; Prospective Studies; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Treatment Outcome; Valproic Acid; Weight Gain

Topics: Adult; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Body Weight; Central Nervous System Agents; Cholesterol; Drug Therapy, Combination; Female; Glucose; Humans; Male; Olanzapine; Piperazines; Psychiatric Status Rating Scales; Quinolones; Schizophrenia; Treatment Outcome; Triglycerides; Weight Gain

Olanzapine is a second-generation antipsychotic that may cause weight gain and metabolic syndrome in some cases. The peroxisome proliferator-activated receptor (PPAR)-gamma is an important gene in the progress of type II diabetes and metabolic syndrome. In recent studies the polymorphism of the PPAR-gamma has been studied in type II diabetes mellitus, polycystic ovary syndrome, and insulin resistance syndrome. It is aimed to evaluate the association between polymorphism of PPAR-gamma gene and olanzapine-induced weight gain. Our study comprised 95 unrelated subjects who strictly met Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria for schizophrenia, and all were of Turkish origin. All patients were evaluated with rating scales, and genetic analyses were performed. We found statistically significant differences between pretreatment and posttreatment body mass index and weight change in Pro12Ala polymorphism of PPAR-gamma2. Our results suggest that genetic polymorphism of PPAR might be important in olanzapine-induced weight gain and that genetic variance of people might be considered in antipsychotic medication selection.

Topics: Adult; Alanine; Antipsychotic Agents; Base Sequence; Benzodiazepines; DNA Primers; Humans; Middle Aged; Olanzapine; PPAR gamma; Proline; Schizophrenia; Weight Gain

Substantial increases in body weight can be induced by several antipsychotic drugs, most notably olanzapine and clozapine. Antagonism at certain receptors, particularly 5-HT2C and histamine H1 receptors, is implicated in this effect.. We have investigated the contribution of effects at these receptors to olanzapine-induced weight gain occurring over 5 days following daily intraperitoneal drug injections in groups of eight female rats.. Olanzapine (2 mg/kg) and the 5-HT2C antagonist SB 243213 (1 mg/kg), but not the histamine H1 antagonist mepyramine (1 mg/kg), produced significant increases in percentage body weight above vehicle; olanzapine showed a significantly greater effect than SB 243213. Haloperidol (0.1 mg/kg) alone or with mepyramine had no significant effects on weight gain, while with SB 243213 and with both SB 243213 and mepyramine, it showed olanzapine-like increases in weight.. These results suggest that 5-HT2C receptor antagonism or inverse agonism, in the presence of D2 receptor antagonism, may contribute to olanzapine-induced weight gain.

Topics: Analysis of Variance; Animals; Behavior, Animal; Benzodiazepines; Dopamine Antagonists; Drug Interactions; Female; Haloperidol; Histamine H1 Antagonists; Indoles; Olanzapine; Pyridines; Pyrilamine; Rats; Receptor, Serotonin, 5-HT2C; Receptors, Histamine H1; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT2 Receptor Agonists; Time Factors; Weight Gain

Diana is a 21-year-old student who lives with her parents. She had been enrolled in college but has taken a temporary leave of absence due to the instability of her bipolar disorder. Since being diagnosed at age 18, Diana's treatment team has been unable to find a medication regimen that would maintain her stability. She has had several breakthrough manic episodes that resulted in significant risky and inappropriate behaviors on campus. The cognitive, motivational, and energy limitations of depression left her unable to keep up with school requirements. Dr. Spiker, her regular psychiatrist, prescribed olanzapine Zyprexa 5 mg. Both Diana and Dr. Spiker are concerned about potential weight gain but consider this intervention necessary, as other medication trials have been unsuccessful.

Topics: Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Combined Modality Therapy; Cooperative Behavior; Empathy; Female; Humans; Interdisciplinary Communication; Menu Planning; Olanzapine; Patient Care Team; Self Efficacy; Social Support; Weight Gain; Young Adult

Cardiometabolic effects of second-generation antipsychotic medications are concerning but have not been sufficiently studied in pediatric and adolescent patients naive to antipsychotic medication.. To study the association of second-generation antipsychotic medications with body composition and metabolic parameters in patients without prior antipsychotic medication exposure.. Nonrandomized Second-Generation Antipsychotic Treatment Indications, Effectiveness and Tolerability in Youth (SATIETY) cohort study, conducted between December 2001 and September 2007 at semi-urban, tertiary care, academic inpatient and outpatient clinics in Queens, New York, with a catchment area of 4.5-million individuals. Of 505 youth aged 4 to 19 years with 1 week or less of antipsychotic medication exposure, 338 were enrolled (66.9%). Of these patients, 272 had at least 1 postbaseline assessment (80.5%), and 205 patients [corrected] completed the study (60.7%). Patients had mood spectrum (n = 130; 47.8%), schizophrenia spectrum (n = 82; 30.1%), and disruptive or aggressive behavior spectrum (n = 60; 22.1%) disorders. Fifteen patients who refused participation or were nonadherent served as a comparison group.. Treatment with aripiprazole, olanzapine, quetiapine, or risperidone for 12 weeks.. Weight gain and changes in lipid and metabolic parameters.. After a median of 10.8 weeks (interquartile range, 10.5-11.2 weeks) of treatment, weight increased by 8.5 kg (95% confidence interval [CI], 7.4 to 9.7 kg) with olanzapine (n = 45), by 6.1 kg (95% CI, 4.9 to 7.2 kg) with quetiapine (n = 36), by 5.3 kg (95% CI, 4.8 to 5.9 kg) with risperidone (n = 135), and by 4.4 kg (95% CI, 3.7 to 5.2 kg) with aripiprazole (n = 41) compared with the minimal weight change of 0.2 kg (95% CI, -1.0 to 1.4 kg) in the untreated comparison group (n = 15). With olanzapine and quetiapine, respectively, mean levels increased significantly for total cholesterol (15.6 mg/dL [95% CI, 6.9 to 24.3 mg/dL] P < .001 and 9.1 mg/dL [95% CI, 0.4 to 17.7 mg/dL] P = .046), triglycerides (24.3 mg/dL [95% CI, 9.8 to 38.9 mg/dL] P = .002 and 37.0 mg/dL [95% CI, 10.1 to 63.8 mg/dL] P = .01), non-high-density lipoprotein (HDL) cholesterol (16.8 mg/dL [95% CI, 9.3 to 24.3 mg/dL] P < .001 and 9.9 mg/dL [95% CI, 1.4 to 18.4 mg/dL] P = .03), and ratio of triglycerides to HDL cholesterol (0.6 [95% CI, 0.2 to 0.9] P = .002 and (1.2 [95% CI, 0.4 to 2.0] P = .004). With risperidone, triglycerides increased significantly (mean level, 9.7 mg/dL [95% CI, 0.5 to 19.0 mg/dL]; P = .04). Metabolic baseline-to-end-point changes were not significant with aripiprazole or in the untreated comparison group.. First-time second-generation antipsychotic medication use was associated with significant weight gain with each medication. Metabolic changes varied among the 4 antipsychotic medications.

Topics: Adolescent; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Body Composition; Child; Child, Preschool; Cohort Studies; Dibenzothiazepines; Female; Humans; Lipid Metabolism; Lipids; Male; Olanzapine; Piperazines; Quetiapine Fumarate; Quinolones; Risk; Risperidone; Weight Gain

This analysis evaluated the usefulness of different predictors in identifying patient risk of substantial weight gain (SWG) during olanzapine treatment. Data were from 58 studies with 3826 patients diagnosed with schizophrenia, schizophrenia spectrum disorders, bipolar mania, bipolar depression, or borderline personality disorder. The primary definition for SWG was gaining >/=12% of baseline weight by endpoint (30 weeks +/-5 weeks); other definitions of SWG were also examined. Potential predictors of SWG included baseline patient characteristics, weight change, and percent weight change at Weeks 1, 2, 3, and 4 after olanzapine initiation. To facilitate model building and validation, the data set was randomly partitioned into training (N = 1912), validation (N = 1149), and test (N = 765) sets and 2 complementary analytic techniques were used: logistic regression with stepwise variable selection followed by receiver operating characteristic analysis for evaluation of resulting candidate models and decision trees. Approximately 24% of patients gained >/=12% of their initial weight, about 30% gained >/=10%, and 45% gained >/=7% or >/=5 kg by the 30-week endpoint. Baseline covariates significantly and positively associated with probability of SWG were lower baseline body mass index, younger age, female sex, United States residency, and African ethnicity. Early weight changes substantially improved the prediction of the risk for longer-term SWG. These results confirm that cut-offs for weight gain during the first 4 weeks of treatment may be useful in evaluating SWG risk for an individual patient.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Female; Humans; Male; Mental Disorders; Middle Aged; Models, Statistical; Olanzapine; Randomized Controlled Trials as Topic; Risk Factors; ROC Curve; Time Factors; Weight Gain

A mouse model of atypical antipsychotic-associated adverse effects was used to compare the liability to induce weight gain, food intake, and metabolic alterations after chronic olanzapine (OL; LY170053, 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-[2,3-b][1,5] benzodiazepine) and ST2472 (ST; 9-piperazin-1-ylpyrrolo[2,1-b][1,3]benzothiazepine) administration. By adding two equipotent doses (3 and 6 mg/kg) of either OL or ST to a high-sweet, high-fat (HS-HF) diet, mice were allowed to self-administer drugs up to 50 days. Body weight and food intake were evaluated daily. Locomotor activity was recorded over 48 h at two different time points. Dyslipidemia was measured by central visceral obesity. Blood serum levels of insulin (IN), glucose (Glu), triglycerides (TGs), nonesterified fatty acids (NEFAs), cholesterol (Ch), and ketone (Ke) bodies were quantified. OL treatment at 3 mg/kg enhanced body weight, whereas at the highest dose, the increase became evident only during the last 10 days of treatment. OL (3 mg/kg) increased HS-HF intake over time, whereas the highest dose reduced intake during the second 10 and final 10 days of administration. Both compounds induced nocturnal hypomotility at the highest dose. In contrast to ST, 3 mg/kg OL elevated serum levels of IN, Glu, TG, NEFA, Ch, and Ke, whereas 6 mg/kg OL elevated those of Glu, TG, and Ch. In contrast, ST did not affect weight gain, food intake, and metabolic markers. Given the similarities between OL-induced obesogenic effects and medical reports, this study further supports the view that ST may represent a new class of agents characterized by a low propensity to induce side effects with promising clinical safety.

Topics: Animals; Benzodiazepines; Body Weight; Hyperphagia; Metabolic Diseases; Mice; Olanzapine; Piperazines; Pyrroles; Thiazepines; Weight Gain

Therapeutic use of atypical antipsychotic agents is often associated with weight gain and impaired glucose tolerance. The once-daily human GLP-1 analog liraglutide improves glycemic control and reduces body weight. We have investigated the ability of liraglutide to improve olanzapine-induced metabolic effects in female rats. Female Sprague-Dawley rats were implanted with subcutaneous osmotic mini pumps for delivery of olanzapine (1.75 mg/24 h) or vehicle for 28 days (n=20). After 14 days, ten animals from each group were given liraglutide (0.2 mg/kg) or vehicle twice daily for the remainder of the study. Compared to vehicle treated animals, olanzapine infusion for 4 weeks significantly increased end point cumulated food intake (667.3+/-7.0 versus 593.2+/-13.2g, p<0.01), body weight (306.6+/-4.2 versus 276.4+/-3.6 g, p<0.001), subcutaneous inguinal fat (3.4+/-0.3 versus 1.9+/-0.1 g, p<0.001), mesenteric fat (3.1+/-0.2 versus 1.7+/-0.2g, p<0.001), retroperitoneal fat (6.2+/-0.6 versus 2.8+/-0.3 g, p<0.001), and impaired glucose tolerance, measured as total area under the glucose curve during an oral glucose tolerance test (1906+/-66 versus 1770+/-28 mMxmin, p<0.05). These olanzapine-induced elevations were significantly reduced by liraglutide (cumulated food intake: 601.8+/-20.4 g, p<0.01; body weight: 280.2+/-5.6 g, p<0.001; subcutaneous inguinal fat: 2.4+/-0.2 g, p<0.001; mesenteric fat: 1.8+/-0.1 g, p<0.001; retroperitoneal fat: 3.5+/-0.4 g, p<0.001; AUC: 1764+/-32 mMxmin, p<0.05). In conclusion, subcutaneous olanzapine infusion in female rats leads to weight gain and metabolic changes of which several are reversed following liraglutide treatment. It may therefore be relevant to study these effects of liraglutide in patients treated with atypically antipsychotics.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Body Composition; Body Weight; Drug Administration Schedule; Eating; Female; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Intra-Abdominal Fat; Liraglutide; Olanzapine; Rats; Rats, Sprague-Dawley; Subcutaneous Fat, Abdominal; Weight Gain

We investigated the relationships between functional genetic variants of the 5-HT(2C) receptor and multidrug-resistant protein (MDR1), coding for P-glycoprotein, and second generation antipsychotic (SDA)-induced weight gain among 108 female schizophrenic patients treated with olanzapine or risperidone for up to 4 months. No significant differences in -759C/T allelic and genotype variants of 5-HT(2C) were found between patients who gained more than 7% of their initial weight compared with those who gained less. Haplotype-based analysis of two MDR1 loci, exon 21 G2677T and exon 26 C3435T, revealed a slightly lower representation of the G2677/C3435 haplotype in the >or=7% group. In the subgroup of patients treated with risperidone, we found borderline overrepresentation of 2677T, significant overrepresentation of 3435T variant and borderline overrepresentation of 2677T/3435T haplotype the >or=7% group, whereas G2677/C3435 haplotype was found to be less represented in the >or=7% group. Our data indicate a nonsignificant role of 759C/T 5-HT(2C) in SDA-induced weight gain, and a stronger influence of the MDR1 G2677T and C3435T polymorphisms on risperidone-induced weight gain in female schizophrenic patients. 3435T and 2677T MDR1 variants, both associated with lower P-gp function, might predispose to higher risperidone accessibility to the brain that would lead to stronger effects, including weight gain.

Topics: Adult; Antipsychotic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzodiazepines; Drug Resistance, Multiple; Exons; Female; Gene Frequency; Genes, MDR; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Linkage Disequilibrium; Obesity; Olanzapine; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Receptor, Serotonin, 5-HT2C; Risperidone; Schizophrenia; Weight Gain

The aim of this study was to evaluate long-term weight gain associated with clozapine, olanzapine, and risperidone treatment and its clinical risk factors in children and adolescents. At four child and adolescent psychiatric departments, the weight and body mass index of initially hospitalized patients (aged 9.0-21.3 years) treated with clozapine (n = 15), olanzapine (n = 8), and risperidone (n = 10) were prospectively monitored for 45 weeks. Clinical risk factors (age, gender, baseline weight, dosage, drug-naivety) were tested for their association with weight gain in the three groups. All three groups experienced significant weight gain between baseline and endpoint. The absolute and percentage average weight gains were significantly higher for the olanzapine group (16.2 +/- 8.8 kg; 30.1 +/- 18.9%) than for the clozapine (9.5 +/- 10.4 kg; 14.8 +/- 15.8%) and the risperidone (7.2 +/- 5.3 kg; 11.5 +/- 6.0%) groups. Olanzapine is associated with extreme long-term weight gain in children and adolescents that, in addition, is much higher than that expected in adults. Clozapine and risperidone are associated with a less marked weight gain in children and adolescents but also much higher than that expected in adults. These differences may affect compliance with medication and health risk.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Child; Clozapine; Female; Hospitals, Psychiatric; Humans; Inpatients; Male; Olanzapine; Patch-Clamp Techniques; Risk Factors; Risperidone; Weight Gain; Young Adult

To make well informed treatment decisions for their patients, clinicians need credible information about potential risk for substantial weight gain. We therefore conducted a post-hoc analysis of clinical trial data, examining early weight gain as a predictor of later substantial weight gain.. Data from 669 (Study 1) and 102 (Study 2) olanzapine-treated patients diagnosed with schizophrenia, schizophreniform, or schizoaffective disorder were analyzed to identify and validate weight gain cut-offs at Weeks 1-4 that were predictive of substantial weight gain (defined as an increase of > or = 5, 7, 10 kg or 7% of baseline weight) after approximately 30 weeks of treatment. Baseline characteristics alone, baseline characteristics plus weight change from baseline to Weeks 1, 2, 3 or 4, and weight change from baseline to Weeks 1, 2, 3, or 4 alone were evaluated as predictors of substantial weight gain. Similar analyses were performed to determine BMI increase cut-offs at Weeks 1-4 of treatment that were predictive of substantial increase in BMI (1, 2 or 3 kg/m2 increase from baseline).. At Weeks 1 and 2, predictions based on early weight gain plus baseline characteristics were more robust than those based on early weight gain alone. However, by Weeks 3 and 4, there was little difference between the operating characteristics associated with these two sets of predictors. The positive predictive values ranged from 30.1% to 73.5%, while the negative predictive values ranged from 58.1% to 89.0%. Predictions based on early BMI increase plus baseline characteristics were not uniformly more robust at any time compared to those based on early BMI increase alone. The positive predictive values ranged from 38.3% to 83.5%, while negative predictive values ranged from 42.1% to 84.7%. For analyses of both early weight gain and early BMI increase, results for the validation dataset were similar to those observed in the primary dataset.. Results from these analyses can be used by clinicians to evaluate risk of substantial weight gain or BMI increase for individual patients. For instance, negative predictive values based on data from these studies suggest approximately 88% of patients who gain less than 2 kg by Week 3 will gain less than 10 kg after 26-34 weeks of olanzapine treatment. Analysis of changes in BMI suggests that approximately 84% of patients who gain less than .64 kg/m2 in BMI by Week 3 will gain less than 3 kg/m2 in BMI after 26-34 weeks of olanzapine treatment. Further research in larger patient populations for longer periods is necessary to confirm these results.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Female; Humans; Male; Obesity; Olanzapine; Psychotic Disorders; Risk Factors; Schizophrenia; Time Factors; Treatment Outcome; Weight Gain

Topics: Adult; Anorexia Nervosa; Antipsychotic Agents; Benzodiazepines; Bias; Cognitive Behavioral Therapy; Day Care, Medical; Double-Blind Method; Female; Humans; Motivation; Multicenter Studies as Topic; Obsessive Behavior; Olanzapine; Patient Compliance; Patient Dropouts; Randomized Controlled Trials as Topic; Treatment Refusal; Weight Gain

Leptin dysregulation has been implicated in the body weight gain and metabolic dysfunction observed with the second generation antipsychotic drugs (SGAD) olanzapine and clozapine.. This study quantified the frequency of subjects with abnormal correlation between leptin and the body mass index controlling for gender (defined as being out of the upper or lower 95% confidence interval in the regression line when combining each group with the drug-free subjects) after prolonged treatment with olanzapine (n=126), clozapine (n=62), first generation antiypsychotics (n=91), other SGAD (n=22), other psychotropic drugs (n=65) and drug-free subjects (n=229).. None of the analysis was significant (p>0.05). In fact, in 17 out of 20 comparisons, the drug-free group had numerically higher frequencies of outliers than the corresponding treatment group. There were 28 outliers (4.7% of the total sample). In agreement with previous studies, cross-sectional analysis did not report gross alterations in serum leptin levels during olanzapine or clozapine administration.. Longitudinal studies should focus on leptin regulation early on treatment, on the frequency of abnormal leptin receptor sensitivity and/or specific polymorphisms in the leptin allele and on several confounding factors in order to design personalized preventive and therapeutic measures.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Body Mass Index; Body Weight; Clozapine; Cross-Sectional Studies; Female; Humans; Insulin Resistance; Leptin; Male; Mental Disorders; Middle Aged; Olanzapine; Outliers, DRG; Receptors, Leptin; Schizophrenia; Sex Factors; Weight Gain

The aim of the study was to assess the effects of chronic olanzapine (Ola) administration on feeding behavior. Although atypical antipsychotics (AAPs) have greatly improved the management of schizophrenia and extrapyramidal symptoms, substantial bodies of literature point out that most of these agents are highly related to a major risk of metabolic drawbacks, leading to dyslipidemia and obesity. Among these compounds, Ola is one of the more weight gain-inducing AAPs. In the present study, we analyzed the Behavioral Satiety Sequence (BSS) in female mice given a palatable diet (wet mash) and chronically administered Ola (0.75, 1.5, 3 mg/kg per os) for 36 days. The results showed that administration of the highest dose of Ola postponed the onset of satiation, as suggested by the rightward shift of the BSS. This effect was confirmed by an increase in the actual food intake by the Ola (3 mg/kg) mice. These results suggest that one of the possible mechanisms involved in AAPinduced weight gain is alteration of the hunger-satiety regulation in female mice. These findings are consistent with the hypothesis that enhanced food intake and diminished central sensitivity to satiation signaling may cooperate in promoting weight gain and metabolic dysregulation in rodents and patients taking antipsychotic medications.

