olanzapine and Body-Weight

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

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

The purpose of this project was to provide evidence-based guidance concerning when and how it is appropriate to undertake elective changes in antipsychotic medications in order to reduce adverse effects, with a focus on those adverse effects associated with increased long-term health risks. This project extends the results of the National Institute of Mental Health-funded 2009 Schizophrenia Patient Outcomes Research Team (PORT) psychopharmacologic treatment recommendations. The authors reviewed the literature on switching antipsychotics, focusing on randomized controlled trials published since the 2009 Schizophrenia PORT. The studies reviewed support a recommendation that an elective switch from higher to lower metabolic risk antipsychotics can produce weight and lipid benefits without significant risk of clinical deterioration. Evidence also suggests that certain antipsychotic switches may improve other adverse effects, including extrapyramidal symptoms and prolactin elevation. In deciding to make an elective change of antipsychotic medication, it is important to conduct a careful risk/benefit assessment with the patient. Before initiating a switch, patients should be educated about what to expect during the process. Studies also support gradual discontinuation of the current medication in order to minimize problems early in the switching process.

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Body Weight; Drug Substitution; Dyskinesia, Drug-Induced; Evidence-Based Medicine; Humans; Lipids; Olanzapine; Patient Outcome Assessment; Piperazines; Psychiatric Status Rating Scales; Quinolones; Randomized Controlled Trials as Topic; Schizophrenia; Schizophrenic Psychology

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

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

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

Treatment-emergent weight gain has been reported in younger patients receiving atypical antipsychotics, but less is known about weight gain in adults aged 65 years and older. This was a post hoc analysis of 1267 patients with dementia and behavioral disturbances treated with olanzapine (1 to 20 mg/d) in clinical trials, most of whom were underweight (body mass index <18.5 kg/m2) or of normal weight (body mass index, 18.5-24.9 kg/m2) at baseline. Weight changes over the first 20 weeks of treatment in olanzapine-treated patients, as estimated by a repeated measures analysis model, were significantly greater in the combined categories of underweight and normal weight (1.22 kg and 1.29 kg, respectively) versus overweight and obese (0.56 kg and 0.53 kg, respectively; P = .006). The estimated probability of gaining more than 7% of initial body weight was significantly greater in patients treated with olanzapine versus active comparator (P < .001) or placebo (P < .001). Weight gain in olanzapine-treated older patients with dementia and behavioral disturbances was significantly greater in individuals with a baseline body mass index of less than 25 kg/m2.

Topics: Age Factors; Aged; Aged, 80 and over; Alzheimer Disease; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Clinical Trials as Topic; Dose-Response Relationship, Drug; Humans; Mental Disorders; Olanzapine; Product Surveillance, Postmarketing

After the introduction of the so-called "atypical antipsychotics" in the clinical experience hyperglycemia as well as increased triglyceride and cholesterol serum levels were reported in patients treated with some of these agents. In this article, the recently published population-based studies are reviewed.. According to the available data, the risk to develop type 2 diabetes mellitus or hyperlipidemia in patients treated with clozapine and olanzapine is increased. The underlying pathomechanism still remains widely unclear. Since overweight is a known risk factor for type 2 diabetes mellitus, the weight-inducing effect of atypical antipsychotics may play an important role.. Since metabolic disorders often lead to severe diseases, these side effects of antipsychotics should be paid more attention.

Topics: Antipsychotic Agents; Benzodiazepines; Body Weight; Clozapine; Diabetes Mellitus, Type 2; Humans; Hypercholesterolemia; Hypertriglyceridemia; Olanzapine; Pirenzepine; Risk

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

Schizophrenia is associated with a lowered bone mineral density. The antidiabetic and body weight lowering glucagon-like peptide-1 receptor agonist liraglutide has shown to mitigate overweight and impaired glucose tolerance associated with olanzapine and clozapine. As liraglutide has been proposed to affect bone metabolism, we evaluated the effect of liraglutide on bone turnover markers (BTM) in patients with prediabetes and schizophrenia treated with olanzapine or clozapine. Patients diagnosed with a schizophrenia spectrum disorder treated with the antipsychotic compounds clozapine and/or olanzapine, having prediabetes and a BMI above 27 kg/m

Topics: Adult; Antipsychotic Agents; Biomarkers; Body Weight; Bone and Bones; Bone Density; Bone Remodeling; Clozapine; Collagen Type I; Fasting; Humans; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Olanzapine; Overweight; Prediabetic State; Schizophrenia

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

This study examined the effect of adjunctive telmisartan on body metabolism in clozapine- or olanzapine-treated patients with schizophrenia.. Each subject had been on stable dose of olanzapine or clozapine for at least 1 month. In a 12-week randomized, double-blind, placebo-controlled study, subjects received either telmisartan (80 mg once per day) or placebo. The homeostasis model of assessment of insulin resistance (HOMA-IR) was calculated based on fasting blood levels of insulin and glucose. Fasting blood levels of triglycerides and cholesterols, as well as serum levels of high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) were measured. The whole-body dual-energy X-ray absorptiometry (DXA) was used to assess body composition. Lipid particles were assessed using nuclear magnetic resonance (NMR) spectroscopy. All assessments were conducted at baseline and repeated at week 12.. Fifty-four subjects were randomized and 43 completed the study (22 in the telmisartan group, 21 in the placebo group). There were no significant differences between the two groups in week 12 changes for HOMA-IR or fasting triglycerides (- 0.18 ± 1.24 vs 0.39 ± 1.39, p = 0.181; - 26 ± 76 vs - 10 ± 81 mg/dL, p = 0.679, respectively) (telmisartan vs placebo). Further, there were no significant between group differences in week 12 changes for other fasting lipids, body weight, body mass index, waist circumference, as well as various measures of lipid particles (p's > 0.100). The DXA assessment showed no significant differences between the two groups in week 12 changes for fat mass, lean mass, or total mass (p's > 0.100).. In the present study, adjunctive treatment of telmisartan did not seem to improve body metabolism in schizophrenia patients receiving olanzapine or clozapine. The implications for future studies were discussed. CLINICALTRIALS.. NCT00981526.

Topics: Adult; Antipsychotic Agents; Body Composition; Body Mass Index; Body Weight; Clozapine; Double-Blind Method; Drug Therapy, Combination; Female; Glucose; Humans; Insulin; Male; Middle Aged; Olanzapine; Schizophrenia; Telmisartan; Treatment Outcome; Triglycerides

This study was conducted to evaluate the efficacy and metabolic effects of paliperidone palmitate (PP) injections against oral olanzapine in first-episode schizophrenia (FES) patients.. Eligible patients were randomized to receive PP or olanzapine. Efficacy assessments and weight-related parameters were assessed at baseline, weeks 1, 5, 9, and endpoint or at early withdrawal. Lipid, glucose, insulin and prolactin were evaluated at baseline and endpoint or at early withdrawal.. The Positive And Negative Syndrome Scale (PANSS) scores declined significantly after treatment in both groups. Significant increases in weight-related parameters from baseline to endpoint were shown in both groups. Although there was no significant difference in PANSS scores and weight-related parameters between the two groups through the whole 13-week study. The increased level of triglyceride and HOMA-IR at endpoint from baseline in the olanzapine group was higher than the PP group. There was a stronger elevation of prolactin level in the PP group.. In summary, PP and olanzapine showed similar improvement in the treatment of FES patients. This study also reinforced the necessity for regular monitoring of metabolic parameters in schizophrenia patients prescribed atypical antipsychotics. Clinical trial registration numbers: ChiCTR-IOR-14005304. Date of registration: 2014-10-11.

Topics: Acute Disease; Adipose Tissue; Administration, Oral; Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Female; Humans; Injections; Lipids; Male; Olanzapine; Paliperidone Palmitate; Prolactin; Psychiatric Status Rating Scales; Schizophrenia; Treatment Outcome; Waist Circumference; Young Adult

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

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

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

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

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

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

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

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

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

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

Excessive weight gain has been identified as a serious metabolic side-effect of second-generation antipsychotics (SGAs), including olanzapine. While hyperphagia has been suggested to be the main contributor for this side-effect in the short term, reduced energy expenditure, in particular thermogenesis and locomotor activity, has been considered to contribute to the maintenance of heavy weight under long-term SGA treatments. Recent studies have identified metabolically active brown adipose tissues (BAT) in adult humans, suggesting potential clinical significance for the involvement of BAT thermogenesis in SGA-induced weight gain. However, to date there has been little research elucidating the central neuronal pathways affecting BAT thermogenesis or the morphological changes of the BAT. The present study aimed to investigate the role of BAT thermogenesis and locomotor activity in olanzapine-induced weight gain during the prolonged time courses of olanzapine treatment in an established female rat model. Although short- to mid-term olanzapine treatment had no effect on BAT temperature, we observed that long-term olanzapine treatment (from day 18 to 34) induced a significant reduction in BAT temperature, with an acute effect being observed between 45 and 150 min post-treatment in the long-term cohort. Additionally, in the long-term olanzapine group, the reduced BAT temperature was accompanied by decreased UCP1 and PGC-1α expressions in the BAT. Moreover, TH mRNA expressions in both hypothalamus and brainstem were also downregulated after mid- to long-term olanzapine treatment. Further, olanzapine led to reduced percentage of brown adipocytes in BAT during mid- to long-term treatments. Finally, locomotor activity was reduced throughout the three treatment cohorts. In summary, our results suggest that the reduction of BAT thermogenesis plays an important role during the long-term of olanzapine-induced weight gain, which was accompanied by an earlier onset of BAT adipocyte morphological changes and biochemical changes in the hypothalamus and the brainstem, while locomotor activity contributes to the entire olanzapine treatment courses.

Topics: Adipose Tissue, Brown; Analysis of Variance; Animals; Antipsychotic Agents; Benzodiazepines; Body Weight; Cohort Studies; Down-Regulation; Eating; Exploratory Behavior; Female; Ion Channels; Mitochondrial Proteins; Motor Activity; Olanzapine; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Rats; RNA, Messenger; Thermogenesis; Time Factors; Transcription Factors; Tyrosine 3-Monooxygenase; Uncoupling Protein 1

The objective of this study was to assess the long-term safety and efficacy of olanzapine long-acting injection (LAI). A 6-year, single-arm, open-label extension study of olanzapine LAI was conducted at 127 sites in 25 countries. Patients were 18-76 years of age, were diagnosed with schizophrenia or schizoaffective disorder (N=931), and had been previously enrolled in one of three clinical trials of olanzapine LAI. Patients received flexibly dosed (45-405 mg) olanzapine LAI every 2-4 weeks. The mean duration of exposure was ∼3 years. A total of 393 (42.2%) patients completed the study. The mean weight change was +2.1 kg (P<0.001), with 40.6% of patients experiencing 7% or higher weight gain. Treatment-emergent categorical changes occurred in fasting glucose, total cholesterol, and triglyceride levels. Pharmacokinetic analyses revealed no systemic accumulation of olanzapine after long-term treatment. There were 36 occurrences of post-injection delirium/sedation syndrome, all resolving within 72 h. The mean Positive and Negative Syndrome Scale total and subscale scores did not change significantly over the course of the study, indicating clinical stability. Olanzapine LAI appeared effective as a long-term maintenance treatment, with a safety profile generally consistent with the known profile of oral olanzapine, except for injection-related events (including post-injection delirium/sedation syndrome).

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Cholesterol; Delayed-Action Preparations; Delirium; Double-Blind Method; Female; Humans; Injections, Intramuscular; International Cooperation; Male; Middle Aged; Olanzapine; Psychotic Disorders; Quality of Life; Schizophrenia; Treatment Outcome; Triglycerides; Young Adult

This study examined the effect of adjunctive intranasal insulin therapy on body metabolism in patients with schizophrenia.. Each subject had a DSM-IV diagnosis of schizophrenia or schizoaffective disorder and had been on stable dose of antipsychotic agent for at least one month. In an 8-week randomized, double-blind, placebo-controlled study, subjects received either intranasal insulin (40 IU 4 times per day) or placebo. The whole body dual-energy X-ray absorptiometry (DXA) was used to assess body composition. Lipid particles were assessed using nuclear magnetic resonance (NMR) spectroscopy. All assessments were conducted at baseline, and repeated at week 8.. A total number of 39 subjects completed the study (18 in the insulin group, 21 in the placebo group). There were no significant differences between the two groups in week 8 changes for body weight, body mass index, waist circumference, as well as various measures of lipid particles (p's>0.100). The DXA assessment showed no significant differences between the two groups in week 8 changes for fat mass, lean mass or total mass (p's>0.100).. In the present study, adjunctive therapy of intranasal insulin did not seem to improve body metabolism in patients with schizophrenia. The implications for future studies were discussed.

Topics: Absorptiometry, Photon; Administration, Intranasal; Adolescent; Adult; Aged; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Double-Blind Method; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Insulin; Lipid Metabolism; Male; Metabolic Diseases; Middle Aged; Nuclear Magnetic Resonance, Biomolecular; Olanzapine; Psychiatric Status Rating Scales; Schizophrenia; Sex Factors; Time Factors; Waist Circumference; Young Adult

To compare matched paliperidone-ER- and olanzapine-treated schizophrenic patients on measures of glucose and lipid metabolism.. Eighty hospitalized patients with schizophrenia (DSM-IV) were randomly assigned to treatment with paliperidone ER or olanzapine for a period of 12 weeks. At baseline and every 4 weeks, we assessed weight, subcutaneous fat, waist and hip circumferences, fasting glucose, insulin, glycohemoglobin A1, cholesterol, triglycerides, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, and prolactin. We also assessed at every time point body mass index (BMI), homeostasis insulin resistance (HOMA-IR), and homeostasis β-cell function (HOMA-B).. Thirty-three patients randomly assigned to paliperidone ER and 23 patients randomly assigned to olanzapine groups completed the entire 12-week treatment. Within-group analyses showed that fasting measures in both groups increased for weight, BMI, waist circumferences, hip circumference, subcutaneous fat, cholesterol, triglycerides, and prolactin. In contrast, fasting glucose, LDL, and HOMA-B increased during treatment only in the olanzapine group. We also detected significantly different serum prolactin levels at all time point between the paliperidone ER- and olanzapine-treated groups, as well as a statistical trend for HOMA-B to increase more in the olanzapine compared to paliperidone-ER group over the 12 weeks of the trial. We did not detect, however, differential drug effects over the 12 weeks of the trial on fasting measures of BMI, glucose, glycohemoglobin A1, insulin, HDL, LDL, cholesterol, triglyceride, or HOMA-IR.. This study reinforces the necessity of regularly monitoring metabolic parameters in patients with schizophrenia taking atypical antipsychotics, including paliperidone ER.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Delayed-Action Preparations; Female; Follow-Up Studies; Humans; Insulin Resistance; Insulin-Secreting Cells; Isoxazoles; Lipid Metabolism; Male; Olanzapine; Paliperidone Palmitate; Prospective Studies; Pyrimidines; Schizophrenia; Time Factors; Young Adult

