olanzapine and Obesity

Schizophrenia is associated with an increased prevalence of the metabolic syndrome. Patients receiving antipsychotic medications, including olanzapine, are at further risk. Ghrelin is an appetite-stimulating peptide hormone, although whether blood levels are altered by antipsychotic treatment, remains unclear. We performed a systematic review and meta-analysis comparing blood ghrelin levels in patients with schizophrenia before and after treatment with olanzapine.. Two authors independently searched major electronic databases from inception until February 2018 for studies measuring blood ghrelin levels among patients with schizophrenia before and after olanzapine therapy. Random effects meta-analysis calculating standardized mean difference (SMD) and 95% confidence intervals (CI) and meta-regression analyses were performed.. Six studies met the inclusion criteria. Across these studies, there were 111 patients with schizophrenia (mean age 40, 85% male, baseline BMI 22, and endpoint BMI 23). Olanzapine treatment (mean [standard deviation] duration = 12.3 [7.6] weeks) was associated with a significant decrease in blood ghrelin levels with a medium effect size (SMD = -0.48, 95% CI -0.88 to -0.08, p = 0.018). Age, sex, baseline BMI, geography, olanzapine dose and duration, year of publication, study quality, inpatient status, and antipsychotic washout did not moderate this association.. Our results suggest that in patients with schizophrenia, olanzapine therapy is associated with decreased blood ghrelin levels, a paradoxical phenomenon known to occur in obesity. Future studies should investigate the contribution of dietary factors (e.g., caloric intake) and physical activity to this association, as well as the effects of other antipsychotics on ghrelin levels.

Topics: Antipsychotic Agents; Ghrelin; Humans; Metabolic Syndrome; Obesity; Olanzapine; Schizophrenia

This study was conducted to review systematically adjunctive treatments for weight reduction in patients with schizophrenia and compare efficacies of clinical trials through meta-analysis, so as to provide effective clinical guideline regarding weight control for patients taking atypical antipsychotics.. Candidate clinical trials were identified through searching the Cochrane Central Register of Controlled Trials, PubMed, and PsycINFO. Fourteen randomized clinical trials were included for systematic review and meta-analysis from 132 potential trials. The Comprehensive Meta-Analysis version 2 was used for meta-analysis.. Difference in means and significances from meta-analyses regarding weight control by adjunctive treatments showed that topiramate, aripiprazole, or sibutramine was more effective than metformin or reboxetine. Psychiatric evaluations did not show statistically significant changes between treatment groups and placebo groups except topiramate adjunctive treatments. Adverse effects regarding adjunctive therapies were tolerable and showed statistically no significances compared to control groups.. Though having several reports related to exacerbation of psychiatric symptoms, topiramate and aripiprazole are more efficacious than other medications in regard to weight reduction and less burden of critical adverse effects as well as being beneficial for clinical improvement.

Topics: Anti-Obesity Agents; Antipsychotic Agents; Benzodiazepines; Clozapine; Drug Therapy, Combination; Humans; Obesity; Olanzapine; Schizophrenia

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

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

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

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

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

Disruptive behavior disorders, including conduct disorder, oppositional defiant disorder, and disruptive behavior disorder not otherwise specified, are serious conditions in children and adolescents that include a behavior pattern of violating the basic rights of others and age-appropriate rules or standards and may include aggressive behavior. Although no pharmacotherapy is currently approved for use in this population, evidence suggests that atypical antipsychotic treatment may be useful in patients with these conditions who present with problematic aggression. Currently, research on risperidone shows it to be effective in treating aggressive behavior in this patient population. Limited research is also available on olanzapine, quetiapine, and aripiprazole, but more research is needed on these and other agents. As with any pharmacotherapy, adverse events (including weight gain, headache, and somnolence) should be carefully considered with these medications, especially in children and adolescents, and it is important to properly dose and monitor patients during medication therapy.

Topics: Adolescent; Antipsychotic Agents; Aripiprazole; Attention Deficit and Disruptive Behavior Disorders; Attention Deficit Disorder with Hyperactivity; Benzodiazepines; Child; Dibenzothiazepines; Disorders of Excessive Somnolence; Headache; Humans; Methylphenidate; Obesity; Olanzapine; Piperazines; Quetiapine Fumarate; Quinolones; Risperidone

Atypical antipsychotics are emerging as the first-line pharmacologic treatment for irritability (i.e., aggression, self-injurious behavior, and severe tantrums) in children and adolescents with autistic and other pervasive developmental disorders. Results from placebo-controlled and open-label studies of clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole in this subject population are reviewed. Additional placebo-controlled trials and studies of longer-term safety and tolerability are needed.

Topics: Adolescent; Aggression; Antipsychotic Agents; Aripiprazole; Autistic Disorder; Benzodiazepines; Child; Child Development Disorders, Pervasive; Child, Preschool; Clozapine; Dibenzothiazepines; Disorders of Excessive Somnolence; Humans; Obesity; Olanzapine; Piperazines; Quetiapine Fumarate; Quinolones; Risperidone; Thiazoles

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clozapine; Diabetes Mellitus; Dibenzothiazepines; Dyslipidemias; Glucose Metabolism Disorders; Humans; Insulin Resistance; Mental Disorders; Obesity; Olanzapine; Phenothiazines; Piperazines; Quetiapine Fumarate; Quinolones; Risperidone; Schizophrenia; Thiazoles

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

Recently, increasing attention has been drawn to the potential diabetogenic effect of novel antipsychotics. Until now, large prospective studies examining the relationship between atypical antipsychotics and impaired glucose metabolism have been lacking. However, the case reports and retrospective studies that we review here suggest an increased risk of developing diabetes mellitus (DM) in patients treated with atypical antipsychotics compared to schizophrenic patients treated with conventional antipsychotics or those without treatment. Although most atypical antipsychotic agents might have a diabetogenic potential, the risk of developing DM might be higher in patients treated with either clozapine or olanzapine than with risperidone, whereas data on quetiapine and ziprasidone is presently limited and needs further attention. Possible mechanisms include the induction of peripheral insulin resistance and the direct influence on pancreatic beta-cell function by 5-HT1A/2A/2C receptor antagonism, by inhibitory effects via alpha 2-adrenergic receptors or by toxic effects. On the other hand, atypical antipsychotics might not be an independent risk factor for the development of DM, but hasten the onset of DM in patients bearing other risk factors. It is suggested that schizophrenic patients should be monitored for the occurrence of glucose metabolism abnormalities before starting atypical antipsychotics, and at a 3-month interval at least during therapy.

Topics: Antipsychotic Agents; Benzodiazepines; Diabetes Mellitus; Dibenzothiazepines; Glucose; Humans; Insulin Resistance; Islets of Langerhans; Obesity; Olanzapine; Pancreas; Piperazines; Quetiapine Fumarate; Risperidone; Schizophrenia; Thiazoles

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

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

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

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

Treatment with most antipsychotics is associated with an increased risk of weight gain and metabolic disturbances. In a randomized trial, we previously demonstrated that 16 weeks of glucagon-like peptide-1 receptor agonist liraglutide treatment vs. placebo significantly reduced glucometabolic disturbances and body weight in prediabetic, overweight/obese schizophrenia-spectrum disorder patients treated with clozapine or olanzapine. The aim of this study was to investigate whether the beneficial effects of the 16-week intervention were sustained beyond the intervention period.. One year after completion of the intervention, we investigated changes in body weight, fasting glucose, glycated hemoglobin, C-peptide, and lipids comparing 1-year follow-up levels to end of treatment (week 16) and baseline (week 0) levels.. From end of treatment to the 1-year follow-up, body weight had increased in the liraglutide-treated group. However, compared to baseline levels, the placebo-subtracted body weight loss remained significantly reduced (-3.8 kg, 95% CI: -7.3 to -0.2, P = 0.04). Fasting glucose, glycated hemoglobin, C-peptide, and lipids had each returned to baseline levels 1 year after stopping liraglutide.. The body weight reduction during 16 weeks of liraglutide treatment was partially sustained 1 year after the intervention was completed. However, the improvements in other metabolic parameters returned to baseline levels.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Blood Glucose; Body Weight; C-Peptide; Clozapine; Denmark; Fasting; Female; Follow-Up Studies; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipid Metabolism; Liraglutide; Male; Middle Aged; Obesity; Olanzapine; Overweight; Placebos; Prediabetic State; Schizophrenia; 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

Compared with the general population, patients with schizophrenia have a 2- to 3-fold higher mortality rate primarily caused by cardiovascular disease. Previous interventions designed to counteract antipsychotic-induced weight gain and cardiometabolic disturbances reported limited effects.. To determine the effects of the glucagon-like peptide-1 receptor agonist liraglutide added to clozapine or olanzapine treatment of schizophrenia spectrum disorders.. This randomized clinical double-blind trial enrolled participants at 2 clinical sites in Denmark. Of 214 eligible participants with a schizophrenia spectrum disorder, 103 were randomized to liraglutide or placebo. Participants received stable treatment with clozapine or olanzapine, were overweight or obese, and had prediabetes. Data were collected from May 1, 2013, through February 25, 2016.. Treatment for 16 weeks with once-daily subcutaneous injection of liraglutide or placebo. Trial drug therapy was titrated during the first 2 weeks of the study.. The primary end point was change in glucose tolerance estimated by a 75-g oral glucose tolerance test result. Secondary end points included change in body weight and cardiometabolic parameters.. Of the 103 patients undergoing randomization (60 men [58.3%] and 43 women [41.7%]), 97 were included in the efficacy analysis, with a mean (SD) age of 42.5 (10.5) years and mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) of 33.8 (5.9). The liraglutide and placebo groups had comparable characteristics (mean [SD] age, 42.1 [10.7] vs 43.0 [10.5] years; 30 men in each group; mean [SD] body mass index, 33.7 [5.1] vs 33.9 [6.6]). A total of 96 randomized participants (93.2%) completed the trial. Glucose tolerance improved in the liraglutide group compared with the placebo group (P < .001). Altogether, 30 liraglutide-treated participants (63.8%) developed normal glucose tolerance compared with 8 placebo-treated participants (16.0%) (P < .001; number needed to treat, 2). Body weight decreased with liraglutide compared with placebo (-5.3 kg; 95% CI, -7.0 to -3.7 kg). Reductions in waist circumference (-4.1 cm; 95% CI, -6.0 to -2.3 cm), systolic blood pressure (-4.9 mm Hg; 95% CI, -9.5 to -0.3 mm Hg), visceral fat (-250.19 g; 95% CI, -459.9 to -40.5 g), and low-density lipoprotein levels (-15.4 mg/dL; 95% CI, -23.2 to -7.7 mg/dL) occurred with liraglutide compared with placebo. Adverse events with liraglutide affected mainly the gastrointestinal tract.. Liraglutide significantly improved glucose tolerance, body weight, and cardiometabolic disturbances in patients with schizophrenia spectrum disorders treated with clozapine or olanzapine.. clinicaltrials.gov Identifier: NCT01845259.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Double-Blind Method; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Obesity; Olanzapine; Outcome Assessment, Health Care; Overweight; Prediabetic State; Schizophrenia

To discuss the impacts of abdominal acupuncture on serum leptin, adiponectin, total cholesterol and triglyceride in the patients of obesity induced by olanzapine.. Eighty-six obesity patients induced by olanzapine were randomized into an observation group (47 cases) and a control group (39 cases). The healthcare guide and the adjustment on diet and physical exercise were given in the two groups. Additionally, in the observation group, the abdominal acupuncture therapy was applied to Zhongwan (CV 12), Xiawan (CV 10), Qihai (CV 6), Guanyuan (CV 4), Tianshu (ST 25) and Shuidao (ST 28), once a day, 5 times a week. The treatment lasted for 3 months in the two groups. The body mass index (BMI), serum leptin, adiponectin, total cholesterol and triglyceride were compared before and after treatment in the patients of the two groups.. After treatment, BMI, serum leptin, total cholesterol and triglyceride were all lower than those before treatment in the patients of the two groups (all. Abdominal acupuncture regulates the transfer capacity of leptin signal and the secretion of adiponectin, promotes lipid metabolism and reduces the body mass in obesity patients induced by olanzapine.

Topics: Abdomen; Acupuncture Points; Acupuncture Therapy; Adiponectin; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Cholesterol; Humans; Leptin; Lipid Metabolism; Obesity; Olanzapine; Triglycerides

Increased body weight and hyperlipidemia caused by antipsychotics may be associated with improved antipsychotic efficacy in schizophrenia. If this association has a causal interrelationship via a genuine pathophysiological mechanism, then body weight loss in antipsychotic-treated patients would be accompanied by worsened psychopathology. This could have clinical implications.. To explore whether the decreased body weight in these patients is associated with a worsened psychopathology.. In our previously published study, a 16 week treatment period with add-on orlistat (but not placebo) resulted in body weight loss in male (but not female) clozapine- or olanzapine-treated overweight or obese patients. In the current study, we investigated whether body weight loss in those male patients could worsen psychosis. Changes in the Positive and Negative Syndrome Scale (PANSS) scores within groups and body weight changes and lipid profiles over the treatment period were analysed by the paired samples t-test. Between-group comparisons were analysed by the independent samples t-test.. Over the treatment period body weight decreased by 2.56 ± 3.25 kg from initial 106.02 ± 12.61 kg (p = 0.04) for the orlistat group, with no statistically significant changes for the placebo group. Lipid levels did not change in either group. The orlistat-induced weight decrease was not associated with worsening in the PANSS scores.. Weight loss was not associated with a worsening of psychosis. The interrelationship between the antipsychotic-induced weigh gain and improved schizophrenia psychopathology observed in earlier studies appears to be indirect. Orlistat treatment in our study did not worsen psychopathology in this population.