Topics: Administration, Oral; Analysis of Variance; Animals; Antipsychotic Agents; Benzodiazepines; Dose-Response Relationship, Drug; Eating; Feeding Behavior; Female; Mice; Olanzapine; Satiety Response; Time Factors; Weight Gain

Topics: Adult; Animals; Antipsychotic Agents; Benzodiazepines; Body Composition; Drugs, Chinese Herbal; Female; Humans; Mice; Olanzapine; Psychiatric Status Rating Scales; Schizophrenia; Weight Gain

Topics: Adolescent; Anorexia Nervosa; Antipsychotic Agents; Benzodiazepines; Child; Child Development Disorders, Pervasive; Feeding Behavior; Female; Humans; Olanzapine; Weight Gain

One of the clinically significant adverse effects of olanzapine treatment is weight gain, which shows substantial inter-individual differences and may be influenced by genetic variation. The aim of this investigation was identification of genetic risk factors associated with olanzapine-induced weight gain.. Inpatients with DSM-IV-TR schizophrenia (N = 164) were administered olanzapine for 8 to 24 (mean +/- SD = 17.9 +/- 9.4) weeks. The clinical background, body mass index (BMI), and clinical response to olanzapine were investigated. Twenty-one loci of diverse candidate genes encoding dopamine, serotonin (5-HT), histamine, and adrenergic receptors, tumor necrosis factor-alpha, ghrelin, adiponectin, and peroxisome proliferator-activated receptor gamma-2, were analyzed. The study was conducted from June 2001 to June 2003 at 4 psychiatric hospitals in Japan.. BMI increased by a mean +/- SD 4.3 +/- 10.7% after treatment with olanzapine (mean +/- SD dose = 15.5 +/- 5.8 mg/day). Olanzapine-induced weight gain correlated negatively with baseline BMI and positively with clinical global improvement and the length of olanzapine treatment (p < .0001), but it did not correlate with the daily dose of olanzapine, concomitant antipsychotics, sex, age, or smoking. Four genetic variants, the 102T allele of HTR2A, the 825T allele of GNB3, the 23Cys allele of HTR2C, and the 64Arg/Arg genotype of ADRB3, were significantly associated with olanzapine-induced weight gain. Stepwise regression analysis revealed that the baseline BMI predicted 12.5% of the weight gain, and the 2 latter genetic factors added 6.8%. The patients with double and triple genetic risk factors showed 5.1% and 8.8% BMI increases, respectively, during olanzapine treatment, whereas the patients with a single or no risk factor showed approximately a 1% BMI increase.. We identified genetic variants of 5-HT(2A) and 5-HT(2C) receptors, the G-protein beta-3 subunit, and the adrenergic receptor beta-3, as genetic risk factors for olanzapine-induced weight gain, and they showed additive genetic effects on weight gain.

Topics: Adult; Alleles; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Chromosome Mapping; Cohort Studies; Female; Genetic Predisposition to Disease; Genotype; Heterotrimeric GTP-Binding Proteins; Humans; Male; Middle Aged; Olanzapine; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Psychiatric Status Rating Scales; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Receptors, Adrenergic, beta-3; Risk Factors; Schizophrenia; Treatment Outcome; Weight Gain

Antipsychotic-induced weight gain has important effects on treatment compliance and long-term health. Several reports have indicated that a -2548A/G single-nucleotide polymorphism (SNP) of the leptin gene is associated with antipsychotic-induced weight gain. We hypothesized that there is a similar relationship between the -2548A/G SNP and olanzapine-induced weight gain. A total of 74 Korean schizophrenic patients were examined. Their weight was measured before starting olanzapine and after long-term treatment lasting for at least 3 months. The weight gain was significantly higher for patients with the AG genotype than for those with the AA genotype (p=0.029). Analysis of covariance also showed the difference of weight gain was still significant when adjusted for sex and treatment duration (p=0.046). This finding supports the presence of a relationship between the -2548A/G SNP of the leptin gene and weight gain in Korean schizophrenic patients receiving olanzapine treatment.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Female; Gene Frequency; Genotype; Humans; Korea; Leptin; Male; Middle Aged; Olanzapine; Polymorphism, Single Nucleotide; Schizophrenia; Weight Gain

The ability of clozapine to induce weight gain in female rats was investigated in three studies with progressively lowered doses of clozapine. In an initial preliminary high dose study, clozapine at 6 and 12 mg/kg (i.p., b.i.d.) was found to induce weight loss. In a subsequent intermediate dose study, we obtained no evidence for clozapine-induced weight gain despite using identical procedures and doses of clozapine (1-4 mg/kg, i.p., b.i.d.) with which we have observed olanzapine-induced weight gain, hyperphagia, enhanced adiposity and metabolic changes [Cooper G, Pickavance L, Wilding J, Halford J, Goudie A (2005). A parametric analysis of olanzapine-induced weight gain in female rats. Psychopharmacology; 181: 80-89.]. Instead, clozapine induced weight loss without alteration in food intake and muscle mass or changes in levels of glucose, insulin, leptin and prolactin. However, these intermediate doses of clozapine enhanced visceral adiposity and elevated levels of adiponectin. In a final study, low doses of clozapine (0.25-0.5 mg/kg, i.p, b.i.d.) induced weight loss. These data demonstrate that clozapine-induced weight gain can be much more difficult to observe in female rats than olanzapine-induced weight gain. Moreover, these findings contrast with clinical findings with clozapine, which induces substantial weight gain in humans. Clozapine-induced enhanced adiposity appears to be easier to observe in rats than weight gain. These findings, along with other preclinical studies, suggest that enhanced adiposity can be observed in the absence of antipsychotic-induced weight gain and hyperphagia, possibly reflecting a direct drug effect on adipocyte function independent of drug-induced hyperphagia [e.g. Minet-Ringuet J, Even P, Valet P, Carpene C, Visentin V, Prevot D, Daviaud D, Quignard-Boulange A, Tome D, de Beaurepaire R (2007). Alterations of lipid metabolism and gene expression in rat adipocytes during chronic olanzapine treatment. Molecular Psychiatry; 12: 562-571.]. These and other findings which show that the results of studies of antipsychotic treatment in animals do not always mimic clinical findings have important implications for the use of animal models of antipsychotic-induced weight gain. With regard to weight gain the results obtained appear to depend critically on the experimental procedures used and the specific drugs studied. Thus such models are not without limitations. However, they do consistently demonstrate the ability of various ant

Topics: Adiponectin; Adiposity; Animals; Antipsychotic Agents; Behavior, Animal; Benzodiazepines; Body Mass Index; Body Weight; Clozapine; Dose-Response Relationship, Drug; Eating; Female; Hyperinsulinism; Hyperphagia; Models, Animal; Olanzapine; Rats; Rats, Wistar; Research Design; Sex Factors; Weight Gain; Weight Loss

Weight gain induced by some second-generation anti-psychotics such as olanzapine has emerged as a most debilitating side-effect. This study investigates whether co-administration with either ziprasidone or aripiprazole, which have little propensity to induce weight gain, can attenuate the hyperphagic effect of olanzapine. Female hooded-Lister rats (n=8 per group) were treated acutely with either vehicle, olanzapine (1 mg/kg), ziprasidone (1 mg/kg), aripiprazole (2 mg/kg) or olanzapine in combination with ziprasidone or aripiprazole and placed in automated locomotor activity (LMA) boxes with preweighed palatable mash. Food intake and LMA were measured for 60 min postdrug treatment. All olanzapine-treated groups demonstrated significant increases in food intake (P<0.001). This effect was attenuated following co-administration of olanzapine with either ziprasidone or aripiprazole (P<0.001), neither of which affected food intake alone. The lack of hyperphagia induced by aripiprazole and ziprasidone may reflect an inherent pharmacological mechanism preventing weight gain.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Eating; Female; Hyperphagia; Motor Activity; Olanzapine; Piperazines; Quinolones; Rats; Thiazoles; Weight Gain

Weight gain can be an adverse effect of antipsychotics that significantly affects long-term health and treatment compliance. Many reports have suggested that the 5-HT2C receptor gene (HTR2C) is related to appetite and eating behaviours associated with body weight change. We hypothesized that there was a relationship between the HTR2C -759C/T polymorphism and olanzapine-induced weight gain.. Seventy-nine Korean schizophrenic patients were examined. Their weight was measured before starting olanzapine and after long-term treatment for at least 3 months. We controlled the use of drugs other than olanzapine except benzodiazepines and anticholinergics. Genotyping for the HTR2C -759C/T polymorphism was performed on all participants.. We found that long-term treatment with olanzapine resulted in mean gains in weight and BMI of 5.2 kg and 1.93 kg/m(2), respectively. However, body weight changes from baseline to the study endpoint were not significantly associated with genotypes. The frequency of the T allele did not differ significantly between subjects with weight gains below and above a clinically significant cutoff, defined as 7% relative to baseline (chi(2) = 0.213, P = 0.445), indicating that the T allele had no protective effect against olanzapine-induced weight gain.. The findings from this study do not support the presence of a relationship between the -759C/T polymorphism of the HTR2C gene and weight gain in Korean schizophrenic patients receiving olanzapine treatment.

Topics: Adult; Alleles; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Female; Humans; Korea; Longitudinal Studies; Male; Middle Aged; Olanzapine; Polymorphism, Genetic; Receptor, Serotonin, 5-HT2C; Schizophrenia; Weight Gain

Some atypical antipsychotics clinically used to treat schizophrenia induce weight gain by unknown mechanisms. The dorsal vagal complex (DVC) of the brainstem and the endogenous cannabinoid system are implicated in the regulation of appetite signalling and food intake. We investigated whether antipsychotic drugs alter cannabinoid receptor-binding density in the DVC. Female Spraguewk (short-term) or 120.83, p=0.01). In addition, only chronic olanzapine treatment increased food intake. These results show that olanzapine, an antipsychotic with a high risk of weight gain as a side-effect, significantly decreased cannabinoid receptor binding in the DVC, whilst aripiprazole and haloperidol, antipsychotics with a low risk of weight gain had little or no effect on binding. These results suggest that a mechanism for antipsychotic-induced weight gain may be through the modulation of cannabinoid receptors in the DVC.

Topics: Animals; Antipsychotic Agents; Autoradiography; Benzodiazepines; Binding, Competitive; Cyclohexanols; Female; Immunosuppressive Agents; Medulla Oblongata; Olanzapine; Protein Binding; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Tritium; Weight Gain

The aim of this study was to assess effectiveness and tolerability of oral olanzapine treatment of adolescents with schizophrenic disorders.. Adolescent patients (12-19 years) with schizophrenia, schizoaffective, or schizophreniform disorders according to the Diagnostic and Statistical Manual of Mental Disorders, 4(th) edition (DSM-IV) were enrolled in a multicenter, prospective, open-label study. Following a 2- to 9-day washout period, patients initially received 10 mg/day olanzapine. Dose modification was allowed during week 2 (dose range 5-15 mg/day) and during weeks 3-6 (dose range, 5-20 mg/day). Responders (improvement > or =30% on the Brief Psychiatric Rating Scale, BPRS) continued olanzapine for additional 18 weeks. Psychopathology was assessed using BPRS and Clinical Global Impressions (CGI) scales; side effects were assessed by adverse event reporting.. Out of 96 patients enrolled at 10 sites, 60 (62.5%) met response criteria at week 6. Mean BPRS total scores decreased significantly (p < 0.001) from baseline (39.2 +/- 13.4) to week 6 last observation carried forward (LOCF) (22.2 +/- 14.7). The rate of patients considered markedly ill or worse (CGI-S) decreased from 83.3% (baseline) to 37.5% (week 6, LOCF). The most common reported adverse event was weight gain (30.2%, 29/96). Three patients (3.1%) discontinued due to adverse events.. In this study of young patients with schizophrenia, schizoaffective, or schizophreniform disorders, olanzapine treatment was associated with marked symptom improvement. As changes in weight and prolactin levels may be greater in adolescent than in adult patients, potential risks and benefits of olanzapine treatment in adolescents should be considered carefully.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Child; Electrocardiography; Electroencephalography; Female; Humans; Male; Olanzapine; Prolactin; Prospective Studies; Psychotic Disorders; Schizophrenia; Weight Gain

Atypical antipsychotic drug therapy may result in substantial weight gain, increased adiposity and the promotion of metabolic abnormalities. The mechanism(s) which underlie such effects remain unclear. Previous studies in our laboratory have demonstrated significant weight gain in female rats maintained on a standard laboratory diet after sub-chronic administration of olanzapine and risperidone, but not ziprasidone. The aim of this paper is to investigate the effect of antipsychotic drugs on body weight, ingestive behaviour and adiposity in female rats with access to a high fat diet. Adult female rats given free access to a high fat diet received either olanzapine (2 mg/kg), risperidone (0.5 mg/kg), ziprasidone (2.5 mg/kg) or vehicle for 28 days. Body weight, food and water intake in addition to intra-abdominal fat deposition were assessed. Olanzapine initially increased body weight but by the end of the study olanzapine animals appeared to have lost weight compared to the vehicle-treated group. Olanzapine-induced reductions in body weight were accompanied by a significant hypophagia during weeks 3 and 4. Risperidone increased body weight during week 1 only and reduced intake of a high fat diet during weeks 3 and 4. Ziprasidone was without effect on indices of body weight and ingestive behaviour. There were no effects of antipsychotic drugs on intra-abdominal fat deposition. Access to a diet high in fat attenuated weight gain induced by olanzapine and risperidone in female rats.

Topics: Abdominal Fat; Animals; Antipsychotic Agents; Benzodiazepines; Dietary Fats; Drinking Behavior; Feeding Behavior; Female; Injections, Intraperitoneal; Olanzapine; Piperazines; Rats; Risperidone; Thiazoles; Weight Gain

Olanzapine (OLZ), one of the second-generation atypical antipsychotics (SGAs), has shown relative advantages in patient adherence and outcomes. However, OLZ has also been associated with a higher incidence of weight gain than most other SGAs. Excessive weight gain may in turn contribute to long-term health concerns for some individuals. Zonisamide (ZNS), a medication approved in the United States as an adjunct in the management of epilepsy, has a diverse pharmacological profile, including sodium channel blockade, monoamine enhancement, and inhibition of carbonic anhydrase. ZNS has also been reported to cause weight loss in both humans and rodents. We hypothesized that this profile might be beneficial when co-administered with OLZ. To test this hypothesis, we evaluated the effects of OLZ on body weight, as well as the pathways known to regulate feeding behavior and arousal in the Sprague-Dawley rat. As indicated via c-Fos expression, we found an OLZ-induced activation in the nucleus accumbens and orexin neurons in the lateral hypothalamus. An OLZ-associated development of hyperphagia, weight gain and elevated blood glucose in the rat was also found. These outcomes were attenuated and reversed in the presence of concomitant ZNS. These results suggest the hypothesis that ZNS may effectively treat or prevent weight gain or metabolic changes associated with the SGAs. Future studies of this combination in patients through appropriately designed human clinical studies are encouraged.

Topics: Animals; Anticonvulsants; Appetite Regulation; Benzodiazepines; Biomarkers; Body Weight; Diabetes Mellitus; Female; Hyperglycemia; Hyperphagia; Hypothalamic Area, Lateral; Intracellular Signaling Peptides and Proteins; Isoxazoles; Neurons; Neuropeptides; Nucleus Accumbens; Obesity; Olanzapine; Orexins; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Treatment Outcome; Weight Gain; Zonisamide

Antipsychotic (AP) treatment, in particular with some second-generation drugs, is associated with weight gain and other metabolic side effects. However, the relationship between drug-induced weight gain and dyslipidemia is not well understood. We investigated how cardiometabolic risk factors were related to body mass during treatment with different APs under real-life conditions.. This cross-sectional naturalistic study included 242 subjects with severe mental disorders who were on monotherapy with olanzapine (OLZ) or clozapine (CLZ) (n = 80), monotherapy with other APs (n = 80), or unmedicated (n = 82). Groups were adjusted for age and compared for prevalence of the metabolic syndrome and its components. Groups were further adjusted for body mass and compared for mean values of blood pressure, lipids, and fasting glucose.. There was no significant intergroup difference in the prevalence of metabolic syndrome, obesity, hypertension, or hyperglycemia. Despite similar body mass index, OLZ/CLZ-treated subjects had significantly higher prevalence of dyslipidemia (high triglyceride and low HDL cholesterol levels) than unmedicated subjects. They also had higher mean values of triglycerides (P = 0.003) and lower mean values of HDL cholesterol (P < 0.001). Patients treated with other APs had intermediate values.. Intergroup differences in body mass index were minimal in this naturalistic setting, probably because of awareness of this treatment hazard among clinicians. However, independently of body mass, dyslipidemia was significantly associated with AP treatment, in particular with OLZ and CLZ. These findings indicate a primary effect of APs on lipid regulation, important in understanding their mechanism of action, and with clinical implications.

Topics: Adolescent; Adult; Age Factors; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Cholesterol, HDL; Clozapine; Cross-Sectional Studies; Drug Therapy, Combination; Dyslipidemias; Female; Humans; Hypertension; Male; Metabolic Syndrome; Middle Aged; Obesity; Olanzapine; Prevalence; Psychotic Disorders; Schizophrenia; Sex Factors; Triglycerides; Weight Gain

The present study investigated body weight gain, food intake, open-field activity and brain histamine H1 receptor mRNA and protein expression in rats treated with three types of antipsychotics. Rats were divided into eight groups and treated with aripiprazole (2.25mg/kg/day), olanzapine (1.5mg/kg/day), haloperidol (0.3mg/kg/day) or vehicle (as control) for 1 or 12 weeks. Administration of olanzapine for 1 week led to a threefold increase in body weight gain and a 35% increase in fat deposits compared to controls (p<0.05). In the 12-week olanzapine treatment group, accumulative food intake was significantly higher in the first 7 weeks of treatment compared to controls (p<0.018), while body weight gain was significantly greater in the first 8 weeks compared to controls (p<0.045). Using in situ hybridization, we found that olanzapine treatment, but not aripiprazole or haloperidol treatment, significantly reduced H1 receptor mRNA expression in the arcuate hypothalamic nucleus (Arc: -18%, p=0.006, 1 week; -20%, p=0.008, 12 weeks) and ventromedial hypothalamic nucleus (VMH: -22%, p=0.006, 1 week; -19%, p=0.042, 12 weeks) compared to controls. The quantitative autoradiography data showed a reduction in VMH H1 receptor binding density after 1 (-12%, p=0.040) and 12 (-10%, p=0.094) weeks of olanzapine treatment. There were significant negative correlations between the levels of H1 receptor mRNA expression, and body weight gain and energy efficiency in the Arc and VMH after 1- and 12-week antipsychotic treatments in all groups. In addition, H1 receptor mRNA expression in the Arc showed a significant negative correlation with food intake and fat mass in all groups. Furthermore, there were negative correlations between H1 receptor binding density in the VMH and total fat mass and body weight gain after 1 week of antipsychotic treatment. The present study suggests that downregulated VMH and Arc H1 receptor expression may be a key factor contributing to olanzapine-induced obesity.

Topics: Adipose Tissue; Animals; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Eating; Female; Haloperidol; Olanzapine; Piperazines; Quinolones; Rats; Rats, Sprague-Dawley; Receptors, Histamine H1; RNA, Messenger; Time Factors; Ventromedial Hypothalamic Nucleus; Weight Gain

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Humans; Male; Metabolic Syndrome; Olanzapine; Schizophrenia; Weight Gain

Weight gain is a risk factor for hypertension, diabetes, ischemic heart disease, respiratory illnesses, various forms of cancer, and the metabolic syndrome. Obesity is common among psychiatric patients in general and among schizophrenia patients in particular. Antipsychotic treatment may contribute to obesity by increasing appetite. Weight gain may also be related to apathy regarding body enhancement, reduction of interest, and need for oral gratifications associated with psychiatric disorders.. We examined weight gain among inpatients who received anti-psychotic drug therapy for one year or longer and compared weight gain in patients treated with first and second generation antipsychotic therapy.. The study group included 70 patients treated with second-generation antipsychotic agents for one year or longer (risperidone N=40; olanzapine N=30). The control group included 30 patients who were treated with first generation antipsychotics. We compared weight prior to initiation of antipsychotic treatment and one year later, and demographic and medical data as recorded in the patients' medical files. Following one year of treatment 55% of the patients increased their weight, 2% remained at the same weight and 43% had lost weight.. Our study showed that there are differences in the direction of weight changes among the patients: while most of the patients gain weight during treatment, some lose weight. Consequently there is no alternative to personal follow up for each individual patient and personal treatment plans for medication, diet and physical exercise.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Female; Follow-Up Studies; Humans; Israel; Long-Term Care; Male; Middle Aged; Olanzapine; Risperidone; Schizophrenia; Weight Gain

The atypical antipsychotic drugs (AAPDs) have markedly enhanced the treatment of schizophrenias but their use has been hindered by the major weight gain elicited by some AAPDs. We report that orexigenic AAPDs potently and selectively activate hypothalamic AMP-kinase, an action abolished in mice with deletion of histamine H1 receptors. These findings may afford a means of developing more effective therapeutic agents and provide insight into the hypothalamic regulation of food intake.