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

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

The highly selective and fast dissociating D2 receptor antagonist JNJ-37822681 may be associated with lower risk for weight gain and undesirable metabolic effects compared with available antipsychotics.. In this double-blind, randomized study, patients were randomly assigned (1:1:1:1:1) to 12 weeks of JNJ-37822681 (10 mg, 20 mg, or 30 mg, twice daily) or olanzapine (10 mg/d during week 1; 15 mg/d after week 1), or 6 weeks of placebo (followed by 6 weeks of olanzapine, 15 mg/d). Metabolic and body mass parameters were assessed at weeks 6 and 12.. For metabolic parameters, at week 6 none of the JNJ-37822681 groups demonstrated significant change vs placebo; however, significant changes (P < .05) were observed in the olanzapine vs placebo group in triglycerides, low-density lipoprotein (LDL) and very-LDL cholesterol, and free fatty acids. For all JNJ-37822681 groups, mean weight changes at week 12 (-0.3 [10 mg], + 0.3 [20 mg], + 0.8 kg [30 mg]) were significantly less (P < .001) than for the olanzapine group (+ 2.7 kg). A higher percentage of overweight or obese patients (baseline body mass index: ≥25 kg/m2) receiving olanzapine had ≥7% increase in weight than those receiving JNJ-37822681 (9.8% vs 2.3%, respectively).. JNJ-37822681 treatment was associated with a more favorable outcome on weight and metabolic adverse effects vs olanzapine for treating schizophrenia; the 10 mg twice-daily dose demonstrated minimal to no weight gain.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Biomarkers; Blood Glucose; Body Mass Index; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Insulin; Male; Middle Aged; Olanzapine; Piperidines; Pyridazines; Schizophrenia; Triglycerides; Waist Circumference

Gender differences exist in psychiatric disorders; however, gender has not been well studied in psychotic depression. This analysis of the largest clinical trial in psychotic depression examined the effects of age and gender on clinical characteristics and predictors of treatment outcome and treatment-associated changes in body mass index (BMI) and metabolic measures.. Secondary analyses were performed on data from 259 subjects with major depressive disorder with psychotic features (DSM-IV-TR) aged 18-93 years in the double-blind randomized controlled trial of olanzapine plus sertraline versus olanzapine plus placebo for psychotic depression (Study of Pharmacotherapy of Psychotic Depression). Sociodemographic factors, clinical characteristics, treatment outcome, and treatment-associated changes in BMI and metabolic measures were analyzed by gender and age. Subjects were enrolled from December 2002 to June 2007.. Female gender was associated with divorced (χ(2)(1) = 5.3, P = .03) or widowed (χ(2)(1) = 8.1, P ≤ .01) marital status. Comorbid anxiety disorders were more common in women than in men (χ(2)(1) = 4.9, P = .03). Hallucinations (χ(2)(1) = 7.8, P = .005) and delusions with disorganization (t(257) = -2.10, P = .04) were significantly associated with female gender, as were higher cholesterol measures (χ(2)(1) = 7.15, P = .008). There were no significant interactions between treatment and gender in terms of change in BMI. Gender was not associated with treatment response.. This study is the first analysis of gender and age as predictors of treatment outcome and treatment-associated changes in BMI and metabolic adverse effects in psychotic depression. Gender differences exist in patients with psychotic depression, most notably with regard to the presence of hallucinations. Female gender was associated with metabolic measures. Future studies with larger sample sizes may detect small gender differences in treatment outcome and treatment-associated changes in BMI and metabolic measures in psychotic depression.. ClinicalTrials.gov identifier: NCT00056472.

Topics: Adult; Age Factors; Aged; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Depressive Disorder, Major; Diagnostic and Statistical Manual of Mental Disorders; Double-Blind Method; Drug Monitoring; Drug Therapy, Combination; Female; Hallucinations; Humans; Male; Metabolism; Middle Aged; Olanzapine; Outcome Assessment, Health Care; Psychiatric Status Rating Scales; Sertraline; Sex Factors; Socioeconomic Factors; Treatment Outcome

The objective of the study was to compare metabolic effects of ziprasidone versus olanzapine treatment in patients with first-episode schizophrenia.. In this 6-week, multicenter, open-label trial, 260 patients were randomly assigned to receive ziprasidone or olanzapine treatment (130 per group). Primary metabolic measures were changes in weight and body mass index (BMI). Secondary metabolic measures were changes in glucose, insulin, lipids, and blood pressure. Efficacy and safety were also measured additionally.. A total number of 230 patients completed the study. The mean daily dosages were 138.2(28.6) mg for ziprasidone and 19.0(2.3) mg for olanzapine. After 6-week treatment, there were significant between-group differences in change scores on weight [4.22(3.49) kg versus -0.84(2.04) kg, p < 0.001] and BMI [1.59(1.37) versus -0.30(0.74), p < 0.001]. In addition, there were significant between-group differences in change scores on fasting plasma glucose, insulin, homeostasis model assessment 2-insulin resistance, low-density lipoprotein, total cholesterol, and triglycerides (p < 0.001); all the changes were clinically in favor of ziprasidone treatment. Both medications were effective in improving schizophrenia symptoms, but the decreases in Positive and Negative Syndrome Scale total scores of the olanzapine group were significantly greater than that of the ziprasidone group (p < 0.05). Compared with olanzapine, ziprasidone also induced more prolonging of corrected QT interval and extrapyramidal side effects (p < 0.05). Both medications were well tolerated, and no serious adverse events were observed in either group.. Compared with olanzapine, ziprasidone treatment was associated with less adverse effects on glucose and lipid metabolism in patients with first-episode schizophrenia.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Body Weight; Female; Glucose; Humans; Insulin; Lipid Metabolism; Male; Middle Aged; Olanzapine; Piperazines; Schizophrenia; Thiazoles; Young Adult

Olanzapine has frequently been reported to induce substantial weight gain, which is associated with an increased prevalence of dyslipidemia and type 2 diabetes. Several reports have described that olanzapine orally disintegrating tablets (ODT) induce less weight gain than oral standard tablets (OST) do, although both forms have equal bioavailability. We tried to clarify whether or not body weight change differed between olanzapine ODT and OST treatments in olanzapine-naïve schizophrenia patients. An open-label, 12-month, multicenter, randomized, flexible-dose study was conducted for direct comparison of the effects of OST (mean dosage, 15.7 mg; N=57) and ODT (mean dosage, 15.2 mg; N=61) on body weight and metabolic measures such as blood glucose, hemoglobin(A1c), total cholesterol and HDL-cholesterol, and triglycerides in olanzapine-naïve patients with schizophrenia. Outcome measures included Positive and Negative Syndrome Scale (PANSS), Global Assessment of Function (GAF), The World Health Organization Quality of Life 26 (WHO-QOL26), Drug Attitude Inventory (DAI)-10, and tolerability assessed by the UKU side-effect rating scale. This study was conducted between June 2007 and April 2010. No significant difference was found in the weight gain between the two forms of olanzapine. No significant difference was found between the two groups in any metabolic measure, efficacy, tolerability, WHO-QOL26, or DAI-10 score. Previous reports describing that olanzapine ODT induced less weight gain than OST were not supported by results of this randomized study.

Topics: Administration, Oral; Adult; Benzodiazepines; Blood Glucose; Body Weight; Cholesterol; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Olanzapine; Psychiatric Status Rating Scales; Quality of Life; Schizophrenia; Schizophrenic Psychology; Tablets; Triglycerides

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

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

Metabolic effects are generally more pronounced with second-generation than first-generation antipsychotics. This study was designed to compare long-term metabolic effects and efficacy of paliperidone extended release (ER) with those of oral olanzapine in patients with schizophrenia. In this 6-month, multicenter, prospective, randomized, controlled, open-label, parallel-group study, adults with schizophrenia were treated with paliperidone ER (6-9 mg/d; n = 239) or oral olanzapine (10-15 mg/d; n = 220). The primary outcome was mean change in the ratio of serum triglyceride level to high-density lipoprotein level (TG/HDL), a marker of insulin resistance. Other outcome measures included the Positive and Negative Syndrome Scale scores, measures of lipid and glucose metabolism, and body weight. Significant improvements in psychotic symptoms were observed with both treatments (P < 0.0001). The TG/HDL ratio was significantly higher at end point versus baseline with olanzapine compared with that of paliperidone ER. Mean end point change in TG/HDL ratio was 0.97 ± 2.72 [corrected] for olanzapine (P < 0.0001, reflecting worsening), with no significant change for paliperidone ER (-0.17 ± 2.51). Newly diagnosed impairment in TG and metabolic syndrome was more common with olanzapine (P < 0.05). Insulin resistance, as measured by the homeostasis model assessment of insulin resistance, worsened significantly with olanzapine (P = 0.0003), but not with paliperidone ER. Glucose sensitivity for insulin worsened significantly with olanzapine (P < 0.03), with no significant changes for paliperidone ER. End point increase in body weight was significantly higher with olanzapine than paliperidone ER (3.8 vs 1.2 kg; P = 0.0013). In summary, both paliperidone ER and olanzapine effectively treated schizophrenia; however, undesirable metabolic effects were significantly greater with olanzapine.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Delayed-Action Preparations; Female; Glucose Tolerance Test; Humans; Isoxazoles; Lipoproteins, HDL; Male; Metabolic Syndrome; Middle Aged; Olanzapine; Paliperidone Palmitate; Psychiatric Status Rating Scales; Pyrimidines; Schizophrenia; Triglycerides; Waist Circumference

Head-to-head comparisons of antipsychotics have predominantly included patients with chronic conditions. The aim of the present study was to compare the efficacy and tolerability of ziprasidone and olanzapine in patients with recent-onset schizophrenia.. The study was an 8-week, double-blind, parallel-group, randomized, controlled multicenter trial (NCT00145444). Seventy-six patients with schizophreniform disorder, schizophrenia or schizoaffective disorder (diagnosis < 5 y), and a maximum lifetime antipsychotic treatment < 16 weeks participated in the study. Efficacy of ziprasidone (80-160 mg/d) and olanzapine 10-20 mg was measured using the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression (CGI) Scale, the Calgary Depression Scale for Schizophrenia (CDSS), and the Heinrich Quality of Life Scale (HQLS); tolerability assessments included laboratory assessments, body weight, and electroencephalogram.. Olanzapine (n = 34) and ziprasidone (n = 39) showed equal efficacy as measured by the PANSS, CDSS, CGI, and HQLS. However, mean weight gain was significantly higher in the olanzapine group (6.8 vs 0.1 kg, P < .001). Ziprasidone was associated with decreasing levels of triglycerides, cholesterol, and transaminases, while these parameters increased in the olanzapine group (all P values < .05). There were no significant differences in fasting glucose and prolactin levels or in cardiac or sexual side effects. Patients on ziprasidone used biperiden for extrapyramidal side effects more frequently (P < .05).. The results of this study indicate that ziprasidone and olanzapine have comparable therapeutic efficacy but differ in their side effect profile. However, there is a risk of a type II error with this sample size. Clinically significant weight gain and laboratory abnormalities appear early after initiating treatment and are more prominent with olanzapine, while more patients on ziprasidone received anticholinergic drugs to treat extrapyramidal symptoms.

Topics: Adult; Alanine Transaminase; Antipsychotic Agents; Aspartate Aminotransferases; Basal Ganglia Diseases; Benzodiazepines; Biperiden; Blood Glucose; Body Weight; Cholesterol; Chronic Disease; Electrocardiography; Female; Humans; Male; Muscarinic Antagonists; Olanzapine; Piperazines; Prolactin; Psychiatric Status Rating Scales; Psychometrics; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Thiazoles; Triglycerides; Young Adult

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

A positive relationship between cholesterol levels and cognition has been reported in various human and animal studies, but has never been investigated in schizophrenia. The goal of this study was to examine this relationship in schizophrenic patients randomized to clozapine, olanzapine or haloperidol.. This was a double-blind randomized prospective 12-week study. Participants received a baseline evaluation including a cognitive battery consisting of an evaluation of psychomotor function, general executive function, visual and verbal memory, and visuospatial ability. Their fasting serum cholesterol level was also assessed. The participants were then randomized to clozapine, olanzapine, or haloperidol. They were evaluated at the end of 12 weeks. A general cognitive index (GCI) derived from the cognitive battery was the primary variable.. 82 patients had both baseline and endpoint neurocognitive assessments and cholesterol levels. There was a statistically and clinically significant positive association between change in cholesterol levels and change in GCI. This association was especially pronounced for verbal memory. There was no interaction between medication grouping and cholesterol level; the positive association was observable separately in each medication group. It was very robust and remained significant after we controlled for glucose and triglyceride levels, anticholinergic side effects, medication serum levels, cholesterol lowering medications, and pre-study antipsychotic medications.. Cholesterol levels show a strong association with cognition in schizophrenia in all medication groups. Further research on the role of lipid metabolism in cognition may suggest new treatments for this core deficit of schizophrenia.

Topics: Adolescent; Adult; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Cholesterol; Clozapine; Cognition Disorders; Double-Blind Method; Female; Follow-Up Studies; Haloperidol; Humans; Male; Middle Aged; Neuropsychological Tests; Olanzapine; Prospective Studies; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Triglycerides; Young Adult

The purpose of this study is to compare the efficacy of olanzapine and risperidone for the acute treatment of first-episode schizophrenia patients with cannabis use disorders. This secondary analysis of a previously published study included 49 first-episode patients with a diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective disorder and a co-occurring lifetime diagnosis of cannabis use disorders randomly assigned to treatment with either olanzapine (n=28) or risperidone (n=21) for 16weeks. The olanzapine group did not differ significantly from the risperidone group for initial response rates of positive symptoms, and rates of cannabis use or alcohol use during the study. Positive symptoms and the Scale for Assessment of Negative Symptoms (SANS) global asociality-anhedonia scores improved over time but did not differ between study medications. In both groups, cannabis use during the study was higher in patients who used cannabis within three months of the admission. Thus, our results suggest that olanzapine and risperidone had a similar initial efficacy on psychotic symptoms and substance use in first-episode patients with co-occurring cannabis use disorders. If clinicians are choosing between olanzapine versus risperidone treatment for this population, their decision should be based upon factors other than symptom response and short-term substance misuse.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Body Weight; Female; Humans; Longitudinal Studies; Male; Multivariate Analysis; Olanzapine; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Single-Blind Method; Statistics, Nonparametric; Substance-Related Disorders; Surveys and Questionnaires; Young Adult

The objective of this study was to explore whether the addition of olanzapine versus placebo increases weight gain and improves psychological symptoms in adolescents with anorexia nervosa-restricting type who are participating in a comprehensive eating disorders treatment program.. Twenty underweight females participated in this 10-week, double-blind, placebo-controlled pilot study of olanzapine. The primary efficacy measure was change in percentage of median body weight measured at baseline and weeks 5 and 10. Secondary efficacy measures included clinician-rated and self-reported measures of psychological functioning measured at 2-week intervals and eating disorder symptoms measured at baseline and weeks 5 and 10 as well as laboratory assessments (including indirect calorimetry), which were also performed at baseline and weeks 5 and 10. A mixed models approach to repeated measures analysis of variance was utilized to detect any treatment-by-time interaction.. Fifteen of 20 enrolled females (median age, 17.1 years; range, 12.3-21.8 years; mean body mass index, 16.3) completed this 10-week pilot study. Change in % median body weight did not differ between the treatment groups at midpoint or end of study. Both groups gained weight at a similar rate and had similar improvements in eating attitudes and behaviors, psychological functioning, and resting energy expenditure. A trend of increasing fasting glucose and insulin levels was found only in the olanzapine group at week 10.. These preliminary findings do not support a role for adjunctive olanzapine for underweight adolescent females with anorexia nervosa-restricting type who are receiving standard care in an eating disorder treatment program (clinical trials.gov; no. NCT00592930).