Topics: Adult; Anti-Obesity Agents; Antipsychotic Agents; Benzodiazepines; Clozapine; Double-Blind Method; Female; Humans; Lactones; Lipid Metabolism; Male; Middle Aged; Obesity; Olanzapine; Orlistat; Psychiatric Status Rating Scales; Psychopathology; Schizophrenia; Weight Loss

We tested the hypothesis that a common functional variant in brain-derived neurotrophic factor (BDNF), Val66Met, which has been shown to be associated with increased body mass index (BMI) in schizophrenia (SCZ) and schizoaffective disorder (SAD), is also associated with antipsychotic-induced weight gain in bipolar disorder (BPD). Association of Val66Met with other metabolic measures, including high- and low-density cholesterol, triglycerides, total cholesterol, fasting blood glucose, and hemoglobin A1c, was also tested.. This was a 12-month, prospective, randomized trial of two atypical antipsychotic drugs (APDs) with moderate (risperidone) or high (olanzapine) risk to cause weight gain. Subjects were diagnosed as having BPD (n = 90) and SCZ or SAD (n = 76).. BMI was significantly greater in all diagnoses for Met66 allele carriers at six months (p = 0.01). Met66 carriers with BPD showed a greater increase in the triglycerides/high-density (HDL) cholesterol ratio (p = 0.01), a key marker for metabolic syndrome related to insulin resistance, and log-triglycerides (p = 0.04), after three or six months of treatment. Met66 carriers had the greatest increase in log-triglycerides (p = 0.03) and triglycerides/HDL cholesterol ratio after three months of treatment with risperidone (p = 0.003), and the highest BMI at six months (p = 0.01).. The positive association of BNDF Val66Met with high BMI values replicates previous findings in patients with SCZ and indicates the BDNF Val66Met genotype as a potential risk factor for obesity and insulin resistance measures in patients with BPD receiving antipsychotics as well.

Topics: Adult; Alleles; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Blood Glucose; Body Mass Index; Brain-Derived Neurotrophic Factor; Cholesterol, HDL; Cholesterol, LDL; Dyslipidemias; Female; Genotype; Glycated Hemoglobin; Humans; Insulin Resistance; Male; Middle Aged; Obesity; Olanzapine; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Prospective Studies; Psychotic Disorders; Risk Factors; Risperidone; Schizophrenia; Triglycerides

Metabolic disturbances, obesity and life-shortening cardiovascular morbidity are major clinical problems among patients with antipsychotic treatment. Especially two of the most efficacious antipsychotics, clozapine and olanzapine, cause weight gain and metabolic disturbances. Additionally, patients with schizophrenia-spectrum disorders not infrequently consume alcohol. Glucagon-like peptide-1 (GLP-1) has shown to improve glycaemic control and reduce alcohol intake among patients with type 2 diabetes.. To investigate whether the beneficial effects of GLP-1 analogues on glycaemic control and alcohol intake, in patients with type 2 diabetes, can be extended to a population of pre-diabetic psychiatric patients receiving antipsychotic treatment.. Trial design, intervention and participants: The study is a 16-week, double-blinded, randomised, parallel-group, placebo-controlled clinical trial, designed to evaluate the effects of the GLP-1 analogue liraglutide on glycaemic control and alcohol intake compared to placebo in patients who are prediabetic, overweight (body mass index ≥27 kg/m(2)), diagnosed with a schizophrenia-spectrum disorder and on stable treatment with either clozapine or olanzapine.. The primary endpoint is the change in glucose tolerance from baseline (measured by area under the curve for the plasma glucose excursion following a 4 h 75 g oral glucose tolerance test) to follow-up at week 16. The secondary endpoints include changes of dysglycaemia, body weight, waist circumference, blood pressure, secretion of incretin hormones, insulin sensitivity and β cell function, dual-energy X-ray absorption scan (body composition), lipid profile, liver function and measures of quality of life, daily functioning, severity of the psychiatric disease and alcohol consumption from baseline to follow-up at week 16. Status: Currently recruiting patients.. Ethical approval has been obtained. Before screening, all patients will be provided oral and written information about the trial. The study will be disseminated by peer-review publications and conference presentations.. ClinicalTrials.gov: NCT01845259, EudraCT: 2013-000121-31.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Clinical Protocols; Clozapine; Double-Blind Method; Glucagon-Like Peptide-1 Receptor; Glucose Intolerance; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Liraglutide; Obesity; Olanzapine; Prediabetic State; Research Design; Schizophrenia

This study was designed to investigate whether a preventive weight management program (WMP) reduces weight gain during olanzapine (OLZ) treatment. Moreover, we examined the effects of intervention on metabolic parameters.. Patients (N = 100) with schizophrenia or schizoaffective disorder (DSM-IV) who had commenced treatment with OLZ were recruited. Following a run-in period of 4 weeks, 74 patients who had gained at least 1.5 kg body weight were randomized to receive either 12 bi-weekly WMP sessions (prevention group (PG), n = 36), or usual care (control group (CG), n = 38). Anthropometric and metabolic parameters were assessed after the 24-week intervention phase and a 24-week follow-up.. Forty-two percent of 74 participants (PG: 36.1%, CG: 47.4%) finished the 24-week intervention phase while 34% of them (PG: 30.6%, CG: 36.8%) completed the 48-week study. There was no significant difference in weight gain between groups (PG: + 3.4 ± 4.2 kg vs. CG: + 4.5 ± 6.1 kg, P = 0.184) after 24 weeks. Nevertheless, PG showed a significantly smaller increase in waist circumference than CG (PG: + 4.6 ± 8.3 cm, CG: + 10.1 ± 7.3 cm, P = 0.019) after 48 weeks. Furthermore, PG showed a significantly smaller increase in fasting glucose (P = 0.031) and 2-h glucose after oral glucose load (P = 0.018) than CG.. These results suggest that preventive WMP may reduce the risk of abdominal obesity and deterioration of glucose metabolism in OLZ-treated patients.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Dyslipidemias; Early Medical Intervention; Female; Glucose Intolerance; Humans; Male; Middle Aged; Obesity; Olanzapine; Psychotic Disorders; Schizophrenia; Weight Reduction Programs

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

Constipation is a common and potentially fatal side effect of clozapine treatment. Another important side effect of clozapine may also be significant weight gain. Orlistat is a weight-control medication that is known to induce loose stools as a common side effect. This study aimed to explore whether orlistat used to control clozapine-induced weight gain can simultaneously tackle clozapine-related constipation. In this 16-week randomized-controlled study, clozapine-treated patients received add-on orlistat (n=30) or add-on placebo (n=24). Colonic function was measured using the Bristol Stool Form Scale. There was a significant (P=0.039) difference in the prevalence of constipation in favor of orlistat over placebo in completers (n=40) at the endpoint. A decrease in the prevalence of constipation within the orlistat group (P=0.035) was observed (vs. no statistically significant changes in the placebo group). In clozapine-treated patients, orlistat may be beneficial not only for weight control but also as a laxative. As no established treatments for clozapine-induced constipation exist, orlistat can be considered for this population, although more studies are required.

Topics: Anti-Obesity Agents; Antipsychotic Agents; Benzodiazepines; Clozapine; Colon; Constipation; Cross-Sectional Studies; Diarrhea; Double-Blind Method; Finland; Humans; Incidence; Lactones; Laxatives; Obesity; Olanzapine; Orlistat; Overweight; Patient Dropouts; Prevalence; Psychotic Disorders; Schizophrenia; Severity of Illness Index; Weight Loss

To explore long-term effects of orlistat in adult clozapine- or olanzapine-treated patients with DSM-IV-diagnosed schizophrenia and overweight or obesity who tolerate orlistat.. Orlistat or placebo was added to clozapine or olanzapine in stable doses in a 16-week randomized controlled trial. Open-label orlistat was added to the antipsychotics during a 16-week extension phase for those completing the double-blind phase. No low-calorie diet or participation in behavioral programs was required. Body weight (primary outcome) and some metabolic parameters were measured prospectively. Analyses were performed for those completing both phases (ie, population differing from that reported earlier). The study was conducted from 2004 through 2005.. During the open-label phase, the 44 patients experienced mean ± SD body weight loss of -1.29 ± 3.04 kg, P = .007. During both phases, men (but not women) showed a weight loss of -2.39 ± 5.45 kg, P = .023. Some subgroups showed desirable changes in several metabolic parameters. Prolonged (32 weeks) orlistat treatment yielded no additional benefits as compared to short (16 weeks) treatment.. In clozapine- or olanzapine-treated overweight or obese patients able to take orlistat on a long-term basis, the drug, with no concomitant hypocaloric diet or behavioral interventions, caused moderate weight loss only in men. However, some metabolic benefits may be achieved independently of weight changes. In patients who do not respond to orlistat within the first 16 weeks, continuation treatment may provide no additional benefits.. controlled-trials.com Identifier: ISRCTN65731856.

Topics: Adult; Anti-Obesity Agents; Antipyretics; Benzodiazepines; Cholesterol; Cholesterol, LDL; Clozapine; Double-Blind Method; Female; Humans; Lactones; Male; Obesity; Olanzapine; Orlistat; Schizophrenia; Sex Factors; Treatment Outcome; Weight Loss

In recent years, several pharmacological and psychosocial interventions have examined ways to prevent or treat weight gain in people receiving second-generation antipsychotics. While there has been some success, in general, results have not been compelling. Atomoxetine is a selective norepinepherine reuptake inhibitor found to be associated with appetite suppression. Therefore, we examined whether atomoxetine may be of benefit for those who have gained weight on either clozapine or olanzapine.. The study was a double-blind, placebo-controlled trial. All participants received the same psychosocial platform: a structured support and exercise group. People with schizophrenia or schizoaffective disorder, on olanzapine or clozapine, who had gained at least 7% of their pre-clozapine or pre-olanzapine weight were eligible for a 24-week, randomized, parallel group, double-blind comparison of adjunctive atomoxetine or placebo.. Thirty-seven participants (20 atomoxetine, 17 placebo) were randomized and 26 participants (14 atomoxetine, 12 placebo; 70.2%) completed the study. There were no significant group differences in baseline BMI (atomoxetine: 34.5±4.9; placebo: 35.7±7.0) or weight (atomoxetine: 102.2±15.7 kg; placebo: 104.3±17.5 kg). Both treatment groups showed modest, not significant, trends in weight loss, averaging about 2 kg. Gender or baseline antipsychotic treatment did not modify treatment effects on weight. Secondary outcomes included neuropsychological assessments, symptom assessments (BPRS, SANS) and safety assessments. Of these, only the group difference in Gordon distractibility test scores was statistically significant and favored treatment with atomoxetine.. Atomoxetine is not effective for weight loss in this population, but both olanzapine and clozapine participants can lose weight with structured group support and exercise.

Topics: Adrenergic Uptake Inhibitors; Adult; Antipsychotic Agents; Appetite Depressants; Atomoxetine Hydrochloride; Attention; Benzodiazepines; Body Mass Index; Body Weight; Brief Psychiatric Rating Scale; Clozapine; Combined Modality Therapy; Diet, Reducing; Double-Blind Method; Exercise; Female; Humans; Life Style; Male; Maryland; Middle Aged; Neuropsychological Tests; Obesity; Olanzapine; Propylamines; Psychotic Disorders; Schizophrenia

The second-generation antipsychotics are associated with metabolic abnormalities in patients with schizophrenia. Elderly patients with Alzheimer's disease are frequently treated with these antipsychotics, but limited data are available on their metabolic effects.. The authors assessed 186 male and 235 female Alzheimer's disease outpatients from the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) for changes in weight, waist circumference, blood pressure, fasting glucose, and lipids in relation to duration of second-generation antipsychotic use (i.e., olanzapine, quetiapine, and risperidone) throughout the 36-week trial, using logistic regression and mixed-effects models.. Women showed significant weight gain (0.14 lb/week of use) while change was nonsignificant in men. Clinically significant weight gain (i.e., > or = 7% of body weight) was seen among patients with antipsychotic use < or = 12 weeks (odds ratio [OR]=1.56, 95% CI=0.53 to 4.58), between 12 and 24 weeks (OR=2.89, 95% CI=0.97 to 8.64), and > 24 weeks (OR=3.38, 95% CI=1.24 to 9.23) relative to patients who did not use antipsychotics during the trial. Olanzapine and quetiapine treatments were significantly associated with weight gain (0.12 and 0.14 lb/week, respectively). In addition, olanzapine was significantly associated with decreases in HDL cholesterol (-0.19 mg/dl/week) and increased girth (0.07 inches/week) relative to the placebo group. No treatment effects were noted for changes in blood pressure, glucose, and triglycerides.. Second-generation antipsychotic use was associated with weight gain in women, with olanzapine and quetiapine in particular, and with unfavorable change in HDL cholesterol and girth with olanzapine. The potential consequences of these effects suggest that patients with Alzheimer's disease treated with second-generation antipsychotics should be monitored closely.

Topics: Aged; Alzheimer Disease; Antipsychotic Agents; Benzodiazepines; Dibenzothiazepines; Double-Blind Method; Drug Monitoring; Female; Humans; Male; Mental Disorders; Obesity; Olanzapine; Quetiapine Fumarate; Risperidone

Olanzapine treatment has been associated with clinically meaningful weight increases, hypertriglyceridemia, insulin resistance, and diabetes mellitus. There are few options for olanzapine responders who fail other antipsychotic agents. Aripiprazole is a potent (high-affinity) partial agonist at D2 and 5-HT1A receptors and a potent antagonist at 5-HT2A receptor and is associated with less weight gain than olanzapine. We report the results of a 10-week placebo-controlled, double-blind crossover study that examined 15 mg/d aripiprazole's effects on weight, lipids, glucose metabolism, and psychopathology in overweight and obese schizophrenia and schizoaffective disorder subjects treated with a stable dose of olanzapine. During the 4 weeks of aripiprazole treatment, there were significant decreases in weight (P = 0.003) and body mass index (P = 0.004) compared with placebo. Total serum cholesterol (P = 0.208), high-density lipoprotein cholesterol (HDL-C; P = 0.99), HDL-2 (P = 0.08), HDL-3 (P = 0.495), and low-density lipoprotein cholesterol (P = 0.665) did not change significantly comparing aripiprazole treatment to placebo treatment. However, total serum triglycerides (P = 0.001), total very low-density lipoprotein cholesterol (VLDL-C; P = 0.01), and VLDL-1C and VLDL-2C (P = 0.012) decreased significantly during the aripiprazole treatment phase. The VLDL-3C tended lower during aripiprazole, but the decrease was not significant (P = 0.062). There was a decrease in C-reactive protein comparing aripiprazole treatment to placebo, although it did not reach significance (P = 0.087). The addition of aripiprazole to a stable dose of olanzapine was well tolerated and resulted in significant improvements on several outcome measures that predict risk for medical morbidity.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Body Mass Index; C-Reactive Protein; Cholesterol; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Female; Glucose; Humans; Male; Middle Aged; Obesity; Olanzapine; Overweight; Piperazines; Quinolones; Schizophrenia; Schizophrenic Psychology; Triglycerides

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 evaluate metabolic and hormonal side effects in children and adolescents after 6 months of treatment with 3 different second-generation antipsychotics (SGAs).. 66 children and adolescents (44 male [66.7%], mean +/- SD age = 15.2 +/- 2.9 years) treated for 6 months with risperidone (N = 22), olanzapine (N = 20), or quetiapine (N = 24) composed the study sample. 34 patients (51.5%) suffered from schizophrenia or other psychosis (according to DSM-IV criteria). Patients were consecutively attending different programs from March 2005 to October 2006. Prior to enrollment in the study, patients were either antipsychotic-naive (37.9%, N = 25) or had been taking an antipsychotic drug for fewer than 30 days. Significant weight gain was defined as a > or = 0.5 increase in body mass index (BMI) z score (adjusted for age and gender) at 6 months. Based on recent criteria for pediatric populations, patients were considered "at risk for adverse health outcome" if they met at least 1 of the following criteria: (1) > or = 85th BMI percentile plus presence of 1 or more negative weight-related clinical outcomes, or (2) > or = 95th BMI percentile.. After the 6 months, BMI z scores increased significantly in patients receiving olanzapine and risperidone. At the 6-month follow-up, 33 patients (50.0%) showed significant weight gain. The number of patients at risk for adverse health outcome increased from 11 (16.7%) to 25 (37.9%) (p = .018). The latter increase was significant only in the olanzapine group (p = .012). Total cholesterol levels increased significantly in patients receiving olanzapine (p = .047) and quetiapine (p = .016). Treatment with quetiapine was associated with a significant decrease in free thyroxin (p = .011).. Metabolic and hormonal side effects of SGAs in children and adolescents should be carefully monitored when prescribing these drugs.