Topics: Adenylate Kinase; Animals; Antipsychotic Agents; Enzyme Activation; Hypothalamus; Immunohistochemistry; Mice; Phosphorylation; Receptors, Histamine H1; Weight Gain

The receptor binding affinities of the three drug candidates 1 (SLV310), 2 (SLV313), and 3 (SLV314) were positioned against the results from nine (a)typical antipsychotic drugs. The receptor binding data from sixteen monoaminergic receptors served as the input in a principal component analysis (PCA). The PCA outcome revealed a unique binding profile of 1, 2, and 3 as compared with the reference compounds 4-8 and 10-12. The weight gain inducing antipsychotics 6-8 clustered in the PCA by scoring strongly negative for factor 1. The hyperprolactinaemia related antipsychotics 4, 5, 10, and 12 clustered by their negative scores for factor 2.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Benzoxazines; Biogenic Monoamines; Humans; Hyperprolactinemia; Indoles; Metabolic Diseases; Phthalimides; Piperazines; Principal Component Analysis; Pyridines; Radioligand Assay; Receptors, Biogenic Amine; Weight Gain

The atypical antipsychotic drug olanzapine increases body weight and visceral adiposity in schizophrenia. In rats, aging-associated increased body weight and visceral adiposity are reversed by administration of the pineal hormone melatonin. We asked if melatonin similarly would reverse olanzapine-induced increased weight and visceral adiposity in rats. Four groups (n=11/group) of female rats (240-250 g) were treated for 8 weeks with olanzapine, melatonin, olanzapine+melatonin, or vehicle alone in drinking water. Body weight and food and water consumption were determined weekly, locomotor activity at weeks 3 and 6, and nocturnal plasma melatonin concentration at week 7. At week 8, the rats were killed and visceral (perirenal, retroperitoneal, omental, and mesenteric) fat pads dissected and weighed. Olanzapine treatment reduced nocturnal plasma melatonin by 55% (p<0.001), which was restored to control levels by olanzapine+melatonin. Body weight increased 18% in rats treated with olanzapine alone, but only 10% with olanzapine+melatonin, 5% with melatonin alone, and 7% with vehicle control. Body weight and visceral fat pad weight increases in rats treated with olanzapine alone were greater than in each of the other three groups (all p<0.01), which were not significantly different. These results suggest that olanzapine-induced increases in body weight and visceral adiposity may be at least in part secondary to olanzapine-induced reduction of plasma melatonin levels, and that melatonin may be useful for the management of olanzapine-induced weight gain in humans.

Topics: Abdominal Fat; Animals; Antipsychotic Agents; Benzodiazepines; Energy Metabolism; Female; Lipid Metabolism; Melatonin; Obesity; Olanzapine; Pineal Gland; Rats; Rats, Sprague-Dawley; Schizophrenia; Up-Regulation; Weight Gain

Many of olanzapine's (OLZ) actions in humans related to weight regulation can be modelled in female rats (Cooper et al., 2005). Such effects include weight gain, hyperphagia, enhanced visceral adiposity and elevated Levels of insulin and adiponectin. As sex differences have been reported in the effects of antipsychotic drugs, including OLZ, in rats, the current study extended our study in female rats by directly comparing the actions of OLZ in maLes using identical methodology. Individually housed male Han Wistar rats were administered OLZ twice daily (i.p.), at 0, 1, 2, and 4 mg/kg over 21 days. Both differences from, and simiLarities to, the data obtained in females were obtained. Males treated with OLZ showed reduced weight gain, enhanced visceral adiposity and reduced lean muscle mass. There were no accompanying changes in food or water intake. OLZ did not induce changes in plasma levels of insulin, leptin or glucose. Significant elevation of adiponectin was observed. OLZ-treated males displayed elevated prolactin and suppressed testosterone. OLZ's effects in humans can very clearly be most validly modelled in female rats, although the cause(s) of the sex difference in OLZ's actions in rats are not clear. However, the finding that significantly enhanced adiposity is seen in both male and female rats, in other animal species (mice and dogs) and in humans suggests that studies in male rats of OLZ's effects may be of value, by highlighting the consistent ability of OLZ to increase visceral adiposity. It is hypothesized that such adiposity is a key, clinically relevant, common component of OLZ's actions which may be, at Least partially, independent of both OLZinduced weight gain and hyperphagia, and which is induced reliably in male and female rats and other animal species. Possible mechanisms involved in the effects reported are discussed.

Topics: Adiponectin; Adiposity; Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Dose-Response Relationship, Drug; Drinking; Eating; Female; Hyperphagia; Insulin; Leptin; Male; Metabolic Diseases; Olanzapine; Prolactin; Rats; Rats, Wistar; Sex Factors; Testosterone; Weight Gain

The study was aimed at the evaluation of weight gain associated with atypical antipsychotics and its clinical risk factors in children and adolescents. Weight and body mass index (BMI) of initially hospitalised patients treated with clozapine (n = 15), olanzapine (n = 15), and risperidone (n = 15) were prospectively monitored on a weekly basis for the first 6 weeks. Different clinical risk factors were tested for their association with weight gain in the three groups. All three groups experienced significant weight gain between baseline and endpoint (p < 0.0001). For all weight measures, planned comparisons were all significant between olanzapine vs. clozapine and risperidone, respectively. Average weight gain was significantly higher for the olanzapine group (mean = 4.6 kg, SD = 1.9) than for the risperidone (mean = 2.8 kg, SD = 1.3) and clozapine (mean = 2.5 kg, SD = 2.9) groups. Olanzapine and risperidone, but not clozapine, caused a disproportionately higher weight gain in children and adolescents in comparison to adults.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Body Weight; Child; Clozapine; Female; Humans; Male; Mental Disorders; Olanzapine; Risperidone; Weight Gain

Although antipsychotics are established drugs in schizophrenia treatment, they are admittedly known to induce side effects favoring the onset of obesity and worsening its complications. Despite potential involvement of histamine receptor antagonism, or of other neurotransmitter systems, the mechanism by which antipsychotic drugs increase body weight is not elucidated. The aim of the present study was to investigate whether chronic antipsychotic treatments can directly alter the regulation of two main functions of white adipose tissue: lipolysis and glucose utilization. The influence of a classical antipsychotic (haloperidol) was compared to that of two atypical antipsychotics, one known to favor weight gain (olanzapine), the other not (ziprasidone). Cell size, lipolytic capacity and glucose transport activity were determined in white adipocytes of rats subjected to 5-week oral treatment with these antipsychotics. Gene expression of adipocyte proteins involved in glucose transport or fat storage and mobilization, such as glucose transporters (GLUT1 and GLUT4), leptin, matrix metallo-proteinase-9 (MMP9), hormone-sensitive lipase (HSL) and fatty acid synthase (FAS) was also evaluated. Adipocytes from chronic olanzapine-treated rats exhibited decreased lipolytic activity, lowered HSL expression and increased FAS expression. These changes were concomitant to enlarged fat deposition and adipocyte size. Alterations were observed in adipocytes from olanzapine-treated rats whereas the other antipsychotics did not induce any notable disorder. Our results therefore show evidence of an effect of chronic antipsychotic treatment on rat adipocyte metabolism. Thus, impairment of fat cell lipolysis should be considered as a side effect of certain antipsychotics, leading, along with the already documented hyperphagia, to the excessive weight gain observed in patients under prolonged treatment..

Topics: Adipocytes; Animals; Antipsychotic Agents; Benzodiazepines; Cell Size; Drug Administration Schedule; Fatty Acid Synthases; Gene Expression Regulation; Glucose Transport Proteins, Facilitative; Haloperidol; Lipid Metabolism; Male; Obesity; Olanzapine; Piperazines; Rats; Rats, Sprague-Dawley; RNA; Statistics, Nonparametric; Sterol Esterase; Thiazoles; Weight Gain

Atypical antipsychotic drugs (AAD) induce significant weight gain in female C57BL/6J mice. The effect of dietary fat on weight gain and serum lipids in this model is unknown.. Test the hypothesis that the obesigenic effects of these drugs are greater in the presence of a high-fat diet.. Female C57BL/6J mice were treated with atypical antipsychotics for 3 weeks and fed either a low-fat or high-fat diet (4.6 vs 15.6% fat by wt). Food intake (FI), body weight (BW), body composition, and serum lipids were measured during treatment with optimized doses of olanzapine, quetiapine, and risperidone. Energy intake (EI) and feed efficiency (FE) were calculated. Group differences in change were analyzed via repeated measures analysis of variance (ANOVA). Serum lipid concentrations, EI and FE were compared using two-way ANOVA.. AAD-treated mice gained significantly more weight than controls after 3 weeks (P<0.001). Treatment and diet had significant effects on FI and EI over time (P<0.001). AAD-treated mice had significantly higher FE than controls (P<0.05); however, there was no significant drug by diet interaction (P=0.65). Risperidone low-fat mice gained significantly more absolute fat mass than placebo low-fat mice (P<0.05). All treatment groups, except quetiapine low-fat and olanzapine high-fat, gained significantly more absolute lean mass than placebo controls (P<0.05). Cholesterol levels were significantly lower in quetiapine and risperidone than placebo (P<0.05). Risperidone low-fat mice had significantly higher triglyceride levels than placebo and risperidone high-fat mice (P<0.05).. A high-fat diet does not increase AAD-induced BW gain in female mice during a 3-week treatment period.

Topics: Adipose Tissue; Administration, Oral; Animals; Antipsychotic Agents; Benzodiazepines; Body Composition; Bone Density; Dibenzothiazepines; Dietary Fats; Drug Administration Schedule; Eating; Energy Intake; Female; Lipids; Mice; Mice, Inbred C57BL; Olanzapine; Quetiapine Fumarate; Risperidone; Weight Gain

The objective of the current investigation was to determine the relationship between polymorphisms of the leptin system (leptin gene and leptin receptor) and olanzapine-induced weight gain in persons with schizophrenia.. Pharmacogenetic association reanalysis of a longitudinal, open label, six week, fixed dose trial of olanzapine response and adverse effects.. Thirty-seven males and females with clinically symptomatic schizophrenia (age, 23-52) meeting DSM-IV criteria.. Baseline and endpoint weight, BMI, olanzapine dose, plasma levels, and psychopathology measures were completed in a prior study. These subjects were subsequently genotyped for the -1548 G/A polymorphism of the leptin gene and the Q223R polymorphism of the leptin receptor. The relationship between alleles at each locus, olanzapine plasma levels, and percent change in body mass index (BMI) from baseline were conducted.. Genotypes and alleles for each locus were not individually associated with olanzapine-induced weight gain in this study population. Changes in BMI from baseline increased significantly in persons with olanzapine plamsa levels >20.6 ng/mL for subjects carrying at least one G allele at both candidate loci compared to those who did not have a G allele at each (P = 0.049).. This study suggests that genetic variability in the leptin gene and leptin receptor may predispose some individuals to excessive weight gain from increased exposure to olanzapine.

Topics: Adult; Alleles; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Female; Genetic Predisposition to Disease; Genotype; Humans; Leptin; Longitudinal Studies; Male; Middle Aged; Olanzapine; Pharmacogenetics; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Receptors, Cell Surface; Receptors, Leptin; Schizophrenia; Weight Gain

Significant weight gain is a serious side effect of many antipsychotic medications, yet successful strategies for significant weight loss are lacking. The transtheoretical model for weight management can be used to identify people who are ready to change (contemplation-preparation group) their eating habits and physical activity. This study compared characteristics of patients in Canada who had a psychotic disorder and were ready to make lifestyle changes with characteristics of patients who were not considering lifestyle changes.. Participants were surveyed to determine their stages of change for eating habits and physical activity, and various characteristics were measured, including body mass index, body image, nutritional intake, and level of physical activity.. A total of 101 participants (64 men) (mean+/-SD age 35+/-11 years) were taking antipsychotic medications. Seventy-one percent had schizophrenia spectrum disorders, and 15% had affective psychosis. The prevalence of patients identified as being ready for change was higher than expected: 68% for eating habits and 54% for physical activity. Participants who were ready to change eating habits were also ready to change physical activity habits (p<.04). Stages of change for eating habits were associated with body mass index (p<.004), whereas stages of change for physical activity were associated with self-reported vigorous (p<.001) and moderate (p<.005) physical activity but not mild physical activity.. Clinicians may help patients develop healthier eating and physical activity habits by using the transtheoretical model, because it identifies patients who are ready to change to healthier lifestyle strategies and may help patients with antipsychotic-induced weight gain.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clozapine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Exercise; Feeding Behavior; Female; Health Knowledge, Attitudes, Practice; Humans; Life Style; Male; Middle Aged; Nutrition Surveys; Olanzapine; Psychotic Disorders; Risperidone; Schizophrenia; Schizophrenic Psychology; Weight Gain

We compared stable patients with schizophrenia who were treated with either amisulpride or olanzapine in terms of symptomatic outcome, neurocognitive functioning, functionality, and subjective outcome.. Sixty outpatients with chronic schizophrenia who had been treated with either amisulpride or olanzapine for at least six months were investigated.. The scores of positive, negative, and cognitive symptoms did not differ between the two groups, but patients treated with olanzapine had significantly lower scores on the excitement and depression/anxiety components of the PANSS. With regard to cognitive variables, patients treated with amisulpride showed significantly lower values regarding verbal fluency and significantly better verbal memory than patients treated with olanzapine. Both treatment groups were comparable with respect to functional and subjective outcome variables.. These observations add to the evidence that continuous treatment with different second-generation antipsychotics with relatively few side effects leads to comparable outcomes in patients with schizophrenia.

Topics: Adult; Amisulpride; Antipsychotic Agents; Benzodiazepines; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Olanzapine; Outpatients; Psychiatric Status Rating Scales; Quality of Life; Schizophrenia; Schizophrenic Psychology; Social Behavior; Sulpiride; Treatment Outcome; Weight Gain

Topics: AMP-Activated Protein Kinase Kinases; Antipsychotic Agents; Benzodiazepines; Dibenzothiazepines; Humans; Hypothalamus; Olanzapine; Protein Kinases; Quetiapine Fumarate; Risperidone; Schizophrenia; Weight Gain

In this study, we investigated the effects of antipsychotic drugs, olanzapine and haloperidol, on the density of the muscarinic M2 receptors in the dorsal vagal complex (DVC) and hypoglossal nucleus (HN). Female Sprague Dawley rats were treated with olanzapine, haloperidol or vehicle (control) for 1 (short-term) or 12 weeks (long-term). Quantitative autoradiography was used to investigate the M2 receptor density in the DVC and HN using a muscarinic antagonist [(3)H] AF-DX384. Olanzapine, but not haloperidol, treatment induced a significant decrease in the binding density of M2 receptors in the DVC compared to control groups. Although the HN showed a higher density of [(3)H] AF-DX384 binding than the DVC, treatment with both olanzapine and haloperidol did not induce any significant changes in [(3)H] AF-DX384 binding in the HN. These results suggest that olanzapine-induced body weight gain may be associated with functional changes in the muscarinic neurotransmission in the DVC.

Topics: Animals; Antipsychotic Agents; Autoradiography; Benzodiazepines; Binding, Competitive; Female; Gene Expression Regulation; Medulla Oblongata; Olanzapine; Parasympatholytics; Pirenzepine; Rats; Rats, Sprague-Dawley; Receptor, Muscarinic M2; Tritium; Weight Gain

Atypical antipsychotics are often addressed as one class of drugs, although there are marked differences in their pharmacological profiles. It is unknown how this is seen by practitioners and to what extent they differentiate between the various atypical compounds. In a drug utilization study, 472 schizophrenic outpatients who were switched for individual reasons from either olanzapine or risperidone to amisulpride were monitored. Data on patients, illness and treatment as well as on reasons to switch were collected. The reasons to switch from olanzapine to amisulpride were preferably 'weight gain' (72.6% of the physicians), or the 'expectancy of less weight gain with amisulpride' (84.1%) and 'patient request' (60.2%). Specific reasons to switch from risperidone were 'extrapyramidal symptoms' (58.5%), or the 'expectancy of few extrapyramidal symptoms with amisulpride' (82.5%). In conclusion, this study confirms that physicians do not consider 'atypical antipsychotics' as one homogeneous class of drugs but make differences that reflect the specific pharmacological profiles of the respective drugs.

Topics: Adolescent; Adult; Amisulpride; Antipsychotic Agents; Benzodiazepines; Drug Utilization; Dyskinesia, Drug-Induced; Female; Germany; Humans; Male; Middle Aged; Olanzapine; Risperidone; Schizophrenia; Schizophrenic Psychology; Structure-Activity Relationship; Sulpiride; Weight Gain

Topics: Antipsychotic Agents; Benzodiazepines; Histamine H2 Antagonists; Humans; Nizatidine; Olanzapine; Schizophrenia; Weight Gain

Various antipsychotics are associated with body weight gain. However, most study samples include high proportions of patients with chronic schizophrenia. We examined neuroleptic-induced weight gain in drug-naïve first-episode psychotic patients to limit confounding variables such as multiple past medication trials, history of partial adherence; or poor diet and a sedentary lifestyle, associated with chronic mental illness.. Newly diagnosed first-episode psychosis patients treated with antipsychotic medication, a small group of patients not receiving antipsychotics, and healthy comparisons were followed for one year. Body weight differences and proportions of subjects with more than 7% weight gain were calculated. The effects of concomitant psychotropic medication on weight gain were explored.. Ninety-eight first-episode psychotics patient and 30 healthy controls were examined. Patients receiving neuroleptics gained significantly more weight than healthy controls (p=0.002). Olanzapine (91% gained >7%) increased body weight by 37.3+/-27.7 lb, followed by risperidone (51%; +16.6+/-22) and haloperidol (47%; +9+/-12), and perphenazine (10%; +3.4+/-6). Younger patients (r=-0.24, p=0.02) and patients with more negative symptoms at baseline (SANS global; r=0.22, p=0.04) gained more weight. A greater number of co-medications per patient, and co-prescription of antidepressants significantly and independently increased antipsychotic-associated weight gain.. The results confirm substantial and clinically significant weight gain introduced by antipsychotic treatment in drug-naïve first-episode psychotic patients, and identify several treatment-associated risk factors for weight gain. The magnitude of weight gain induced highlights potential health risks and points to the need for preventive measures such as behavioral weight control programs along with the initiation of pharmacotherapy.

Topics: Adult; Affective Disorders, Psychotic; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Haloperidol; Humans; Male; Olanzapine; Perphenazine; Psychiatric Status Rating Scales; Reference Values; Risperidone; Schizophrenia; Weight Gain

Following our report of a linkage at 12q24 with a phenotype of obesity under antipsychotics, we tested the pro-melanin-concentrating hormone (PMCH) candidate gene for a possible association in humans with the body mass index (BMI; kg/m2) in unrelated schizophrenic patients (SZ) receiving antipsychotics (N = 300) and in controls (CTL; N = 150). Subjects were classified in obese (OB) (BMI > or = 30 kg/m2), overweight (25 < or = BMI < 30 kg/m2), and normal weight (BMI < 25 kg/m2) groups. Single nucleotide polymorphisms (SNP) rs7973796 and rs11111201, located 5' at -4.5 kb and 3' at +1.8 kb, respectively, of PMCH were genotyped. Interaction effects of genotypes and antipsychotic treatment on BMI were tested in a covariance analysis with age and gender as covariates. Interaction effects on the prevalence of obesity were tested in a logistic regression analysis. For subjects under 50 years, the effect of the rs7973796 genotype on BMI differed between the SZ patients taking olanzapine and CTL group (interaction P = 0.025). Olanzapine-treated SZ patients carrying the ancestral homozygote genotype showed a higher BMI for rs7973796 (P = 0.016 with the LSMeans t-test) than the variant homozygotes. Accordingly, the ORs for obesity associated with rs7973796 genotypes differed in the SZ patients taking olanzapine compared to the CTL group (interaction P = 0.0094). The G allele was associated with an increase in the odds of obesity in SZ patients taking olanzapine. No association was observed for those over 50 years, or for rs11111201. These results suggest that the common allele of PMCH rs7973796 may be associated with a greater BMI in olanzapine-treated SZ patients.