Topics: Adolescent; Anorexia Nervosa; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Child; Double-Blind Method; Feeding Behavior; Female; Humans; Insulin; Models, Statistical; Olanzapine; Pilot Projects; Treatment Outcome; Young Adult

The authors conducted a multisite randomized controlled trial examining the strategy of switching from olanzapine, quetiapine, or risperidone to aripiprazole to ameliorate metabolic risk factors for cardiovascular disease.. Patients with schizophrenia or schizoaffective disorder with a body mass index ≥ 27 and non-high-density lipoprotein (non-HDL) cholesterol ≥ 130 mg/dl who were on a stable treatment dosage of olanzapine, quetiapine, or risperidone were randomly assigned to switch to ari-piprazole (N=109) for 24 weeks or stay on their current medication (N=106). All participants were enrolled in a behaviorally oriented diet and exercise program. Clinical raters were blinded to treatment assignment. The primary and key secondary outcomes were change in non-HDL cholesterol and efficacy failure, respectively.. The prespecified primary analysis included 89 switchers and 98 stayers who had at least one postbaseline non-HDL cholesterol measurement. The least squares mean estimates of non-HDL cholesterol decreased more for the switch group than for the stay group (-20.2 mg/dl and -10.8 mg/dl, respectively). Switching was associated with larger weight reductions (least squares mean=2.9 kg) and a net reduction of serum triglycerides of 32.7 mg/dl. Twenty-two switchers (20.6%) and 18 stayers (17.0%) experienced protocol-defined efficacy failure. Forty-seven switchers (43.9%) and 26 stayers (24.5%) discontinued the assigned antipsychotic medication before 24 weeks.. Switching to aripiprazole led to improvement of non-HDL cholesterol levels and other metabolic parameters. Rates of efficacy failure were similar between groups, but switching to aripiprazole was associated with a higher rate of treatment discontinuation. In the context of close clinical monitoring, switching from an antipsychotic with high metabolic risk to one with lower risk to improve metabolic parameters is an effective strategy.

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Body Mass Index; Body Weight; Cholesterol; Cholesterol, LDL; Combined Modality Therapy; Dibenzothiazepines; Diet, Reducing; Drug Substitution; Exercise; Humans; Hypercholesterolemia; Olanzapine; Piperazines; Psychiatric Status Rating Scales; Psychotic Disorders; Quetiapine Fumarate; Quinolones; Risk; Risperidone; Schizophrenia; Treatment Outcome; Triglycerides

This randomized, open-label trial aimed to compare the metabolic effects of olanzapine orally disintegrating tablets (ODT) and solid oral tablets (SOT) in bipolar depressed and mixed outpatients.. Participants were openly randomized to receive olanzapine ODT (n = 13) or SOT (n = 10), 10 to 20 mg, once daily. Weight, body mass index (BMI), Food Craving Inventory (FCI), and Three-Factor Eating Questionnaire (3-FEQ) scores were assessed at baseline and at weeks 1, 2, 4, 6, and 8. Fasting glucose and lipid levels were assessed at baseline and at week 8. Insulin and leptin concentrations were measured just prior to olanzapine baseline dosing, 1 and 2 hours following administration of baseline dose, and at weeks 4 and 8.. Patients showed significant increases in weight, BMI, and leptin area under the concentration-time curve (AUC), but not in FCI or 3-FEQ scores, over 8 weeks of treatment with olanzapine ODT and SOT. However, no significant differences between olanzapine formulations (ODT vs SOT) were observed in any of the measures assessed, except for a significantly lower triglyceride concentration in the ODT group at week 8.. There was no consistent difference in metabolic profile between olanzapine ODT and SOT formulations during short-term treatment of bipolar depressed patients. Potential differences related to effects on triglyceride concentration warrant further confirmation.

Topics: Administration, Oral; Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Body Weight; Drug Administration Schedule; Feeding Behavior; Female; Gastrointestinal Hormones; Glycemic Index; Humans; Male; Middle Aged; Olanzapine; Tablets

Metabolic changes were examined in patients with schizophrenia during treatment with either oral olanzapine or olanzapine long-acting injection (LAI). Data were collected from patients who had been stabilized on oral olanzapine (10, 15, or 20 mg/day) for ≥4 weeks and then randomized to either continued olanzapine oral treatment (n = 322) or LAI (n = 599; 150 mg/2 weeks, 405 mg/4 weeks, or 300 mg/2 weeks) for up to 24 weeks. Mean and categorical changes in metabolic parameters were analyzed. Mean changes in weight, glucose, and most lipids were generally not significantly different between treatment groups. Weight changes over time followed similar patterns and were not significantly different at endpoint between the two treatment-formulation groups. Low-density lipoprotein cholesterol decreased significantly less among olanzapine LAI-treated patients. Percentages of patients with potentially clinically significant changes in blood glucose and lipid concentrations were similar for the two treatments. Percentages of patients experiencing adverse events related to weight, diabetes, or dyslipidemia were also not significantly different between treatments. Metabolic changes in patients with schizophrenia appeared generally similar during treatment with oral olanzapine or olanzapine LAI.

Topics: Administration, Oral; Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Cholesterol, LDL; Delayed-Action Preparations; Diabetes Mellitus; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Humans; Injections, Intramuscular; Lipids; Male; Middle Aged; Olanzapine; Schizophrenia; Time Factors

Atypical antipsychotics exhibit metabolic side effects including diabetes mellitus and obesity. The adverse events are preceded by acute worsening of oral glucose tolerance (oGTT) along with reduced plasma free fatty acids (FFA) and leptin in animal models. It is unclear whether the same acute effects occur in humans.. A double blind, randomized, placebo-controlled crossover trial was conducted to examine the potential metabolic effects of olanzapine in healthy volunteers. Participants included male (8) and female (7) subjects [18-30 years old, BMI 18.5-25]. Subjects received placebo or olanzapine (10 mg/day) for three days prior to oGTT testing. Primary endpoints included measurement of plasma leptin, oral glucose tolerance, and plasma free fatty acids (FFA). Secondary metabolic endpoints included: triglycerides, total cholesterol, high- and low-density lipoprotein cholesterol, heart rate, blood pressure, body weight and BMI. Olanzapine increased glucose Area Under the Curve (AUC) by 42% (2808±474 vs. 3984±444 mg/dl·min; P = 0.0105) during an oGTT. Fasting plasma leptin and triglycerides were elevated 24% (Leptin: 6.8±1.3 vs. 8.4±1.7 ng/ml; P = 0.0203) and 22% (Triglycerides: 88.9±10.1 vs. 108.2±11.6 mg/dl; P = 0.0170), whereas FFA and HDL declined by 32% (FFA: 0.38±0.06 vs. 0.26±0.04 mM; P = 0.0166) and 11% (54.2±4.7 vs. 48.9±4.3 mg/dl; P = 0.0184), respectively after olanzapine. Other measures were unchanged.. Olanzapine exerts some but not all of the early endocrine/metabolic changes observed in rodent models of the metabolic side effects, and this suggest that antipsychotic effects are not limited to perturbations in glucose metabolism alone. Future prospective clinical studies should focus on identifying which reliable metabolic alterations might be useful as potential screening tools in assessing patient susceptibility to weight gain and diabetes caused by atypical antipsychotics.. ClinicalTrials.gov NCT00741026.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cross-Over Studies; Double-Blind Method; Dyslipidemias; Fatty Acids, Nonesterified; Female; Follow-Up Studies; Glucose Tolerance Test; Humans; Leptin; Male; Olanzapine; Triglycerides; Young Adult

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

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

The purpose of the study was to determine the effectiveness of megestrol acetate (MA) and olanzapine (OLN) for the treatment of cancer-related anorexia (CRA).. Eighty adult patients with advanced gastrointestinal cancer or lung cancer (stages III and IV) with CRA (loss of appetite and greater than or equal to 5% loss of preillness stable weight) were randomized to receive daily MA or MA plus OLN for a period of 8 weeks. Patients were assessed weekly using the M.D. Anderson Symptom Inventory with specific measurement of weight, appetite, nausea, and quality of life (QOL) measures.. For the 37 patients receiving MA, 15 patients had a greater than or equal to 5% weight gain, 2 patients had an appetite improvement, 3 patients had an improvement in nausea, and 5 patients had an improvement in QOL at both 4 and 8 weeks. For the 39 patients receiving MA plus OLN, 33 patients had a greater than or equal to 5% weight gain, 25 patients had an appetite improvement, 21 patients had an improvement in nausea, and 23 patients had an improvement in QOL at both 4 and 8 weeks, and there was an improvement in general activity, mood, work, walking, and enjoyment at 8 weeks. There were no grade III or IV treatment-related toxicities in patients receiving MA or the combination of MA plus OLN.. The combination of MA and OLN appears to be an effective intervention for patients with CRA.

Topics: Adult; Aged; Aged, 80 and over; Anorexia; Appetite; Appetite Stimulants; Benzodiazepines; Body Weight; Drug Therapy, Combination; Female; Gastrointestinal Neoplasms; Humans; Lung Neoplasms; Male; Megestrol Acetate; Middle Aged; Nausea; Neoplasm Staging; Olanzapine; Quality of Life; Selective Serotonin Reuptake Inhibitors

The aim of this study was to evaluate the efficacy of olanzapine in girls with anorexia nervosa, restricting subtype (ANr).. Thirteen patients (mean age 13.7 +/- 2.3 years, age range 9.6-16.3 years) enrolled in a multimodal treatment for ANr were evaluated with standardized measures at baseline and after 1 and 6 months after starting low-dose olanzapine monotherapy (mean dose 4.13 mg/day).. A significant improvement was evident on weight (body mass index, BMI), global functioning (Children's Global Assessment Scale, CGAS), eating attitudes (Eating Attitudes Test-26, EAT-26), anxious-depressive symptoms (Child Behavior Checklist, CBCL) and hyperactivity (Structured Inventory for Anorexic and Bulimic Syndromes, SIAB). At the end of the 6-month follow up, 7 patients were responders according to an improvement of at least 50% in the EAT-26 results. The only measure that improved significantly in responders, but not in nonresponders, was hyperactivity (SIAB). Clinical improvement, in terms of both body mass index (BMI) recovery and global functioning, paralleled the improvement of hyperactivity, was evident at the end of the first month of treatment, and further increased in the following 5 months, with minimal side effects.. Low-dose olanzapine monotherapy may be useful as adjunctive treatment of youths with ANr. It is suggested that efficacy may be mediated by a decrease of hyperactivity.

Topics: Adolescent; Anorexia Nervosa; Antipsychotic Agents; Benzodiazepines; Body Weight; Child; Dose-Response Relationship, Drug; Female; Humans; Hyperkinesis; Olanzapine

The aim of this study was to compare patients' preference for olanzapine orodispersible tablet (ODT) with oral conventional tablet (OCT).. A 12-week randomized, crossover, multinational, open-label study was conducted to estimate the proportion of patients preferring ODT or OCT. Outpatients with stable schizophrenia on OCT monotherapy were randomly assigned 1:1 to ODT or OCT. Compliance and drug attitude were measured using the Drug Attitude Inventory (DAI-10) and Medication Adherence Form (MAF) scales; tolerability and safety by Association for Methodology and Documentation in Psychiatry (AMDP-5) questionnaire and adverse event summary.. A total of 175 patients answered a preference question: 106 (61%) preferred ODT and 48 (27%) preferred OCT (P<0.001 adjusted for treatment sequence); 21 (12%) expressed no preference. There was no significant change in DAI-10 with either formulation. MAF was above 75% in 94% vs. 93% of patients on ODC and OCT, respectively. Compliance as measured by tablet count was above 98% on both formulations. The adverse event profiles did not differ between formulations. Mean weight increase over 6 weeks on ODT was 0.8 kg and on OCT was 0.6 kg.. Given the importance of patients' preference for treatment planning and success, the ODT formulation should be routinely considered as a treatment option.

Topics: Administration, Oral; Adult; Antipsychotic Agents; Benzodiazepines; Body Weight; Choice Behavior; Cross-Over Studies; Female; Humans; Male; Medication Adherence; Middle Aged; Olanzapine; Patient Participation; Patient Satisfaction; Schizophrenia; Schizophrenic Psychology

Few studies have directly compared the efficacy and tolerability of atypical agents.. This multicenter, randomized, double-blind study compared the efficacy and tolerability of aripiprazole (n = 355) with olanzapine (n = 348) in patients with schizophrenia experiencing acute relapse. After a 6-week acute treatment phase, patients with Clinical Global Impression-Improvement = 1-3 or > or = 20% reduction in the Positive and Negative Symptom Scale (PANSS) Total score could progress to the 46-week outpatient extension phase. Co-primary study objectives were to compare efficacy at Week 6 and weight gain liability from baseline to Week 26.. The mean olanzapine dose was 15.4 mg/day compared with a mean aripiprazole dose of 23.0 mg/day. More patients treated with olanzapine (47%) completed the 52-week study than those treated with aripiprazole (39%); time to discontinuation was significantly in favor of olanzapine (p < .05). At Week 6, mean change in PANSS Total score (olanzapine, -29.5; aripiprazole, -24.6 [random regression model]) showed a treatment difference of 4.9 points. As the pre-specified non-inferiority margin (6 points) was within the 95% confidence interval (2.2-7.6) for treatment difference, olanzapine proved to be superior to aripiprazole on this measure. More patients experienced significant weight gain at Week 26 with olanzapine (40%) than with aripiprazole (21%; p < .05 [weighted generalized estimating equation analysis]), with significant differences observed from Week 3. Mean weight gain at Week 26 was significantly greater with olanzapine than with aripiprazole (+4.30 kg vs. +.13 kg, respectively).. Olanzapine had a statistically significant efficacy advantage over aripiprazole, whereas aripiprazole was associated with significantly less weight gain.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Body Weight; Double-Blind Method; Electrocardiography; Female; Glucose; Humans; Lipid Metabolism; Male; Middle Aged; Olanzapine; Piperazines; Prolactin; Quinolones; Schizophrenia

Excessive body weight gain (BWG), hyperglycemia and dyslipidemia are important side effects of olanzapine. We assessed the effects of rosiglitazone on BWG, the insulin resistance index (HOMA-IR), lipids, glycated hemoglobin and fibrinogen in olanzapine-treated schizophrenia patients.. Thirty patients taking olanzapine (10-20 mg daily for 8 months) were randomly allocated to rosiglitazone (n=15; 4 to 8 mg daily) or placebo (n=15) in a 12-week double-blind protocol. Anthropometric and biochemical variables were evaluated at baseline, weeks 6 and 12.. The rosiglitazone and placebo groups gained 3.2+/-4.5 and 2.2+/-2.3 kg, respectively (p=0.65). Insulin and the HOMA-IR significantly decreased after rosiglitazone (p<0.05). Rosiglitazone did not improve the lipid profile, fibrinogen and Hb1c levels.. The positive impact of rosiglitazone was limited to improved glycemic control. It cannot be recommended for metabolic control during olanzapine treatment.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Double-Blind Method; Female; Fibrinogen; Hemoglobins; Humans; Hypoglycemic Agents; Insulin Resistance; Lipid Metabolism; Male; Metabolic Diseases; Middle Aged; Olanzapine; Pilot Projects; Rosiglitazone; Schizophrenia; Statistics as Topic; Thiazolidinediones