Topics: Adolescent; Benzodiazepines; Blood Glucose; Body Mass Index; Child; Diagnostic and Statistical Manual of Mental Disorders; Dibenzothiazepines; Female; Follow-Up Studies; Humans; Male; Obesity; Olanzapine; Prevalence; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Schizophrenia; Substance-Related Disorders; Thyroxine; Triglycerides

Major mental disorders are associated with an increased risk for obesity-related cardiovascular mortality, leading to interest in risk-reduction approaches that target weight and risk-related plasma lipids, including use of antipsychotic agents with low metabolic risk. This multicenter, randomized, double-blind study compared the metabolic effects of aripiprazole versus olanzapine in overweight persons with schizophrenia or schizoaffective disorder who were previously on olanzapine treatment.. In total, 173 subjects with DSM-IV-TR-defined schizophrenia or schizoaffective disorder were randomly assigned to receive aripiprazole (N = 88) or olanzapine (N = 85) for 16 weeks in a study conducted from March 30, 2004, to August 8, 2006. Primary and secondary endpoints were mean weight change from baseline and percentage change from baseline in fasting triglyceride levels, respectively.. At week 16, weight decreased significantly with aripiprazole versus olanzapine (-1.8 vs. +1.41 kg; p < .001). Significant differences in percentage change in triglyceride levels were observed with aripiprazole (decreases) versus olanzapine (increases) at all time-points. In addition, significantly more subjects receiving aripiprazole had clinically relevant (> or = 7%) weight loss versus olanzapine (11.1% vs. 2.6%; p = .038), and a lower percentage of subjects receiving aripiprazole had clinically relevant weight gain (2.5% vs. 9.1%; p = .082). Mean percentage changes in fasting total cholesterol and high-density lipoprotein cholesterol at week 16 were significantly different with aripiprazole versus olanzapine, with no significant effects on glycemic laboratory measures. Mean Clinical Global Impressions-Improvement (CGI-I) scores for both groups were in the range of "no change" to "minimal improvement." CGI-I endpoint scores were statistically significantly better with olanzapine (mean +/- SE = 3.09 +/- 0.16) versus aripiprazole (mean +/- SE = 3.74 +/- 0.15; p < .001), and more subjects discontinued aripiprazole (N = 32/88; 36%) than olanzapine (N = 22/85; 26%).. Significant improvements in weight and lipids observed during discontinuation of olanzapine and switch to aripiprazole treatment occurred with limited evidence of negative psychiatric effects, relative to uninterrupted continuation of olanzapine treatment. The results suggest that the potential value of therapeutic substitutions involving specific antipsychotic medications should be considered in overall efforts to reduce cardiovascular risk in this population.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Body Mass Index; Diagnostic and Statistical Manual of Mental Disorders; Double-Blind Method; Drug Administration Schedule; Electrocardiography; Female; Humans; Hypercholesterolemia; Male; Middle Aged; Obesity; Olanzapine; Overweight; Piperazines; Psychotic Disorders; Quinolones; Schizophrenia; Triglycerides

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

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

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

This is a secondary analysis of clinical trial data collected in 12 European countries. We examined changes in weight and weight-related quality of life among community patients with schizophrenia treated with aripiprazole (ARI) versus standard of care (SOC), consisting of other marketed atypical antipsychotics (olanzapine, quetiapine, and risperidone).. Five-hundred and fifty-five patients whose clinical symptoms were not optimally controlled and/or experienced tolerability problems with current medication were randomized to ARI (10-30 mg/day) or SOC. Weight and weight-related quality of life (using the IWQOL-Lite) were assessed at baseline, and weeks 8, 18 and 26. Random regression analysis across all time points using all available data was used to compare groups on changes in weight and IWQOL-Lite. Meaningful change from baseline was also assessed.. Participants were 59.7% male, with a mean age of 38.5 years (SD 10.9) and mean baseline body mass index of 27.2 (SD 5.1). ARI participants lost an average of 1.7% of baseline weight in comparison to a gain of 2.1% by SOC participants (p<0.0001) at 26 weeks. ARI participants experienced significantly greater increases in physical function, self-esteem, sexual life, and IWQOL-Lite total score. At 26 weeks, 20.7% of ARI participants experienced meaningful improvements in IWQOL-Lite score, versus 13.5% of SOC participants. A clinically meaningful change in weight was also associated with a meaningful change in quality of life (p<0.001). A potential limitation of this study was its funding by a pharmaceutical company.. Compared to standard of care, patients with schizophrenia treated with aripiprazole experienced decreased weight and improved weight-related quality of life over 26 weeks. These changes were both statistically and clinically significant.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Body Mass Index; Body Weight; Dibenzothiazepines; Dose-Response Relationship, Drug; Europe; Female; Humans; Male; Middle Aged; Obesity; Olanzapine; Piperazines; Quality of Life; Quetiapine Fumarate; Quinolones; Risperidone; Schizophrenia; Schizophrenic Psychology; Self Concept; Social Adjustment

Undesirable metabolic effects of modern antipsychotics, especially clozapine and olanzapine, merit development of new weight-control strategies, including pharmacologic ones. We investigated the feasibility of treatment with orlistat, a weight-control drug with no central effects, for overweight/obesity in clozapine- or olanzapine-treated male and female patients.. Add-on orlistat was prescribed for 16 weeks in a randomized, double-blind, placebo-controlled clinical trial to patients who were receiving stable clozapine or olanzapine medication and were aged 18 to 65 years, with no compliance with nonpharmacologic programs or hypocaloric diet required. The primary efficacy variable was body weight change. The study was conducted from 2004 through 2005.. Of 71 randomly assigned subjects, 63 were eligible for modified intent-to-treat analysis. While no statistically significant effect was observed in the whole population, male (but not female) patients benefited from treatment with orlistat (-2.36 kg vs. 0.62 kg on placebo, p = .011). There were 5 responders (16.1%) (those with >or= 5% weight loss) that received orlistat versus 2 responders (6.3%) that received placebo (number needed to treat = 11), but the difference was not statistically significant.. Without a hypocaloric diet, the effect of orlistat in overweight/obese clozapine-or olanzapine-treated patients is modest and may only be seen in men. More studies should define the optimal length of treatment and feasibility of combination of orlistat with behavioral programs in this population.

Topics: Adolescent; Adult; Aged; Anti-Obesity Agents; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clozapine; Double-Blind Method; Female; Humans; Lactones; Male; Middle Aged; Obesity; Olanzapine; Orlistat; Overweight; Psychotic Disorders

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 presence of obesity and increases in body mass are important risk factors for cardiovascular disease and diabetes. This study examined the effects of olanzapine, risperidone, and haloperidol on weight, body mass index (BMI), and development of obesity in a drug-naive population compared with a matched healthy control group.. Consecutive patients during the period from June through October 2006 with DSM-IV schizophrenia at our referral psychiatric hospital were recruited for an extensive prospective study that included anthropometric measures of weight, waist circumference, waist-hip ratio, and BMI. Subjects were randomly assigned to receive haloperidol, olanzapine, or risperidone and compared with a matched healthy control group. The prevalence of obesity, which was the main outcome measure, was assessed on the basis of 2 criteria: revised World Health Organization (WHO) definition for Asians and criteria of the International Diabetes Federation (IDF). Inclusions started in June 2006, and patients were followed for a period of 6 weeks.. The analysis of 66 patients showed a prevalence of overweight (WHO criteria) at 22.7% and obesity at 31.8% (IDF criteria). The prevalence of obesity (IDF criteria) in our patients is over 30 times as high as that of the matched healthy control group (p < .001). Subjects in the olanzapine group had the greatest weight gain at 5.1 kg, followed by risperidone at 4.1 kg and haloperidol at 2.8 kg.. Obesity is highly prevalent among patients treated with atypical antipsychotics for schizophrenia. Assessment and monitoring of obesity along with preventive and curative measures should be part of the clinical management of patients treated with antipsychotics.. ClinicalTrials.gov, NCT00534183, www.clinicaltrials.gov.

Topics: Adult; Anthropometry; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Diagnostic and Statistical Manual of Mental Disorders; Double-Blind Method; Female; Haloperidol; Humans; India; Male; Obesity; Olanzapine; Prevalence; Prospective Studies; Risperidone; Schizophrenia; Time Factors

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

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

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

The main objective was to assess the efficacy of a weight management program designed for outpatients taking olanzapine for schizophrenia or schizoaffective disorder and to compare these patients with a randomized control group. The effects of the weight management program were also assessed with regard to safety and quality of life.. Forty-eight patients were enrolled in a 12-week, randomized, multicenter weight management study. Thirty-three patients were randomly allocated to an intervention group in which they received olanzapine within a weight management program. Fifteen patients were allocated to a control group in which they were given olanzapine treatment as usual outpatients. Weight, body mass index (BMI), and measurements of safety and quality of life were evaluated. The study was conducted from January 7, 2003, to September 16, 2003.. Thirty-six patients (75%) completed this study. We found significant differences in weight (-3.94 +/- 3.63 kg vs. -1.48 +/- 1.88 kg, p = .006) and BMI (-1.50 +/- 1.34 vs. -0.59 +/- 0.73, p = .007) change from baseline to endpoint between the intervention and control groups, respectively. Significant differences in weight reduction were initially observed at week 8 (p = .040). No significant differences were found with regard to the safety outcomes. When the ratio of low-density lipoproteins to high-density lipoproteins was calculated, change from baseline was greater in the intervention group than the control group (-0.19 vs. -0.04), but the difference was not statistically significant (p = .556). After the completion of the weight management program, there was a trend toward statistical difference in the physical health score changes between the weight management and control groups (1.12 in the intervention group vs. -0.93 in the control group, p = .067).. The weight management program was effective in terms of weight reduction in patients with schizophrenia or schizoaffective disorder taking olanzapine and was also found to be safe in terms of psychiatric symptoms, vital signs, and laboratory data. In addition, such a weight management program might improve quality of life in patients with schizophrenia or schizoaffective disorder with respect to their physical well-being.

Topics: Adult; Ambulatory Care; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Cognitive Behavioral Therapy; Diet, Reducing; Exercise Therapy; Female; Health Status; Humans; Male; Middle Aged; Obesity; Olanzapine; Psychiatric Status Rating Scales; Psychotic Disorders; Quality of Life; Schizophrenia; Treatment Outcome; Weight Loss

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

Olanzapine has been hypothesized to have superior efficacy in patients with treatment-resistant schizophrenia. The authors examined the comparative efficacy and safety of olanzapine and haloperidol in outpatients with partially responsive schizophrenia.. Sixty-three outpatients with schizophrenia who met retrospective and prospective criteria for either residual positive or residual negative symptoms entered a 16-week double-blind, parallel-groups comparison of olanzapine and haloperidol.. There were no significant differences between the two drugs in their effect on positive or negative symptoms. There were no significant differences between the two treatment groups on measures of social and functional outcome. Olanzapine-treated patients had a significant reduction in extrapyramidal symptoms and subjective measures of stiffness and dry mouth, but the increases in systolic blood pressure and weight in olanzapine-treated patients were significantly greater than they were in haloperidol-treated patients.. Olanzapine has limited differential benefit for either positive or negative symptoms in patients with treatment-resistant schizophrenia. Although olanzapine is associated with fewer extrapyramidal symptoms, other side effects may offset this benefit.

Topics: Adult; Ambulatory Care; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Body Weight; Double-Blind Method; Female; Haloperidol; Humans; Male; Middle Aged; Obesity; Olanzapine; Prospective Studies; Psychiatric Status Rating Scales; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

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

Obesity is common in persons with schizophrenia. Besides its adverse health effects, obesity reduces quality of life and contributes to the social stigma of schizophrenia.. This 14-week, multicenter, open-label, rater-blinded, randomized study evaluated the effects of a group-based behavioral treatment (BT) for weight loss in overweight and obese stable patients with DSM-IV schizophrenia or schizoaffective disorder who had been switched from olanzapine to risperidone. Participants were randomly assigned to receive BT or usual clinical care (UC). BT included 20 sessions during which patients were taught to reduce caloric intake. In UC, patients were encouraged to lose weight but received no special advice about weight reduction. The primary outcome measure was change in body weight.. Seventy-two patients were enrolled. The mean +/- SD weight loss at endpoint was significant in both groups (p < .05) and numerically greater in patients receiving BT than in those receiving UC (-2.0 +/- 3.79 and -1.1 +/- 3.11 kg, respectively). More patients in the BT group than in the UC group had lost > or = 5% of their body weight at endpoint (26.5% [9/34] and 10.8% [4/37], respectively; p = .082). A post hoc analysis of patients attending at least 1 BT session showed that significantly more patients in the BT than the UC group had lost > or = 5% of their body weight at endpoint (32.1% [9/28] vs. 10.8% [4/37], respectively, p = .038) and at week 14 (complete population; 40.9% [9/22] and 14.3% [4/28], respectively, p = .027).. BT may be an effective method for weight reduction in patients with chronic psychotic illness.