Topics: Adult; Age Distribution; Aged; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Case-Control Studies; Female; Genetic Linkage; Genetic Predisposition to Disease; Genotype; Homozygote; Humans; Hypothalamic Hormones; Male; Middle Aged; Obesity; Olanzapine; Polymorphism, Single Nucleotide; Protein Precursors; Psychotic Disorders; Schizophrenia; Sex Distribution; Weight Gain

Weight gain is common adverse effect associated with the use of most typical and atypical antipsychotic. Aim of this study was to investigate plasma lipids, lipoproteins and some hormones levels during olanzapine treatment in patients with psychosis. The study population comprised twenty nine patients (29) diagnosed with psychosis and eleven patients (11) with endogenous depression. Plasma cholesterol, triglicerides, phospholipids, high-density lipoprotein cholesterol (HDL-C), very-low-density lipoprotein cholesterol (VLDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A-I (ApoA-I) and apolipoprotein B (Apo B), and hormones - prolactin, cortisol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone and estradiol were measured by auto-analyzer and by classic photometric methods. All measurements were performed before and during one-year treatment with olanzapine and antidepressant. Treatment of the schizophrenic patients with olanzapine caused a great metabolic impact that is primarily expressed in body mass, cholesterol increase and statistically significant rise of BMI, respectively. Body mass increase could be explained by the fact that olanzapine blocked not only dopaminergic, serotonergic, cholinergic, alpha-adrenergic but histaminergic receptors as well.

Topics: Antipsychotic Agents; Benzodiazepines; Depressive Disorder; Hormones; Humans; Lipids; Lipoproteins; Olanzapine; Psychotic Disorders; Selective Serotonin Reuptake Inhibitors; Weight Gain

The aim of this study was to compare clinical and health services outcomes in pediatric inpatients prescribed an atypical antipsychotic (AA) to those not prescribed an AA at discharge.. Descriptive statistics, analysis of variance (ANOVA), and, where necessary, analysis of covariance (ANCOVA) were used to compare differences between and within an inpatient group prescribed risperidone, olanzapine, or quetiapine (n=1,131) with an inpatient group not prescribed an antipsychotic at discharge (n=1,741).. The AA treatment group showed greater psychiatric symptom difficulty at admission as measured by the Brief Psychiatric Rating Scale for Children (Mean BPRS-C) than the group not prescribed AAs (40.3 [n=433] vs. 35.2 [n=452], respectively, p<0.001). AA-treated inpatients also had a higher number of mental health outpatient visits during the 6 months prior to admission. Patients receiving AAs (n=1,050) had significantly longer adjusted length of stay (LOS) than those not receiving antipsychotics (n=1,664): 26.4 days versus 22.4 days, respectively (p<0.04).. The findings suggested pediatric inpatients presenting with greater psychiatric symptom difficulty at hospital admission were more likely to be prescribed an AA. Choice of AA may influence certain clinical and health services outcomes. Additional prospective controlled studies evaluating AA efficacy and safety, including head-to-head comparisons, in pediatric inpatients are warranted.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Brief Psychiatric Rating Scale; Child; Child, Preschool; Dibenzothiazepines; Female; Humans; Length of Stay; Male; Mental Disorders; Olanzapine; Outcome and Process Assessment, Health Care; Practice Patterns, Physicians'; Quetiapine Fumarate; Retrospective Studies; Risperidone; Weight Gain

Olanzapine is a second-generation atypical antipsychotic drug (AAPD). Major side effects of olanzapine are weight gain and development of diabetes mellitus, which are risk factors of cardiovascular diseases. The possible causes of metabolic adverse effects are known as poor satiety and increased food intake due to blockade of receptors such as 5-HT(2C) in CNS. In this study, we examine the effect of olanzapine on peripheral adipogenesis using cultured 3T3-L1 cell model. Olanzapine increased triacylglyceride (TG) accumulation during 3T3-L1 preadipocyte differentiation to mature adipocyte phenotype. TG accumulation was accompanied by overexpression of fatty acid synthase and adiponectin that are the downstream genes of sterol regulatory element binding protein-1 (SREBP-1), one of the key transcription factors in lipid homeostasis. We further consisted that mostly SREBP-1 and at a lesser extent peroxisome proliferator-activated receptor gamma (PPAR-gamma), but not CCAAT/enhancer binding protein-alpha (C/EBP-alpha), were overexpressed and activated in 3T3-L1 adipocytes exposed to olanzapine. Furthermore, we showed that olanzapine enhanced the activity of SRE-1-containing LDLR promoter in transfected 3T3-L1 adipocytes and HepG2 cells. Taken together, olanzapine may cause body weight gain not only through influencing CNS receptors, but also affecting the peripheral adipogenesis regulated by SREBP-1.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Adiponectin; Animals; Antipsychotic Agents; Benzodiazepines; Cell Line, Tumor; Fatty Acid Synthases; Gene Expression Regulation; Hepatocytes; Humans; Mice; Olanzapine; Phenotype; PPAR gamma; Promoter Regions, Genetic; Receptors, LDL; RNA, Messenger; Sterol Regulatory Element Binding Protein 1; Transfection; Triglycerides; Up-Regulation; Weight Gain

We compared the changes in weight (kg) and body mass index (BMI) (kg/m(2)) in 52 hospitalized adolescents between baseline and after 12 weeks of monotherapy with either (i) olanzapine (OLZ) orally disintegrating tablets (ODT) (N=16; 16.6 mg/day+/-4.4 [SD]), or (ii) OLZ standard oral tablets (SOT) (N=10; 18.0 mg/day+/-4.2), or (iii) risperidone (N=26; 2.8 mg/day+/-1.2). Significantly greater increases in mean weight and BMI were observed in the patients treated with OLZ SOT (8.9+/-5.1 [SD] kg; 1.9+/-0.6 kg/m(2), respectively) than in those with ODT (3.0+/-2.1 kg; 1.1+/-0.8 kg/m(2)). Similarly, OLZ ODT treatment was associated with significantly greater increases in weight and BMI than risperidone (1.0+/-1.8 kg; 0.4+/-0.7 kg/m(2)). These findings suggest that adolescents gain less weight with OLZ ODT than OLZ SOT, possibly because the former formulation shortens the time of interaction with digestive serotonin receptors mediating satiety.

Topics: Administration, Oral; Adolescent; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Drug Administration Routes; Female; Humans; Male; Olanzapine; Risperidone; Schizophrenia; Tablets; Weight Gain

Many antipsychotics cause weight gain in humans, but usually not in rats, when injected once or twice daily. Since blood antipsychotic half-lives are short in rats, compared to humans, chronic administration by constant infusion may be necessary to see consistent weight gain in rats. Male and female rats were implanted with mini-pumps for constant infusion of olanzapine (5 mg/kg/day), clozapine (10 mg/kg/day) or vehicle for 11 days. Food intake and body weight were measured; blood drug levels were measured by HPLC. Olanzapine increased food intake and body weight in female, but not male rats. Serum olanzapine concentrations were 30-35 ng/ml. Clozapine had no effect on food intake or body weight in female or male rats. Serum clozapine concentrations were about 75 ng/ml. Single-dose pharmacokinetic analysis revealed a serum terminal half-life of 1.2-1.5 h for each drug, with no sex differences. Despite the fact that olanzapine and clozapine promote weight gain in humans, these drugs appear to have minimal effects on body weight and food intake in rats, except for a modest effect of olanzapine in female rats, even though therapeutic levels of olanzapine are achieved in serum during chronic infusion. Hence, the rapid clearance of drug following single administration in previous studies cannot explain the weak or absent effects of antipsychotics on weight gain in this species. The rat thus appears to be an inadequate model of weight gain produced by some antipsychotics in humans.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Clozapine; Eating; Female; Male; Olanzapine; Rats; Rats, Sprague-Dawley; Weight Gain

Topics: Adult; Akathisia, Drug-Induced; Antipsychotic Agents; Appetite; Aripiprazole; Benzodiazepines; Drug Therapy, Combination; Female; Humans; Male; Metabolic Diseases; Obesity; Olanzapine; Piperazines; Quinolones; Schizophrenia; Weight Gain

Topics: Adolescent; Age Factors; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Humans; Obesity; Olanzapine; Psychology, Adolescent; Randomized Controlled Trials as Topic; Risk Assessment; Weight Gain

Topics: Antipsychotic Agents; Benzodiazepines; Drug Labeling; Humans; Olanzapine; Weight Gain

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Diabetes, Gestational; Female; Humans; Olanzapine; Pregnancy; Pregnancy Complications; Weight Gain

Topics: Antipsychotic Agents; Benzodiazepines; Humans; Olanzapine; Outcome Assessment, Health Care; Proportional Hazards Models; Research Design; Schizophrenia; Weight Gain

Despite advances in schizophrenia treatment, nearly 30% of patients do not respond to atypical antipsychotic agents, such as olanzapine. Furthermore, 30-60% of patients will gain significant weight during the course of olanzapine therapy. Little research has been done to investigate the relationship between antipsychotic treatment outcomes and genetic variability in second messengers coupled to serotonin (5HT) receptors. The purpose of this investigation was examine associations between the second messenger G-Protein Beta3 Subunit Gene (GNB3) C825T polymorphism and olanzapine response and weight gain treatment.. We conducted a pharmacogenetic association study to examine GNB3 genotypes in relation to olanzapine clinical response (as measured by the Brief Psychiatric Rating Scale or Scale for the Assessment of Negative Symptoms) or weight gain. Subjects included forty-two individuals meeting DSM-IV criteria for schizophrenia that started olanzapine, were titrated to a fixed dose for 6 weeks, and subsequently genotyped for this investigation.. No statistically significant associations existed between our outcome variables and GNB3 genotypes. However we did observe trends suggesting a potential relationship between the TT genotype, response, and weight gain that warrant further investigation.. Preliminary results showed no statistical relationship between the C825T polymorphism and olanzapine response or weight gain. Numerical differences in outcome measures between the TT vs. CT/CC genotype groups indicate that G-protein second messenger systems variability coupled to primary targets of atypical antipsychotics may relate to clinical outcomes in persons with schizophrenia and that future research in this area is warranted.

Topics: Adult; Antipsychotic Agents; Base Sequence; Benzodiazepines; DNA; Female; Heterotrimeric GTP-Binding Proteins; Humans; Male; Obesity; Olanzapine; Pilot Projects; Polymorphism, Single Nucleotide; Protein Subunits; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Weight Gain

There is retrospective evidence of a correlation between psychosis in multiple sclerosis (MS) patients and temporal lobe pathology. A 35-year-old woman with MS presented with psychosis. There was no concurrent history of medication/substance use or family history. Comparison with previous MRI scans showed significant progression of lesions within the periventricular white matter of the left temporal lobe. This case highlights the association of psychosis and MS progression with worsening of left temporal lobe lesions. Prospective studies are required to ascertain the extent to which left temporal lobe lesions are predictive of future psychosis.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Delusions; Excitatory Amino Acid Antagonists; Female; Hallucinations; Humans; Lamotrigine; Magnetic Resonance Imaging; Multiple Sclerosis; Olanzapine; Pain; Psychotic Disorders; Risperidone; Temporal Lobe; Triazines; Weight Gain

Body weight gain is a worrying side effect of many new antipsychotic drugs. The mechanisms by which antipsychotic drugs increase weight in humans are not known. Attempts to model the metabolic effects of antipsychotic drugs in the animal have not been successful. Female rats appear to be sensitive to the effects of antipsychotics, but male rats less, and this does not match the clinical situation in humans. In previous rodent studies, antipsychotics were always given by daily gavage or injections. Antipsychotics have different pharmacokinetics in rodents and humans, and in the present study, we tested the hypothesis that the insensitivity of male rats to the effects of antipsychotics could be related to their mode of administration. Thus, we administered antipsychotic drugs mixed with the food. Animals were treated during 6 weeks with haloperidol (1mg/kg), olanzapine (1mg/kg), ziprasidone (10mg/kg), or a control solution. Animals were allowed to self-select food among three macronutrients (carbohydrates, lipids and proteins). Food selection was measured throughout the study. At the end of the study, body composition was measured by dissection and weighing of the rat's main organs and tissues. Mitochondrial thermogenesis was measured in brown adipose tissue in olanzapine-treated animals. Circulating leptin, insulin, glucose, triglycerides, cholesterol, high-density lipoprotein (HDL) were also assayed at the end of the study. The results show that none of the antipsychotic treatments modified caloric intake, food selection or body weight. Olanzapine did not alter mitochondrial thermogenesis. However, haloperidol and olanzapine induced a significant increase in adiposity and circulating leptin. Ziprasidone produced a moderate fat accumulation. It is concluded that mixing antipsychotic treatments with the food provides a reliable animal model of antipsychotic-induced fat accumulation.

Topics: Adipose Tissue; Animal Feed; Animals; Antipsychotic Agents; Benzodiazepines; Eating; Haloperidol; Male; Olanzapine; Organ Size; Random Allocation; Rats; Rats, Sprague-Dawley; Thermogenesis; Weight Gain

In a putative animal model of antipsychotic drug-induced weight gain, female rats received either vehicle, ziprasidone (2.0, 6.0, 10 mg/kg) or olanzapine (2.0 mg/kg), orally, twice daily, for 7 days. Body weights were assessed daily and prolactin assayed at the end of the regimen. Ziprasidone caused significant weight gain, as did olanzapine, while stimulating distinct patterns of prolactin secretion. Thus, assessment of body weight provides only limited predictive validity in differentiating between weight gain-inducing and weight-neutral drugs.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Body Weight; Female; Olanzapine; Piperazines; Prolactin; Rats; Rats, Sprague-Dawley; Thiazoles; Weight Gain

The following is a case report analysis intended to draw attention to the need for better care coordination by describing the observed relationship of olanzapine to metabolic changes manifested as uncontrolled diabetes mellitus and weight gain. A 47-year-old male with bipolar I disorder/hallucinations presented to the Veterans Affairs Medical Center (VAMC) with suicidal ideations. He was referred to the psychiatry service where he was treated with olanzapine. He was followed exclusively by the psychiatry service for more than a year. During that time,weight issues and diabetes status were not addressed. Upon presenting to the primary care service a year and a half later, the patient was taking 40 mg per day of olanzapine and had gained 62 pounds, a 30% increase in body weight; glycosylated hemoglobin (A1c) was 11.1%. The patient was enrolled in a weight-loss clinic, and his diabetes medications were adjusted.Subsequently, olanzapine was discontinued because of weight gain and uncontrolled diabetes. Blood sugar and A1c were finally stabilized one month after discontinuation of olanzapine (A1c,6.9%). The patient experienced a relapse in his bipolar disorder,and olanzapine was restarted at 20 to 40 mg per day. His blood sugar became uncontrolled, he gained 13 pounds, and his A1c increased to 9.4%.

Topics: Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Diabetes Mellitus, Type 2; Humans; Hyperglycemia; Hypoglycemic Agents; Male; Middle Aged; Olanzapine; Weight Gain

Topics: Antipsychotic Agents; Benzodiazepines; Heterotrimeric GTP-Binding Proteins; Humans; Olanzapine; Pharmacogenetics; Polymorphism, Single Nucleotide; Protein Subunits; Schizophrenia; Weight Gain

Weight gain and the risk of developing alterations in lipid and glucose metabolism are possible side effects of atypical antipsychotic therapy in young and adult patients. The objective of this study was to examine whether elderly patients with Alzheimer's disease (AD) gain weight or develop disturbances in lipid and glucose metabolism while being treated with atypical antipsychotic drugs.. This retrospective study identified 36 out of 99 patients (mean age: 75.4+/-7.1, 27 female, 9 males) who were taking risperidone (N=9, mean dosage: 1.42+/-0.49 mg/day), olanzapine (N=17: 4.42+/-1.10 mg/day), and quetiapine (N=10: 75+/-27 mg/day) over a 12 months period. Anthropometric parameters, mini nutritional assessment (MNA), total, HDL and LDL cholesterol, triglycerides, glycaemia were assessed at baseline (T0) and 12 (T1) months.. Body weight (BMI=23+/-5 vs 23+/-5), MNA score (21+/-4 vs 21+/-4), blood glucose (5.7+/-2 vs 4.9+/-0.9 mmol/L) or total cholesterol (4.9+/-1.1 vs 4.3+/-0.7 mmol/L), HDL cholesterol (1.3+/-0.3 vs 1.1+/-0.3 mmol/L), LDL cholesterol (3.3+/-0.7 vs 3 +/- 0.4 mmol/L), triglycerides (1.1+/-0 vs 1+/-0.3 mmol/L) did not reveal treatment-induced changes in the patients evaluated (T0 vs T1).. These results suggest that the treatment with low-dose of atypical antipsychotic drugs is not associated with weight gain or increase the risk of developing type II diabetes or abnormalities of lipid metabolism among elderly patients with AD, who were residing in long-term nursing home.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Dibenzothiazepines; Female; Humans; Lipids; Male; Mental Disorders; Nursing Homes; Olanzapine; Quetiapine Fumarate; Retrospective Studies; Risperidone; Weight Gain

Atypical antipsychotics, such as olanzapine, have been associated with clinically significant weight gain. Changes to the hypothalamic pituitary adrenal axis may partially mediate this weight increase. Two experiments were conducted to test the effects of mifepristone on both mitigating and preventing olanzapine-induced weight gain. In the first experiment, adult female Sprague-Dawley rats gained significantly more weight on average when administered olanzapine for 35 days compared to vehicle controls. Subsequently, the olanzapine-treated rats were randomized to three dose levels of mifepristone (20, 60, and 200 mg/kg) in conjunction with olanzapine. Weight measurements were taken for 21 additional days. Rats receiving olanzapine plus mifepristone rapidly lost a significant portion of the weight gained during the olanzapine only phase (p = 0.0001). Rats in the 200 mg/kg dose group had significantly less abdominal fat compared to controls (p < 0.001) at study end. In the second experiment, daily mifepristone (20, 60, 200 mg/kg) initiated concomitantly with olanzapine was compared with olanzapine alone to determine if mifepristone prevented olanzapine-induced weight gain. After 21 days of treatment, mifepristone treated rats gained significantly less weight and had significantly less abdominal fat than rats administered olanzapine alone (p = 0.0002). Results suggest that mifepristone, a potent glucocorticoid antagonist, may both reduce and prevent olanzapine-induced weight gain in rats.

Topics: Abdominal Fat; Analysis of Variance; Animals; Antipsychotic Agents; Benzodiazepines; Body Weight; Dose-Response Relationship, Drug; Drug Interactions; Female; Hormone Antagonists; Mifepristone; Olanzapine; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Glucocorticoid; Receptors, Progesterone; Weight Gain

Weight gain is a common and severe side effect of antipsychotic drugs. A usual tool to study the side effects of psychotropic drugs is animal models. However, attempts to create an animal model of antipsychotic-induced weight gain were not successful so far. Female rodents are sensitive to the effects of antipsychotics, but not males. This does not match the human clinical situation. Antipsychotics have different pharmacokinetic properties in rats and humans, and rats and humans have different spontaneous diets.. In the present study, we tested the hypothesis that the insensitivity of male rats to the weight-promoting effects of antipsychotics could be related to the mode of administration of antipsychotics and to the animals' diet. Antipsychotics were mixed with the food, and rats were fed a diet resembling the human diet. Rats were treated with 0.01, 0.1, 0.5, and 2 mg/kg of olanzapine or with a control solution for 6 weeks. Their weight and food intake were recorded, and their body composition were analyzed. The effects on weight and food intake of olanzapine (1 mg/kg), haloperidol (1 mg/kg), and ziprasidone (10 mg/kg) were also compared in a 3-week treatment experiment.. The results showed that 0.5 and 2 mg of olanzapine, but not lower doses, increase body weight and subcutaneous fat deposition. After the 3-week treatment, olanzapine-treated rats, but not haloperidol- or ziprasidone-treated rats, had significantly increased their weight.. This study shows that a rat model of obesity induced by antipsychotics can be created under specific conditions of drug administration, diet, and dose.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Body Composition; Body Weight; Circadian Rhythm; Diet; Disease Models, Animal; Dose-Response Relationship, Drug; Eating; Feeding Behavior; Haloperidol; Male; Obesity; Olanzapine; Piperazines; Rats; Rats, Sprague-Dawley; Thiazoles; Time Factors; Weight Gain

We compared fasting lipids and other metabolic parameters in 211 normoglycemic patients meeting the DSM-IV diagnosis of schizophrenia or schizoaffective disorder undergoing continuous treatment with olanzapine, risperidone, or typical antipsychotics for at least 1 year. Blood samples were obtained after an 11-hour (+/-1 h) observed fast. Olanzapine-treated patients had significantly higher mean fasting triglyceride levels (2.3 +/- 1.8 mmol/L) than risperidone- (1.7 +/- 0.9 mmol/L, P = 0.022), but not typical antipsychotic-treated patients (1.8 +/- 1 mmol/L). There were no significant differences in total low-density (LDL-C) or high-density lipoprotein cholesterol levels. Apolipoprotein-B and very low density lipoprotein cholesterol levels were significantly higher in the olanzapine- versus risperidone-treated patients, but there were no significant differences between olanzapine- and typical antipsychotic-treated patients. Treatment groups did not differ significantly in LDL particle size, the prevalence of an "atherogenic" lipid profile, or estimated insulin sensitivity. Although interpretation of this study is limited by the cross-sectional study design, it provides additional insight concerning the relationship between antipsychotic use and plasma lipid parameters in this population.