Signal detection methods were used to identify values of metabolic variables that predict development of prediabetes or diabetes before (moderators) or associated with treatment (mediators), utilizing data from two multi-center clinical trials of patients with schizophrenia, treated for 6 months with olanzapine (OLZ) or ziprasidone (ZIP). At baseline, participants were often overweight/obese (63% with a body mass index >or=25.0kg/m(2)), dyslipidemic [more than one-third had elevated triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentrations], and prediabetic (20%). Weight gain was significantly greater in OLZ-treated patients, as was accentuation of dyslipidemia. However, there were no significant correlations between weight gain and lipid changes from baseline to weeks 2, 4, 8 or to last observation. Type 2 diabetes developed in 4% and prediabetes in 18% of the population. Significant baseline predictors of diabetes were a HDL-C concentration <28mg/dL, or being >or=58-years-old if HDL-C concentration was >or=28mg/dL. Baseline plasma glucose concentration >or=92mg/dL was the only significant predictor of developing prediabetes, accounting for 60% of cases. Post-treatment increments in plasma TG concentrations >or=145mg/dL or >or=59mg/dL were significant predictors of diabetes (23%) or prediabetes (27%), respectively. If the increase in TG was <145mg/dL, rapid weight gain >or=6.1kg in 2 weeks predicted development of diabetes (18%). These findings provide a quantitative approach to identify those at greatest treatment-associated risk to develop glucose intolerance, and emphasize the need to address co-morbid medical disorders in these patients.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; Dose-Response Relationship, Drug; Female; Humans; Hyperglycemia; Lipid Metabolism; Lipoproteins, HDL; Male; Middle Aged; Olanzapine; Piperazines; Prediabetic State; Predictive Value of Tests; Randomized Controlled Trials as Topic; Schizophrenia; Thiazoles; Time Factors; Treatment Outcome

This study sought to examine the effect of ziprasidone on olanzapine or clozapine-associated medical morbidity such as insulin resistance, diabetes mellitus (DM) and impaired fasting glucose, obesity, and hyperlipidemia in patients with schizophrenia or schizoaffective disorder.. This was a 6-week, open label trial of ziprasidone 160 mg/day added to a stable dose of olanzapine or clozapine in 21 schizophrenia or schizoaffective patients with DM, impaired fasting glucose, or insulin resistance.. Ten olanzapine-treated subjects and 11 clozapine-treated subjects were enrolled in the study. There were no significant differences between the two groups at baseline for age, gender, education, ethnicity, BMI, cholesterol levels, or fasting glucose. At week 6, there were no significant changes in weight, BMI, cholesterol levels, or fasting glucose. There was no significant difference in psychotic, negative, or depressive symptoms. QTc significantly increased at week 2 but not at week 6.. The addition of 160 mg/day of ziprasidone was well tolerated but did not produce significant improvement in fasting glucose, insulin resistance, hyperlipidemia or lead to weight loss in olanzapine- or clozapine-treated subjects with schizophrenia or schizoaffective disorder.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Body Weight; Chronic Disease; Clozapine; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hyperglycemia; Insulin Resistance; Male; Middle Aged; Morbidity; Olanzapine; Piperazines; Schizophrenia; Thiazoles; Time Factors

Patients with schizophrenia and bipolar disorder have frequently reported weight gain during olanzapine treatment. Previous studies have observed a decrease in weight gain, or weight loss, in patients switching from standard olanzapine tablets (SOT) to orally disintegrating olanzapine (ODO) tablets. The primary objective of this study was to investigate the change in body mass index (BMI) in patients who had previously gained weight with SOT and continued with this therapy during the study period, compared with those patients who switched to ODO during the study period.. This was a 16-week, multicentre, randomized, double-blind, double-dummy, study of outpatients diagnosed with schizophrenia, schizoaffective disorder, related psychotic disorder or bipolar disorder, who were taking 5-20 mg SOT daily. Patients continued treatment with 5-20 mg olanzapine in a flexible single daily dose, and were randomized to either receive sublingual ODO plus an oral placebo, or sublingual placebo plus SOT.. No statistically significant between group differences in mean change from baseline in BMI, weight or waist circumference were observed. Analysis of change in body weight from baseline, by pre-specified category (no change, loss of >or=1.5 kg, gain of >or=1.5 kg), revealed a significant difference between groups, favoring ODO patients, who also experienced a significant reduction in subjective appetite and better treatment compliance, compared to patients in the SOT group.. In this study, patients treated with ODO experienced a similar mean change in BMI and weight from baseline, to those patients treated with SOT.

Topics: Administration, Oral; Administration, Sublingual; Adolescent; Adult; Aged; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Body Weight; Cholesterol; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Olanzapine; Patient Compliance; Psychotic Disorders; Quality of Life; Waist Circumference; Young Adult

Topics: Administration, Oral; Adult; Aged; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Cholesterol; Female; Humans; Male; Metabolism; Olanzapine; Triglycerides; Young Adult

Asenapine is approved for bipolar disorder and schizophrenia. This was a 3-week, randomized, double-blind, placebo-controlled trial of asenapine for treating acute bipolar mania.. After a single-blind placebo run-in period, adults (n = 488) experiencing manic or mixed episodes were randomized to flexible-dose sublingual asenapine (10 mg BID on day 1; 5 or 10 mg BID thereafter; n = 194), placebo (n = 104), or oral olanzapine (15 mg BID on day 1; 5-20 mg QD thereafter; n = 191). Primary efficacy, change in Young Mania Rating Scale (YMRS) total score from baseline to day 21, was assessed using analysis of covariance with last observation carried forward [(LOCF); primary analysis]. A mixed model for repeated measures [(MMRM); prespecified secondary analysis] was also used to assess efficacy. Tolerability and safety assessments included adverse events, physical examinations, extrapyramidal symptom ratings, and laboratory values.. Mean daily dosages were asenapine 18.2 mg and olanzapine 15.8 mg. Significantly greater least squares (LS) mean +/- SE changes in YMRS scores were observed on day 2 with asenapine (-3.0 +/- 0.4) and olanzapine (-3.4 +/- 0.4) versus placebo (-1.5 +/- 0.5, both p < 0.01) and were maintained until day 21 (-10.8 +/- 0.8 with asenapine, -12.6 +/- 0.8 with olanzapine; both p < or = 0.0001 versus placebo, -5.5 +/- 1.1) with LOCF. The results of MMRM analyses were consistent with those of LOCF. Asenapine had a modest impact on weight and metabolic measures.. These results indicate that asenapine is rapidly acting, efficacious, and well tolerated for patients with bipolar I disorder experiencing an acute manic episode.

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Body Weight; Dibenzocycloheptenes; Dose-Response Relationship, Drug; Double-Blind Method; Electroencephalography; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Male; Middle Aged; Models, Statistical; Olanzapine; Patient Compliance; Psychiatric Status Rating Scales; Single-Blind Method; Time Factors; Treatment Outcome; Young Adult

Anorexia nervosa is associated with high mortality, morbidity, and treatment costs. Olanzapine, an atypical antipsychotic, is known to result in weight gain in other patient populations. The objective of this trial was to assess the efficacy of olanzapine in promoting weight gain and in reducing obsessive symptoms among adult women with anorexia nervosa.. The study was a double-blind, placebo-controlled, 10-week flexible dose trial in which patients with anorexia nervosa (N=34) were randomly assigned to either olanzapine plus day hospital treatment or placebo plus day hospital treatment.. Compared with placebo, olanzapine resulted in a greater rate of increase in weight, earlier achievement of target body mass index, and a greater rate of decrease in obsessive symptoms. No differences in adverse effects were observed between the two treatment conditions.. These preliminary results suggest that olanzapine may be safely used in achieving more rapid weight gain and improvement in obsessive symptoms among women with anorexia nervosa. Replication, in the form of a large multicenter trial, is recommended.

Topics: Adolescent; Adult; Anorexia Nervosa; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Combined Modality Therapy; Compulsive Behavior; Day Care, Medical; Double-Blind Method; Female; Humans; Length of Stay; Obsessive Behavior; Olanzapine; Thinking; Thinness

Tobacco consumption has been recognized as a factor mediating the interindividual variations in olanzapine's pharmacokinetics and pharmacodynamics. The primary objective of this study was to describe the dose effect of smoking on the dose-plasma concentration relationship and the pharmacokinetics of oral olanzapine in male schizophrenic patients using high-performance liquid chromatography coupled with electrochemical detector. Twenty-seven male schizophrenic inpatients were recruited and were stratified into the following groups according to smoking behaviors: non-smokers (n=9), light-smokers (1-4 cigarettes per day; n=9), and heavy-smokers (>or=5 cigarettes per day; n=9). Plasma olanzapine concentrations were determined up to 120 h following a single oral dose of 10 mg olanzapine. The pharmacokinetic parameters were calculated by the non-compartment method using WinNonlin software. Results show that there was a significant correlation among non-smokers (n=9; 0.79; p=0.01) or combined with light-smokers (n=18; 0.62; p<0.01) between peak plasma olanzapine concentrations (Cmax) and their individual dose-corrected by body weight, but this correlation did not appear in heavy-smokers. There were no significant differences between non-smokers and light-smokers except for significant decreased AUC0-->120 by 45.1% in light-smokers. The mean C(max) and the mean area under the plasma concentration-time curve from time zero to 120 h (AUC0-->120) of the heavy-smoking patients was 9.3+/-4.3 ng/ml (65.2% reduction compared to the non-smokers) and 302.4+/-167.8 h ng/ml (67.6% reduction compared to the non-smokers), respectively. In summary, a daily consumption of 5 cigarettes is probably sufficient for induction of olanzapine metabolism. Smoking cessation is recommended for olanzapine therapy to have better prediction for therapeutic dosages particularly in heavy-smokers. Compared to non-smokers, heavy-smokers therefore require a 50-100% increase in olanzapine doses. Therapeutic drug monitoring will need to be considered when schizophrenic patients change their smoking behaviors.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Area Under Curve; Asian People; Benzodiazepines; Body Weight; Chromatography, High Pressure Liquid; Humans; Male; Middle Aged; Olanzapine; Schizophrenia; Schizophrenic Psychology; Smoking; Taiwan; Time Factors; Young Adult

To measure the long-term changes in weight and plasma lipids after switching antipsychotic treatment to ziprasidone, three 52-week, open-label extension studies of ziprasidone in outpatients (N=185) with schizophrenia or schizoaffective disorder successfully completing one of three, 6-week switch studies were carried out. Pre-switch treatment consisted of risperidone (n=43), olanzapine (n=71), or conventional antipsychotic agents (n=71). The maximum length of exposure to ziprasidone was 58 weeks. Nonfasting total cholesterol and triglyceride levels were obtained at baseline and at weeks 6, 19, 32, 45, and 58. Weight was measured at baseline and during each follow-up visit; height was recorded at baseline for the purpose of body mass index (BMI) calculation. Efficacy measures included the Positive and Negative Syndrome Scale and Clinical Global Impression-Severity scale which were obtained at baseline and major follow-up points. Clinically significant sustained improvements in weight, BMI, total cholesterol, and triglyceride levels were observed among patients switched to ziprasidone from risperidone or olanzapine. Switching from conventional antipsychotics was not associated with significant changes in weight and lipid parameters. Mean reductions in weight from baseline to study endpoint were 9.8 kg (p<0.001) and 6.9 kg (p<0.005) for patients previously treated with olanzapine and risperidone, respectively. These findings demonstrate that switching from risperidone or olanzapine to ziprasidone is associated with sustained, clinically significant improvements in weight and plasma lipids.

Topics: Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Brief Psychiatric Rating Scale; Cross-Sectional Studies; Female; Follow-Up Studies; Humans; Lipids; Male; Mental Disorders; Olanzapine; Piperazines; Retrospective Studies; Single-Blind Method; Thiazoles; Time Factors

The second generation antipsychotic drugs, such as risperidone, olanzapine, and quetiapine, are effective in treating patients with schizophrenia and have been considered as the first line therapy. Recently, increasing attention has been drawn to the potential diabetogenic effect of these novel antipsychotics. The goal of this study was to evaluate the effect of metformin treatment on the olanzapine-induced metabolic disturbance in schizophrenic patients. Twenty-four schizophrenic subjects who had received olanzapine treatment at least 3 months were assigned to the therapy with metformin 1500 mg/day for 8 weeks. The metabolic parameters were quantitatively assessed at baseline, weeks 2, 4, and 8 by using the intravenous glucose tolerance test. After an 8-week treatment with metformin, the body weight, fasting levels of glucose, triglyceride, and insulin, insulin secretion, and insulin resistance significantly decreased. Half of study subjects with metabolic syndrome obtained improvement after the metformin trial. Subjects' psychopathological condition remained unchanged during the study period. The olanzapine-induced metabolic disturbance could be reversed after 8-week metformin treatment. Based on the results of this study, we hypothesize that metformin could modulate the effect of olanzapine-induced metabolic disturbance.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Female; Glucose; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Lipids; Male; Metabolic Diseases; Metabolic Syndrome; Metformin; Middle Aged; Olanzapine; Prospective Studies; Schizophrenia; Sex Characteristics

Atypical antipsychotics induce weight gain and are linked to increased diabetes risk, but their relative impact on factors that elevate disease risk are unknown.. We performed a 6-month, randomized, double-blind study to evaluate the effects of risperidone and olanzapine in patients with schizophrenia. At baseline and weeks 6 and 24, we quantified: (1) total adiposity by DEXA, (2) visceral adiposity by abdominal CT, and (3) insulin sensitivity (SI) and (4) pancreatic function ("disposition index", DI) by intravenous glucose tolerance test.. At baseline, groups (risperidone: n=28; olanzapine: n=31) were overweight or obese by body mass index (risperidone: 28.4+/-5.4, olanzapine: 30.6+/-7.0kg/m2). Both drugs induced weight gain (p<0.004). Total adiposity was increased by olanzapine at 6 weeks (p=0.0006) and by both treatments at 24 weeks (p<0.003). Visceral adiposity was increased by olanzapine and risperidone by 24 weeks (p<0.003). S(I) did not deteriorate appreciably, although a downward trend was observed with risperidone. Given known ethnic differences in adiposity and S(I), we performed secondary analysis in African American and Hispanic subjects. In this subset, olanzapine expanded both total and visceral adiposity (p<0.02); no increase was observed with risperidone. There were modest downward trends for SI with both treatments. By week 24, olanzapine-treated subjects exhibited diminished DI (p=0.033), indicating inadequate pancreatic compensation for insulin resistance.. This is the first prospective study in psychiatric patients that quantified antipsychotic effects on the multiple metabolic processes that increase diabetes risk. Results indicate that ethnic minorities may have greater susceptibility to antipsychotic-induced glucoregulatory complications.