Topics: Adult; Antipsychotic Agents; Behavior Therapy; Benzodiazepines; Body Mass Index; Chronic Disease; Comorbidity; Double-Blind Method; Feasibility Studies; Female; Humans; Male; Middle Aged; Obesity; Olanzapine; Prevalence; Psychotherapy, Group; Risperidone; Schizophrenia; Treatment Outcome; Weight Loss

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

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

This study sought to determine if amantadine affects weight gain in psychiatric patients taking olanzapine.. Twenty-one adults who had gained at least 5 lb with olanzapine were randomly assigned to receive amantadine (N=12) or placebo (N=9) in addition to olanzapine. The length of time taking olanzapine ranged from 1 to 44 months. Body mass index, psychiatric status, and fasting blood levels were assessed at baseline and 12 weeks.. Significantly fewer subjects taking amantadine gained weight, with a mean change in body mass index of -0.07 kg/m2 for the amantadine group and 1.24 kg/m2 for the placebo group. This effect remained significant when the authors controlled for baseline body mass index and length of olanzapine treatment. No changes in fasting glucose, insulin, leptin, prolactin, and lipid levels were seen. Positive and Negative Syndrome Scale scores remained stable.. Amantadine induced weight stabilization in subjects taking olanzapine and was well tolerated.

Topics: Amantadine; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Dopamine Agents; Double-Blind Method; Female; Humans; Male; Obesity; Olanzapine; Placebos; Schizophrenia; Treatment Outcome; Weight Loss

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

A major contributor to mortality inpatients with schizophrenia or schizoaffective disorder is cardiovascular disease, an important risk factor for which is the cluster of clinical abnormalities that define the metabolic syndrome (eg, abdominal/visceral obesity, hypertriglyceridemia, impaired glucose tolerance).. The aim of this article was to examine the effects of switching from the antipsychotic olanzapine to risperidone on the prevalence of the metabolic syndrome in high-risk overweight or obese patients with schizophrenia or schizoaffective disorder.. This post hoc analysis was based on data from a previous 2-phase, 20-week, multicenter (19 US sites), rater-blinded, open-label study. High-risk overweight or obese (body mass index [BMI], >26 kg/m(2)) patients aged 18 to 65 years with schizophrenia or schizoaffective disorder whose treatment was switched from olanzapine to risperidone were enrolled. Patients who entered the phase 1 switch from olanzapine to risperidone (6 weeks) and the phase 2 extension (14 weeks) were included in the assessment. The primary end point was the difference from baseline in the prevalence of the metabolic syndrome at week 20, determined using measurements of weight, BMI, waist circumference, and systolic and diastolic blood pressure (SBP/DBP).. Baseline assessments for the metabolic syndrome were available from 121 of 123 patients recruited for phase 1 of the study (61 men, 60 women; mean [SD] age, 41.1 [10.2] years; mean [SD] BMI, 33.9 [6.9] kg/m(2)); 71 patients entered phase 2 (29 men, 42 women; mean [SD] age, 40.2 [10.3] years; mean [SD] BMI, 35.1 [7.3] kg/m(2)), of whom 39 (54.9%) ere diagnosed with schizophrenia, and 32 (45.1%) with schizoaffective disorder. The metabolic syndrome was identified in 63 (52.1%) patients at study entry. In the 71 patients with data available from baseline and week 20 (using the last observation carried forward method), the prevalence of the metabolic syndrome was reduced from 38 (53.5%) patients at baseline to 26 (36.6%) at study end (McNemar chi(2) = 8.0, P < 0.005). Significant improvements at study end were seen in mean weight (P = 0.031), BMI (P = 0.002), waist circumference (P = 0.003), SBP (P = 0.006), and DBP (P = 0.010). There was no significant difference in the reduction in the prevalence of the metabolic syndrome between patients who did or did not receive the behavioral therapy for weight loss.. In this post hoc analysis of switching from the antipsychotic olanzapine to risperidone on the prevalence of the metabolic syndrome in high-risk overweight or obese patients with schizophrenia or schizoaffective disorder, the metabolic syndrome was highly prevalent at baseline. Switching from olanza- pine to risperidone was associated with a significant reduction in this prevalence.

Topics: Adult; Antipsychotic Agents; Behavior Therapy; Benzodiazepines; Blood Pressure; Body Mass Index; Body Weight; Female; Humans; Male; Metabolic Syndrome; Obesity; Olanzapine; Prevalence; Psychotic Disorders; Risperidone; Schizophrenia; Systole; United States; Waist-Hip Ratio

The association of hyperglycaemia and weight gain with the use of atypical antipsychotics has been documented. However, there is still not enough data from India. The fact that Indian patients usually have a lower body weight compared to European and American counterparts makes it difficult to extrapolate available data to the Indian context. The purpose of this study is: (a) To compare the prevalence of hyperglycaemia in schizophrenic patients taking olanzapine with those taking typical antipsychotics, and (b) to follow-up non-diabetic, non-obese schizophrenics on a stable regimen of antipsychotic monotherapy and determine the proportion of patients who develop weight gain, diabetes or impaired glucose tolerance; comparing the effects of olanzapine versus typical antipsychotics. Fifty-five schizophrenic patients attending psychiatry outpatients' department and on stable antipsychotic monotherapy for at least 6 weeks were included in the study. Those with a family or personal history of diabetes were excluded. There were 28 cases on olanzapine and 27 on either haloperidol or trifluoperazine. Fasting blood glucose estimation and body-mass Index (BMI) were recorded at baseline, at 6 weeks, and at 12 weeks. The two groups were comparable with respect to age, genderwise composition, and duration of illness. There was no significant difference in baseline glycaemic status or BMI. At the end of 12 weeks, olanzapine was not associated with any significant change in body weight, BMI or plasma fasting glucose. Duration of use of antipsychotic emerged as the only statistically significant risk factor for developing hyperglycaemia across both groups.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus; Female; Haloperidol; Humans; Hyperglycemia; India; Male; Obesity; Olanzapine; Prospective Studies; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Time Factors; Trifluoperazine

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

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

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

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

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

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

Detrimental dietary habits with high-fat food are common in the psychiatric population, leading to higher obesity rate. Olanzapine (OLZ), as one of the mainstream antipsychotic drugs, shows superior efficacy in treating schizophrenia but limited by adverse effects such as obesity, dyslipidemia and liver injury, which are risk factors for the development of nonalcoholic fatty liver disease (NAFLD). Progesterone receptor component 1 (PGRMC1) is a key regulator associated with antipsychotic drug-induced metabolic disorders. Our study aims to investigate whether high-fat supplementation worsens OLZ-induced NAFLD and to validate the potential role of PGRMC1 pathway. In vivo, eight-week OLZ treatment successfully induced hepatic steatosis in female C57BL/6 mice fed with either a high-fat or normal diet, which is independent of body weight gain. Likewise, in vitro, OLZ markedly led to hepatocyte steatosis along with enhanced oxidative stress, which was aggravated by free fatty acids. Moreover, in vivo and in vitro, high-fat supplementation aggravated OLZ-induced hepatic lipid accumulation and oxidative stress via inhibition of hepatic PGRMC1-AMPK-mTORC1/Nrf2 pathways. Inspiringly, PGRMC1 overexpression effectively reversed OLZ-induced hepatocyte steatosis in vitro. Hence, hepatic PGRMC1 is attributable to OLZ-induced NAFLD especially with high-fat supplementation and potentially serves as a novel therapeutic target.

Topics: Animals; Diet, High-Fat; Female; Lipid Metabolism; Liver; Membrane Proteins; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; Olanzapine; Receptors, Progesterone

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

Olanzapine (OLZ) is an atypical antipsychotic agent for psychotic disorders. Evidence has shown that OLZ is related to metabolic side effects, including obesity, hypertension, and insulin resistance. Thymoquinone (TQ) is the principal bioactive component of Nigella sativa. Several studies have been conducted to investigate the effectiveness of TQ in alleviating metabolic abnormalities. In the current research work, the protective effects of TQ on metabolic disorders induced by OLZ and possible underlying mechanisms were investigated.. Wistar rats were exposed to TQ alone (10 mg/kg), OLZ (5 mg/kg), or OLZ plus TQ (2.5, 5, or 10 mg/kg) given daily by intraperitoneal injection. After the treatment, variations in body weight, food intake, systolic blood pressure, serum leptin, biochemical factors, liver malondialdehyde (MDA), and glutathione (GSH) content were evaluated. Protein expression of AMPK in the liver was also measured by a western blotting test. OLZ increased body weight, food intake, MDA levels, and blood pressure. OLZ also elevated glucose, triglyceride, low-density lipoprotein cholesterol, and leptin serum levels. It decreased GSH. In the western blot, decreased AMPK protein level was obtained. These changes were attenuated by TQ co-administration.. The present study demonstrates the effectiveness of TQ on OLZ-induced metabolic abnormalities related to its antioxidant activity and regulation of glucose homeostasis and lipid metabolism.

Topics: AMP-Activated Protein Kinases; Animals; Benzoquinones; Glucose; Insulin Resistance; Leptin; Obesity; Olanzapine; Rats; Rats, Wistar

Antipsychotic medications increase the risk of abnormal glucose metabolism. However, in clinical practice, it is difficult to predict this risk because it is affected by medication-related and background factors. This study aimed to identify the risk factors for abnormal glucose metabolism during antipsychotic treatment. We conducted a multicenter, prospective, cohort study in patients with schizophrenia, schizoaffective disorder, or bipolar disorder. Of these patients, those with prediabetes or possible diabetes were excluded. Finally, 706 patients were included in the analysis. The hazard ratio (HR) for each factor was calculated for events of progression to hyperglycemia using time-dependent Cox regression analysis stratified according to facility type and adjusted for available background and drug-related factors. Treatments with olanzapine (HR = 2.06, 95% confidence interval [CI] = 1.05-4.05), clozapine (HR = 4.25, 95% CI = 1.56-11.60), and chlorpromazine (HR = 4.48, 95% CI = 1.21-16.57), overweight and obesity (HR = 1.57, 95% CI = 1.02-2.41), and hypertriglyceridemia (HR = 1.72, 95% CI = 1.02-2.88) were associated with a significantly higher occurrence of hyperglycemic progression. The number and daily dose of antipsychotics were not associated with their occurrence. Our study demonstrated that more careful monitoring is necessary during olanzapine, clozapine, and chlorpromazine treatment because of the higher occurrence of abnormalities in glucose metabolism. Furthermore, patients with obesity or hypertriglyceridemia warrant monitoring for the occurrence of abnormal glucose metabolism, regardless of the type of antipsychotic medication.

Topics: Antipsychotic Agents; Benzodiazepines; Chlorpromazine; Clozapine; Cohort Studies; Glucose; Humans; Hypertriglyceridemia; Obesity; Olanzapine; Prospective Studies; Risk Factors

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

Obesity induced by antipsychotics have plagued more than 20 million people worldwide. However, no drug is available to eliminate the obesity induced by antipsychotics. Here we examined the effect and potential mechanisms of a gold nanoclusters (AuNCs) modified by N-isobutyryl-L-cysteine on the obesity induced by olanzapine, the most prescribed but obesogenic antipsychotics, in a rat model. Our results showed that AuNCs completely prevented and reversed the obesity induced by olanzapine and improved glucose metabolism profile in rats. Further mechanism investigations revealed that AuNCs exert its anti-obesity function through inhibition of olanzapine-induced dysfunction of histamine H1 receptor and proopiomelanocortin signaling therefore reducing hyperphagia, and reversing olanzapine-induced inhibition of uncoupling-protein-1 signaling which increases thermogenesis. Together with AuNCs' good biocompatibility, these findings not only provide AuNCs as a promising nanodrug candidate for treating obesity induced by antipsychotics, but also open an avenue for the potential application of AuNCs-based nanodrugs in treating general obesity.

Topics: Animals; Antipsychotic Agents; Gold; Humans; Metal Nanoparticles; Obesity; Olanzapine; Rats

Antipsychotics have been widely accepted as a treatment of choice for psychiatric illnesses such as schizophrenia. While atypical antipsychotics such as aripiprazole are not associated with obesity and diabetes, olanzapine is still widely used based on the anticipation that it is more effective in treating severe schizophrenia than aripiprazole, despite its metabolic side effects. To address metabolic problems, metformin is widely prescribed. Hypothalamic proopiomelanocortin (POMC) neurons have been identified as the main regulator of metabolism and energy expenditure. Although the relation between POMC neurons and metabolic disorders is well established, little is known about the effects of olanzapine and metformin on hypothalamic POMC neurons. In the present study, we investigated the effect of olanzapine and metformin on the hypothalamic POMC neurons in female mice. Olanzapine administration for 5 days significantly decreased Pomc mRNA expression, POMC neuron numbers, POMC projections, and induced leptin resistance before the onset of obesity. It was also observed that coadministration of metformin with olanzapine not only increased POMC neuron numbers and projections but also improved the leptin response of POMC neurons in the olanzapine-treated female mice. These findings suggest that olanzapine-induced hypothalamic POMC neuron abnormality and leptin resistance, which can be ameliorated by metformin administration, are the possible causes of subsequent hyperphagia. [BMB Reports 2022; 55(6): 293-298].

Topics: Animals; Antipsychotic Agents; Aripiprazole; Female; Hypothalamus; Leptin; Metformin; Mice; Neurons; Obesity; Olanzapine; Pro-Opiomelanocortin

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

Topics: Anthocyanins; Diabetes Mellitus, Type 2; Elaeocarpaceae; Fatty Liver; Glucosides; Hep G2 Cells; Hepatocytes; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipid Metabolism; Lipids; Liver; Muscle Fibers, Skeletal; Muscle, Skeletal; Obesity; Olanzapine; Plant Extracts; Polyphenols

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

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

Contradiction overwhelms chemerin link to feeding behavior. Neither the chemerin central role on appetite regulation nor its relation to hypothalamic histamine and AMPK is verified.. Chemerin-injected rats exhibited anorexigenic behavior in both acute and chronic studies that was associated with a decreased AMPK activity in the arcuate nucleus (ARC). However, with long-term administration, chemerin anorexigenic effect gradually ceased. Contrarily to food restriction, 8-week HFD increased ARC expression of chemerin and its receptor CMKLR1, reducing food intake via an interplay of H. Chemerin is an anorexigenic adipokine, whose dysregulation is implicated in diet, and olanzapine-induced obesity through a histamine/AMPK axis in the ARC. Hypothalamic chemerin/CMKLR1 expression is a dynamic time-dependent response to changes in body weight and/or food intake. Targeting chemerin as a novel therapeutic approach against antipsychotic- or diet-induced obesity is worth to be further delineated.