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Cross-Sectional Studies; Drug Therapy, Combination; Fasting; Female; Humans; Lipids; Lipoproteins, VLDL; Male; Middle Aged; Olanzapine; Risperidone; Schizophrenia; Triglycerides; Waist-Hip Ratio; Weight Gain

Topics: Adolescent; Age Factors; Antipsychotic Agents; Benzodiazepines; Ethics, Medical; Ethics, Research; Female; Hippocratic Oath; Humans; Male; Obesity; Olanzapine; Placebos; Randomized Controlled Trials as Topic; Schizophrenia; Schizophrenic Psychology; Weight Gain

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Dose-Response Relationship, Drug; Humans; Hypertriglyceridemia; Male; Obesity; Olanzapine; Schizophrenia; Weight Gain

P-glycoprotein (PGP) is a polymorphic efflux transporter located on the blood brain barrier that potentially affects the penetration of atypical antipsychotics into the central nervous system. Increased antipsychotic penetration to the primary site of activity may result in greater symptom improvement or the occurrence of side effects. This investigation examined the relationship between three common PGP polymorphisms (C1236T, G2677TA, and C3435T) and response to 6 weeks of open-label olanzapine treatment in patients with schizophrenia. Individuals with a PGP T allele at any of these polymorphisms would be expected to have greater antipsychotic penetration through the blood brain barrier, due to lower PGP activity. Forty-one patients were included in this reanalysis. For subjects in the 3435T allele carrier group, the plasma olanzapine level alone was positively associated with percent change in Brief Psychiatric Rating Scale score (p = 0.02). This relationship was not seen for the 3435CC group (p = 0.583). A similar trend was observed for negative symptom reduction, olanzapine plasma concentration, and the 3435T allele (p = 0.06), but this relationship did not meet statistical significance. There was no relationship between the PGP genotypes and changes in weight over the course of this 6 week study. The analysis using C1236T or G2677AT genotypes gave similar results, due to linkage of these polymorphisms.PGP polymorphisms may affect the penetration of olanzapine into the central nervous system as seen by a relationship between the 3435T allele, olanzapine plasma levels, and reduction in the positive symptoms of schizophrenia. This may stem from greater olanzapine central nervous system latency due to the presence of the 3435T allele and reduced PGP activity. The PGP C3435T genotype may help to determine positive symptom reduction from olanzapine clinically, but these findings should be replicated in a larger sample of subjects.

Topics: Adolescent; Adult; Antipsychotic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzodiazepines; Female; Genotype; Humans; Male; Middle Aged; Olanzapine; Pharmacogenetics; Polymorphism, Genetic; Schizophrenia; Weight Gain

In the present study, we examined the effect of olanzapine on weight gain, systolic blood pressure and metabolic changes in rats. Female Sprague Dawley rats were treated with either vehicle or olanzapine (1 and 2 mg/kg i.p, twice daily) for 20 days. Body weight, food and water intake, systolic blood pressure, plasma glucose, insulin and lipid were measured. Olanzapine (1 and 2 mg/kg) significantly increased the body weight and systolic blood pressure. Whereas, food intake and plasma insulin and insulin resistance index, were elevated only at 1 mg/kg. In conclusion, olanzapine induced weight gain in rats is associated with elevation of systolic blood pressure.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Blood Pressure; Dose-Response Relationship, Drug; Drinking; Eating; Female; Insulin; Insulin Resistance; Lipids; Models, Animal; Olanzapine; Rats; Rats, Sprague-Dawley; Systole; Time Factors; Weight Gain

Topics: Antipsychotic Agents; Benzodiazepines; Brain; Humans; Lipid Metabolism; Olanzapine; Research Design; Schizophrenia; Weight Gain

To report a case in which a patient tolerated and responded to high-dose aripiprazole and lost weight after having been on olanzapine for several years; a secondary objective is to discuss the use of aripiprazole dosages at higher than those recommended in the product's labeling.. A 57-year-old man with a 30 year history of schizophrenia had been taking olanzapine for 4 years, with the dosage titrated to 20 mg/day, to control the psychosis. After he had gained significant weight with olanzapine (the highest was 102.7 kg), his treatment was switched to aripiprazole. The patient required a high dose of aripiprazole (60 mg/day) to achieve full control of the psychiatric symptoms, and during aripiprazole therapy, he lost the weight he had gained while on olanzapine, weighing 85.9 kg within 7 months after the therapy switch.. Dosages of atypical antipsychotics higher than those recommended by the Food and Drug Administration are often used in clinical practice for refractory patients, despite the lack of evidence. The literature available on this subject is limited to small, double-blind trials; open-label trials; and case reports. Although certain patients may benefit from higher doses of atypical antipsychotics, the lack of evidence limits their use.. High-dose aripiprazole (60 mg/day) was well tolerated and controlled this patient's symptoms effectively. In addition, he lost weight that was gained while being treated with olanzapine. High-dose aripiprazole may be beneficial and safe in refractory patients; however, large, double-blind, randomized clinical trials are needed.

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Blood Glucose; Humans; Male; Metabolic Diseases; Olanzapine; Piperazines; Quinolones; Schizophrenia; Weight Gain

To assess the perceptions of clinicians in the psychiatric community about pharmacotherapy and its impact on weight gain and adverse metabolic effects in patients with bipolar disorder.. In November 2005, self-administered questionnaires were sent to 7000 psychiatrists who treat bipolar disorder in their clinical practice. An additional mailing of these questionnaires was sent in January 2006 to a different group of 7000 psychiatrists who treat bipolar disorder in their clinical practice. The first 298 completed surveys were analyzed.. Almost half of the respondents (48%) were psychiatrists in individual private practice and 32% were in community mental health centers. About two-thirds of respondents reported that 30-60% of their bipolar patients were overweight. Thirty-eight percent of respondents reported metabolic syndrome present in 20-40% of their patients. Almost all respondents (96%) reported a 20 lb increase in patients' weight as a troublesome potential adverse event associated with the use of some agents. After initiating a new medication, more than 80% of respondents monitored their patients' weight, fasting plasma glucose level, and fasting lipid profile at regular intervals. However, 80% did not monitor waist circumference. Overall, respondents viewed several agents (aripiprazole, ziprasidone, carbamazepine, and lamotrigine) as not (or minimally) problematic in terms of weight gain and adverse metabolic concerns. Clozapine and olanzapine were viewed as highly problematic due to their propensity to induce weight gain and negatively influence lipid and glucose metabolism. Other agents considered to be minimally to moderately problematic in terms of weight gain and metabolic issues were quetiapine, risperidone, lithium, and valproate. Respondents reported that the profile of a bipolar agent in terms of weight gain and adverse metabolic effects was an important consideration in the management of bipolar disorder.. Although the study is limited by a low response rate and self-selection of respondents, clinicians who did respond were concerned about the risks of weight gain and metabolic disturbances in their patients treated with bipolar agents. For most parameters, such concerns were being integrated into clinical care. However, it appears that there is a need to increase clinicians' appreciation of the importance of abdominal obesity and the need to monitor waist circumference. A growing recognition of the differences in weight-gain potential and adverse metabolic effects among agents appears to have had a definite impact on prescribing patterns in the management of bipolar disorder.

Topics: Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Blood Glucose; Clozapine; Female; Humans; Lipids; Male; Metabolic Syndrome; Olanzapine; Overweight; Perception; Practice Patterns, Physicians'; Weight Gain

Fibromyalgia is a significant clinical problem associated with generalized pain and significant interference with daily activities. Although a variety of treatment modalities have been utilized, clinicians have struggled to find an effective means of treatment. Therefore, this study assessed the efficacy of the atypical neuroleptic olanzapine for the treatment of fibromyalgia symptoms. To examine the efficacy of olanzapine for the treatment of fibromyalgia symptoms, the charts of 51 patients treated with olanzapine were evaluated for improvements in pain and daily life functioning. At the time of initial assessment, patients had been diagnosed with a variety of medical and psychiatric disorders and a history of neuroleptic treatment. Pain was widespread and characteristic of pain associated with fibromyalgia. Pretreatment ratings on pain and the interference scales averaged 6.54-8.69 on a 0-10 scale. Post-treatment ratings on the same scales revealed significant improvement on virtually all scales. The benefits of olanzapine to improve fibromyalgia symptoms must, however, be carefully considered because there were a variety of side effects (i.e., weight gain, somnolence/sedation) that were of sufficient strength to cause a number of patients to discontinue treatment. In general, the data provide strong support that olanzapine can, in certain patients, improve symptoms associated with fibromyalgia in patients who have had limited success with other treatment modalities.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Benzodiazepines; Dose-Response Relationship, Drug; Female; Fibromyalgia; Humans; Male; Middle Aged; Olanzapine; Pain Measurement; Pain Threshold; Quality of Life; Retrospective Studies; Sleep Stages; Treatment Outcome; Weight Gain

Fibromyalgia is a common and disabling chronic pain syndrome. Although a wide array of symptomatic pharmacological treatments has been used to treat this condition, only modest results have been obtained. Olanzapine has been proven effective in some chronic pain conditions. The authors present a case series of patients suffering from fibromyalgia who received olanzapine as add-on therapy during a 3-month period. Olanzapine (2.5-20.0 mg/day) was administered to 25 consecutive patients (24 females, 1 male) meeting the American College of Rheumatology diagnostic criteria for fibromyalgia, and who were receiving nonsteroidal anti-inflammatory drugs (NSAIDs; 68%), benzodiazepines/zolpidem (48%), antidepressants (32%), and cyclobenzaprine (4%), either alone or in combination. Overall, 6 of the 14 patients (43%) who completed the 12-week trial reported to be much or very much improved ('responders'), according to the Clinical Global Impression (CGI) scale and 7 of them (50%) reported a good or very good sense of well-being. Olanzapine's modal dose among responders was 10.0 mg/day. It was discontinued in 11 patients (44%) due to adverse reactions, most commonly weight gain (n=5, 20%). Our preliminary findings suggest a possible role for olanzapine in treating fibromyalgia. Unfortunately, the beneficial outcome of olanzapine was largely obscured by its poor tolerability, which could be explained by the greater propensity of patients with fibromyalgia to adverse drug reactions, and the greater risk of antipsychotic-induced weight gain among women. Whether other atypical antipsychotics will provide similar symptomatic relief, while showing a better tolerability profile than olanzapine in patients with fibromyalgia, should be further investigated.

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Female; Fibromyalgia; Humans; Male; Middle Aged; Olanzapine; Treatment Outcome; Weight Gain

Antipsychotic drugs may contribute to weight gain in children and adolescents.. We used Medline's PubMed in the pediatric age using key words 'weight gain' and 'obesity', for each newer antipsychotic drug.. We found 21 articles linking weight gain and obesity with newer antipsychotic drugs among youths. Risperidone was the most commonly cited agent. Weight gain from olanzapine was the largest among the more commonly prescribed newer agents. All studies reported absolute weight gain. Only a few studies used the better measure of body mass index (BMI). None incorporated growth charts to allow for changes in weight and height over time because of growth.. Weight gain may be a major problem when prescribing newer antipsychotic drugs in the pediatric population. Risperidone is associated with less weight gain than olanzapine. Published reports and studies have not utilized state-of-the-art techniques using BMI with readily available growth charts.

Topics: Adolescent; Age Factors; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Child; Child, Preschool; Humans; Infant; Obesity; Olanzapine; Prospective Studies; Psychotic Disorders; Risperidone; Weight Gain

Some novel antipsychotics, including olanzapine, induce weight gain and metabolic abnormalities, which represent the major adverse effects of these drugs. However, the mechanism(s) involved in such effects are unclear.. The aim of this study was to develop, in female rats, a parametric model of olanzapine-induced weight gain and metabolic abnormalities and evaluate it against clinical findings.. Female rats were administered olanzapine b.i.d. at doses of 0, 1, 2 and 4 mg/kg over 20 days, and a wide range of variables were recorded during and after drug administration.. Olanzapine increased both 24 h and total food intake. This was associated with rapid onset weight gain and increased adiposity (assessed by visceral fat pad masses). Insulin, but not glucose, concentrations were elevated, with a significant increase in the HOMA-IR index, indicative of insulin resistance. A nonsignificant trend towards higher levels of leptin was observed. Paradoxically, there was a significant increase in adiponectin. All of these variables showed maximal increases at either 1 or 2 mg/kg and attenuated effects at 4 mg/kg. Prolactin levels were also increased by olanzapine. However, for this variable, there was a clear dose-response curve, with the maximal effect at the highest dose (4 mg/kg).. These data suggest that aspects of olanzapine-induced weight gain and metabolic abnormalities can possibly be modelled in female rats. It is suggested that olanzapine-induced hyperphagia acts as an initial stimulus which leads to weight gain, enhanced visceral adiposity and subsequent insulin resistance, although the latter may be ameliorated by compensatory responses in adiponectin levels. Prolactin elevation appears likely not to be involved in the weight gain, adiposity and metabolic changes seen in this model.

Topics: Adipose Tissue; Animals; Antipsychotic Agents; Benzodiazepines; Dose-Response Relationship, Drug; Drinking; Eating; Estradiol; Female; Homeostasis; Hyperinsulinism; Insulin Resistance; Leptin; Metabolic Diseases; Olanzapine; Prolactin; Rats; Rats, Wistar; Statistics as Topic; Weight Gain

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Child; Geriatrics; Humans; Olanzapine; Weight Gain

Topics: Antipsychotic Agents; Benzodiazepines; Case-Control Studies; Humans; Olanzapine; Receptors, Cell Surface; Receptors, Leptin; Schizophrenia; Weight Gain

Weight gain, leading to further morbidity and poor treatment adherence, is a common consequence of treatment with antipsychotic drugs. Two recent studies in the same cohort of Chinese Han subjects have shown that polymorphisms of the promoter regions of both the serotonin 5-hydroxytryptamine 2C (5-HT2C) receptor and the leptin genes, are associated with antipsychotic-induced weight gain over 10 weeks. We have investigated whether these effects remain true in a Caucasian population and following longer term treatment.. Seventy-three Spanish caucasian patients with a first-episode psychosis and initially drug-naive were genotyped for the 5-HT2C receptor -759C/T and leptin -2548A/G polymorphisms. Body mass index and plasma leptin levels were monitored after 6 weeks, 3 months and 9 months of antipsychotic treatment.. Patients with the -759T variant allele showed significantly less weight gain than those without this allele. This effect held true in the smaller group of patients receiving olanzapine. The -2548 leptin polymorphism was not associated with short-term (6 week and 3 month) weight increases but did show significant association with 9-month antipsychotic-induced weight gain. The 5-HT2C -759 genotype was significantly associated with pre-treatment plasma leptin levels.. These findings confirm the importance of two genetic factors associated with long-term antipsychotic-induced weight increases in schizophrenia, and implicate a role for leptin in the 5-HT receptor-mediated weight regulation.

Topics: Adult; Affective Disorders, Psychotic; Alleles; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Female; Genetic Variation; Genotype; Humans; Leptin; Male; Models, Genetic; Olanzapine; Pharmacogenetics; Polymorphism, Genetic; Promoter Regions, Genetic; Receptor, Serotonin, 5-HT2C; Receptors, Leptin; Schizophrenia; Time Factors; Weight Gain

Weight gain is an important issue in the use of atypical antipsychotics, including olanzapine. A retrospective analysis of patterns of weight gain and possible covariates was performed for 1191 patients diagnosed with schizophrenia or schizoaffective disorder who were treated with olanzapine for up to 52 weeks. Patients were dichotomized into 2 main groups according to the percentage of body weight gained during the first 6 weeks of treatment with olanzapine: (1) patients who gained > or =7% of their body weight (Rapid Weight Gain Group [RWG]), and (2) patients who lost weight, gained no weight, or gained <7% of their body weight (Nonrapid Weight Gain Group [NRWG]). Results demonstrated that approximately 15% of the patient population showed rapid increases in weight (RWG group), whereas 85% of patients gained weight more slowly or not at all (NRWG group). Patients in the RWG group gained an average of 4% of their body weight (approximately 4-7 lb) within the first 2 weeks of treatment with olanzapine. Furthermore, patients in the RWG group were younger, had a lower baseline body mass index, were more likely to report an increase in appetite, and showed a more robust clinical response compared with patients in the NRWG group. Over the course of 52 weeks, patients in the RWG group gained significantly more weight and reached a higher plateau for mean weight increase at 38 weeks compared with the mean increase observed for patients in the NRWG group. By measuring the weight of patients during the first few weeks of olanzapine treatment and by assessing changes in appetite, clinicians may be able to identify those patients at risk for substantial weight gain.

Topics: Adult; Analysis of Variance; Benzodiazepines; Female; Humans; Male; Olanzapine; Randomized Controlled Trials as Topic; Retrospective Studies; Schizophrenia; Time Factors; Weight Gain

Topics: Anorexia Nervosa; Antipsychotic Agents; Benzodiazepines; Clinical Trials as Topic; Fluoxetine; Humans; Olanzapine; Personality Inventory; Research Design; Sample Size; Selective Serotonin Reuptake Inhibitors; Treatment Outcome; Weight Gain

The present study aimed to compare health outcomes and tolerability according to antipsychotic medication (olanzapine, risperidone or an oral typical antipsychotic) after 6 months of treatment in a group of 919 schizophrenic patients who had never previously been treated with antipsychotics. Demographic and clinical predictors of outcome were also identified. Data were extracted from the Schizophrenia Outpatient Health Outcomes (SOHO) study, a prospective, observational study of schizophrenia treatment in 10 European countries. Patients who initiated olanzapine were more likely to have a clinical response than those in the risperidone cohort, and had a greater improvement in quality of life than patients in the risperidone or typical antipsychotic cohorts. High negative and depression symptom scores at baseline and the presence of extrapyramidal symptoms at baseline predicted a worse clinical response, whereas hostile behaviour, paid employment and substance abuse predicted a better clinical outcome. The olanzapine cohort gained more weight than patients in the risperidone cohort, but no significant difference in weight gain was observed between olanzapine and the oral typical antipsychotic cohort. The results should be interpreted conservatively due to the observational study design.