Topics: Absorptiometry, Photon; Adult; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Brief Psychiatric Rating Scale; Double-Blind Method; Ethnicity; Female; Follow-Up Studies; Glucose Tolerance Test; Humans; Insulin Resistance; Male; Middle Aged; Olanzapine; Psychotic Disorders; Risperidone; Schizophrenia; Time Factors; Tomography, X-Ray Computed

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

The use of certain atypical antipsychotics has been associated with metabolic disturbances. We have assessed the evolution of body weight and glycaemia during a 6-month randomized comparative trial of amisulpride and olanzapine. Three hundred and seventy-seven adult patients with schizophrenia were randomized to either amisulpride (200-800 mg/day) or olanzapine (5-20 mg/day) for 6 months. Body weight and fasting blood glucose were measured. Both treatments showed comparable antipsychotic activity. Weight gain over the study was significantly greater (P=0.0004) in the olanzapine group (3.9+/-5.3 kg) than in the amisulpride group (1.6+/-4.9 kg). Mean fasting blood glucose increased in the olanzapine group by 4.42 mg/dl to a mean maximum value (118+/-38 mg/dl). In the amisulpride group, mean glucose levels fell by 2.82 mg/dl. The difference between groups was significant at 2 (P=0.0066) and 6 months (P=0.017). One olanzapine-treated patient was diagnosed with diabetes. Metabolic changes in the amisulpride group were restricted to patients with high body mass index at inclusion. At doses that provide comparable control of psychosis, treatment with olanzapine was associated with greater increase in weight and blood glucose compared with amisulpride. This should be taken into account in assessing risk-benefit of treatment options in schizophrenia.

Topics: Adult; Amisulpride; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Male; Middle Aged; Olanzapine; Psychiatric Status Rating Scales; Risk Factors; Schizophrenia; Sulpiride

Excessive body weight gain (BWG) is a clinically relevant side effect of olanzapine administration. The primary objective of this study was to assess whether metformin prevents or reverses BWG in patients with schizophrenia or bipolar disorder under olanzapine administration. Secondarily we evaluated diverse metabolic variables.. Eighty patients taking olanzapine (5-20 mg daily for more than 4 consecutive months) were randomly allocated to metformin (n=40; 850 to 2550 mg daily) or placebo (n=40) group in a 12-week double-blind protocol. Waist circumference (WC) body weight (BW), body mass index (BMI) fasting glucose, glycated hemoglobin (Hb1c), insulin, an insulin resistance index (HOMA-IR) lipids, leptin, c-reactive protein, fibrinogen, cortisol and the growth hormone (GH) were evaluated at baseline and at week 12 of treatment.. The metformin group lost 1.4+/-3.2 kg (p=0.01) and tended to decrease its leptin levels, whereas the placebo group maintained a stable weight: -0.18+/-2.8 kg (p=0.7). The HOMA-IR significantly increased after placebo (p=0.006) and did not change after metformin (p=0.8). No ostensible differences were observed in the other variables, even though metformin did not improve the lipid profile and the Hb1c levels.. Metformin may safely assist olanzapine-treated patients in body weight and carbohydrate metabolism control.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Blood Glucose; Body Mass Index; Body Weight; Brief Psychiatric Rating Scale; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Energy Metabolism; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Resistance; Leptin; Lipids; Male; Metformin; Middle Aged; Olanzapine; Schizophrenia; Statistics as Topic

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

The objective of this study was to assess the effectiveness and safety of olanzapine in the treatment of schizophrenia among Asian patients in an outpatient setting.. This was an open-label, prospective, observational study involving 339 patients from Indonesia, Pakistan, Malaysia, Thailand, and Singapore. Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression Severity scale (CGI-S), and safety parameters were assessed.. 62% of patients responded to olanzapine treatment, defined a priori as a reduction in BPRS of > 40% from baseline. Following the 8-week treatment period, the BPRS total, BPRS positive, BPRS negative, and CGI-S scores decreased by 18.7 (95% CI: 17.4, 20.2), 6.1 (5.6, 6.6), 2.9 (2.6, 3.2), and 1.5 points (median 1.0), respectively (p < 0.0001). In total, 31 of the 339 patients (9.1%) failed to complete the study according to the study description. Loss to follow-up and personal conflict were the most common reasons for discontinuation. There were 30 treatment-emergent adverse events with six serious cases, assessed as unrelated to study drug, reported.. This study further demonstrates the effectiveness and safety of olanzapine in actual clinical practice settings, in reducing the severity of psychopathological symptoms in Asian patients with schizophrenia.

Topics: Adolescent; Adult; Antipsychotic Agents; Asian People; Benzodiazepines; Blood Pressure; Body Weight; Female; Heart Rate; Humans; Male; Middle Aged; Olanzapine; Outpatients; Schizophrenia

Although treatment with antipsychotics, particularly olanzapine and clozapine, has been implicated in weight gain and higher incidence of diabetes, the mechanism of these adverse reactions remains unclear. The purposes of this study were to explore the early effects of olanzapine on serum levels of ghrelin, adiponectin and leptin, three recently identified hormones that play crucial roles in the regulation of energy balance and glucose metabolism. Thirteen patients with schizophrenia who had not received any medication in the 4 weeks prior to this study were included. The patients received olanzapine at an average dose of 14.5mg/day. Serum levels of ghrelin, adiponectin, leptin and insulin, as well as weight and fasting glucose, were investigated at the baseline and at 4 weeks. Serum ghrelin levels had decreased (p 0.03) and leptin had increased (p 0.02), while adiponectin and insulin levels had not significantly changed at Week 4 (p 0.29 and p 0.25, respectively). Weight had increased (p 0.01), while fasting glucose had not significantly changed (p 0.46). These findings suggest that ghrelin levels decrease and leptin levels increase after initiation of olanzapine therapy. Weight gain is also considered to be an early change, while change in insulin sensitivity is not an early change of treatment with olanzapine. Further large-scale and longitudinal studies are warranted to elucidate metabolic changes involving ghrelin, adiponectin, leptin and insulin and their impact on weight and glucose metabolism during treatment with olanzapine and other antipsychotics.

Topics: Adiponectin; Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Female; Ghrelin; Humans; Insulin; Insulin Resistance; Leptin; Male; Olanzapine; Peptide Hormones; Prospective Studies; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

This open-label, prospective, 4-month study in hyperprolactinemic patients with schizophrenia explored whether prolactin levels decrease after switching antipsychotic therapy to olanzapine. A secondary objective was to determine if reproductive morbidities and sexual dysfunction occurring with hyperprolactinemia improved with prolactin normalization. Clinically stable patients with schizophrenia, who had hyperprolactinemia defined as >18.8 ng/ml for males and >24.2 ng/ml for females, were randomized to: remain on current therapy (n=27) or switch to olanzapine, 5-20 mg/day, (n=27). Baseline prolactin levels in female patients randomized to receive olanzapine (n=14) were 66.3+/-38.7 ng/ml and were 82.0+/-37.6 (p=.32) in those remaining on their pre-study antipsychotic medication (n=14). In male patients, baseline prolactin levels were 33.7+/-12.1 and 33.5+/-13.8 ng/ml (p=.97), respectively, for those randomized to olanzapine (n=13) or remaining on pre-study treatment (n=13). At study end, patients switched to olanzapine experienced significant reductions in mean serum prolactin levels of 19.8+/-18.1 ng/ml in males (p=.02), and 32.3+/-47.5 ng/ml in females (p=.01), but prolactin continued to be elevated in patients who remained on pre-study antipsychotic treatment. After switching to olanzapine treatment, male patients experienced significantly (p=.03) increased free testosterone levels but there were no significant improvements in total testosterone levels; some female patients experienced improved menstrual cycling, as well as resolution of galactorrhea and gynecomastia, and sexual functioning was significantly improved in both genders. Patients switched to olanzapine, as well as those remaining on their pre-study medication, maintained clinical stability, their symptoms continued to improve, although there were no significant between-treatment differences in improvement. Treatment-emergent adverse events did occur in both treatment groups; however, they were not significantly different between groups. Olanzapine-treated patients experienced significantly lower eosinophil counts and higher elevations in low-density lipoproteins and standing blood pressure than non-switched patients. Olanzapine treatment may offer sustained reduction in serum prolactin and improvement in sexual and reproductive comorbid symptoms in patients with schizophrenia who have treatment-emergent hyperprolactinemia.

Topics: Antipsychotic Agents; Benzodiazepines; Body Weight; Estradiol; Female; Galactorrhea; Gynecomastia; Humans; Male; Menstrual Cycle; Olanzapine; Premenopause; Prolactin; Reproduction; Risperidone; Schizophrenia; Sex Characteristics; Sexual Dysfunction, Physiological; Testosterone

In the treatment of schizophrenia, changing antipsychotics is common when one treatment is suboptimally effective, but the relative effectiveness of drugs used in this strategy is unknown. This randomized, double-blind study compared olanzapine, quetiapine, risperidone, and ziprasidone in patients who had just discontinued a different atypical antipsychotic.. Subjects with schizophrenia (N=444) who had discontinued the atypical antipsychotic randomly assigned during phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) investigation were randomly reassigned to double-blind treatment with a different antipsychotic (olanzapine, 7.5-30 mg/day [N=66]; quetiapine, 200-800 mg/day [N=63]; risperidone, 1.5-6.0 mg/day [N=69]; or ziprasidone, 40-160 mg/day [N=135]). The primary aim was to determine if there were differences between these four treatments in effectiveness measured by time until discontinuation for any reason.. The time to treatment discontinuation was longer for patients treated with risperidone (median: 7.0 months) and olanzapine (6.3 months) than with quetiapine (4.0 months) and ziprasidone (2.8 months). Among patients who discontinued their previous antipsychotic because of inefficacy (N=184), olanzapine was more effective than quetiapine and ziprasidone, and risperidone was more effective than quetiapine. There were no significant differences between antipsychotics among those who discontinued their previous treatment because of intolerability (N=168).. Among this group of patients with chronic schizophrenia who had just discontinued treatment with an atypical antipsychotic, risperidone and olanzapine were more effective than quetiapine and ziprasidone as reflected by longer time until discontinuation for any reason.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Weight; Chronic Disease; Cross-Over Studies; Dibenzothiazepines; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Olanzapine; Patient Dropouts; Piperazines; Proportional Hazards Models; Quetiapine Fumarate; Risperidone; Schizophrenia; Schizophrenic Psychology; Survival Analysis; Thiazoles; Time Factors; Treatment Outcome

The objective of the study was to examine whether patients with schizophrenia who were judged to be stable on long-term treatment with conventional antipsychotic medications would further benefit from a switch to an atypical antipsychotic drug. Thirty-six subjects with schizophrenia spectrum disorder, on conventional antipsychotic medication therapy for at least 2 years, were randomized in double-blind fashion to risperidone versus olanzapine. Patients were titrated up to 6 mg risperidone or 15 mg olanzapine as tolerated, followed by tapering and discontinuation of conventional antipsychotic medication. Atypical antipsychotic agents were then administered alone (monotherapy) for 12 weeks. Efficacy and tolerability were assessed using the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Scale, and Simpson Angus Scale. Body weight was measured at each visit. Both treatment groups exhibited marked and similar improvement in the total PANSS score from baseline to study endpoint (22 weeks) [risperidone: baseline=59.3 (SE 3.1), 22 weeks=44.3 (SE 2.3) (p<0.001); olanzapine: baseline=55.9 (SE 3.3), 22 weeks=46.9 (SE 3.2) (p<0.001). Both groups also exhibited significant reductions in PANSS factor scores for positive and negative symptoms and disorganized thoughts. Only risperidone-treated patients exhibited significant decreases in uncontrolled hostility/excitement and anxiety and depression. Of note, while positive factor scores exhibited the majority of change within the first 10 weeks, negative factor scores continued to decline significantly in both treatment groups throughout the study. Tolerability assessments did not differ between groups. The results indicate that both atypical antipsychotic medications provided significant additional improvement in symptom severity in patients with schizophrenia previously on conventional antipsychotic agents.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Weight; Chronic Disease; Double-Blind Method; Female; Humans; Long-Term Care; Male; Middle Aged; Olanzapine; Psychiatric Status Rating Scales; Psychotic Disorders; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Childhood-onset schizophrenia (COS) is a clinically severe form of schizophrenia, which causes severe impairment to cognitive, linguistic, and social development. There are few prospective and retrospective open clinical trials of risperidone and olanzapine in COS. In this open-label, randomized, prospective study, we compared the tolerability and effectiveness of risperidone versus olanzapine in the treatment of COS patients.. The study population consisted of 25 children with COS (mean age 11.09 +/- 1.55 years). After an evaluation, patients received risperidone (0.25-4.5 mg/day, mean dose 1.62 +/- 1.02 mg/day) or olanzapine (2.5-20 mg/day, mean dose 8.18 +/- 4.41 mg/day) for 12 weeks, with weekly evaluations.. Both groups showed comparable significant (p < 0.001) within-group improvement from baseline to endpoint (LOCF) in Positive and Negative Symptoms Scale (PANSS) total and subscale scores. Of the olanzapine-treated children, 11 (91.7%) completed the 12 weeks of the study, whereas in the risperidone-treated children only 9 (69.2%) did. No significant differences between risperidone-treated children and olanzapine-treated children were observed on Barnes Akathisia Rating Scale (BAS) and Simpson-Angus Scale (SAS) rating scales. Both treatment groups showed significant (p < 0.001) increase in weight from baseline to endpoint.. Our open-label, small-scale comparative study suggests that both risperidone and olanzapine appear to be efficacious antipsychotic medications in COS, with a slight nonsignificant advantage of olanzapine in the dropout rate.

Topics: Adolescent; Akathisia, Drug-Induced; Antipsychotic Agents; Benzodiazepines; Body Weight; Child; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hospitalization; Humans; Israel; Male; Olanzapine; Patient Dropouts; Prospective Studies; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Treatment Outcome

Metabolic side effects have been found earlier during treatment with second-generation antipsychotics. Among those disturbances serum lipids are less investigated. We conducted a prospective, open study in schizophrenia patients in order to compare body weight and serum lipids during treatment with amisulpride, ziprasidone, clozapine or olanzapine over a period of 4 weeks. Body mass index, total cholesterol and triglycerides increased in patients treated with clozapine and olanzapine whereas high-density lipoprotein cholesterol decreased in those patients. In patients treated with amisulpride or ziprasidone, we found a decrease in body mass index and total cholesterol whereas high-density lipoprotein cholesterol increased. Our results indicate that treatment with ziprasidone and amisulpride is more favourable than treatment with clozapine and olanzapine with respect to the risk to induce weight gain and hyperlipidaemia. These results are important with regard to the increased risk for cardiovascular complications in patients with schizophrenia.