Topics: AMP-Activated Protein Kinases; Animals; Arcuate Nucleus of Hypothalamus; Betahistine; Body Weight; Caloric Restriction; Chemokines; Diet; Diet, High-Fat; Feeding Behavior; Female; Histamine; Histamine H1 Antagonists; Hypothalamus; Injections, Intraperitoneal; Obesity; Olanzapine; Rats, Wistar; Receptors, Chemokine; Receptors, Histamine H1

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

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

Transient receptor potential vanilloid type 1 (TRPV1) channels are emerging therapeutic targets for metabolic disorders. Berberine, which is a modulator of TRPV1, has proven antiobesity and antidiabetic potentials. The present study was aimed to investigate the protective effects of berberine in olanzapine-induced alterations in hypothalamic appetite control, inflammation and metabolic aberrations in mice targeting TRPV1 channels. Female BALB/c mice (18-23 g) were treated with olanzapine (6 mg/kg, p.o.) for six weeks to induce metabolic alterations, while berberine (100 and 200 mg/kg, p.o.) and metformin (100 mg/kg, p.o) were used as test and standard interventions respectively. Weekly assessment of feed-water intake, body temperature and body weight was done, while locomotion was measured at the end of week 1 and 6. Serum glucose and lipid profile were assessed by biochemical methods, while other serum biomarkers were assessed by ELISA. qPCR was used to quantify the mRNA expression in the hypothalamus. Olanzapine treatment significantly increased the feed intake, weight gain, adiposity index, while reduced body temperature and locomotor activity which were reversed by berberine treatment. Berberine treatment reduced serum ghrelin and leptin levels as well decrease in hypothalamic mRNA expression of orexigenic neuropeptides, inflammatory markers and ghrelin receptor in olanzapine-treated mice. Olanzapine treatment increased expression of TRPV1/TRPV3 in the hypothalamus which was significantly decreased by berberine treatment. Our results suggest that berberine, by TRPV1/TRPV3 modulation, attenuated the olanzapine-induced metabolic alterations in mice. Hence berberine supplementation in psychiatric patients could be a preventive approach to reduce the metabolic adverse effects of antipsychotics.

Topics: Animals; Antipsychotic Agents; Berberine; Body Temperature; Body Weight; Cytokines; Drinking; Female; Gene Expression Regulation; Ghrelin; Hypothalamus; Leptin; Metabolic Diseases; Metformin; Mice; Mice, Inbred BALB C; Molecular Targeted Therapy; Neuropeptides; Obesity; Olanzapine; RNA, Messenger; Signal Transduction; Treatment Outcome; TRPV Cation Channels

Olanzapine is effective to treat for schizophrenia and other mood disorders, but limited by side effects such as weight gain, dyslipidemia, and liver injury. Obesity in the US is at epidemic levels, and is a significant risk factor for drug-induced liver injury. Obesity incidence in the psychiatric population is even higher than in the US population as a whole. The purpose of this study was to test the hypothesis that obesity worsens olanzapine-induced hepatic injury, and to investigate the potential protective effects of sulforaphane. 8-week old female C57BL/6 mice were fed either a high-fat or low-fat control diet (HFD and LFD). Mice also received either olanzapine (8 mg/kg/d) or vehicle by osmotic minipump for 4 weeks. A subset of mice in the HFD + olanzapine group was administered sulforaphane, a prototypical Nrf2 inducer (90 mg/kg/d). Olanzapine alone increased body weight, without a commensurate increase in food consumption. Olanzapine also caused hepatic steatosis and injury. Combining olanzapine and HFD caused further dysregulation of glucose and lipid metabolism. Liver damage from concurrent HFD and olanzapine was worse than liver damage from high-fat diet or olanzapine alone. Sulforaphane alleviated many metabolic side effects of olanzapine and HFD. Taken together, these data show that olanzapine dysregulates glucose and lipid metabolism and exacerbates hepatic changes caused by eating a HFD. Activation of the intrinsic antioxidant defense pathway with sulforaphane can partially prevent these effects of olanzapine and may represent a useful strategy to protect against liver injury.

Topics: Animals; Antioxidants; Antipsychotic Agents; Body Weight; Chemical and Drug Induced Liver Injury; Diet, Fat-Restricted; Diet, High-Fat; Fatty Liver; Female; Humans; Isothiocyanates; Lipid Metabolism; Liver; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Obesity; Olanzapine; Oxidative Stress; Prevalence; Sulfoxides

Olanzapine, an atypical antipsychotic medication, has been associated with weight gain and metabolic toxicity, especially in long term usage. Carnosic acid (CA), a major constituent of rosemary extract, has been shown to improve metabolic abnormalities. In this experiment, the effect of CA on olanzapine-induced obesity and metabolic toxicity has been evaluated. Female Wistar rats were divided into six groups. (1) control; (2) olanzapine (5 mg/kg/day, IP); (3, 4 and 5) olanzapine (5 mg/kg/day, IP) plus CA (5, 10 and 20 mg/kg/day, gavage) and (6) CA (20 mg/kg/day, gavage). Bodyweight and food intake were measured during the study. After 14 days, mean systolic blood pressure (MSBP), glycemia, serum lipid profile, the serum concentration of leptin, insulin, AMPK, P-AMPK, and P-ACC liver protein levels were evaluated. The mean weight in the group received olanzapine increased by 4.8 g at the end of the study. The average food intake was increased by olanzapine. Olanzapine increased triglyceride, fasting blood glucose (FBG), and leptin levels. It increased MSBP and down-regulated P-AMPK/AMPK ratio and P-ACC protein levels. CA (three doses) decreased body weight gain and reduced average food intake at 10 and 20 mg/kg. CA especially at the highest dose decreased the changes in lipid profile, FBG, leptin level, and MSBP. P-AMPK/AMPK and P-ACC protein levels were increased by carnosic acid. In conclusion, the activation of AMPK by CA can be proposed as a key mechanism against olanzapine-induced metabolic toxicity where the activation of AMPK increases fat consumption and regulates glucose hemostasis in the liver.

Topics: Abietanes; AMP-Activated Protein Kinases; Animals; Enzyme Activation; Female; Metabolic Diseases; Obesity; Olanzapine; Rats; Rats, Wistar

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

Clinical use of the antipsychotic drug olanzapine (OLA) is associated with metabolic side effects to variable degrees. N-desmethyl-olanzapine (DMO) is one major metabolite of OLA, but its potential involvement in the metabolic responses remains unclear. Here we examined whether DMO can directly impact the metabolic, endocrinal and inflammatory parameters under conditions of metabolic disturbance. DMO administration (2 mg/kg, i.g.) to high-fat diet induced obesity mice for 4 weeks induced a remarkable loss of body weight and fat mass. DMO improved insulin resistance and energy expenditure in mice, but had no significant effects on dyslipidemia or hepatic steatosis. Moreover, DMO induced morphological changes in the white adipose tissue, accompanied by reduced interleukin-1β (IL-1β) production and increased UCP1 expression. These findings demonstrate that DMO is devoid of the metabolic side effects commonly observed for OLA during obesity, which suggests that the N-desmethyl metabolism may function to regulate the metabolic responses to OLA.

Topics: Animals; Benzodiazepines; Blood Glucose; Body Weight; Dyslipidemias; Energy Metabolism; Fatty Liver; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Obesity; Olanzapine; Pirenzepine

Olanzapine is a second-generation antipsychotic used in the management of schizophrenia and various off-label conditions. The acute metabolic responses of olanzapine recapitulate many of the side effects associated with obesity. Obesity rates are high in the schizophrenic population, but it is unknown whether pre-existing obesity-associated metabolic dysfunction augments the acute side effects of olanzapine. To address this question, we compared the responses to olanzapine in lean and high-fat diet-induced (HFD) obese mice. Four weeks of HFD (60%kcal from fat) led to obese, hyperglycemic, and insulin resistant mice. Olanzapine-induced hyperglycemia and systemic insulin resistance were exacerbated in HFD-induced obese mice. Olanzapine also profoundly inhibited insulin signalling in skeletal muscle and liver, which appears to be exacerbated by obesity. The greater olanzapine-induced hyperglycemia may also result from increased hepatic glucose output in obese mice as pyruvate challenge led to significantly higher blood glucose concentrations, with associated increases in hepatic content of gluconeogenic enzymes. Olanzapine also suppressed RER while acutely increasing oxygen consumption in obese mice. A single olanzapine treatment reduced physical activity for up to 24h, regardless of obesity. Considering obesity is very common in the schizophrenic population, these data suggest that previous research may be under-estimating the severity of olanzapine's acute side effects.

Topics: Animals; Blood Glucose; Diet, High-Fat; Hyperglycemia; Insulin; Insulin Resistance; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Muscle, Skeletal; Obesity; Olanzapine

Topics: Humans; Insulin Resistance; Obesity; Olanzapine

The precise effect of antipsychotic drugs on either central or peripheral inflammation remains unclear. An important issue in this debate is to what extent the known peripheral metabolic effects of antipsychotics, including increased adiposity, may contribute to increased inflammation. Adipose tissue is known to contribute to the development of systemic inflammation, which can eventually lead to insulin resistance and metabolic dysregulation. As a first step to address this question, we evaluated whether chronic exposure to clinically comparable doses of haloperidol or olanzapine resulted in the immune activation of rat adipose tissue. Samples of visceral adipose tissue were sampled from male Sprague-Dawley rats exposed to, haloperidol, olanzapine or vehicle (all n = 8), for 8 weeks. From these we measured a cytokine profile, protein expression of F4/80 (a phenotypic macrophage marker) and translocator protein (TSPO), a target for radiotracers putatively indicating microgliosis in clinical neuroimaging studies. Chronic olanzapine exposure resulted in significantly higher adipose IL-6 levels compared with vehicle-controls (ANOVA p = 0.008, Bonferroni post-hoc test p = 0.006); in parallel, animals exposed to olanzapine had significantly higher F4/80 expression when compared with vehicle-controls (Mann Whitney Test, p = 0.014), whereas there was no difference between haloperidol and vehicle groups (Mann Whitney test, p = 0.1). There were no significant effects of either drug on adipose TSPO protein levels. Nevertheless, we found a positive correlation between F4/80 and TSPO adipose protein levels in the olanzapine-exposed rats (Spearman's rho = 0.76, p = 0.037). Our data suggest that chronic exposure to olanzapine, but not haloperidol, increases production of the pro-inflammatory cytokine IL-6 in adipose tissue and increased macrophages expression (F4/80), in the absence of measurable changes in TSPO with respect to vehicle. This may have potentially important consequences in terms of metabolic dysregulation associated with long-term antipsychotic treatment.

Topics: Adipose Tissue; Adiposity; Animals; Antigens, Differentiation; Antipsychotic Agents; Biomarkers; Carrier Proteins; Cytokines; Gene Expression; Haloperidol; Inflammation; Insulin Resistance; Interleukin-6; Intra-Abdominal Fat; Macrophages; Male; Obesity; Olanzapine; Rats; Rats, Sprague-Dawley; Receptors, GABA-A

Metabolic disturbance is commonly observed in schizophrenia patients, and the metabolic impacts of atypical antipsychotics such as olanzapine (OLA) have received much attention. Drug naive schizophrenia patients display metabolic abnormality to varying degrees, but how this shapes the metabolic responses to chronic OLA exposure is unknown. Using high-fat diet (HFD, 8 weeks) induced obesity, here we explored the metabolic outcome of chronic OLA exposure in conditions of pre-existing metabolic disturbance. OLA treatment (2 mg/kg) for 4 weeks led to markedly reduced body weight and adiposity in obese mice, concomitant with reduced adipose inflammation and hepatic steatosis. No significant change was observed on insulin sensitivity or energy expenditure after OLA exposure. Mechanistically, OLA restored autophagic clearance in the subcutaneous adipose tissue of obese mice, in line with its potentiation of lysosomal function in adipocytes. The metabolic phenotypes induced by OLA were partially reversed by chemical suppression of autolysosome. Together, these data uncover distinct metabolic effects of OLA in obesity involving the regulation of adipose tissue autophagy, and suggest a complicated link between OLA therapy and metabolic disturbance in schizophrenia.

Topics: 3T3 Cells; Animals; Antipsychotic Agents; Autophagy; Body Weight; Lysosomes; Male; Mice; Mice, Inbred C57BL; Obesity; Olanzapine; Signal Transduction

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

Olanzapine, an antipsychotic agent mainly used for treating schizophrenia, is frequently associated with body weight gain and diabetes mellitus. Nonetheless, studies have shown that not every individual is equally susceptible to olanzapine's weight-gaining effect. Therefore, Roman high and low avoidance rat strains were examined on their responsiveness to olanzapine treatment. The Roman high avoidance rat shares many behavioral and physiological characteristics with human schizophrenia, such as increased central dopaminergic sensitivity, whereas the Roman low avoidance rat has been shown to be prone to diet-induced obesity and insulin resistance. The data revealed that only the Roman high avoidance rats are susceptible to olanzapine-induced weight gain and attenuated glucose tolerance. Here it is suggested that the specific olanzapine-induced weight gain in Roman high avoidance rats could be related to augmented dopaminergic sensitivity at baseline through increased expression of prefrontal cortex dopamine receptor D1 mRNA and nucleus accumbens dopamine receptor D2 mRNA expression. Regression analyses revealed that olanzapine-induced weight gain in the Roman high avoidance rat is above all related to increased prolactin levels, whereas changes in glucose homeostasis is best explained by differences in central dopaminergic receptor expressions between strains and treatment. Our data indicates that individual differences in dopaminergic receptor expression in the cortico-mesolimbic system are related to susceptibility to olanzapine-induced weight gain.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Body Weight; Dopamine; Gene Expression; Glucose; Homeostasis; Insulin Resistance; Nucleus Accumbens; Obesity; Olanzapine; Prefrontal Cortex; Rats; Schizophrenia

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

Meal-induced insulin sensitization (MIS), an endogenous adaptive mechanism is activated post-prandially. Reduced MIS leads to diabetes, but its activation improves insulin sensitivity. MIS is preserved to single olanzapine administration, therefore we aimed to investigate the chronic effect of olanzapine on fasted-state insulin sensitivity and on MIS in female Sprague-Dawley rats. Daily food and water intake, stool and urine production and body weight were determined. The MIS was characterized by a rapid insulin sensitivity test. Fasting hepatic and peripheral insulin sensitivity were determined by a hyperinsulinaemic euglycaemic glucose clamping supplemented with radiotracer technique. Fasted and post-prandial blood samples were obtained for plasma insulin, leptin, ghrelin, amylin, GLP-1, GIP, PYY and PP determination. Adiposity was characterized by weighing intra-abdominal and inguinal fat pads. Olanzapine caused hepatic insulin resistance and a reduced metabolic clearance rate of insulin, but the MIS retained its function. Body weight and adiposity were enhanced, but olanzapine failed to increase food intake. Fasting insulin and leptin were elevated and the post-prandial reduction in ghrelin level was inhibited by olanzapine.The MIS remained functionally intact after long-term olanzapine treatment. Altered insulin, leptin and ghrelin levels indicate olanzapine-induced metabolic derangements. Pharmacological activation of MIS could potentially be exploited to treat or prevent olanzapine-induced insulin resistance.