Topics: Administration, Oral; Adult; Antipsychotic Agents; Benzodiazepines; Cohort Studies; Demography; Depression; Female; Health Status; Hostility; Humans; Male; Middle Aged; Olanzapine; Prognosis; Prospective Studies; Quality of Life; Risperidone; Schizophrenia; Substance-Related Disorders; Treatment Outcome; Weight Gain

We describe a patient in whom improvement in negative symptoms contributed to early weight loss and subsequent long-term improvement in weight management.. Case report.. A 26-year-old woman with schizophrenia gained 7 kg over the course of 1 year after starting treatment with olanzapine. However, as negative symptoms gradually improved with treatment, she became motivated to diet and exercise regularly. She quickly lost 9 kg and subsequently maintained optimal weight (55 kg; body mass index, 24.1 kg/m(2) ).. Important strategies for minimizing weight gain in patients taking antipsychotic agents include improving negative symptoms of avolition and apathy, regular monitoring of body weight and potential medical consequences of overweight and obesity, and educating the patient about the importance of diet and regular exercise.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Chlorpromazine; Diet; Exercise; Female; Haloperidol; Humans; Olanzapine; Schizophrenia; Weight Gain

Atypical antipsychotic drug (APD)-induced weight gain causes non-compliance, increasing the risk of relapse and medical complications.. In an animal model, we assessed body weights, food intake, body fat/lean body mass contents and blood serum levels of glucose and lipids in female rats treated with olanzapine (Experiment 1). Also, we investigated the effect of aripiprazole vs olanzapine treatment on weight gain (WG) and plasma prolactin secretion in two strains (Wistar and Sprague-Dawley) and in two housing conditions (singly and group housed; Experiment 2).. In Experiment 1, Wistar females received either vehicle or olanzapine (5.0 mg kg(-1), p.o.) twice daily for 14 days. In Experiment 2, female rats (Wistar or Sprague-Dawley), housed singly or in groups, received either vehicle, aripiprazole (2.0-8.0 mg kg(-1), p.o.), or olanzapine (1.0-10 mg kg(-1), p.o.) twice daily for 7 days. Body weights and food intake were assessed daily. Body composition and blood assays were analyzed at the end of the treatment.. WG induced by chronic olanzapine treatment was characterised by hyperphagia, increased body fat, and serum free fatty acid content and reduced lean tissue and serum glucose content. Subchronic aripiprazole treatment resulted in rapid and robust WG similar to those observed with olanzapine. In spite of similar effects on body weight, aripiprazole and olanzapine stimulated markedly different patterns of prolactin secretion. Body weight changes and prolactin secretion induced by these APDs were significantly modulated by housing and by strain.. Assessment of body weight in the present model may not have predictive validity, and other measures may be needed to differentiate between WG-inducing and weight-neutral drugs.

Topics: Animals; Aripiprazole; Benzodiazepines; Body Weight; Cholesterol, HDL; Fatty Acids, Nonesterified; Female; Olanzapine; Piperazines; Prolactin; Quinolones; Rats; Rats, Sprague-Dawley; Rats, Wistar; Weight Gain

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Drug Prescriptions; Humans; Hypersensitivity; Male; Medication Errors; Metabolic Syndrome; Obesity; Olanzapine; Weight Gain

Topics: Antipsychotic Agents; Benzodiazepines; Diet; Energy Intake; Energy Metabolism; Humans; Obesity; Olanzapine; Research Design; Schizophrenia; Weight Gain

Topics: Adult; Benzodiazepines; Body Mass Index; Cholesterol, HDL; Cholesterol, LDL; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Hyperlipidemias; Male; Olanzapine; Prospective Studies; Psychotic Disorders; Weight Gain

The present cross-sectional study examined the relationships of psychopathology, side effects, and sociodemographic factors with treatment outcomes in terms of patients' quality of life (QOL), functioning, and needs for care.. Sixty outpatients with chronic schizophrenia who had been treated with either clozapine or olanzapine for at least 6 months were investigated.. Most psychopathological symptoms as well as psychic side effects, weight gain, and female sex were associated with lower QOL, while cognitive symptoms correlated with better QOL. Female sex, cognitive symptoms, and parkinsonism negatively influenced occupational functioning, and negative symptoms determined a lesser likelihood of living independently. Age, education, depression/anxiety, negative symptoms, and psychic side effects were predictors of patients' needs for care.. Our results highlight the complex nature of patient outcomes in schizophrenia. They reemphasize the need of targeting effectiveness, i.e. both symptomatic improvement as well as drug safety, in such patients.

Topics: Adult; Age Factors; Antipsychotic Agents; Anxiety Disorders; Benzodiazepines; Clozapine; Cognition; Comorbidity; Cross-Sectional Studies; Depressive Disorder; Educational Status; Female; Humans; Male; Olanzapine; Parkinsonian Disorders; Quality of Life; Schizophrenia; Schizophrenic Psychology; Sex Factors; Socioeconomic Factors; Treatment Outcome; Weight Gain

Patients treated with atypical antipsychotic drugs commonly gain excess weight. Because obesity is associated with considerable morbidity and decreased life expectancy, treatment of weight gain in these patients is critical. Topiramate, a fairly new anticonvulsant, promotes bodyweight loss in healthy obese subjects, patients with bipolar disorder, and patients with eating disorder. However, there are very few reports about the efficacy of topiramate for weight management in schizophrenic patients. We present the cases of three Taiwanese patients with schizophrenia whose bodyweight increased as a result of atypical antipsychotics treatment, then was controlled by topiramate without aggravation of their psychotic symptoms.

Topics: Adult; Anti-Obesity Agents; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Child, Preschool; Clozapine; Dibenzothiazepines; Female; Fructose; Humans; Male; Olanzapine; Psychiatric Status Rating Scales; Quetiapine Fumarate; Risperidone; Schizophrenia; Taiwan; Topiramate; Weight Gain

Topics: Antipsychotic Agents; Benzodiazepines; Diabetes Mellitus, Type 2; Humans; Olanzapine; Receptor, Muscarinic M3; Schizophrenia; Weight Gain

Treatment-emergent weight gain may be a general marker of therapeutic improvement, even when improvements occur in the absence of active antipsychotic treatment. To investigate the association between treatment-emergent weight gain and therapeutic improvement across placebo and active treatments, and to examine the association between reported treatment-emergent weight changes and the treatments' reported efficacy. Data from a randomized, double-blind trial comparing treatment of schizophrenia with placebo and olanzapine were used to correlate weight change and change in psychopathology. Additionally, we correlated effect sizes of the efficacy of clozapine, olanzapine, risperidone, haloperidol and placebo (reported in meta-analytical reviews), with their reported weight changes. Weight gain significantly correlated with clinical improvements for placebo and olanzapine. The correlation between treatments' efficacy and corresponding weight changes was high (r 0.88, p 0.05). Treatment-emergent weight gain appears to be an important marker of symptom reduction, and may not be exclusively attributable to pharmacological perturbations.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Double-Blind Method; Female; Haloperidol; Humans; Linear Models; Male; Meta-Analysis as Topic; Middle Aged; Olanzapine; Placebo Effect; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Schizophrenic Psychology; Time Factors; Treatment Outcome; Weight Gain

Second generation antipsychotics (SGA) are obesitogenic and diabetogenic. Role of ghrelin (RIA), resistin and TNF-alpha (ELISA) in weight gain and insulin resistance (fasting plasma insulin, HOMA, ELISA) was studied in Hungarian psychiatryic patients (n=60) treated with SGA (clozapine, olanzapine, risperidone, quetiapine, 15 each). After 1 year, 80% of patients became overweight/obese (BMI > 27/30) and 35% (n= 21/60) presented impaired glucose tolerance (13/60) or diabetes (8/60). Ghrelin (1.3 +/- 0.6 ng/ml), resistin (9.8 +/- 3.7 ng/ml), TNF-alpha (5.8 +/- 1.7 pg/ml), insulin (10.4 +/- 7.6 U/ml, HOMA A: 2.5 +/- 1.8, HOMA B: 133 +/- 62.5) were significantly higher in patients than in healthy matched controls. Resistin and TNF-alpha positively correlated with each other, insulin, HOMA, and negatively with ghrelin. Ghrelin contributes to weight gain, resistin and TNF-alpha to insulin resistance. A negative feedback regulation may exist between adipocytokines and ghrelin production. SGA drugs enhance ghrelin production despite the suppressive effect of adipocytokines. All four SGA drugs are equally obesitogenic and diabetogenic.

Topics: Antipsychotic Agents; Benzodiazepines; Carbohydrate Metabolism; Case-Control Studies; Clozapine; Dibenzothiazepines; Female; Ghrelin; Humans; Insulin Resistance; Male; Metabolic Syndrome; Middle Aged; Obesity; Olanzapine; Overweight; Peptide Hormones; Quetiapine Fumarate; Resistin; Risperidone; Tumor Necrosis Factor-alpha; Weight Gain

Although olanzapine is known as a widely used atypical antipsychotic there have been very few studies about its use in children and adolescents. Eight adolescent patients who were diagnosed as having schizophrenia or schizoaffective disorder, and treated with olanzapine are reported in this case series. The patients were followed-up for 17.5 weeks in the range 4-26 weeks. According to the CGI improvement assessment at the end of the follow-up period, three of eight cases were rated as very much or much improved, three as minimally improved and two as not improved. Olanzapine was well tolerated by the adolescents in this case series except for weight gain. Our results suggest that olanzapine may be an effective antipsychotic for some psychotic adolescents and during olanzapine trials weight gain. Should be monitored.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Child; Female; Humans; Male; Olanzapine; Psychotic Disorders; Schizophrenia; Treatment Outcome; Weight Gain

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Depressive Disorder, Major; Dibenzothiazepines; Female; Fluvoxamine; Humans; Olanzapine; Quetiapine Fumarate; Weight Gain

The Intercontinental Schizophrenia Outpatient Health Outcomes (IC-SOHO) study was designed to provide information regarding use and outcome of antipsychotic treatments in a large, diverse population in real practice settings.. Outpatients with schizophrenia (ICD-10 or DSM-IV) who initiated or changed to a new antipsychotic entered this 3-year, naturalistic, prospective observational study. Four monotherapy treatment groups were defined according to the antipsychotic prescribed at baseline, namely olanzapine, risperidone, quetiapine, and haloperidol. Efficacy was assessed using the Clinical Global Impressions-Severity of Illness rating scale (CGI-S), inclusive of subscales for positive, negative, depressive, and cognitive symptoms. Tolerability was assessed by adverse event questionnaires and weight measurements. Six-month findings are described.. At baseline, 5833 participants were prescribed monotherapy and the mean severity of illness was moderate to marked (CGI-S). At 6 months, olanzapine resulted in significantly greater improvements in overall, positive, negative, depressive, and cognitive symptoms compared with quetiapine, risperidone or haloperidol (p <.001). Improvements in overall, negative, and cognitive symptoms were significantly higher for risperidone compared with haloperidol (p <.001), whereas improvements across all symptoms were comparable for quetiapine and haloperidol. Extra-pyramidal symptoms and tardive dyskinesia decreased compared with baseline in the olanzapine, quetiapine, and risperidone groups but increased in the haloperidol group (p <.001, likelihood of extrapyramidal symptoms with haloperidol compared with olanzapine, quetiapine, or risperidone). Sexual function adverse events were most prominent in the haloperidol and risperidone treatment groups. Weight change was significantly greater for olanzapine compared with the other antipsychotics (p <.001).. Our results support the previously reported positive impact of atypical antipsychotics, particularly olanzapine, in patients with schizophrenia.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Cognition Disorders; Diagnostic and Statistical Manual of Mental Disorders; Dibenzothiazepines; Dyskinesia, Drug-Induced; Female; Haloperidol; Humans; Hyperprolactinemia; International Classification of Diseases; Male; Observation; Olanzapine; Prospective Studies; Quetiapine Fumarate; Risperidone; Schizophrenia; Severity of Illness Index; Sexual Dysfunction, Physiological; Surveys and Questionnaires; Weight Gain

It is important to assess cardiovascular risk factors to properly verify the potential consequences of atypical antipsychotic-related weight gain. The objective of the present study was to evaluate whether 2 atypical antipsychotics differ regarding their impact on the cardiovascular disease risk profile compared with a reference group.. We conducted a cross-sectional, multicenter study to assess anthropometric indices of obesity and to obtain a comprehensive fasting metabolic risk profile. Either risperidone or olanzapine had to be prescribed as the first and only antipsychotic for a minimum of 6 months. Patients were compared with a reference group of nondiabetic men. Data were collected from August 1999 to August 2001.. Eighty-seven patients treated with olanzapine (N = 42) or risperidone (N = 45) were evaluated. Olanzapine-treated patients had significantly higher plasma triglyceride concentrations (2.01 +/-1.05 vs. 1.34 +/-0.65 mmol/L, p < or =.05), lower high-density lipoprotein (HDL)-cholesterol levels (0.92 +/-0.17 vs. 1.04 +/- 0.21 mmol/L, p < or =.05), higher cholesterol/HDL-cholesterol ratios (5.62 +/-1.70 vs. 4.50 +/- 1.44, p < or =.05), higher apolipoprotein B levels (1.07 +/- 0.35 vs. 0.92 +/- 0.27 g/L, p < or =.05), smaller low-density lipoprotein peak particle diameters (252.6 +/-4.1 vs. 255.2 +/-4.3 A, p <.01), and higher fasting insulin concentrations (103.9 +/- 67.6 vs. 87.5 +/- 56.1 pmol/L, p < or =.05) than risperidone-treated patients. Moreover, 33% of olanzapine-treated patients were carriers of 3 atherogenic features of the metabolic syndrome as opposed to a prevalence of only 11% of risperidone-treated patients.. These results suggest that olanzapine-treated patients are characterized by a more deteriorated metabolic risk factor profile compared with risperidone-treated patients. These observations raise concerns about the potential differential long-term deleterious effects of some antipsychotics, such as olanzapine, on cardiovascular health.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Biomarkers; Carrier State; Cholesterol, HDL; Coronary Artery Disease; Cross-Sectional Studies; Factor Analysis, Statistical; Fasting; Health Surveys; Humans; Hypertriglyceridemia; Insulin; Male; Metabolic Syndrome; Obesity; Olanzapine; Prevalence; Psychotic Disorders; Risk Factors; Risperidone; Weight Gain

We have established an animal model for olanzapine-induced body weight gain, and used it to explore the relation between this weight gain, excessive food consumption, gross motor activity, and macronutrient choice. Female Sprague-Dawley rats received olanzapine (OLAN) or diluent (1.2mg/kg per day) via gavage for 10 days. Rats receiving OLAN exhibited significant increases in body weight when compared with control rats. Body weight returned to control levels once OLAN treatment was discontinued. Food consumption among the OLAN-treated group was significantly greater than among control rats between 6 and 10 days of treatment. Between 4 and 10 days of treatment, feed efficiency (grams of weight gained/grams of food consumed) was also significantly greater among animals receiving OLAN. In contrast, chronic administration of haloperidol (0.04mg/kg; q.d.; gavage) did not influence body weight or food consumption of treated rats. Gross motor activity was significantly reduced by OLAN between 1 and 10 days of treatment, also returning to control levels when treatment was discontinued. No significant changes were observed in brain DA, DOPAC, HVA or 5-HIAA among animals receiving OLAN daily for 30 days; however, 5-HT levels were significantly elevated. In contrast, acute (1.2mg/kg; 2h; i.p.) administration of OLAN significantly increased brain DOPAC and HVA levels without affecting those of 5-HT or 5-HIAA. OLAN (1.2mg/kg; q.d.; 10 days) administration did not alter macronutrient choice (carbohydrate:protein ratio) of rats. These data show that an animal model of OLAN-induced weight gain is readily generated, and suggest that the weight gain results at least in part from increased food intake, reduced gross motor activity, and enhanced feed efficiency.

Topics: 3,4-Dihydroxyphenylacetic Acid; Analysis of Variance; Animals; Antipsychotic Agents; Behavior, Animal; Benzodiazepines; Body Weight; Brain Chemistry; Chromatography, High Pressure Liquid; Darkness; Dopamine; Eating; Electrochemistry; Female; Food Preferences; Homovanillic Acid; Hydroxyindoleacetic Acid; Models, Animal; Motor Activity; Olanzapine; Photoperiod; Rats; Rats, Sprague-Dawley; Serotonin; Time Factors; Weight Gain

Olanzapine is an effective drug for the long-term treatment of bipolar disorder but is associated with burdensome weight gain. Topiramate is a novel anticonvulsant that may induce weight loss in some patients. This is the first study to address the long-term efficacy and impact on weight of the combination of olanzapine and topiramate in bipolar patients. Twenty-six Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition bipolar spectrum patients received olanzapine plus topiramate cotherapy for treatment of their manic (n = 14), hypomanic (n = 6), depressive (n = 2), and mixed (n = 1) symptoms for 1 year. Three rapid cycling patients were also enrolled despite being euthymic. Efficacy was assessed with the Young Mania Rating Scale, the Hamilton Depression Rating Scale, and the Modified Clinical Global Impressions for Bipolar Disorder. Weight, body mass index, and side effects were collected at every visit. Thirteen (50%) patients completed the 1-year follow-up. By intent-to-treat, patients significantly improved from baseline in Young Mania Rating Scale scores (P < 0.0001), Hamilton Depression Rating Scale (P < 0.05), and Modified Clinical Global Impressions for Bipolar Disorder subscales (mania P < 0.0001, depression P < 0.05, overall P < 0.0001). Most patients gained weight during the first month of combined treatment (mean weight gain 0.7 +/- 0.6 kg), but at the 12-month endpoint, the mean weight change was -0.5 +/- 1.1 kg. The combination of olanzapine and topiramate was efficacious for the long-term treatment of bipolar patients and appeared to carry some benefits for controlling weight gain. Given the limitations of the open, uncontrolled design, further trials are warranted with this combination.

Topics: Adult; Benzodiazepines; Bipolar Disorder; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Fructose; Humans; Male; Middle Aged; Olanzapine; Statistics, Nonparametric; Topiramate; Treatment Outcome; Weight Gain

Sexual dysfunction is a major, although poorly understood, side-effect of treatment with antipsychotic drugs. We have recently show marked disruption of reproductive function and weight gain in female rats treated subchronically with risperidone and haloperidol. The aim of the present study was to examine further the potential relationship between reproductive dysfunction and weight gain in female rats treated with olanzapine. The effects of olanzapine on weight gain, food and water intake, intra-abdominal fat, the oestrous cycle and uterine weight were assessed in group-housed adult female hooded-Lister rats. Olanzapine (0.5-4.0 mg/kg i.p.) or vehicle was administered once daily for 21 days and body weight, food and water intake measured, with histological examination of vaginal lavage to determine the stage of the oestrous cycle. On day 22, animals were sacrificed and intra-abdominal fat, wet and dry uterine weights measured. Olanzapine induced significant weight gain with concomitant increases in food and water intake and intra-abdominal fat without an effect on the oestrous cycle, wet and dry uterine weights or plasma prolactin levels. These results confirm the ability of olanzapine to induce weight gain in female rats on unrestricted normal diet with a concomitant increase in food and water intake and increased intra-abdominal fat. These effects of olanzapine were produced in the absence of any apparent impairment in reproductive function, in contrast to the substantial disruption of oestrous and uterine atrophy previously shown in rats treated with risperidone and haloperidol.

Topics: Abdomen; Adipose Tissue; Animals; Antipsychotic Agents; Benzodiazepines; Body Composition; Dose-Response Relationship, Drug; Drinking; Drug Administration Schedule; Eating; Estrous Cycle; Female; Injections, Intraperitoneal; Olanzapine; Organ Size; Prolactin; Rats; Reproduction; Time Factors; Uterus; Weight Gain

To compare the effect of olanzapine with that of risperidone on weight change among Chinese patients in Hong Kong.. The body weight of subjects maintained on olanzapine or risperidone treatment was recorded at the outpatient clinic of a teaching hospital. Pretreatment weight of the subjects was retrieved from case records. Subjects on olanzapine treatment were matched in sex, age, and diagnosis with those on risperidone treatment, and demographic and clinical data were analyzed. The study was conducted in May and June 2002.. Twenty-eight olanzapine-risperidone matched pairs were studied. All were diagnosed with DSM-IV schizophrenia. In patients treated with olanzapine and risperidone, respectively, mean +/- SD duration of treatment with atypical neuroleptics was 103.5 +/- 47.4 weeks and 93.2 +/- 50.6 weeks (range, 21-255 weeks), and mean doses were 12.4 +/- 6.7 mg/day and 4.5 +/- 2.8 mg/day. The mean +/- SD weight gain of subjects on treatment with olanzapine and risperidone, respectively, was 8.34 +/- 5.97 kg (18.53 +/- 13.27 lb) and 2.74 +/- 8.09 kg (6.09 +/- 17.98 lb) with a statistically significant difference at p < .005. Lower baseline body weight and body mass index were associated with greater weight gain in both olanzapine- and risperidone-treated subjects. Gender, age, mean daily dose, and duration of treatment had no effect on weight change.. Treatment with olanzapine was associated with significantly greater weight gain than treatment with risperidone in Chinese schizophrenia patients in Hong Kong. The effect of adjunctive anticonvulsant treatment on weight gain requires further study.