Topics: Adolescent; Adult; Aged; Amisulpride; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Cholesterol; Clozapine; Humans; Lipids; Middle Aged; Olanzapine; Piperazines; Prospective Studies; Schizophrenia; Sulpiride; Thiazoles; Time Factors; Triglycerides

To compare the long-term efficacy and safety of aripiprazole with olanzapine in patients with either acute relapsing or chronic, stable schizophrenia.. A 52-week, open-label extension to a 26-week, multicenter, randomized, double-blind, placebo-controlled trial in patients with chronic schizophrenia. Patients who completed the initial treatment or who met the protocol definition of relapse after > or =2 weeks of double-blind treatment were randomized to aripiprazole (15-30 mg/day, n = 104) or olanzapine (10-20 mg/day, n = 110) for 52 weeks.. Sixty-nine percent of patients completed the study. Efficacy improvements were similar between groups at endpoint, mean reductions in Positive and Negative Syndrome Scale (PANSS) Total scores from baseline for patients completing the study (observed cases) were similar in chronic stable patients (aripiprazole, -7.94; olanzapine, -7.36) and in patients with acute relapse (aripiprazole, -31.19; olanzapine, -29.55). Olanzapine-treated patients reported more extrapyramidal symptoms (EPS)-related adverse events (18%) than aripiprazole-treated patients (10%). No significant differences in EPS were seen between treatments at endpoint. Olanzapine was associated with significantly greater weight gain than aripiprazole at all time points (week 52 [LOCF]: +2.54 vs +0.04 kg; p < 0.001). Changes in fasting glucose and lipid levels at endpoint favored aripiprazole over olanzapine, with significant differences observed for total cholesterol, low- and high-density lipoprotein. While differences observed for changes in fasting glucose and triglycerides favored aripiprazole, they were not statistically significant.. Aripiprazole showed similar efficacy to olanzapine for long-term treatment of acutely psychotic and chronic, stable schizophrenia patients, with a lower liability for weight gain or increased lipid levels.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Body Weight; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Double-Blind Method; Electrocardiography; Female; Humans; Male; Middle Aged; Olanzapine; Piperazines; Prolactin; Quinolones; Recurrence; Schizophrenia; Treatment Outcome; Triglycerides

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

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

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

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

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

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

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

Anorexia nervosa (AN) patients often show extreme hypophagia and excessive physical activity. Activity-based anorexia (ABA) is considered an animal model of AN and mimics food restriction and hyperactivity in rats. This study investigated whether treatment with olanzapine (Zyprexa) reduces the development of ABA in rats. The effect of olanzapine treatment in AN patients was also evaluated in a small open-label study.. Rats were chronically (1 week) infused with olanzapine (7.5 mg/kg) and exposed to the ABA model or ad libitum feeding. Hyperactive AN patients were followed for up to 3 months of olanzapine treatment (5 mg/kg).. Olanzapine treatment reduced development of ABA in rats by reducing running wheel activity, starvation-induced hypothermia and activation of the hypothalamus-pituitary-adrenal axis. Olanzapine treatment reduced activity levels of AN patients compared with untreated AN patients, without affecting body weight and plasma leptin levels.. Olanzapine treatment reduced wheel running and thereby diminished development of ABA in rats. Olanzapine treatment also reduced physical activity in hyperactive AN patients in a small open-label study. These data support the need for controlled studies investigating the putative beneficial effects of olanzapine treatment in AN patients.

Topics: Adipose Tissue; Adolescent; Adrenocorticotropic Hormone; Animals; Anorexia; Antipsychotic Agents; Behavior, Animal; Benzodiazepines; Body Temperature; Body Weight; Corticosterone; Disease Models, Animal; Drug Administration Schedule; Eating; Female; Humans; Male; Motor Activity; Olanzapine; Radioimmunoassay; Rats; Rats, Wistar; Running; Time Factors

The efficacy and tolerability of risperidone long-acting injectable were investigated in patients with schizophrenia or other psychotic disorders who had previously been symptomatically stable on olanzapine treatment. Patients received risperidone long-acting injectable, 25 mg, by intramuscular injection every 2 weeks; the dose could be increased to 37.5 or 50 mg if necessary. Patients were transferred directly from their previous medication to risperidone long-acting injectable without a run-in period of oral risperidone treatment. Of 192 patients recruited, 134 patients (70%) completed the study. The principal reasons for discontinuation were withdrawal of consent (8%), adverse events (6%), insufficient response (5%) and non-compliance (4%). Risperidone long-acting injectable produced a significant improvement (p = 0.0001) in Positive and Negative Syndrome Scale (PANSS) total scores, from 74.2+/-21.3 at baseline to 65.8+/-21.4 at endpoint. There were also significant reductions in PANSS subscales (positive symptoms, negative symptoms, general psycho-pharmacology) and Marder factor scores. The Clinical Global Impression increased significantly from baseline to endpoint (p = 0.0001), as reflected by the increase in the proportion of patients rated as 'not ill' or 'borderline ill' from 10% at baseline to 21% at endpoint. Risperidone long-acting injectable was also associated with significant improvements in Global Assessment of Function, patient satisfaction with treatment, and quality of life, measured on the SF-36 scale. Movement disorders, measured on the Extrapyramidal Symptom Rating Scale, were significantly reduced following the change to risperidone long-acting injectable. Treatment with risperidone long-acting injectable was well tolerated, and no significant weight gain occurred during the study. This open study suggests that risperidone long-acting injectable produces symptomatic improvement in schizophrenia patients previously considered symptomatically stable with olanzapine, along with improvement in movement disorders. The combination of improved efficacy and good tolerability may have important implications for patient adherence to therapy and subsequent long-term outcomes.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Delayed-Action Preparations; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Olanzapine; Prospective Studies; Psychiatric Status Rating Scales; Psychotic Disorders; Quality of Life; Risperidone; Treatment Outcome

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

Clozapine has been the gold standard for treatment of patients with refractory schizophrenia but is associated with serious safety liabilities. This has prompted the search for therapeutic alternatives for treatment-resistant schizophrenia. The objective of this study was to compare the efficacy and safety of olanzapine versus clozapine in schizophrenic patients who failed to respond adequately to antipsychotic medication or who experienced intolerable adverse effects associated with the medication. This 18-week, randomized, double-blind, parallel study compared treatment with either olanzapine (5-25 mg/day, n=75) or clozapine (100-500 mg/day, n=72) in patients with schizophrenia who were nonresponsive to, or intolerant of, standard acceptable antipsychotic therapy. At the 18-week endpoint, no statistically significant differences were found between olanzapine and clozapine in any efficacy measure used: Positive and Negative Syndrome Scale (PANSS) total, positive, negative, or general psychopathology or Clinical Global Impression severity (CGI-S). Response rates based on the criteria of Kane et al. [Arch. Gen. Psychiatry 45 (1988) 789] were also not significantly different between olanzapine-treated (57.9%) and clozapine-treated patients (60.8%). There were no significant differences in measurements of extrapyramidal symptoms or electrocardiography, and no clinically and statistically significant changes were seen in vital signs or laboratory measures in either group. Both treatments were well tolerated. Olanzapine demonstrated similar efficacy to clozapine in patients who had failed previous treatment because of lack of efficacy (treatment resistance) or intolerable side effects (treatment intolerance). Olanzapine therefore presents a safe alternative in the treatment of refractory schizophrenia.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Body Weight; Clozapine; Double-Blind Method; Drug Resistance; Female; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Schizophrenia

The purpose of the present paper was to investigate the effects of the dopamine agonist amantadine in those patients with weight gain induced by olanzapine. An open trial was conducted in those patients who gained >3 kg in weight induced by olanzapine use. All subjects were evaluated by weight, body mass index (BMI), the Brief Psychiatric Rating Scale (BPRS), and the Extrapyramidal Symptom Rating Scale (ESRS) before and after the use of amantadine in addition to olanzapine. Twenty-five of 30 enrolled patients completed the present study. Mean bodyweight and BMI was increased by 6.44 +/- 4.42 kg and 5.04 +/- 3.47 kg/m2 significantly with olanzapine alone (P < 0.001). When amantadine and olanzapine were used together, the average weight and BMI decreased by 1.07 +/- 3.19 kg and 0.84 +/- 2.5 kg/m2, but did not have statistical significance. The average values of BPRS showed a significant decrease (P < 0.001). No significant changes were present in ESRS. Amantadine did not have an effect on weight gain induced by olanzapine. Randomized placebo-controlled prospective studies are needed.

Topics: Adult; Amantadine; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Body Mass Index; Body Weight; Brief Psychiatric Rating Scale; Depressive Disorder, Major; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Neurologic Examination; Olanzapine; Psychotic Disorders; Schizophrenia; Treatment Outcome

This open-label study investigated the strategy of switching patients who had gained excessive weight on olanzapine to quetiapine, with assessments of safety and continued efficacy as well as weight change. Patients who were psychiatrically stable on olanzapine but had gained >20% in weight and had body mass index >25 mg/kg(2) were switched to quetiapine over a 4-week period and followed for 6 weeks, the total study duration being 10 weeks. Assessments included weight change, antipsychotic efficacy using the Positive and Negative Symptom Syndrome Scale (PANSS), extrapyramidal adverse events using the Simpson-Angus Scale (SAS), and laboratory studies for metabolic measures. Of 16 enrolled patients, 12 completed the study. Mean weight loss was 2.25 kg (Cohen's d = 0.12; P = 0.03). There were no significant changes in PANSS total scores, SAS scores, or metabolic parameters. Switching patients to quetiapine, appears to be a viable strategy for managing olanzapine-induced weight gain as indicated by this 10-week open-label study. Prospective controlled trials of longer duration and larger number of subjects are needed.

Topics: Basal Ganglia Diseases; Benzodiazepines; Body Weight; Diagnostic and Statistical Manual of Mental Disorders; Dibenzothiazepines; Female; Humans; Male; Mental Disorders; Middle Aged; Olanzapine; Quetiapine Fumarate; Weight Loss

To describe the antidepressant effectiveness of olanzapine and risperidone and compare their tolerability when employed adjunctively in bipolar I/II disorder.. In an observational study, twenty-one ambulatory subjects with DSM-IV defined bipolar I/II disorder, in any phase of the illness, openly received adjunctive risperidone or olanzapine. The primary efficacy parameters were the Hamilton Depression Rating Scale (HDRS-17) and the Maier and Philips Severity Subscale. Secondary efficacy parameters included the Young Mania Rating Scale (YMRS) along with the Clinical Global Impressions Scale (CGI). Response was defined as a significant change from baseline to endpoint in the total mean HDRS-17 score. The primary tolerability parameters were the Abnormal Involuntary Movement Scale (AIMS) along with changes in weight and body mass index (BMI-kg/m2). Patients were evaluated prospectively with repeated monthly assessments for up to 6 months.. Eleven patients openly received risperidone; 10 received olanzapine adjunctive to either lithium or divalproex. Total mean HDRS-17 scores significantly decreased from baseline to endpoint in both groups (p=0.001), with the mean HDRS-17 total scores falling from 17(SD=3.2) to 5(SD=1.5) by 6 months in the risperidone-treated group and from 18 (SD=1.9) to 7 (SD=2.0) in the olanzapine-treated group. Differences between the risperidone-treated group and the olanzapine-treated group were not significant at 6 months (p=0.754). The mean doses of study medication were 2.88 (SD=1.6) mg/day for the risperidone-treated group and 12.69 (SD=2.3) mg/day for the olanzapine-treated group. Both risperidone and olanzapine were generally well tolerated. No patients developed tardive dyskinesia. Significant weight gain was experienced by patients in both groups [mean weight gain at endpoint was 5.9 kg in risperidone (p=0.023) and 11.3 kg in olanzapine (p=0.001)]. There was a significant difference in weight gain between the risperidone-treated group and the olanzapine-treated group (p=0.001).. These pilot data, from the first prospective comparison study of risperidone and olanzapine in bipolar disorder, suggest that adjunctive administration of either agent may reduce depressive symptom severity. No subjects receiving risperidone or olanzapine developed tardive dyskinesia. Both compounds imparted substantial weight gain with significantly more weight gain accrual with olanzapine. As this was an observational study, the antidepressant effect and tolerability profile of these compounds requires validation via double-blind placebo controlled investigations.

Topics: Adolescent; Adult; Antimanic Agents; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Body Weight; Chemotherapy, Adjuvant; Depression; Female; Humans; Lithium; Male; Middle Aged; Olanzapine; Pilot Projects; Prospective Studies; Psychiatric Status Rating Scales; Risperidone; Time Factors; Valproic Acid

Side effect and health status changes were measured in 3 studies in which outpatients experiencing suboptimal efficacy or tolerability with their current antipsychotic were switched to 6 weeks of open-label ziprasidone. The studies differed only in the patient's prior antipsychotic; 1 study group was on olanzapine (n = 104), a second on risperidone (n = 58), and third on a conventional antipsychotic (n = 108). Baseline and end point health status measures included weight and height, nonfasting cholesterol, and triglyceride levels, prolactin levels, and extrapyramidal side effects. Improvements in health indices and side effects were seen among all 3 groups, but the specific benefits depended on the preswitch antipsychotic. For example, patients switched from olanzapine experienced a mean weight loss of 1.76 kg (P < 0.0001), those switched from risperidone had a lesser reduction in weight (-0.86 kg; P = 0.015), and those switched from conventionals had a nonsignificant increase (+0.27 kg; P = 0.3). Prolactin levels decreased among those switched from risperidone (P < 0.0001) or conventionals (P = 0.05), but not for patients switched from olanzapine. EPS improved among those switched from conventionals (P < 0.0001) and to a lesser extent among those switched from risperidone (P < 0.01), but not in those changed from olanzapine (NS). Thus, in these studies, switching to ziprasidone in patients with continuing symptoms or side effects on their current medication was often associated with improved health status indices, lowered prolactin levels, or less EPS, with the magnitude benefit consistent with the known side-effect profile of the preswitch antipsychotic.

Topics: Adolescent; Adult; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Body Weight; Female; Health Status Indicators; Humans; Male; Middle Aged; Olanzapine; Piperazines; Prolactin; Psychotic Disorders; Risperidone; Schizophrenia; Thiazoles; Withholding Treatment

The primary objective of this study was to evaluate insulin sensitivity in healthy subjects treated with olanzapine or risperidone. Subjects were randomly assigned to single-blind therapy with olanzapine (10 mg/d), risperidone (4 mg/d), or placebo for approximately 3 wk. Insulin sensitivity was assessed pre- and posttreatment using a 2-step, hyperinsulinemic, euglycemic clamp. Glucose and insulin responses were also assessed by a mixed meal tolerance test. Of the 64 subjects randomized, 22, 14, and 19 in the olanzapine, risperidone, and placebo groups, respectively, completed the study procedures. There were no significant within-group changes in the glucose disposal rate or the insulin sensitivity index for the active therapy groups. Further, the results of the mixed meal tolerance test did not demonstrate clinically significant changes in integrated glucose metabolism during treatment with these medications. In summary, this study did not demonstrate significant changes in insulin sensitivity in healthy subjects after 3 wk of treatment with olanzapine or risperidone.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Fasting; Fatty Acids, Nonesterified; Female; Food; Glucose Clamp Technique; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Male; Middle Aged; Olanzapine; Pirenzepine; Placebos; Reference Values; Risperidone

The aim of this study was to compare glucose metabolism in patients with schizophrenia receiving olanzapine with that in control subjects.. We conducted a prospective, controlled, open study comparing body weight, fat mass, and indices of insulin resistance/ sensitivity in 10 olanzapine-treated patients with ICD-10 schizophrenia (olanzapine dose range, 7.5-20 mg/day) with those of a group of 10 mentally and physically healthy volunteers. Weight, fat mass, and indices of insulin resistance/sensitivity were assessed over individual 8-week observation periods from November 1997 to October 1999.. Fasting serum glucose and fasting serum insulin increased significantly in the olanzapine-treated patients (p =.008 for glucose and p =.006 for insulin). The homeostasis model assessment (HOMA) index for beta cell function did not change significantly in the olanzapine-treated patients, whereas the HOMA index for insulin resistance did increase (p =.006). In the control group, these parameters were stable. A significant increase in body weight (p =.001) and body fat (p =.004) was seen in patients treated with olanzapine, while the control group showed no significant changes.. This study indicates that the disturbances in glucose homeostasis during antipsychotic treatment with olanzapine are mainly due to insulin resistance. However, beta cell function remains unaltered in olanzapine-treated patients. We conclude that treatment with some second-generation antipsychotic drugs may lead to insulin resistance.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Composition; Body Weight; Dose-Response Relationship, Drug; Female; Homeostasis; Humans; Insulin Resistance; Islets of Langerhans; Male; Olanzapine; Pirenzepine; Prospective Studies; Schizophrenia

Olanzapine is an atypical neuroleptic drug with mood-stabilising properties and few of the side effects commonly associated with conventional neuroleptic treatment. We used olanzapine, 5-20 mg/day, to treat severe aggression in six non-psychotic teenage boys with neuropsychiatric disorders. All but one started to respond within one week. The therapeutic effect in four of the patients clearly outweighed the side effects (weight gain and sedation). The subjects described a markedly increased sense of well being during the olanzapine treatment.