Topics: Animals; Benzodiazepines; Blood Glucose; Body Weight; Eating; Female; Gastrointestinal Hormones; Ghrelin; Insulin; Insulin Resistance; Leptin; Obesity; Olanzapine; Rats; Rats, Sprague-Dawley

To identify the frequency and characteristics of eating disorders in patients with schizophrenia treated with second generation antipsychotics.. A sample included 56 patients (48 women and 8 men, mean age 28 ± 4.5 years) with schizophrenia and schizoaffective disorder. Patients received risperidone, quetiapine and olanzapine. The study employed clinical-anamnestic, endocrinological methods and assessment of eating behavior with DEBQ (The Dutch Eating Behavior Questionnaire). All of the patients had extra Body mass or obesity: extra Body mass of the 1st grade was found in 18 patients (BMI<30 kg/m²) and obesity grade 2-3 in 38 patients (BMI>30 kg/m²).. Authors identified different types of eating disorders: external, restrictive and emotiogenic as well as the relationship of their prevalence and severity with sex, drug, presence and grade of obesity. Based on these. we developed recommendations for management of patients treated with second generation antipsychotics.. Цель исследования - установление частоты и особенностей пищевого поведения у больных шизофренией при лечении антипсихотиками второго поколения. Материал и методы. Выборку составили 56 пациентов, 48 женщин и 8 мужчин, с диагнозами 'шизофрения' и 'шизоаффективное расстройство'. Их средний возраст был 28±4,5 года. Больные лечились рисперидоном, кветиапином и оланзапином. Исследование включало клинико-анамнестический, эндокринологический методы и тестирование стереотипа пищевого поведения с помощью специального опросника DEBQ. У всех обследованных были выявлены избыточная масса тела или ожирение: избыточная масса тела 1-й степени - у 18 пациентов (ИМТ до 30 кг/м2) и ожирение 2-3-й степени - у 38 (ИМТ более 30 кг/м2). Результаты и заключение. Выявлены разные типы нарушений пищевого поведения - экстернальный, ограничительный и эмоциогенный и зависимость их частоты и выраженности от пола, лечебного препарата, наличия и степени ожирения. На основе полученных данных были сформулированы рекомендации в отношении тактики ведения пациентов, находящихся на терапии антипсихотиками второго поколения.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Dibenzothiazepines; Feeding and Eating Disorders; Female; Humans; Male; Obesity; Olanzapine; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Schizophrenia; Young Adult

The aim of the study was to explore the effects of increased levels of blood sugar and cytokines on impaired cognitive function in the olanzapine-induced obesity rat model. A total of 40 rats were randomly divided into 2 groups; the control and olanzapine groups (N = 20 per group). The control rats were fed regular food, while the olanzapine rats received olanzapine-enriched (1.2 mg/kg) food by gavage for 4 weeks to establish the olanzapine-induced obese rat model. Enzyme-linked immunosorbent assays were used to measure the serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C-reactive protein (CRP). Serum glucose content was measured by biochemical colorimetry. Learning and memory capacity was measured using a Y-maze, and the time before escape from a Morris water maze was recorded. Body weight and levels of blood glucose, lipids, TNF-α, IL-6, and CRP increased in the olanzapine group. In addition, the number of shocks received before reaching the learning and memory standard and the time before escape from the Morris water maze were higher in the olanzapine group than in the control group. Olanzapine causes disorders in glucose and lipid metabolism. Increase in blood glucose promotes the toxicity of cytokines and leads to cognitive dysfunction in rats.

Topics: Animals; Benzodiazepines; Blood Glucose; Body Weight; C-Reactive Protein; Cognition Disorders; Disease Models, Animal; Interleukin-6; Lipid Metabolism; Lipids; Memory; Obesity; Olanzapine; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

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

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

Weight gain and its related metabolic disorders are major side effects associated with second generation antipsychotic drug treatment. The dorsal vagal complex (DVC) and AMP-activated protein kinase (AMPK) are implicated in the regulation of food intake and body weight. Blocking the histamine H1 receptor contributes to antipsychotic-induced weight gain. The present study investigated the time-dependent effect of olanzapine treatment (8, 16, and 36 d) on DVC AMPK signaling in olanzapine-induced weight gain and whether these changes are associated with olanzapine-induced H1 receptor antagonism. During the 8-day olanzapine treatment, the rats were hyperphagic and rapidly gained weight. The phosphorylation of AMPK (pAMPK) (activated AMPK) as well as its directly downstream phospho-acetyl-coenzyme A carboxylase was significantly increased. The pAMPK/AMPK ratio, an indicator of AMPK activity, was significantly positively correlated with feeding efficiency and weight gain. As treatment was prolonged (16 and 36 d of olanzapine treatment), the rats were no longer hyperphagic, and there were no longer any changes in DVC AMPK signaling. Although the DVC H1 receptor protein expression was not significantly altered by olanzapine, the pAMPK expression was significantly positively correlated with the H1 receptor level after the 8-, 16-, and 36-day olanzapine treatments. Moreover, we showed that an H1 receptor agonist, 2-(3-trifluoromethylphenyl) histamine, significantly inhibited the olanzapine-induced hyperphagia and DVC AMPK activation in a dose-dependent manner. These results suggest a time-dependent role of DVC AMPK in olanzapine-induced obesity. Thus, olanzapine-induced DVC AMPK activation may be at least partially related to olanzapine's antagonistic effect on the H1 receptor.

Topics: AMP-Activated Protein Kinases; Animals; Antipsychotic Agents; Benzodiazepines; Body Weight; Drinking; Eating; Female; Histamine Agonists; Hyperphagia; Medulla Oblongata; Obesity; Olanzapine; Random Allocation; Rats, Sprague-Dawley; Receptors, Histamine H1

Topics: Adult; Aggression; Antipsychotic Agents; Autopsy; Benzodiazepines; Bipolar Disorder; Catatonia; Death, Sudden; Female; Humans; Hypothyroidism; Incidence; Lorazepam; Obesity; Olanzapine; Ovarian Neoplasms; Patient Admission; Patient Transfer; Pulmonary Embolism; Restraint, Physical; Risk; Valproic Acid; Venous Thrombosis

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

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

Administration of atypical antipsychotics often induces significant weight gain and metabolic changes. Little is known about subjective weight-related parameters in adolescent patients. Therefore, this cross-sectional, explorative study aimed to assess these parameters and their relationship with biological weight-related parameters.. 74 patients (mean age: 19.9 [SD ± 2.3] years; 66.2% male) with schizophrenia under clozapine or olanzapine treatment were examined. Subjective well-being, eating behavior, body perception and social functioning were assessed, using the Three-Factor-Eating-Questionnaire, FKB-20 Body Perception Questionnaire, Subjective Well-being under Neuroleptics, Short Form and Global Assessment of Functioning. Patients' biological weight-related parameters were measured as well. Gender differences as well as associations between subjective and biological weight-related parameters were evaluated.. Female patients reported significantly worse negative body appraisal and physical functioning than males. An elevated BMI was associated with impaired physical functioning in females and with negative body appraisal and hunger in males.. In our sample of young patients with schizophrenia unter treatment with atypical antipsychotics, an elevated BMI was associated with impaired physical functioning and negative body appraisal, respectively. Bearing in mind the high risk of obesity in this population, the mentioned impairments should be accounted for, especially in terms of compliance and quality of life.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Body Image; Body Mass Index; Body Weight; Clozapine; Cross-Sectional Studies; Feeding Behavior; Female; Ghrelin; Humans; Hunger; Leptin; Male; Obesity; Olanzapine; Physical Fitness; Schizophrenia; Schizophrenic Psychology; Sex Factors; Social Adjustment; Young Adult

Polyunsaturated fatty acids (PUFAs) are bimodally distributed in acute schizophrenia, suggesting two endophenotypes. We intended to characterize these endophenotypes clinically. Our a priori hypothesis was that low PUFA patients have more negative symptoms.. Patients (aged 18-39) with schizophrenia, schizoaffective or schizophreniform disorders were recruited at hospital admission during an acute episode. The baseline Positive and Negative Syndrome Scale, vital signs and biochemical variables were measured in 97 patients with available RBC PUFA levels. Adjustment for multiple testing was not performed.. The median Negative Subscale score was higher (p=0.04) in the low PUFA (25 points, n=30) than in the high PUFA group (19 points, n=67). Among 95 patients with measurements of serum triglycerides, hypertriglyceridaemia was more prevalent (p=0.009) among low PUFA patients (66%) than high PUFA patients (36%). PUFA modified the effect of antipsychotics on triglycerides (p=0.046). Serum glucose and mean corpuscular haemoglobin were higher (p=0.03, 0.001, respectively) in low PUFA than in high PUFA patients. Low PUFA men were heavier (p=0.04) than high PUFA men.. During an acute episode of schizophrenia, patients with low RBC PUFA have more negative symptoms and more metabolic and haematological abnormalities than those with high PUFA. This indicates that PUFA levels define two clinically distinct endophenotypes of the disorder.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Biomarkers; Clozapine; Dibenzothiazepines; Endophenotypes; Erythrocytes; Fatty Acids, Unsaturated; Female; Humans; Hypertriglyceridemia; Linear Models; Logistic Models; Male; Obesity; Olanzapine; Quetiapine Fumarate; Schizophrenia; Schizophrenic Psychology

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

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

In mice and in humans, treatment with the second-generation antipsychotic drug olanzapine (OLZ) produces excessive weight gain, adiposity and secondary metabolic complications, including loss of glucose and insulin homeostasis. In mice consuming a high-fat (HF) diet, a similar phenotype develops, which is inhibited by the analgesic acetaminophen (APAP) and by the antioxidant tetrahydroindenoindole (THII). Therefore, we examined the ability of APAP and THII to prevent metabolic changes in mice receiving OLZ.. C57BL/6J mice received either a normal diet or a HF diet, and were administered daily dosages of OLZ (3 mg kg(-1) body weight), alone or with APAP (30 mg kg(-1) body weight) or THII (4.5 mg kg(-1) body weight), for 10 weeks. Parameters of body composition and metabolism, including glucose and insulin homeostasis and oxidative stress, were examined.. OLZ treatment doubled the HF diet-induced increases in body weight and percent body fat. These increases were partially prevented by both APAP and THII, although food consumption was constant in all groups. The THII protection was associated with an increase in whole body and mitochondrial respiration. OLZ also exacerbated, and both APAP and THII prevented, HF diet-induced loss of glucose tolerance and insulin resistance. As increased body fat promotes insulin resistance by a pathway involving oxidative stress, we evaluated production of reactive oxygen and lipid peroxidation in white adipose tissue (WAT). HF diet caused an increase in lipid peroxidation, NADPH-dependent O(2) uptake and H(2)O(2) production, which were further exacerbated by OLZ. APAP, THII and the NADPH oxidase inhibitor, diphenyleneiodonium chloride, each abolished oxidative stress in WAT.. We conclude that both APAP and THII intervene in the development of obesity and metabolic complications associated with OLZ treatment.

Topics: Acetaminophen; Adipose Tissue; Adipose Tissue, White; Animals; Antioxidants; Antipsychotic Agents; Benzodiazepines; Body Weight; Dietary Fats; Female; Indoles; Insulin Resistance; Lipid Peroxidation; Mice; Mice, Inbred C57BL; NADPH Oxidases; Obesity; Olanzapine; Oxidative Stress

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

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

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

Olanzapine and highly palatable diets can alter metabolism and brain function. We investigated the interaction of chronic treatment (4 months) with olanzapine and a cafeteria diet on metabolic parameters, memory tasks (spatial and aversive), the elevated plus maze and locomotor activity induced by d-amphetamine. Male Wistar rats were separated into the following groups: standard diet vehicle, standard diet and olanzapine, cafeteria diet vehicle and cafeteria diet and olanzapine. Olanzapine was administered in the drinking water (approximately 1.5 mg/kg/day), and after 3 days of treatment, the rats exhibited an expected anxiolytic effect and reduced amphetamine-induced hyperlocomotion. After 4 months of treatment, cafeteria diet vehicle and cafeteria diet olanzapine rats exhibited an increased body weight and heavier fat pads compared with the standard diet groups. Olanzapine increased only the epididymal and mesenteric fat pads. The cafeteria diet and olanzapine group showed greater glucose intolerance compared with all other groups. The cafeteria diet altered the effects of chronic olanzapine on the performance in the water maze and inhibitory avoidance tasks. Chronic olanzapine treatment failed to affect amphetamine-induced locomotion and to produce anxiolytic effects in the elevated plus maze task, regardless of the diet. Our results suggest that chronic olanzapine caused an increase in fat pads, which is putatively involved in the etiology of many metabolic diseases. Rats on the cafeteria diet were overweight and exhibited glucose intolerance. We did not observe these effects with olanzapine treatment with the standard diet. Moreover, the chronic treatment regimen caused tolerance to the antipsychotic and anxiolytic effects of olanzapine and seemed to potentiate some of the metabolic effects of the cafeteria diet. The cafeteria diet also modified the effects of chronic treatment with olanzapine on cognitive tasks, which may represent an undesirable effect of poor diets in psychiatric patients.