Topics: Adult; Antipsychotic Agents; Asian People; Benzodiazepines; Female; Hong Kong; Humans; Male; Obesity; Olanzapine; Risperidone; Schizophrenia; Weight Gain

To evaluate changes in short-term weight and body mass index (BMI) in children and adolescents receiving olanzapine or quetiapine.. Retrospective study Setting. Austin State Hospital, Austin, Texas.. One hundred three patients younger than 18 years who were admitted to the hospital and treated with olanzapine (50 patients) or quetiapine (53) for at least 2 weeks between October 1, 1997, and October 31, 2001.. Treatment with at least 2 weeks of olanzapine or quetiapine.. Mean+/-SD daily doses of olandzapine and quetiapine were 13.9+/-7.3 and 510.9+/-250.3 mg, respectively Weight and height were measured at baseline and 14 or more days after baseline. Body mass index (in kg/m2) was calculated using serial measurements of weight and height, and change in BMI was determined. The olanzapine group gained an average of 3.8 kg, the quetiapine group 0.03 kg. In the olanzapine group, BMI increased by an average of 1.3 kg/m2; in the quetiapine group, BMI decreased by 0.2 kg/m2. After controlling for baseline differences, significant between-group differences in weight and BMI change were noted. Change in BMI correlated significantly with baseline BMI in quetiapine-treated girls.. Patients taking olanzapine had greater increases in weight and BMI than those taking quetiapine. Further studies are necessary to determine the relative risk, magnitude, and time course of antipsychotic-induced weight gain in this patient population.

Topics: Adolescent; Benzodiazepines; Body Mass Index; Child; Dibenzothiazepines; Female; Humans; Male; Olanzapine; Quetiapine Fumarate; Retrospective Studies; Weight Gain

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Body Mass Index; Clozapine; Diabetes Complications; Haloperidol; Humans; Obesity; Olanzapine; Piperazines; Quinolones; Risk Factors; Schizophrenia; Weight Gain

Fluoxetine and olanzapine combination therapy is rapidly becoming an effective strategy for managing symptoms of treatment-resistant depression. Determining drug-drug interactions, drug metabolism and pharmacokinetics is of particular interest for revealing potential liabilities associated with drug augmentation in special patient populations. In the current studies, we chronically administered fluoxetine and olanzapine in non-stressed rats to extend our previous findings regarding body weight dynamics.. Chronic fluoxetine (10 mg/kg) and olanzapine (5 mg/kg and 0.5 mg/kg) treatment decreased weight gain irrespective of olanzapine dosing. At the 10 mg/kg and 5 mg/kg dose, respectively, fluoxetine and olanzapine also significantly reduced food and water consumption. This pharmacodynamic event-related effect, however, was not observed at the 10 mg/kg and 0.5 mg/kg dosing paradigm suggesting differences in tolerability rates as a function of olanzapine dose. The decrease in weight gain was not associated with apparent changes in glucose metabolism as vehicle- and drug-treated rats showed undistinguishable serum glucose levels. The combination of fluoxetine and olanzapine in rats yielded drug plasma concentrations that fell within an expected therapeutic range for these drugs in psychiatric patients.. These data suggest that fluoxetine and olanzapine treatment decreases weight gain in rats; a pharmacodynamic event-related effect that differs considerably from what is observed in the clinical condition. The possibility of mismatched models regarding body weight changes during drug augmentation therapy should be seriously considered.

Topics: Animals; Benzodiazepines; Fluoxetine; Male; Olanzapine; Rats; Rats, Long-Evans; Selective Serotonin Reuptake Inhibitors; Weight Gain; Weight Loss

To assess whether newer antipsychotic medications are associated with weight gain and development of diabetes.. Retrospective cohort study.. Data from a comprehensive electronic medical record serving an urban public hospital and a citywide network of mental health clinics.. Three thousand one hundred fifteen patients at least 18 years old who were prescribed a single antipsychotic drug for at least 1 year.. We identified independent predictors of significant weight gain (> or =7%) and new onset of diabetes mellitus in the first year of antipsychotic drug treatment, using logistic regression adjusted for demographic characteristics, obesity, preexisting psychiatric diagnoses, alcohol and drug abuse, number of primary care, psychiatric clinic, and emergency department visits, and pretreatment weight.. Twenty-five percent of patients taking older phenothiazines developed significant weight gain in the first year of treatment compared to 40% of the patients taking olanzapine (adjusted odds ratio [OR], 2.8; 95% confidence interval [CI], 1.7 to 4.6; P <.0001) and 37% of patients taking risperidone (adjusted OR, 2.3; 95% CI, 1.5 to 3.4; P <.0001). New diabetes developed in 3% of patients taking older phenothiazines was new onset diabetes compared to 8.0% of patients taking olanzapine (adjusted OR, 1.9; 95% CI, 1.1 to 3.3; P=.03) and 3.5% of patients taking risperidone (adjusted OR, 0.7; 95% CI, 0.4 to 1.4; P=.3). No association was found between significant weight gain and developing diabetes (adjusted OR, 0.7; 95% CI, 0.4 to 1.4; P=.4).. Olanzapine and risperidone use was associated with gaining weight in the first year, but only olanzapine was associated with developing diabetes mellitus.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Cohort Studies; Diabetes Mellitus; Female; Humans; Male; Olanzapine; Phenothiazines; Retrospective Studies; Risperidone; Schizophrenia; Weight Gain

The metabolic effect of atypical antipsychotic drugs may manifest itself in weight gain, disturbances in glucose homeostasis and dyslipidemia. One confounding factor is that psychotic disorders themselves make the patients prone to specific metabolic changes. Nevertheless clinical studies have confirmed that atypical anti-psychotic drugs have a different metabolic effect. In the present prospective case-series, four male antipsychotic drug-naive psychiatric patients without any familial history of metabolic disorder were studied. The patients received risperidone or olanzapine monotherapy for 12 weeks; weight, plasma levels of triglyceride, cholesterol, HDL, and fasting glucose were measured in every 4th week. In two patients, oral glucose tolerance test (OGTT) was also performed at days 0 and 56. The average weight gain during the 12-week period was 12%. The cholesterol and triglyceride plasma concentrations were also elevated. The fasting glucose levels did not change during the observation period. In the OGTT performed in two patients, normal fasting glucose and insulin plasma levels were observed after 8 weeks; however, the plasma insulin concentrations were highly elevated after glucose intake, which may suggest the presence of insulin resistance. Our preliminary results confirmed the previous results on the metabolic effect of atypical anti-psychotic drugs, which may lead to metabolic syndrome. The regular control of the metabolic laboratory parameters, early intervention and the modification of the atypical antipsychotic treatment may help to avoid this adverse effect of the drugs.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Cholesterol, HDL; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Male; Olanzapine; Prospective Studies; Risperidone; Serotonin Agents; Triglycerides; Weight Gain

As a result of superior efficacy and overall tolerability, atypical antipsychotic drugs have become the treatment of choice for schizophrenia and related disorders, despite their side effects. Weight gain is a common and potentially serious complication of some antipsychotic drug therapy, and may be accompanied by hyperlipidemia, hypertension and hyperglycemia and, in some extreme cases, diabetic ketoacidosis. The molecular mechanism(s) responsible for antipsychotic drug-induced weight gain are unknown, but have been hypothesized to be because of interactions of antipsychotic drugs with several neurotransmitter receptors, including 5-HT(2A) and 5-HT(2C) serotonin receptors, H(1)-histamine receptors, alpha(1)- and alpha(2)-adrenergic receptors, and m3-muscarinic receptors. To determine the receptor(s) likely to be responsible for antipsychotic-drug-induced weight gain, we screened 17 typical and atypical antipsychotic drugs for binding to 12 neurotransmitter receptors. H(1)-histamine receptor affinities for this group of typical and atypical antipsychotic drugs were significantly correlated with weight gain (Spearman rho=-0.72; p<0.01), as were affinities for alpha(1A) adrenergic (rho=-0.54; p<0.05), 5-HT(2C) (rho=-0.49; p<0.05) and 5-HT(6) receptors (rho=-0.54; p<0.05), whereas eight other receptors' affinities were not. A principal components analysis showed that affinities at the H(1), alpha(2A), alpha(2B), 5-HT(2A), 5-HT(2C), and 5-HT(6) receptors were most highly correlated with the first principal component, and affinities for the D(2), 5-HT(1A), and 5-HT(7) receptors were most highly correlated with the second principal component. A discriminant functions analysis showed that affinities for the H(1) and alpha(1A) receptors were most highly correlated with the discriminant function axis. The discriminant function analysis, as well as the affinity for the H(1)-histamine receptor alone, correctly classified 15 of the 17 drugs into two groups; those that induce weight gain and those that do not. Because centrally acting H(1)-histamine receptor antagonists are known to induce weight gain with chronic use, and because H(1)-histamine receptor affinities are positively correlated with weight gain among typical and atypical antipsychotic drugs, it is recommended that the next generation of atypical antipsychotic drugs be screened to avoid H(1)-histamine receptors.

Topics: Animals; Antipsychotic Agents; Discriminant Analysis; Drug Evaluation, Preclinical; Forecasting; Humans; Protein Binding; Receptors, Histamine H1; Statistics, Nonparametric; Weight Gain

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Diagnostic and Statistical Manual of Mental Disorders; Dibenzothiazepines; Female; Haloperidol; Humans; Leptin; Male; Olanzapine; Pirenzepine; Quetiapine Fumarate; Schizophrenia; Triglycerides; Weight Gain

The authors explored the binge eating symptomatology in 74 patients receiving clozapine (N = 57) or olanzapine (N = 17), and compared body mass index (BMI, kg/m(2)) and weight gain in patients with and without binge eating symptomatology. Subjects who screened positively for binge eating were interviewed using a modified version of the Questionnaire on Eating and Weight Patterns (QEWP). Current BMIs were assessed cross-sectionally, BMIs at initiation of clozapine/olanzapine treatment retrospectively. Thirty-seven subjects (50%) screened positively. Taking clozapine and olanzapine together, 6/27 (22.2%) females and 3/47 (6.4%) males fulfilled criteria for binge eating disorder, 3/27 (11.1%) females and 2/47 (4.3%) males for bulimia nervosa. Patients who screened positively showed higher current BMIs (26.8 +/- 3.9 vs. 24.7 +/- 3.7 kg/m(2)) and higher BMI increments during clozapine/olanzapine treatment (3.9 +/- 3.1 vs. 2.6 +/- 3.4 kg/m(2)) than patients who screened negatively. We conclude that clozapine/olanzapine may induce binge eating and full blown eating disorders which may have predictive value for weight gain. For future research in this field we suggest a novel DSM-IV research classification "Medication-induced eating disorders".

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Bulimia; Clozapine; Female; Humans; Hyperphagia; Male; Olanzapine; Pirenzepine; Risk Factors; Surveys and Questionnaires; Weight Gain

Weight gain is a common adverse effect associated with the use of most antipsychotic drugs. Leptin has been reported to be associated with antipsychotic-induced weight gain. Previous studies have demonstrated a relationship between the atypical antipsychotics clozapine and olanzapine and serum leptin levels. We planned to comparatively investigate the effects of the atypical antipsychotics quetiapine, olanzapine, risperidone, and clozapine on leptin and triglyceride levels and weight gain.. The study population comprised 56 patients with DSM-IV schizophrenia, who were divided into 4 treatment groups: quetiapine (N = 14), olanzapine (N = 14), risperidone (N = 14), or clozapine (N = 14) monotherapy, and a control group of 11 patients receiving no psychopharmacologic treatment. The patients were evaluated at baseline and at the sixth week according to the Positive and Negative Syndrome Scale (PANSS), body mass index (BMI), weight, and fasting serum leptin and triglyceride levels. Data were gathered in 2001 and 2002.. Olanzapine and clozapine caused a marked increase in weight and serum triglyceride and leptin levels, though increases in these variables were modest in the patients receiving quetiapine and minimal in those receiving risperidone. There were positive correlations between serum leptin levels and BMI and triglyceride levels. Clinical efficacy, as indicated by decrease in total PANSS scores, was associated with leptin levels in all atypical antipsychotic groups.. Our results suggest that leptin may be associated with olanzapine- and clozapine-induced weight gain and that quetiapine appears to have modest influence and risperidone appears to have minimal influence on leptin and triglyceride levels and weight gain compared with olanzapine and clozapine.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clozapine; Dibenzothiazepines; Female; Follow-Up Studies; Glucose Tolerance Test; Humans; Leptin; Male; Obesity; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Quetiapine Fumarate; Risperidone; Schizophrenia; Treatment Outcome; Triglycerides; Weight Gain

Several clinical reports have demonstrated that most antipsychotics of the new generation, but not the typical antipsychotic haloperidol, induce weight gain in schizophrenic patients. Since weight gain induces serious health complications in humans, it is crucial to test upcoming antipsychotic compounds in an animal model of weight gain. With the aim of evaluating whether the rat can be used as a model for antipsychotic-induced weight gain, we have investigated the effect of chronic treatment (3 weeks) with one antipsychotic drug inducing weight gain in clinic (olanzapine) and one antipsychotic not inducing weight gain in clinic (haloperidol), on food and water intake and body weight gain in rats. We included both female and male rats in this study. To reduce spontaneous high food intake in rats, and to be able to evaluate the treatment effect on a potential increase of food intake or metabolic changes, we allowed animal to receive only low-palatability chow. In male rats, none of the two compounds induced weight gain, but in female rats, both compounds induced weight gain. Consequently, the effect observed in rats does not match the clinical situation, and Wistar rats in this set-up cannot be considered a relevant model for antipsychotic-induced weight gain in humans.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Body Weight; Diet; Disease Models, Animal; Dose-Response Relationship, Drug; Drinking; Eating; Female; Food Preferences; Haloperidol; Humans; Male; Olanzapine; Pirenzepine; Rats; Rats, Wistar; Sex Characteristics; Weight Gain

The aim of this cross-sectional study, the EIRE study, was to assess the frequency of several side effects with antipsychotics in the clinical setting. This paper addresses the adverse effect of weight gain.. Outpatients diagnosed of schizophrenia according to DSM-IV criteria and receiving a single antipsychotic (risperidone, olanzapine, quetiapine or haloperidol) for at least 4 weeks were consecutively recruited. Data were collected in a single visit, including data on demographic, clinical and treatment characteristics. Mean weight change was evaluated retrospectively by means of clinical charts and the weight at the time of the visit; in addition, the corresponding item of a modified version of the UKU, a Scandinavian side-effect rating scale, was used. Chi-squared test and logistic regression methods were used to analyze frequency of weight gain between treatments.. Out of 669 recruited, 636 evaluable patients were assessed. The treatment with the highest number of patients with weight gain as an adverse reaction on the UKU scale was olanzapine (74.5%), followed by risperidone (53.4%) and haloperidol (40.0%). The proportion of patients with clinically relevant weight gain (>or=7% increase versus initial weight) was also higher with olanzapine (45.7%) than with risperidone (30.6%) and haloperidol (22.4%). Five patients (13.5%) treated with quetiapine had some degree of weight gain according to the UKU scale, although no patient showed a clinically relevant weight gain (>or=7%). Treatment with olanzapine and risperidone were identified as risk factors of weight gain versus haloperidol. The risk of weight gain was higher in women (OR: 4.4), overweight patients (OR: 3.0) and in patients with

Topics: Adult; Adverse Drug Reaction Reporting Systems; Ambulatory Care; Antipsychotic Agents; Benzodiazepines; Cross-Sectional Studies; Dibenzothiazepines; Female; Haloperidol; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Quetiapine Fumarate; Risperidone; Schizophrenia; Schizophrenic Psychology; Spain; Weight Gain

The increasing use of olanzapine for treating adolescent patients has brought with it greater awareness of the recognized side effects of this medication, especially weight gain. Of the reports of glucose dysregulation related to olanzapine therapy, only a few pertain to adolescents. We present five cases: two youths who consequently suffered from overt diabetes and three who responded with glucose dysregulation. According to the Naranjo probability scale, the relation of this phenomenon to olanzapine therapy is "probable." We consider the findings of the presented case series as justification for regular metabolic follow-up for apparently healthy adolescents receiving olanzapine therapy.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Diabetes Mellitus, Type 2; Female; Humans; Hyperglycemia; Male; Olanzapine; Pirenzepine; Psychotic Disorders; Weight Gain

Weight gain in mentally ill patients is an evident problem, and obesity can be two- to three-fold more prevalent in psychiatric patients than in the general population. We report two patients who gained weight during previous antipsychotic treatment but who lost weight when shifted to quetiapine.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Brain Injuries; Chlorpromazine; Dibenzothiazepines; Humans; Male; Obesity; Olanzapine; Quetiapine Fumarate; Schizophrenia, Paranoid; Weight Gain; Weight Loss

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Cholesterol; Cohort Studies; Female; Follow-Up Studies; Humans; Male; Olanzapine; Psychiatric Status Rating Scales; Psychotic Disorders; Risperidone; Schizophrenia; Triglycerides; Weight Gain

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Clozapine; Dibenzothiazepines; Drug Therapy, Combination; Female; Humans; Long-Term Care; Male; Middle Aged; Olanzapine; Pirenzepine; Quetiapine Fumarate; Retrospective Studies; Risk; Risperidone; Schizophrenia; Triglycerides; Weight Gain

Issues to consider when evaluating maintenance drug therapy for patients with schizophrenia are discussed; these include potential adverse effects of antipsychotic therapy, such as weight gain, diabetes mellitus, extrapyramidal symptoms, sexual dysfunction, cognitive dysfunction, and cardiac effects, as well as quality of life. Patients with schizophrenia are more likely to be overweight than the general population. Olanzapine and clozapine have been associated with the greatest weight gain of the newer antipsychotics. While patients with schizophrenia are at increased risk of developing diabetes mellitus independent of antipsychotic therapy, diabetes may be more prevalent in patients taking the newer agents. Acute extrapyramidal symptoms occur in 75-90% of patients receiving first-generation antipsychotics like thioridazine and haloperidol. The probability of tardive dyskinesia (TD) occurring with second- and third-generation agents is less than 1% per year, compared with about 5% per year for the traditional antipsychotics. When patients are switched from a traditional antipsychotic to clozapine or olanzapine, TDs usually abate somewhat. Thioridazine causes a pronounced prolongation of the QTc interval, which can lead to ventricular arrhythmias. The slight increase in QTc interval caused by ziprasidone most likely will not be a problem in healthy individuals. Newer antipsychotics are associated with improved neurocognitive functioning and most cause less prolactin elevation, compared with traditional agents. The newer antipsychotic agents are not devoid of adverse effects, but those that do occur can be managed. Once issues related to adherence are resolved, rehabilitation of patients with schizophrenia will be a high priority.

Topics: Antipsychotic Agents; Benzodiazepines; Clinical Trials as Topic; Clozapine; Continuity of Patient Care; Diabetes Mellitus; Electrocardiography; Humans; Movement Disorders; Olanzapine; Pirenzepine; Quality of Life; Schizophrenia; Weight Gain

Topics: Adolescent; Benzodiazepines; Child; Dopamine Antagonists; Female; Haloperidol; Humans; Male; Obesity; Olanzapine; Pirenzepine; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Weight Gain

The novel antipsychotics are extensively used based on their favorable extrapyramidal side effect profiles. However, accumulating evidence suggests that these agents, particularly clozapine and olanzapine, have serious side effects of their own, including weight gain and elevated glucose and triglyceride levels. The goal of this study is to compare the effects of novel antipsychotics clozapine, olanzapine, risperidone, and quetiapine and typical antipsychotics haloperidol and fluphenazine on glucose and lipid levels.. The charts of 590 patients were retrospectively reviewed. Of those, 215 patients had adequate laboratory data for inclusion. Glucose and lipid level data from 2 1/2 years before and after initiation of the target antipsychotic were included. Covariates, including patients' age, the duration of antipsychotic treatment, other medications that may affect glucose or lipid levels, and the initial laboratory values, were controlled for in the analyses.. Glucose levels were increased from baseline for patients treated with clozapine, olanzapine, and haloperidol. There were statistically and clinically significant differences among the medications' effects on lipid profiles (p < .05). Those receiving clozapine and olanzapine demonstrated statistically significant increases in triglyceride levels compared with the other groups. Over one third of patients treated with any of the novel antipsychotics had clinically meaningful triglyceride elevations.. It has been shown that novel antipsychotics are associated with weight gain. This risk factor along with others, such as elevated glucose and triglyceride levels, compounds the risk for coronary artery disease. Routine monitoring of glucose and lipid levels during treatment with novel antipsychotics should be advocated.