Topics: Adolescent; Adult; Aggression; Antipsychotic Agents; Benzodiazepines; Body Weight; Conduct Disorder; Humans; Male; Olanzapine; Pirenzepine; Time Factors; Treatment Outcome; Violence

To compare the efficacy and safety of the atypical antipsychotics amisulpride and olanzapine in the treatment of acute psychotic exacerbations of schizophrenia.. A multinational, double-blind randomised clinical trial.. Three hundred and seventy-seven patients with predominantly positive symptomatology were treated for six months with either amisulpride (200-800 mg/d) or olanzapine (5-20 mg/d).. Short-term results were analysed after two months of treatment. The primary efficacy measure was the change of score on the Brief Psychiatric Rating Scale (BPRS). Other measures of efficacy and safety were also evaluated.. Psychotic symptoms, as measured on the BPRS score, improved with both treatments, amisulpride being equivalent to olanzapine. All BPRS factor scores, as well as depressive symptoms, improved to a similar extent with both treatments. Less than five per cent of patients withdrew for adverse events, and there was no evidence for the emergence of extrapyramidal symptoms with either treatment. Statistically significant greater weight gain (2.7 +/- 3.9 kg) was observed during the study in the olanzapine group, compared with the amisulpride group (0.9 +/- 3.2 kg, p < 0.0001).. Amisulpride and olanzapine show equivalent efficacy at 2 months in the treatment of acute psychotic exacerbations of schizophrenia. Amisulpride offers a significant advantage in preserving body weight.

Topics: Adolescent; Adult; Aged; Amisulpride; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Body Weight; Double-Blind Method; Female; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Schizophrenia; Schizophrenic Psychology; Selective Serotonin Reuptake Inhibitors; Sulpiride; Time Factors

The aim of this study is to provide long-term data on the effectiveness and safety of olanzapine in a group of patients with severe refractory schizophrenia.. Twenty patients who had previously received treatment with typical antipsychotic agents and who met the DSM-IV criteria of schizophrenia and refractoriness to treatment were evaluated in a 1-year prospective study after switching to olanzapine. The Positive and Negative Symptoms Scale (PANSS) and the Brief Psychiatric Rating Scale (BPRS) were used to measure effectiveness. The extrapyramidal symptoms were also recorded. Serial laboratory tests, electrocardiograms and body weight measurements were also performed. Longitudinal statistical analyses were performed on the global changes in the scores of the scales by means of a repeated measures analysis of variance.. Significant reductions in the global scores from baseline in the PANSS, as well as in the BPRS, were observed. Furthermore, these reductions were also significant when considered only from Week 12. Olanzapine was, in general, well tolerated; a weight gain was observed between baseline and Month 4.5, but, interestingly, it decreased again from this time point to Month 12.. Olanzapine was shown to be a suitable treatment for refractory schizophrenia in this series of seriously ill patients. Although most of the effects were observed before Week 12, improvement persisted after 1 year. Weight gain stopped or even regressed when the treatment was prolonged. Large controlled clinical trials to define the role of atypical antipsychotics for the management of treatment-refractory schizophrenia are necessary.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Body Weight; Chronic Disease; Drug Resistance; Female; Follow-Up Studies; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Schizophrenia

The treatment of schizophrenic patients who fail to respond to adequate trials of neuroleptic drugs is a major challenge. Clozapine has been one treatment option; however, it is not universally effective and is limited in its use by safety concerns. With the introduction of newer agents, their performance relative to clozapine is of great clinical interest.. The primary objective of this study was to evaluate the efficacy and safety of olanzapine versus clozapine among treatment resistant DSM-IV schizophrenic patients. The study was primarily designed to demonstrate the "noninferiority" of olanzapine compared to clozapine after 18 weeks of double-blind treatment. Conclusions were based on the one-sided lower 95% confidence limit about the treatment effect observed from the primary efficacy variable (Positive and Negative Syndrome Scale [PANSS] Total).. Mean changes from baseline to end point in PANSS Total score, using a last observation carried forward technique, showed that both agents were comparably effective in neuroleptic resistant patients, i.e., demonstrated the "noninferiority" of olanzapine when compared to clozapine. Overall, significantly fewer olanzapine-treated patients (4%) discontinued for an adverse event than their clozapine-treated (14%) counterparts (p =.022). Among spontaneously reported adverse events, increased salivation, constipation, dizziness, and nausea were reported significantly more often among clozapine-treated patients, whereas only dry mouth was reported more often among olanzapine-treated patients.. Olanzapine was demonstrated to be noninferior to clozapine and better tolerated among resistant schizophrenic patients clinically eligible for treatment with clozapine.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Pressure; Body Weight; Clozapine; Double-Blind Method; Drug Resistance; Dyskinesia, Drug-Induced; Female; Humans; Male; Olanzapine; Patient Compliance; Pirenzepine; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Time Factors

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

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

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

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

Our purpose was to evaluate the overall efficacy and tolerability of novel antipsychotic medications for patients with bipolar disorder type I.. A retrospective study of the Massachusetts General Hospital Bipolar Clinic database was carried out to identify 50 consecutive treatment trials in patients with DSM-IV bipolar disorder type I who had received adjunctive treatment with risperidone, olanzapine, or clozapine, along with standard mood stabilizers. The treatment charts of those patients (N = 42) were reviewed for details of adverse effects, tolerability, and efficacy of medication.. Overall results indicated equivalent efficacy in novel antipsychotic treatments according to change in Clinical Global Impressions scale score. Levels of extrapyramidal symptoms were similar in all groups and occurred in 12/42 patients (28.6%). Prolactin-related side effects were not observed in any patients. There were no cases of affective switch or worsening of mania. Substantial weight gain of more than 10 lb (4.5 kg) was significantly greater in patients treated with olanzapine.. These results suggest that the efficacy and tolerability of risperidone, olanzapine, and clozapine are similar in patients with bipolar disorder. One major differentiation factor of these drugs appears to be weight gain, particularly between olanzapine and risperidone. This may, in part, also be related to the need to use mood-stabilizing agents, like lithium or divalproex sodium, which may potentiate the weight-gain effect of novel antipsychotics.

Topics: Adult; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Bipolar Disorder; Body Weight; Clozapine; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Lithium; Male; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Retrospective Studies; Risperidone; Treatment Outcome; Valproic Acid

The atypical antipsychotic drug olanzapine is prescribed despite clinical studies on olanzapine treatment showing mixed results on treatment efficacy in anorexia nervosa. We investigated the effect of systemic and intranasal administration of olanzapine in the activity-based anorexia (ABA) model. Rats were habituated to a running wheel and exposed to the ABA model while treated with olanzapine. During ABA rats had 1.5 h of daily access to food and ad libitum access to a running wheel for seven consecutive days. Olanzapine was administered via an osmotic minipump (1, 2.75, and 7.5 mg/kg) or intranasally 2 h before dark onset (1 and 2.75 mg/kg). We monitored body weight, food intake, wheel revolutions, body temperature, and adipose tissue. We found 2.75 and 7.5 mg/kg systemic olanzapine decreased wheel revolutions during ABA. Relative adipose tissue mass was increased in the 7.5 mg/kg olanzapine-treated group while body weight, food intake, and body temperature were unaltered by the systemic olanzapine. 1 and 2.75 mg/kg intranasal olanzapine diminished wheel revolutions and body temperature during the first 2 h after administration. The intranasal olanzapine-treated rats had a higher body weight at the end of ABA. We find that olanzapine has beneficial outcomes in the ABA via two administration routes by acting mainly on running wheel activity. Intranasal olanzapine showed a rapid effect in the first hours after administration in reducing locomotor activity. We recommend further exploring intranasal administration of olanzapine in anorectic patients to assist them in coping with restlessness.

Topics: Administration, Intranasal; Animals; Anorexia; Anorexia Nervosa; Body Weight; Disease Models, Animal; Eating; Olanzapine; Rats

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

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

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

Antipsychotic drugs are associated with adverse events, but serious side effects are not frequent. This study aimed to ascertain whether previous exposure to antipsychotic treatment was associated with metabolic disturbances induced by current antipsychotic medication.. A total of 115 antipsychotic-naïve patients, 65 patients with previous exposure to low-metabolic-risk antipsychotics, and 88 patients with previous exposure to high-metabolic-risk antipsychotics were enrolled in our case-control study. All patients were administered olanzapine. Body weight, body mass index (BMI), biochemical indicators of blood glucose and lipids, the proportion of patients who gained more than 7% of their body weight at baseline, and the percentage of dyslipidemia were evaluated. All assessments were conducted at baseline and at 4 and 6 weeks after treatment.. A history of exposure to antipsychotics, particularly high-metabolic-risk antipsychotics, is associated with current antipsychotic-induced metabolic disturbances.

Topics: Antipsychotic Agents; Benzodiazepines; Body Weight; Case-Control Studies; Humans; Olanzapine; Schizophrenia

Long-term treatment of olanzapine, the most widely-prescribed second-generation antipsychotic, remarkably increases the risk of non-alcoholic fatty liver disease (NAFLD), whereas the mechanism for olanzapine-induced NAFLD remains unknown. Excessive hepatic fat accumulation is the basis for the pathogenesis of NAFLD, which results from the disturbance of TG metabolism in the liver. Apolipoprotein A5 (ApoA5) is a key regulator for TG metabolism in vivo that promotes TG accumulation in hepatocytes, thereby resulting in the development of NAFLD. However, there are no data indicating the role of apoA5 in olanzapine-induced NAFLD. Therefore, this study aims to investigate the role of apoA5 in olanzapine-induced NAFLD.. This study was carried out via animal studies, cell experiment, and ApoA5 gene knockdown experiment. Six-week-old male C57BL/6J mice were randomized into a control group, a low-dose group, and a high-dose group, which were treated by 10% DMSO, 3 mg/(kg·d) olanzapine, and 6 mg/(kg·d) olanzapine, respectively for 8 weeks. The lipid levels in plasma, liver function indexes, and expression levels of ApoA5 were detected. HepG2 cells were treated with 0.1% DMSO (control group), 25 μmol/L olanzapine (low-dose group), 50 μmol/L olanzapine (medium-dose group), and 100 μmol/L olanzapine (high-dose group) for 24 h. HepG2 cells pretreated with 100 μmol/L olanzapine were transfected with siRNA and scrambled siRNA (negative control), respectively. We observed the changes in lipid droplets within liver tissues and cells using oil red O staining and fat deposition in liver tissues using HE staining. The mRNA and protein levels of ApoA5 were determined by real-time PCR and Western blotting, respectively.. After intervention with 3 and 6 mg/(kg·d) olanzapine for 8 weeks, there was no significant difference in body weight among the 3 groups (. The short-term intervention of olanzapine does not significantly increase body weight of mice, but it can directly induce hypertriglyceridemia and NAFLD in mice. Olanzapine inhibits hepatic apoA5 secretion but does not affect hepatic apoA5 synthesis, resulting in the pathogenesis of NAFLD. Inhibition of apoA5 secretion plays a key role in the development of olanzapine-related NAFLD, which may serve as an intervention target for this disease.

Topics: Animals; Apolipoprotein A-V; Body Weight; Dimethyl Sulfoxide; Liver; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Olanzapine; RNA, Messenger; RNA, Small Interfering; Triglycerides

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

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

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

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

Olanzapine is widely prescribed for patients with mental disorders; however, it may induce metabolic dysfunction. Metformin is an efficient adjuvant for preventing olanzapine-induced metabolic dysfunction in clinical practice. Although the mechanism of how metformin prevents this metabolic dysfunction remains unknown, changes in the gut-liver axis are considered a potential explanation.. Forty-eight male rats were gavaged with olanzapine and/or metformin for 35 consecutive days. Body weight, food intake, and water intake were measured daily. Histopathological and biochemical tests were performed to evaluate the metabolic dysfunction. The 16S rRNA obtained from fecal bacterial DNA was assessed.. Olanzapine treatment increased the body weight, blood glucose and triglyceride levels, and the number of adipocytes in the liver. While coadministration of metformin, there was a dose-dependent reverse of the abnormal changes induced by olanzapine treatment. Both olanzapine and metformin treatments altered the composition of the gut microbiota. Bacteroides acidifaciens and Lactobacillus gasseri were possibly played a positive role in metformin-mediated olanzapine-induced metabolic dysfunction prevention.. Metformin prevented olanzapine-induced metabolic dysfunction and regulated the gut microbiota in a dose-dependent manner.

Topics: Adjuvants, Pharmaceutic; Animals; Bacteroides; Blood Glucose; Body Weight; Dose-Response Relationship, Drug; Feces; Gastrointestinal Microbiome; Humans; Lactobacillus gasseri; Liver; Male; Metabolic Diseases; Metformin; Olanzapine; Rats; RNA, Ribosomal, 16S

The primary aim of this study was to standardize the correlated effective dosage of the antidiabetic drug empagliflozin (EMPA) and the antipsychotic drug olanzapine (Ola).. Atypical antipsychotics are associated with BWG and metabolic disturbances for which many approaches have been used to minimize these issues, including antidiabetic drugs. The antidiabetic drugs have been quite effective in reversing BWG induced by the administration of antipsychotic drugs in patients who have psychosis, schizophrenia and bipolar disorder.. The objective of this study was to standardize the correlated effective dosage of EMPA and Ola.. The study was carried out for 28 days to represent the chronic effect of Ola on female Wistar rats. Rats were divided into three groups based on the dose they received: control (vehicle), Ola-4 and Ola-8 (4 and 8 mg/kg/OD, respectively), and EMPA-10 and EMPA-20 (10 and 20 mg/kg/OD, respectively).. Both doses of Ola produced a significant increase in the percentage of BWG, however, Ola-4 produced a higher BWG. Also, both the doses of EMPA were able to reverse the effect of Ola-induced BWG; however, EMPA-20 produced a higher reversal in BWG and normalized the rat's body weight.. We conclude that Ola-4 and EMPA-20 were the most effective dosage for experimental purposes in female Wistar rats. The findings of this study standardized the effective correlated dosage of olanzapine and empagliflozin in female Wistar rats that will help understand the underlying molecular and behavioral mechanisms.