Topics: Amphetamine; Animals; Antipsychotic Agents; Behavior, Animal; Benzodiazepines; Diet; Dietary Fats; Eating; Fast Foods; Glucose Intolerance; Humans; Male; Maze Learning; Motor Activity; Obesity; Olanzapine; Rats; Rats, Wistar

The prediction of resting metabolic rate (RMR) is important to determine the energy expenditure of obese patients with severe mental illnesses (SMIs). However, there is lack of research concerning the most accurate RMR predictive equations. The purpose of this study was to compare the validity of four RMR equations on patients with SMIs taking olanzapine.. One hundred twenty-eight obese (body mass index >30 kg/m(2)) patients with SMIs (41 men and 87 women) treated with olanzapine were tested from 2005 to 2008. Measurements of anthropometric parameters (height, weight, body mass index, waist circumference) and body composition (using the BodPod) were performed at the beginning of the study. RMR was measured using indirect calorimetry. Comparisons between measured and estimated RMRs from four equations (Harris-Benedict adjusted and current body weights, Schofield, and Mifflin-St. Jeor) were performed using Pearson's correlation coefficient and Bland-Altman analysis.. Significant correlations were found between the measured and predicted RMRs with all four equations (P < 0.001), with the Mifflin-St. Jeor equation demonstrating the strongest correlation in men and women (r = 0.712, P < 0.001). In men and women, the Bland-Altman analysis revealed no significant bias in the RMR prediction using the Harris-Benedict adjusted body weight and the Mifflin equations (P > 0.05). However, in men and women, the Harris-Benedict current body weight and the Schofield equations showed significant overestimation error in the RMR prediction (P < 0.001).. When estimating RMR in men and women with SMIs taking olanzapine, the Mifflin-St. Jeor and Harris-Benedict adjusted body weight equations appear to be the most appropriate for clinical use.

Topics: Adult; Antipsychotic Agents; Basal Metabolism; Benzodiazepines; Body Mass Index; Calorimetry, Indirect; Energy Metabolism; Female; Humans; Linear Models; Male; Mathematics; Mental Disorders; Obesity; Olanzapine; Predictive Value of Tests

Race is strongly associated with risk for metabolic dysfunction, but there is limited prospective data concerning the impact of race on antipsychotic metabolic outcomes among patients with schizophrenia.. This study is a post hoc analysis of data from a 26-week, double-blind, randomized trial of aripiprazole (N = 155) and olanzapine (N = 159) conducted from April 2000 through June 2001 in patients aged >or= 18 years with acute schizophrenia according to DSM-IV criteria. The data were analyzed on the basis of racial breakdown: white and black/Hispanic. Between-drug and within-drug outcomes were analyzed separately for each racial cohort across weight, lipid, and glucose parameters.. For white subjects (N = 167), olanzapine significantly worsened all metabolic parameters except high-density lipoprotein (HDL) cholesterol and fasting glucose, and this was significantly different than aripiprazole for every outcome except fasting glucose. In the black/Hispanic cohort (N = 137), olanzapine treatment resulted in adverse metabolic outcomes, and these changes were significantly different from aripiprazole for adiposity, total cholesterol, and non-HDL cholesterol. Aripiprazole decreased the odds of endpoint metabolic syndrome compared with olanzapine for all subjects (OR = 0.33, 95% CI = 0.19 to 0.55), the white cohort (OR = 0.20, 95% CI = 0.10 to 0.41), and black/Hispanic subjects (OR = 0.53, 95% CI = 0.25 to 1.12), but the black/Hispanic result was not statistically significant (p = .096). Within the aripiprazole group, white subjects had significantly lower risk for metabolic syndrome, but there was no significant difference in metabolic syndrome between white and black/Hispanic subjects exposed to olanzapine.. Race may be an important moderator of metabolic risk during atypical antipsychotic therapy. Olanzapine treatment is associated with greater effects on adiposity and lipids than aripiprazole in both white and black/Hispanic subjects, suggesting that antipsychotic choice and intensive monitoring are important in minimizing metabolic risk, especially in nonwhite patients.

Topics: Acute Disease; Adult; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Black or African American; Blood Glucose; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Double-Blind Method; Female; Hispanic or Latino; Humans; Hypercholesterolemia; Male; Metabolic Syndrome; Middle Aged; Obesity; Olanzapine; Piperazines; Quinolones; Randomized Controlled Trials as Topic; White People; Young Adult

Adverse effects from medication vary with age. Weight gain with several psychotropics is well known in adults but less information is available related to extent and complications of psychotropic-induced weight gain in older psychiatric patients. We determined the relative incidence of 2 obesity-related conditions (diabetes and hypertension) in older psychiatric patients receiving antipsychotics, antidepressants, and mood stabilizers.. A population-based case-control study of all psychiatric patients aged 67 years or older in contact with either specialist services or primary care using administrative data from Nova Scotia.. We identified incident cases of diabetes (n = 608) and of hypertension (n = 1056), as well as an equal number of control subjects for each condition. Amitryptiline, selective serotonin reuptake inhibitors (SSRIs), and olanzapine were associated with an increased risk of presenting with hypertension 6 months after initial prescription. By contrast, conventional antipsychotics were associated with a reduced incidence of hypertension. Olanzapine was also significantly associated with diabetes after 6 months (OR adj = 2.58, 95% CI 1.12 to 5.92). The findings for SSRIs and olanzapine remained significant after adjusting for potential confounders such as sociodemographic characteristics, schizophrenia, beta blockers, thiazide diuretics, and corticosteroids.. Our results suggest that the association of psychotropics and 2 obesity-related conditions, hypertension and diabetes, applies to older psychiatric patients as well as younger populations. Within drug classes, there are drugs that have a greater association than others, and this may be a factor when choosing a specific agent.

Topics: Age Factors; Aged; Aged, 80 and over; Antidepressive Agents; Antipsychotic Agents; Benzodiazepines; Chronic Disease; Diabetes Mellitus, Type 2; Female; Humans; Hypertension; Male; Mental Disorders; Obesity; Olanzapine; Psychotropic Drugs; Selective Serotonin Reuptake Inhibitors

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

Topics: Antipsychotic Agents; Benzodiazepines; Diabetes Mellitus, Type 2; Drug Administration Schedule; Humans; Hypoglycemic Agents; Metformin; Obesity; Olanzapine; Schizophrenia; Weight Loss

Topics: Antipsychotic Agents; Asian People; Benzodiazepines; Energy Intake; Exercise; Humans; Hypoglycemic Agents; Life Style; Metformin; Obesity; Olanzapine; Schizophrenia; Triglycerides

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: Antiemetics; Benzodiazepines; Cannabinoid Receptor Modulators; Feeding and Eating Disorders; Growth Hormone; Humans; Nerve Growth Factors; Obesity; Olanzapine

Topics: Adult; Antipsychotic Agents; Bariatric Surgery; Benzodiazepines; Female; Humans; Obesity; Olanzapine; Schizophrenia; Treatment Outcome

We studied the dynamics of serum leptin level and some anthropometric values in patients with schizophrenia treated with risperidone, olanzapine, and clozapine showed gender-dependent specific correlations between the studied parameters.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Humans; Leptin; Male; Obesity; Olanzapine; Risperidone; Schizophrenia, Paranoid; Sex Factors; Young Adult

Bipolar patients have increased prevalence rates of overweight and obesity compared with the general population. Recent increases in the use of atypical antipsychotics and combination therapies have led to growing concern about obesity and metabolic disturbances. We therefore evaluated weight change and its correlates during the treatment of acute mania in a closed-ward hospital setting.. We evaluated weight change over 4 weeks in 179 consecutive patients with bipolar I disorder presenting with acute manic symptoms.. Overall weight change was +2.7+/-3.0 kg (+4.6+/-5.2%). Whereas 24.6% of patients were obese at baseline, 36.3% were obese after 4 weeks. Duration of illness was correlated with weight change, but its effect was not robust. Baseline weight/BMI, sex, age of onset, and history of previous medication were not significantly correlated with weight changes. Patients prescribed olanzapine plus valproate showed the largest increase in weight (3.8+/-2.9 kg). Overall, patients on any kind of atypical antipsychotics showed greater weight gain than those on typical antipsychotics or without antipsychotics. Combination treatment with antipsychotics and mood stabilizer resulted in greater weight gain than monotherapy with an antipsychotic or mood stabilizer.. The short-term assessment (4 weeks) of weight change and the lack of variables previously reported to be related to weight gain, such as number of depressive episodes, warrant caution in the interpretation of our results.. Even during short period of acute treatment, bipolar patients showed significant weight gain and became obese in a closed-ward setting. Clinicians prescribing combination therapies should pay more attention to weight gain and obesity.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Body Mass Index; Body Weight; Drug Administration Schedule; Drug Therapy, Combination; Female; Haloperidol; Hospitalization; Humans; Lithium Carbonate; Male; Obesity; Olanzapine; Risperidone; Smoking; Valproic Acid

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 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

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

To explore the association between eating disorders (EDs) prior to the use of clozapine/olanzapine (pre-clozapine/olanzapine EDs) and after initiation of these antipsychotics (post-clozapine/olanzapine EDs).. Sixty-four consecutively admitted patients receiving clozapine/olanzapine were screened using the M-Composite International Diagnostic Interview (M-CIDI) to identify subjects with pre-clozapine/olanzapine EDs (DSM-IV criteria). We investigated post-clozapine/olanzapine EDs and binge eating behavior using the Questionnaire on Eating and Weight Patterns (QEWP) and used the Naranjo probability scale as objective causality assessment.. Post-clozapine/olanzapine EDs were significantly more frequent in patients with pre-clozapine/olanzapine EDs (5 of 6) when compared to patients without pre-clozapine/olanzapine EDs (4 of 58) [chi(2) = 26.29; df = 1; p < 0.001] [odds ratio (OR) 67.5; 95% CI: 6.3-725.8]. According to the Naranjo probability scale, recurrence or deterioration of EDs in patients with prior EDs was definitely (n = 1) or probably (n = 4) related to the intake of clozapine/olanzapine.. Clozapine/olanzapine may induce recurrence or deterioration of binge eating symptomatology or full-blown EDs in patients with prior EDs.

Topics: Adolescent; Adult; Antipsychotic Agents; Appetite; Benzodiazepines; Brain; Bulimia Nervosa; Clozapine; Feeding Behavior; Female; Humans; Male; Middle Aged; Obesity; Olanzapine; Recurrence; Surveys and Questionnaires

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

Atypical antipsychotics can affect cortical volume differently from traditional drugs. The study of the outcome of grey matter deficits in schizophrenia with olanzapine may be of particular interest in this context.. In this study, we evaluated the changes in the volume of gray matter in the cortex of 11 schizophrenic patients treated with olanzapine and in 11 healthy controls after three years of follow-up. After MR imaging, acquisition data were processed with a volumetric quantification method based on the Talairach atlas. The longitudinal change of volumetric data was corrected for differences in overall brain size.. Patients showed greater reduction than controls in cortical volume in the frontal and parietal regions during follow-up. No relationship was observed between clinical and volumetric changes.. Our data suggest that the profile of action of olanzapine on the cortical volume of chronically ill patients may be similar to that of typical antipsychotics. Other explanations, however, cannot be completely discarded for that outcome with our data.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Brain; Chronic Disease; Female; Humans; Magnetic Resonance Imaging; Male; Obesity; Olanzapine; Schizophrenia

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

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

To characterize a model of atypical antipsychotic drug-induced obesity and evaluate its mechanism.. Chronically, olanzapine or clozapine was self-administered via cookie dough to rodents (Sprague-Dawley or Wistar rats; C57Bl/6J or A/J mice). Chronic studies measured food intake, body weight, adiponectin, active ghrelin, leptin, insulin, tissue wet weights, glucose, clinical chemistry endpoints, and brain dopaminergic D2 receptor density. Acute studies examined food intake, ghrelin, leptin, and glucose tolerance.. Olanzapine (1 to 8 mg/kg), but not clozapine, increased body weight in female rats only. Weight changes were detectable within 2 to 3 days and were associated with hyperphagia starting approximately 24 hours after the first dose. Chronic administration (12 to 29 days) led to adiposity, hyperleptinemia, and mild insulin resistance; no lipid abnormalities or changes in D2 receptor density were observed. Topiramate, which has reversed weight gain from atypical antipsychotics in humans, attenuated weight gain in rats. Acutely, olanzapine, but not clozapine, lowered plasma glucose and leptin. Increases in glucose, insulin, and leptin following a glucose challenge were also blunted.. A model of olanzapine-induced obesity was characterized which shares characteristics of patients with atypical antipsychotic drug-induced obesity; these characteristics include hyperphagia, hyperleptinemia, insulin resistance, and weight gain attenuation by topiramate. This model may be a useful and inexpensive model of uncomplicated obesity amenable to rapid screening of weight loss drugs. Olanzapine-induced weight gain may be secondary to hyperphagia associated with acute lowering of plasma glucose and leptin, as well as the inability to increase plasma glucose and leptin following a glucose challenge.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Clozapine; Disease Models, Animal; Energy Intake; Female; Glucose Tolerance Test; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Olanzapine; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Dopamine; Sex Factors

This study assesses the efficacy of an educational and dietary approach in preventing olanzapine-induced weight gain. Eighteen patients affected by schizophrenic disorders were treated with olanzapine and weighed twice-weekly for 24 weeks. A psychoeducational intervention and referral to a nutritionist was introduced from the beginning of olanzapine treatment in 9 patients, and from the 9th week of therapy in 8 patients. Results showed that after 8 weeks of olanzapine treatment, weight gain was contained in the subjects receiving intervention unlike patients without preventive intervention (+0.99+/-3.34 kg vs. +2.96+/-3.08 kg; p<.03). At the end of the trial these patients partly shed their gain (-1.77 kg), presenting a final weight which was not significantly different from baseline (+1.19 kg). Subjects receiving the psychoeducational approach from the beginning were significantly heavier than at baseline (+3.4 kg). Poor dietary compliance correlated significantly with an increase in body weight, while higher mean dosages of olanzapine correlated with better weight-gain control.