Topics: Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Clozapine; Diabetes Mellitus, Type 2; Dibenzothiazepines; Female; Haloperidol; Humans; Hyperlipidemias; Lipids; Male; Middle Aged; Olanzapine; Pirenzepine; Psychotic Disorders; Quetiapine Fumarate; Retrospective Studies; Risk Factors; Risperidone; Triglycerides; Weight Gain

Topics: Adult; Anticonvulsants; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Drug Therapy, Combination; Fructose; Humans; Male; Olanzapine; Pirenzepine; Schizophrenia, Paranoid; Topiramate; Weight Gain

Novel antipsychotic drugs (APDs) have enhanced therapeutic actions compared to 'typical' APDs. However, clinical studies indicate that some induce marked weight gain. We attempted to model this effect in female Wistar rats given olanzapine chronically at 4 mg/kg b.i.d (4.5 h between injections). Such rats showed marked weight gain, which was statistically significant after only a single day of treatment, although weight gain increased up to a plateau after 10 days of treatment. Cessation of treatment led to rapid weight loss, which was significant after a single day of withdrawal. The weight gain observed was characterized by marked individual differences. As some clinical reports suggest that novel APD-induced weight gain is most pronounced in patients with the lowest body weight, we examined the relationship between weight gain and baseline body weight. However, we observed no significant relationship between baseline body weight and weight gain. The observation that olanzapine can induce weight gain rapidly in rats, in conjunction with the observation of marked individual differences in weight gain, suggests that patients at risk of developing weight gain might be detectable early in treatment. Furthermore, the finding that weight gain is rapidly reversible suggests that patients at risk of weight gain could be switched to APDs with less pronounced tendencies to induce weight gain. The study of APD-induced weight gain in rodents may provide insights into the nature, causes, and treatments for, novel APD-induced weight gain in the clinic. However, it remains to be determined how closely rodent models mimic the clinical situation and whether the mechanism(s) involved in the weight gain we have observed are the same as those involved in the clinical use of these drugs.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Female; Olanzapine; Pirenzepine; Rats; Rats, Wistar; Substance Withdrawal Syndrome; Weight Gain

To evaluate weight gain associated with olanzapine, risperidone, and haloperidol treatment and its clinical risk factors in adolescent patients.. The study was conducted at three adolescent psychiatric departments in two mental health centers in the Tel Aviv area. All patients were Jewish Israelis. Weight and body mass index (BMI) of hospitalized adolescents treated with olanzapine (n = 21), risperidone (n = 21), or haloperidol (n = 8) were prospectively monitored on a weekly basis for the first 12 weeks of treatment. Various clinical risk factors were tested for association with weight gain.. The olanzapine and risperidone groups experienced significant weight gain between baseline and endpoint (p < .01), whereas the average weight of the haloperidol group did not change. Average weight gain was significantly higher for the olanzapine group (7.2 +/- 6.3 kg, 11.1% +/- 7.8%) than for the risperidone (3.9 +/- 4.8 kg, 6.6% +/- 8.6%) and haloperidol (1.1 +/- 3.3 kg, 1.5% +/- 6.0%) groups. Extreme weight gain (>7%) was recorded in 19 patients (90.5%), 9 patients (42.9%), and 1 (12.5%) patient, respectively Gender (males), low concern about gaining weight (females), low baseline BMI, and paternal BMI were positively correlated with weight gain, whereas previous neuroleptic history, neuroleptic dosage, response to treatment, and illness duration were not.. Olanzapine and risperidone are associated with extreme weight gain in adolescents, much higher than that reported in adults. This side effect should be taken into consideration before prescribing these medications, especially in patients at high risk.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Female; Haloperidol; Humans; Male; Mental Disorders; Olanzapine; Pirenzepine; Prospective Studies; Risperidone; Weight Gain

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Female; Humans; Hyperglycemia; Olanzapine; Pirenzepine; Psychotic Disorders; Weight Gain

We describe here a case of olanzapine associated weight gain, hyperglycemia and neuroleptic malignant syndrome in a 64 year-old woman with a significant medical history. Eighteen weeks after initiating olanzapine, Mrs X lost glycemic control, exhibited signs and symptoms consistent with neuroleptic malignant syndrome and gained 8.9 kg. We suggest that utilization of olanzapine in the less medically stable geriatric patient be implemented with vigilant monitoring for such complications mentioned above.

Topics: Antipsychotic Agents; Benzodiazepines; Female; Humans; Hyperglycemia; Middle Aged; Neuroleptic Malignant Syndrome; Olanzapine; Pirenzepine; Weight Gain

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clozapine; Follow-Up Studies; Humans; Male; Obesity; Olanzapine; Pirenzepine; Risperidone; Schizophrenia; Weight Gain

The aim of this study was to evaluate the mechanisms underlying weight gain induced by the atypical antipsychotic, olanzapine. We performed euglycemic, hyperinsulinemic clamp combined with indirect calorimetry on a 48-year-old male with antisocial personality disorder, alcohol dependence and paranoid ideation before and after one month of olanzapine (10 - 15 mg/day) therapy. The patient gave his informed, written consent for this study. The results were a weight gain of 6 kg and a decrease in both basal (from 1673 to 1613 kcal/24 h) and 3-hour (from 22.8 to 20.2 cal/kg fat free mass/min) energy expenditure. Serum thyroid hormone and high-density lipoprotein cholesterol levels decreased, and the triglyceride and low-density lipoprotein cholesterol levels increased. Insulin sensitivity did not change. We conclude that decreased basal energy expenditure may contribute to weight gain in olanzapine treatment.

Topics: Antipsychotic Agents; Benzodiazepines; Calorimetry, Indirect; Energy Metabolism; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Psychotic Disorders; Weight Gain

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Child; Humans; Hypertriglyceridemia; Male; Olanzapine; Pirenzepine; Weight Gain

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Child; Child Development Disorders, Pervasive; Child, Preschool; Humans; Olanzapine; Pilot Projects; Pirenzepine; Weight Gain

Conventional as well as newer antipsychotics cause weight gain, and, in the regulation of body weight, both insulin and leptin are hormones involved.. The aim of the present study was to compare these hormonal levels in patients on treatment with different antipsychotics.. Nineteen patients receiving conventional antipsychotics, 14 patients receiving clozapine and 14 patients receiving olanzapine, were studied. Fasting blood samples for insulin, leptin, glucose, and drug serum concentrations were analyzed. In addition, body mass index (BMI) was calculated.. The median insulin level was significantly higher in the patients receiving olanzapine than in those receiving conventional agents, whereas there was no significant difference in insulin between the clozapine and the other two groups. However, in the clozapine group, insulin levels were positively correlated to the drug serum concentration. BMI was elevated in about half of the patients, with no difference being found between the groups. The leptin level was significantly higher in the women than in the men in the conventional agent group, but not in the olanzapine or clozapine groups.. The higher insulin level in the patients receiving olanzapine than in those receiving conventional antipsychotics, despite similar BMI, points to a probable influence of olanzapine on insulin secretion. The correlation between the insulin levels and the clozapine concentration indicates, in addition, an influence of clozapine on insulin secretion. The gender difference in leptin, i.e. females normally having higher leptin levels than males, was found in the conventional agent group, but not in the olanzapine or clozapine groups, suggesting that also leptin regulation is altered during olanzapine or clozapine treatments. Moreover, it was mainly due to an increase of leptin in the males that leptin levels were equalized between sexes in the olanzapine group. We conclude that the influence of olanzapine and clozapine on both insulin and leptin levels might be associated with their weight-gain-inducing ability, while other mechanisms may be involved in the weight gain caused by conventional antipsychotics.

Topics: Adult; Aged; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Clozapine; Female; Humans; Insulin; Leptin; Male; Middle Aged; Olanzapine; Pirenzepine; Schizophrenia; Statistics, Nonparametric; Weight Gain

Weight gain frequently accompanies treatment with antipsychotics. In order to determine whether newer antipsychotic agents differ from each other with respect to weight gain, we compared two cohorts of patients with DSM-IV schizophrenia who had newly started treatment with either risperidone or olanzapine. After obtaining informed consent, data regarding body weight and height were culled from existing medical records of 100 patients (50 patients in each treatment group). Baseline body weight, close to the time of starting the new medication, and body mass index [BMI = weight (kg)/height (m) squared] were compared to the body weight and BMI following 4 months of treatment. There was no significant change in mean body weight or BMI in the group treated with risperidone (baseline weight = 83.1 kg +/- 20.5, follow-up = 82.8 kg +/- 19.9; matched pair t = 0.66, P = n.s.; baseline BMI = 29.6 +/- 9.4, follow-up = 29.5 +/- 9.1; matched pair t = 0.79, P = n.s.). However, in the group treated with olanzapine, there was a significant increase in both mean body weight and BMI (baseline weight = 84.9 kg +/- 25.0, follow-up = 87.1 kg +/- 25.1; matched pair t = 4.62, P < 0.001; baseline BMI = 29.5 +/- 7.4, follow-up = 30.3 +/- 7.5; matched pair t = 4.43, P < 0.001). In this naturalistic study, treatment with olanzapine was associated with a mean weight gain of about 2 kg from baseline, in patients with schizophrenia, while treatment with risperidone was associated with no mean weight change.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Female; Follow-Up Studies; Humans; Male; Olanzapine; Pirenzepine; Risperidone; Schizophrenia; Weight Gain

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Clozapine; Cognitive Behavioral Therapy; Counseling; Exercise; Female; Humans; Male; Obesity; Olanzapine; Pirenzepine; Relaxation Therapy; Schizophrenia; Treatment Outcome; Weight Gain

This study evaluated the effectiveness of a Weight Watchers program for patients with schizophrenia who had olanzapine-related weight gain and ascertained whether the severity of patients' psychiatric symptoms was correlated with the patients' success in losing weight. Seven men and four women who had been treated with olanzapine and who had gained at least 7 percent of their pretreatment body weight attended Weight Watchers meetings and were offered supervised exercise sessions. The patients' weight, body mass index, and psychiatric symptoms were assessed and were compared with those of a matched comparison group who did not attend the Weight Watchers program. Only the men experienced significant weight loss. No correlation was found between weight loss and exercise or change in psychiatric symptoms.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Case-Control Studies; Diet, Reducing; Female; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Program Evaluation; Schizophrenia; Severity of Illness Index; Sex Factors; Walking; Weight Gain; Weight Loss

The role of olanzapine in treatment-resistant schizophrenia is still unresolved. This article presents an open-label, prospective, 14-week trial with olanzapine in patients with schizophrenia and schizoaffective disorder selected for unambiguous resistance to either clozapine or risperidone and to typical antipsychotics. Forty-three inpatients (mean age, 41.6 years; mean duration of illness, 21.7 years) were enrolled and treated after cross-titration from their previous antipsychotic treatment with olanzapine 10 to 40 mg daily without any concomitant antipsychotic medication. Patients were evaluated with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions Scale, and the Extrapyramidal Symptom Rating Scale. The change with olanzapine treatment was associated with a PANSS total score improvement of 3.7 (SD = 15.6; not significant). There was a significant improvement for the PANSS cognitive and depression/anxiety factors, whereas the PANSS excitement factor worsened. The improvement rate was superior in patients receiving olanzapine doses higher than 20 mg. A total of 16.7% of patients reached response criteria set forth by a previous study. There was a significant decrease in extrapyramidal side effects (t = 2.04; p < 0.05) and statistically significant, yet modest, weight gain. These results indicate that olanzapine is only modestly effective in these severely treatment-resistant patients with schizophrenia. However, a trial with olanzapine can be recommended in these patients before moving to augmentation strategies, given the lack of proven alternatives and the observation that 16.7% of patients reached the response criteria.

Topics: Adult; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Drug Resistance; Female; Humans; Male; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Weight Gain

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Weight; Female; Fructose; Humans; Male; Olanzapine; Pirenzepine; Schizophrenia; Topiramate; Weight Gain

We present here clinical case reports of three adolescents, aged 14-17 years, who were treated with olanzapine. The daily dose was 10 mg. Prior to olanzapine, the patients were unsuccessfully treated with other antipsychotic drugs. The response to olanzapine for psychotic symptoms was clinically significant in all three patients. The major adverse effect was excessive weight gain. The increases in body mass index (BMI) were 9, 8 and 5 kg/m2. One of the patients later lost the additional weight. Especially in adolescents obesity is a serious side effect and potential consequences include numerous health problems.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Female; Humans; Male; Olanzapine; Pirenzepine; Psychotic Disorders; Schizophrenia, Paranoid; Weight Gain

We performed a retrospective analysis of data involving 121 inpatients to examine the rate of weight gain during antipsychotic-free periods and during treatment with various antipsychotic drugs.. Data were analyzed to determine differences in weekly weight change during antipsychotic-free (N = 65), typical antipsychotic (N = 51), or atypical antipsychotic (N = 130) treatment periods. Atypical antipsychotic treatment periods were further subdivided into olanzapine (N = 45), clozapine (N = 47), or risperidone (N = 36) treatment periods. A paired comparison was conducted on 65 patients who had an antipsychotic-free treatment period preceding or following a neuroleptic drug treatment period. In addition, patients were classified as either non-obese (with a body mass index [BMI] < or = 29.9 kg/ml) or obese (BMI > or = 30.0 kg/m2) to test whether the rate of weight gain during treatment periods was related to initial BMI.. Across all treatment periods, weekly weight gain was as follows: 0.89 lb/wk (0.40 kg/wk) on atypical antipsychotic medication, 0.61 lb/wk (0.27 kg/wk) on typical antipsychotic medication, and 0.21 lb/wk (0.09 kg/wk) on no antipsychotic medications. The atypical antipsychotic versus antipsychotic-free comparison was significant (F = 3.51; df = 2,231; p = .031), while the typical antipsychotic versus antipsychotic-free comparison was not. Among the individual atypical antipsychotic medications, significantly more weight gain occurred during olanzapine treatment (1.70 lb/wk) (0.76 kg/wk) than with either clozapine (0.50 lb/wk) (0.22 kg/wk) or risperidone (0.34 lb/wk) (0.15 kg/wk) treatments (F = 7.77; df = 2,117; p = .001). In the paired analysis with patients serving as their own controls, the difference between weekly weight gain during atypical antipsychotic treatment and antipsychotic-free treatment was significant (t = -3.91; df = 44; p = .001), while the difference between weight gain during typical antipsychotic treatment and antipsychotic-free treatment was not significant. With the individual drugs. treatment with both olanzapine and clozapine caused significantly higher weekly weight gain than antipsychotic-free treatment (p = .001 and p = .036, respectively). while treatment with risperidone did not. Non-obese patients (BMI < 29.9 kg/m2) and obese patients (BMI > 30.0 kg/m2) did not differ significantly in their weight gain during typical or atypical antipsychotic treatment.. Treatment with atypical antipsychotics was associated with more weight gain than treatment with typical antipsychotics. Among the atypical drugs, olanzapine was associated with more weight gain than either clozapine or risperidone. The patient's admission BMI was not associated with the amount of weight gained during subsequent antipsychotic treatment.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clozapine; Drug Administration Schedule; Female; Hospitalization; Humans; Male; Obesity; Olanzapine; Pirenzepine; Psychotic Disorders; Regression Analysis; Research Design; Retrospective Studies; Risperidone; Schizophrenia; Weight Gain

We report on three cases of acutely manic prepubertal children diagnosed with bipolar disorder who were treated with olanzapine in addition to their existing mood stabilizer regimens. All three had marked improvement of their manic symptoms within 3-5 days of beginning olanzapine therapy as measured by clinician-rated instruments. Adverse effects included sedation and weight gain. These results suggest that olanzapine may have an antimanic or mood stabilizing effect in acutely manic children with bipolar disorder.

Topics: Antimanic Agents; Antipsychotic Agents; Attention Deficit Disorder with Hyperactivity; Benzodiazepines; Bipolar Disorder; Child; Drug Therapy, Combination; Humans; Lithium Chloride; Male; Olanzapine; Pirenzepine; Sleep Stages; Valproic Acid; Weight Gain

Whereas the Fiji government provides all aspects of mental health care services free of charge to its citizens, many schizophrenics have failed to respond to classical antipsychotic drugs.. To assess the efficacy and safety of olanzapine among various patients with severe psychiatric disorders.. Naturalistic setting.. Descriptive study.. Outcome was based on reduction of symptoms on the PANSS (> or = 40%) and CGI shift to 1-3.. The were 64 patients (30 males) aged 17-77 years. Thirty six (56.3%) had schizophrenia, eight mania, ten severe depression, four obsessive compulsive disorder (OCD), one each had schizo-affective and delusional disorders, while the remaining had chronic brain diseases.. At weeks 3, 8, 12, the proportion of subjects with 40% improvement was 60.6%, 79.9%, and 76.8%, respectively. Positive and negative symptoms improved. Thirteen (48.1%) of the 27 long-stay treatment--resistant schizophrenics achieved clinical recovery at eight weeks. All with primary diagnosis of severe depression and mania achieved full clinical recovery (mostly within two weeks). Two OCD cases achieved clinical recovery at week eight.. Olanzapine was safe for all categories of patients. There was not a single case of extrapyramidal reaction among subjects who did not have it pre-treatment; and the drug was safe in a suicidal overdose of 205 mg. Most patients experienced weight gain; two adolescent girls had temporary amenorrhoea and one subject had transient rise in liver transaminases which normalised without discontinuing the drug.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Depressive Disorder; Female; Fiji; Humans; Male; Middle Aged; Obsessive-Compulsive Disorder; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Schizophrenia; Severity of Illness Index; Treatment Outcome; Weight Gain

Topics: Adult; Benzodiazepines; Female; Humans; Obesity; Olanzapine; Pirenzepine; Psychotic Disorders; Selective Serotonin Reuptake Inhibitors; Weight Gain

Olanzapine is temporally associated, in a number of patients with schizophrenia, with weight gain. H(2) antagonists, like nizatidine, have been shown to control appetite in overweight patients.. A patient with olanzapine temporally associated weight gain was treated with nizatidine as "add-on" therapy.. Nizatidine treatment was associated with good control and subsequent reduction of weight after 4 to 5 weeks of therapy in a patient with repetitive episodes of weight gain during olanzapine treatment. Olanzapine was otherwise well tolerated and effective in controlling psychopathology.. H(2) antagonist treatment with olanzapine may be a valid medical strategy in preventing and/or reducing weight gain in patients with schizophrenia. Controlled studies are recommended to confirm this observation.

Topics: Adult; Benzodiazepines; Brief Psychiatric Rating Scale; Histamine H2 Antagonists; Humans; Male; Nizatidine; Obesity; Olanzapine; Pirenzepine; Schizophrenia, Paranoid; Time Factors; Weight Gain

Leptin is produced by fat cells and is presumed to signal the size of the adipose tissue to the brain. The authors investigated whether antipsychotic drugs that often induce weight gain affect circulating levels of leptin.. Weight, body mass index, and leptin plasma level were measured weekly over 4 weeks in psychiatric inpatients who received clozapine (N = 11), olanzapine (N = 8), haloperidol (N = 13), or no psychopharmacological treatment (N = 12).. In patients receiving clozapine or olanzapine, significant increases in weight, body mass index, and leptin level were found, whereas these measures remained stable in patients who received haloperidol or no pharmacological treatment.. Weight gain induced by clozapine or olanzapine appears to be associated with an increase in leptin level that cannot be attributed to dietary changes upon hospitalization.

Topics: Adipose Tissue; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Clozapine; Haloperidol; Hospitalization; Humans; Leptin; Mental Disorders; Olanzapine; Pirenzepine; Proteins; Weight Gain

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Female; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Retrospective Studies; Serotonin Antagonists; Weight Gain

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Humans; Obesity; Olanzapine; Pirenzepine; Risperidone; Schizophrenia; Weight Gain

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Hypertriglyceridemia; Male; Middle Aged; Olanzapine; Pirenzepine; Schizophrenia; Triglycerides; Weight Gain

Weight gain has been reported with nearly every antipsychotic drug on the market (molindone is an exception). Weight gain occurs no matter what the patient's age, sex, or race and is seen with both oral and depot drug formulations. Numerous studies have found that patients gain weight when treated with a conventional antipsychotic, such as chlorpromazine, fluphenazine, and haloperidol. The newer, novel antipsychotics offer advantages over conventional antipsychotics, especially a relative lack of extrapyramidal symptoms, but some still have the disadvantage of causing weight gain. Clozapine and olanzapine in particular appear to cause substantial weight gain, much more so than do most conventional neuroleptics and novel agents such as risperidone. Given the risks to health and treatment compliance associated with weight gain and obesity, clinicians should monitor weight during the course of antipsychotic therapy and consider switching agents if excessive weight gain occurs.

Topics: Administration, Oral; Antipsychotic Agents; Benzodiazepines; Clozapine; Delayed-Action Preparations; Humans; Obesity; Olanzapine; Pirenzepine; Psychotic Disorders; Schizophrenia; Weight Gain

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Humans; Obesity; Olanzapine; Pirenzepine; Risperidone; Weight Gain

Topics: Adolescent; Benzodiazepines; Body Mass Index; Humans; Male; Obesity; Olanzapine; Pirenzepine; Schizophrenia; Weight Gain

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Female; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Psychotic Disorders; Retrospective Studies; Weight Gain