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Body Weight; Female; Health Education; Humans; Male; Middle Aged; Obesity; Olanzapine; Patient Education as Topic; Prevalence; Schizophrenia

To examine clinical outcomes in Asian patients with schizophrenia receiving monotherapy with olanzapine, risperidone or typical antipsychotics in naturalistic settings.. In this report, data from the first 12 months of the prospective, observational, 3-year Intercontinental Schizophrenia Outpatient Health Outcomes study are presented for patients from participating Asian countries (Korea, Taiwan and Malaysia) who were started on, or switched to, monotherapy with olanzapine (n = 484), risperidone (n = 287) or a typical antipsychotic drug (n = 127) at baseline.. At 12 months, overall reduction in the score of Clinical Global Impressions-Severity of Illness rating scale was greatest with olanzapine (p < 0.001 vs typical agents), followed by risperidone (p = 0.007 vs typical agents) treatment. Olanzapine treatment was found to have significantly better effects than typical agents on negative and depressive symptom scores, and significantly greater improvements than risperidone on negative and cognitive symptoms. The occurrence of extrapyramidal symptoms was least likely with olanzapine (p < 0.001 vs typical agents, and p = 0.012 vs risperidone), while the estimated odds of tardive dyskinesia were greatest in the typical treatment group (p = 0.046 vs olanzapine, and p = 0.082 vs risperidone). Mean weight increase was greater for olanzapine-treated patients compared with the other agents (p = 0.030 vs typical agents and p < 0.001 vs risperidone). The risk of menstrual disturbance was relatively high with risperidone when compared with olanzapine treatment (p < 0.001).. The results of this observational study indicate that, in Asian patients with schizophrenia, olanzapine may offer benefits when compared with typical agents or risperidone. However, the significantly greater odds of weight gain should be considered in the clinical management of olanzapine-treated patients.

Topics: Adult; Antipsychotic Agents; Asian People; Basal Ganglia Diseases; Benzodiazepines; Diagnostic and Statistical Manual of Mental Disorders; Female; Humans; Korea; Malaysia; Male; Obesity; Olanzapine; Risperidone; Schizophrenia; Severity of Illness Index; Taiwan

Most of atypical antipsychotics (AAPs) are highly related to a major risk of metabolic drawbacks leading to dyslipidemia and obesity.. To set up a mouse model of the AAP-associated weight gain in mice under the influence of chronic olanzapine regimen.. Female mice were housed in pairs and habituated to spontaneous feeding with a high-palatable diet (10% sucrose wet mash). Firstly, we orally administered olanzapine (0.75, 1.5 and 3 mg/kg), evaluating body weight and periuterine fat mass, as well as insulin, non-esterified fatty acids, triglycerides, and glucose levels. In a second experiment, we assessed the effect of olanzapine on energy expenditure through indirect calorimetry (IC). A third experiment was conducted to investigate the effects of olanzapine on a high fat-high sweet palatable diet (10% sucrose + 30% fat, HF-HS) in mice implanted with subcutaneous osmotic mini-pumps. Locomotor activity was also assessed.. In experiment 1, the highest dose of chronically administered olanzapine (3 mg/kg) induced significant weight gain accompanied by augmentation of periuterine fat depots, with no changes in locomotor activity. In experiment 2, chronic administration did not alter energy expenditure, whereas, decreased respiratory quotient (RQ). In experiment 3, subcutaneously infused olanzapine evidenced a dose and time-dependent increase of body weight and HF-HS diet consumed. Notably, serum analyses revealed a hyperinsulinemia together with increased levels of triglycerides and glucose.. In this study, we describe in female mice metabolic alterations matching the metabolic syndrome, thus resembling the clinical situation of schizophrenic patients taking AAPs.

Topics: Administration, Oral; Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Calorimetry, Indirect; Disease Models, Animal; Dose-Response Relationship, Drug; Eating; Energy Metabolism; Fatty Acids; Female; Infusion Pumps, Implantable; Insulin; Intra-Abdominal Fat; Lipid Metabolism; Mice; Motor Activity; Obesity; Olanzapine; Time Factors; Triglycerides

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

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

Weight gain is a commonly observed adverse effect of atypical antipsychotic medications, but associated changes in energy balance and body composition are not well defined. The authors report here the effect of olanzapine on body weight, body composition, resting energy expenditure, and substrate oxidation as well as leptin, insulin, glucose, and lipid levels in a group of outpatient volunteers with first-episode psychosis.. Nine adults (six men and three women) experiencing their first psychotic episode who had no previous history of antipsychotic drug therapy began a regimen of olanzapine and were studied within 7 weeks and approximately 12 weeks after olanzapine initiation.. After approximately 12 weeks of olanzapine therapy, the median increase in body weight was 4.7 kg, a significant increase of 7.3% from first observation. Body fat, measured by dual-energy x-ray absorptiometry, increased significantly, with a propensity for central fat deposition. Lean body mass and bone mineral content did not change. Resting energy expenditure, measured by indirect calorimetry, did not change. Respiratory quotient significantly increased 0.12 with olanzapine and was greatest in those who gained >5% of their initial weight. Fasting insulin, C-peptide, and triglyceride levels significantly increased, but there were no changes in glucose levels; total, high density lipoprotein, or low density lipoprotein cholesterol levels; or leptin levels.. Olanzapine appears to have induced an increase in central body fat deposition, insulin, and triglyceride levels, suggesting the possible development of insulin resistance. The decrease in fat oxidation may be secondary or predispose patients to olanzapine-induced weight gain.

Topics: Adipose Tissue; Adult; Antipsychotic Agents; Benzodiazepines; Body Composition; Body Weight; C-Peptide; Energy Metabolism; Female; Humans; Insulin; Male; Obesity; Olanzapine; Oxidation-Reduction; Psychotic Disorders; Respiratory Physiological Phenomena; Schizophrenia; Triglycerides

While the incidence of new-onset diabetes mellitus may be increasing in patients with schizophrenia treated with certain atypical antipsychotic agents, it remains unclear whether atypical agents are directly affecting glucose metabolism or simply increasing known risk factors for diabetes.. To study the 2 drugs most clearly implicated (clozapine and olanzapine) and risperidone using a frequently sampled intravenous glucose tolerance test.. A cross-sectional design in stable, treated patients with schizophrenia evaluated using a frequently sampled intravenous glucose tolerance test and the Bergman minimal model analysis.. Subjects were recruited from an urban community mental health clinic and were studied at a general clinical research center. Patients Fifty subjects signed informed consent and 41 underwent the frequently sampled intravenous glucose tolerance test. Thirty-six nonobese subjects with schizophrenia or schizoaffective disorder, matched by body mass index and treated with either clozapine, olanzapine, or risperidone, were included in the analysis.. Fasting plasma glucose and fasting serum insulin levels, insulin sensitivity index, homeostasis model assessment of insulin resistance, and glucose effectiveness.. The mean +/- SD duration of treatment with the identified atypical antipsychotic agent was 68.3 +/- 28.9 months (clozapine), 29.5 +/- 17.5 months (olanzapine), and 40.9 +/- 33.7 (risperidone). Fasting serum insulin concentrations differed among groups (F(33) = 3.35; P = .047) (clozapine>olanzapine>risperidone) with significant differences between clozapine and risperidone (t(33) = 2.32; P = .03) and olanzapine and risperidone (t(33) = 2.15; P = .04). There was a significant difference in insulin sensitivity index among groups (F(33) = 10.66; P<.001) (clozapineolanzapine>risperidone) (clozapine vs risperidone, t(33) = 2.94; P = .006; olanzapine vs risperidone, t(33) = 2.42; P = .02). There was a significant difference among groups in glucose effectiveness (F(30) = 4.18; P = .02) (clozapine

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Body Weight; Clozapine; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Insulin Resistance; Male; Metabolic Syndrome; Obesity; Olanzapine; Risperidone; Schizophrenia

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

Weight gain is a prominent effect of most atypical antipsychotic drugs (AAPDs); yet, the mechanisms are not fully understood and no well-established mouse models exist for investigating the mechanisms. Thus, we developed a mouse model to evaluate the effects of AAPDs on eating, body weight (BW), and body composition.. Female C57BL/6J mice were used to test olanzapine, quetiapine, ziprasidone, and risperidone. Mice were acclimated to individual housing, given ad libitum access to chow and water, dosed with placebo peanut butter pills for 1 week, and then dosed daily with AAPD-laced peanut butter pills for 4 weeks. Weekly food intakes and BWs were measured, and body compositions were determined at the end of each experiment.. After 4 weeks of treatment, olanzapine, quetiapine, ziprasidone, and risperidone caused significant weight increases, but only olanzapine and quetiapine were associated with significantly increased food intake. Body composition data revealed that olanzapine-treated mice had more relative fat mass and risperidone-treated mice had more relative lean mass than did control mice. Quetiapine and ziprasidone did not significantly affect relative body composition even though BW was increased.. Oral AAPD administration causes increased BW in female mice. Our mouse model of AAPD-induced weight gain resembles the human response to these medications and will be used to investigate the mechanisms for weight gain and fat accumulation.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Body Constitution; Body Weight; Dibenzothiazepines; Eating; Male; Mice; Mice, Inbred C57BL; Models, Animal; Obesity; Olanzapine; Piperazines; Quetiapine Fumarate; Risperidone; Thiazoles

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

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

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

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

This investigation estimates and compares, for the first time, the distribution of body mass index (BMI: kg/m(2)) and the prevalence of obesity among Chinese outpatients with schizophrenia treated with antipsychotics. The BMI of 201 outpatients with schizophrenia-spectrum disorders was studied via a cross-sectional naturalistic study. This investigation also compared the BMI of the subjects with a Taiwanese reference population. This investigation found no significant difference in the prevalence of obesity between male and female subjects. The prevalence of obesity among male and female patients in this investigation was, respectively, 2.74- and 2.51-fold greater than the Taiwanese reference population, and the prevalence of severe obesity among male and female patients was 4.66- and 3.53-fold greater than that in the Taiwanese reference population, respectively. The rate of severe obesity was especially high in patients treated with olanzapine. Atypical antipsychotics other than olanzapine did not seem to be more closely associated with obesity or severe obesity compared to typical antipsychotics.

Topics: Adult; Ambulatory Care; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Obesity; Obesity, Morbid; Olanzapine; Reference Values; Schizophrenia; Sex Factors; Taiwan

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Body Mass Index; Clozapine; Diabetes Complications; Haloperidol; Humans; Obesity; Olanzapine; Piperazines; Quinolones; Risk Factors; Schizophrenia; 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

Topics: Adult; Anticonvulsants; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Cyclohexanols; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Drug Interactions; Drug Therapy, Combination; Humans; Male; Obesity; Olanzapine; Pirenzepine; Risk Factors; Valproic Acid; Venlafaxine Hydrochloride

Atypical antipsychotics successfully treat schizophrenia and other conditions, with a lower incidence of extrapyramidal side effects than other agents used in treatment of these disorders. However, some atypical antipsychotics are associated with weight gain.. To quantify the impact on weight and identify atypical antipsychotics causing the least amount of weight gain among patients switched from risperidone to olanzapine and olanzapine to risperidone.. Patients included in the study (n = 86) were > or =18 years and had received > or =2 prescriptions for risperidone or olanzapine for > or =60 days, switched to the other atypical antipsychotic, and were dispensed > or =2 prescriptions for at least 60 days after the index date. Age, weight, and body mass index (BMI) were retrospectively abstracted from automated databases containing patient-specific prescription and vital sign information.. At the time of their switch, the average patient age was 53.2 years (range 25-83). The average weight change in patients switched to olanzapine (n = 47) was +2.3 kg (p = 0.01) and the BMI change was +0.8 kg/m(2) (p = 0.02). The average percent body weight change was +2.8% and the BMI change was +3.0%. The average weight change after patients switched to risperidone (n = 39) was -0.45 kg (p = 0.69) and BMI change was -0.2 kg/m2 (p = 0.64). The average percentage weight change was -0.4% and BMI change was -0.5%.. Practitioners' concern regarding weight changes after switching atypical antipsychotics seems warranted and patients should be provided consistent, ongoing weight monitoring. Further investigations should examine whether weight changes associated with atypical antipsychotic treatment further jeopardize this already at-risk population for severe comorbid conditions such as hypertension, coronary artery disease, and type 2 diabetes.

Topics: Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Humans; Middle Aged; Obesity; Olanzapine; Pilot Projects; Retrospective Studies; Risperidone; Schizophrenia

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: Adolescent; Benzodiazepines; Child; Dopamine Antagonists; Female; Haloperidol; Humans; Male; Obesity; Olanzapine; Pirenzepine; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Weight Gain

Psychopharmacology research aims to expand the therapeutic ratio between efficacy, on the one hand, and adverse events and safety, on the other. The novel antipsychotics are now the antipsychotics of choice in the treatment of bipolar disorders. They have the advantages of potential antidepressant properties and low risks of extrapyramidal side effects and, especially, of tardive dyskinesia. However, novel antipsychotics may also have varying propensities to cause side effects, such as somnolence, hyperprolactinemia, weight gain (sometimes significant), and possibly diabetes mellitus. The increasing use of these novel agents requires careful assessment and monitoring of emergent side effects and diligent consideration of associated medical complications. Two new anticonvulsants, lamotrigine and topiramate, have recently shown promise in the treatment of bipolar disorders. Most of their adverse effects can be avoided by slow titration toward the recommended doses. In contrast to carbamazepine and valproic acid, topiramate may be associated with weight loss.

Topics: Anticonvulsants; Benzodiazepines; Bipolar Disorder; Dibenzothiazepines; Female; Fructose; Humans; Lamotrigine; Male; Obesity; Olanzapine; Piperazines; Pirenzepine; Quetiapine Fumarate; Risperidone; Thiazoles; Topiramate; Triazines

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clozapine; Follow-Up Studies; Humans; Male; Obesity; 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

One of my patients is taking olanzapine for schizophrenia. She has gained a lot of weight, which, I understand, often happens with some of the new atypical antipsychotics. Due to her weight gain, she failed to notice she had become pregnant. Is she at risk?. Experience with olanzapine is relatively slight, but available prospective data do not show increased teratogenic risk. Adiposity, on the other hand, is associated with increased risk of neural tube defects. Only some of this risk can be reduced by folate supplementation.

Topics: Antipsychotic Agents; Benzodiazepines; Female; Folic Acid; Humans; Infant, Newborn; Neural Tube Defects; Obesity; Olanzapine; Pirenzepine; Pregnancy; Pregnancy Complications; Risk Factors; Schizophrenia

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

Topics: Antipsychotic Agents; Benzodiazepines; Body Weight; Female; Humans; Insulin; Leptin; Male; Metabolic Syndrome; Obesity; Olanzapine; Pirenzepine; Psychotic Disorders

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

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Humans; Obesity; Olanzapine; Pirenzepine; Risperidone; Schizophrenia; 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