Topics: Animals; Antipsychotic Agents; Benzhydryl Compounds; Body Weight; Dose-Response Relationship, Drug; Drug Dosage Calculations; Female; Glucosides; Hypoglycemic Agents; Models, Animal; Olanzapine; Rats; Rats, Wistar

Olanzapine and clozapine are atypical antipsychotics (AAPs) with the greatest risk of weight gain, and changes in feeding behavior are among the most important underlying mechanisms. However, few studies have investigated the role of diet-alone interventions in improving individuals' weight gain by taking AAPs. In closed management mental hospitals of China, family members are allowed to bring food to patients regularly, causing patients to have caloric intake added to their 3 daily meals. However, during the global pandemic of coronavirus disease 2019 (COVID-19), bringing food to the hospital was temporarily prohibited in mental health institutions in China to prevent the spread of the virus. This study sought to compare the body weight and body mass index (BMI) changes of patients taking olanzapine or clozapine undergoing diet-alone interventions caused by this prohibition.. A retrospective self-controlled study was conducted on 90 patients with schizophrenia from a single-center treated with olanzapine or clozapine monotherapy, or combined with aripiprazole or ziprasidone which has a small metabolic impact. A paired-samples t-test was used to compare the changes in body weight and BMI before and after the 3-month prohibition, and general linear regression was used to analyze the effects of gender, age, disease course, duration of drug exposure, and equivalent dose on the BMI improvement. Also, the percentage of people who lost weight and that of individuals who lost 5% of their pre-prohibition body weight were calculated.. Paired-samples t-test showed that after 3-month prohibition, the patients' body weight (71.68±6.83 vs. 66.91±7.03, P<0.001) and BMI (26.43±2.11 vs. 24.63±1.81, P<0.001) decreased significantly. Weight loss rate accounted for 99.1%, and weight loss of 5% from the pre-prohibition body weight accounted for 71.8%. General linear regression showed that the duration of drug exposure (β =-0.678, P<0.001) was significantly and negatively correlated with the BMI changes. No significant correlation of gender, age, disease course, or equivalent dose with BMI changes was found.. Diet-alone interventions facilitate weight loss in chronically hospitalized schizophrenia patients taking AAPs. Conduction of dietary intervention in the early stages of medication may yield greater benefits.

Topics: Antipsychotic Agents; Benzodiazepines; Body Weight; China; Clozapine; COVID-19; Humans; Olanzapine; Pandemics; Retrospective Studies; Risperidone; SARS-CoV-2; Schizophrenia

Gut microbiota plays an important role in host metabolism. Antipsychotic drugs can result in metabolic abnormalities. Probiotics may ameliorate the antipsychotic drug-induced metabolic abnormalities by regulating gut microbiota.. To determine whether Bifidobacterium intervention can ameliorate olanzapine-induced weight increase.. Enrolled patients were assigned to either the olanzapine or olanzapine plus Bifidobacterium group. The following were assessed: body weight, body mass index (BMI), appetite, latency to increased appetite, and baseline weight increase of more than 7%. All assessments were conducted at baseline and at 4, 8, and 12 weeks of treatment.. We enrolled 70 patients with schizophrenia or schizophrenic affective disorder, and 67 completed the study. Treatment for 4 weeks led to between-group differences in weight change (2.4 vs. 1.1 kg, p < 0.05) and BMI (0.9 vs. 0.4, p < 0.05). However, this difference disappeared at 8 and 12 weeks of treatment (both p > 0.05). The two groups did not differ in appetite increase at any time point (p > 0.05). The mean time from olanzapine initiation to appetite increase was also not significantly different between the two groups (t = 1.243, p = 0.220).. Probiotics may mitigate olanzapine-induced weight gain in the early stage of treatment and delay olanzapine-induced appetite increase.

Topics: Antipsychotic Agents; Appetite; Benzodiazepines; Bifidobacterium; Body Mass Index; Body Weight; Humans; Olanzapine; Psychotic Disorders

A combination of olanzapine and samidorphan was recently approved by the US Food and Drug Administration for the treatment of patients with schizophrenia or bipolar I disorder. Population pharmacokinetic models for olanzapine and samidorphan were developed using data from 11 clinical studies in healthy subjects or patients with schizophrenia. A 2-compartment disposition model with first-order absorption and elimination and a lag time for absorption adequately described concentration-time profiles of both olanzapine and samidorphan. Age, sex, race, smoking status, and body weight were identified as covariates that impacted the pharmacokinetics of olanzapine. A moderate effect of body weight on samidorphan pharmacokinetics was identified by the model but was not considered clinically meaningful. The effects of food, hepatic or renal impairment, and coadministration with rifampin on the pharmacokinetics of olanzapine and samidorphan, as estimated by the population pharmacokinetic analysis, were consistent with findings from dedicated clinical studies designed to evaluate these specific covariates of interest. Food intake did not have a clinically relevant effect on the pharmacokinetics of olanzapine or samidorphan. Consistent with the known metabolic pathways for olanzapine (primarily via uridine 5'-diphospho-glucuronosyltransferase-mediated direct glucuronidation and cytochrome P450 [CYP]-mediated oxidation) and for samidorphan (predominantly mediated by CYP3A4), coadministration of olanzapine and samidorphan with rifampin, a strong inducer of CYP3A4 and an inducer of uridine 5'-diphospho-glucuronosyltransferase enzymes, significantly decreased the systemic exposure of both olanzapine and samidorphan. Severe renal impairment or moderate hepatic impairment resulted in a modest increase in olanzapine and samidorphan exposure.

Topics: Adolescent; Adult; Age Factors; Aged; Antipsychotic Agents; Body Weight; Cigarette Smoking; Cytochrome P-450 CYP3A; Drug Combinations; Female; Food-Drug Interactions; Humans; Liver Failure; Male; Middle Aged; Naltrexone; Narcotic Antagonists; Olanzapine; Racial Groups; Renal Insufficiency; Rifampin; Schizophrenia; Sex Factors; Young Adult

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

We conducted a 12-week double-blind study of stabilization pharmacotherapy in patients with remitted psychotic depression (PD).. Seventy-one persons aged 18 years or older who had achieved remission of PD when randomized to either olanzapine plus sertraline or olanzapine plus placebo were continued on the double-blind treatment associated with remission. Symptoms of depression and psychosis, and weight, were measured once every 4 weeks. Cholesterol, triglycerides, and glucose were measured at stabilization phase baseline and Week 12/termination.. The effect of treatment did not significantly change with time for depression, weight, or metabolic measures in the stabilization phase. Eight of the 71 participants (11.3%; 95% CI: 5.8, 20.7) experienced a relapse of major depression, psychosis, or both. Treatment groups did not differ in the frequency of relapse. In the entire study group, the adjusted estimate for change in weight was an increase of 1.66 kg (95% CI: 0.83, 2.48) and the adjusted estimate for change in total cholesterol was a decrease of 14.8 mg/dL (95% CI: 3.5, 26.1) during the 12-week stabilization phase; the remaining metabolic measures did not significantly change.. Continuation of acute treatment was associated with stability of remission.

Topics: Adult; Aged; Antidepressive Agents; Antipsychotic Agents; Blood Glucose; Body Weight; Cholesterol; Depressive Disorder, Major; Diagnostic and Statistical Manual of Mental Disorders; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Olanzapine; Placebos; Psychotic Disorders; Remission Induction; Sertraline; Triglycerides

Olanzapine is an atypical antipsychotic drug commonly used for the treatment of schizophrenia. However, there are still many complications associated with the use of olanzapine, and researchers continually strive to improve the handling of data from regular therapeutic drug monitoring (TDM). The objective of this study is to optimise the individualised treatment of olanzapine by establishing a population pharmacokinetics (PopPK) model in Chinese patients with schizophrenia.. This study integrates an extensive collection of concentration data from healthy volunteers after a single dose and a less extensive collection of samples from patients undergoing TDM. A PopPK model was developed using non-linear mixed-effects modelling. Potential covariates, including the olanzapine manufacturer and patient gender and age, were assessed during model development. A total of 616 plasma concentration levels from 22 healthy male individuals in China and 458 concentration levels from 112 male and 122 female patients with schizophrenia undergoing TDM at 12 hospitals in China were included in the analysis. The concentration profile could be best described using a two-compartment model with first-order absorption and elimination.. The absorption rate (Ka) of olanzapine ranged from 2.85 h. ChiCTR-TRC-10000934; Results.

Topics: Adolescent; Adult; Antipsychotic Agents; Body Weight; China; Female; Healthy Volunteers; Humans; Male; Middle Aged; Models, Biological; Olanzapine; Retrospective Studies; Schizophrenia; Young Adult

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

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

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

Atypical antipsychotic drugs, particularly olanzapine, represent a mainstay in the treatment of psychoses; however, their use is commonly associated with weight gain and diabetes. The aim of this study was to determine whether combined administration of olanzapine and zonisamide can be used to prevent olanzapine-induced metabolic disturbances.. These experiments involved female Sprague Dawley rats (n = 6-8/group) that were administered olanzapine, either acutely (6 mg/kg, s. c) or via continuous osmotic minipump infusion (6 mg/kg/day for 6 or 14 days), in combination with zonisamide (26 mg/kg/day,i.p.). Continuous infusion of olanzapine induced accumulation of adipose tissue and an associated reduction in stimulated lipolysis and reduced protein expression of CGI-58, a critical co-activator of ATGL. Olanzapine treatment caused a preferential shift toward carbohydrate oxidation (or reduced fat oxidation), elevated blood triglycerides and a reduction in locomotor activity. Olanzapine had a direct effect on glucose regulation, causing rapid hyperglycemia, and a reduction in glucose tolerance and insulin sensitivity. Continuous administration of olanzapine caused significant hyperinsulinemia and a significant reduction in insulin sensitivity. Zonisamide did not affect the impact of olanzapine on glucose homeostasis. On the other hand, co-administration of olanzapine with zonisamide completely ameliorated olanzapine-mediated shifts in lipid metabolism resulting in a normalization of olanzapine-induced weight gain.. These data collectively show an impact of olanzapine on body weight and lipid metabolism, which is ameliorated by co-administration with zonisamide. These findings suggest that a combined olanzapine and zonisamide approach might reduce weight gain, but will not provide protection against olanzapine-induced glucose intolerance.

Topics: Adiposity; Animals; Antioxidants; Antipsychotic Agents; Benzodiazepines; Body Weight; Drug Therapy, Combination; Eating; Female; Glucose; Homeostasis; Isoxazoles; Lipid Metabolism; Lipolysis; Motor Activity; Olanzapine; Oxygen Consumption; Random Allocation; Rats, Sprague-Dawley; Triglycerides; Zonisamide

Atypical antipsychotics particularly olanzapine are associated with obesity and serious metabolic disturbances. As green tea (Camellia sinensis) is generally associated with beneficial effects on obesity and other metabolic disturbances, this study was undertaken to evaluate the effect of green tea aqueous extract (GTAE) on olanzapine induced weight gain and metabolic abnormalities in rats. Male Wistar rats were divided into eight groups: control, olanzapine (5mg/kg/day, IP.), GTAE (25, 50 and 100mg/kg/day, IP.) plus olanzapine and GTAE (25, 50 and 100mg/kg/day, IP.). Treatments were continued for 11 days. Body weight gain, average food and water intake were measured during the experiment. Plasma lipid, glucose and leptin levels, mean systolic blood pressure and total locomotion were evaluated at the end of experiment. Olanzapine induced significant weight gain at the end of treatment (10.38% of body weight) when compared to control (3.13% of body weight) in male Wistar rats. Average food and water intake were increased by olanzapine treatment. 11days olanzapine administration led to hyperleptinemia, hyperglycemia and dyslipidemia. Olanzapine also increased mean systolic blood pressure and decreased total locomotion. GTAE decreased significantly body weight gain and average food and water intake, improved the changes in lipid profile as well as fasting blood glucose, and finally decreased hyperleptinemia and hypertension induced by olanzapine. Results of this study demonstrated that GTAE could exert protective effects against olanzapine induced obesity partially due to its lowering effect on leptin. GTAE improved other metabolic abnormalities including dyslipidemia, hyperglycemia and hypertension induced by olanzapine in rats.

Topics: Animals; Benzodiazepines; Blood Glucose; Blood Pressure; Body Weight; Drinking; Feeding Behavior; Leptin; Lipids; Male; Metabolic Syndrome; Motor Activity; Olanzapine; Polyphenols; Protective Agents; Rats, Wistar; Systole; Tea; Triglycerides

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

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

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

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

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

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

Mood disorder patients that are on long-term atypical antipsychotics treatment frequently experience metabolic dysfunctions. In addition to this, accumulating evidences points to increased risk of structural abnormalities, brain volume changes, altered neuroplasticity and behavioral depression with long-term antipsychotics use. However, there is paucity of preclinical evidences for long-term antipsychotic associated depression-like behavior. The objectives of the present study were: (1) to evaluate influence of long-term antipsychotic (olanzapine) treatment on rat behavior in forced swim test (FST) as a model for depression and; (2) to examine impact of glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide - an antidiabetic medication for type II diabetes, on long-term olanzapine associated metabolic and behavioral changes in rats. Daily olanzapine treatment (0.5 mg/kg; p.o.) for 8-9 weeks significantly increased body weights, food and water intake, plasma cholesterol and triglycerides and immobility time in FST with parallel reduction in plasma HDL cholesterol levels. These results points to development of metabolic abnormalities and depression-like behavior with long-term olanzapine treatment. Acute liraglutide (50 μg/kg; i.p.) and imipramine (10 mg/kg, i. p.) treatment per se significantly decreased duration of immobility in FST compared to vehicle treated rats. Additionally, 3-week liraglutide treatment (50 μg/kg; i.p., daily) partially reversed metabolic abnormalities and depression-like behavior with long-term olanzapine-treatment in rats. None of these treatment regimens affected locomotor behavior of rats. In summary, add-on GLP-1 receptor agonists promise novel alternatives to counteract long-term antipsychotics associated behavioral and metabolic complications.

Topics: Animals; Antidepressive Agents, Tricyclic; Antipsychotic Agents; Benzodiazepines; Body Weight; Cholesterol; Depression; Eating; Female; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Imipramine; Liraglutide; Metabolic Diseases; Motor Activity; Olanzapine; Rats; Rats, Wistar; Swimming; Triglycerides

Association between gastric inhibitory polypeptide receptor polymorphism, rs10423928, and body mass index in olanzapine-treated schizophrenia was examined. Body mass index change for the A/T+A/A genotypes was significantly higher than that for the T/T genotype. rs10423928 may predict weight gain in schizophrenia.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Female; Genotype; Humans; Male; Middle Aged; Olanzapine; Pharmacogenetics; Polymorphism, Single Nucleotide; Receptors, Gastrointestinal Hormone; Schizophrenia; Young Adult

Olanzapine, an atypical antipsychotic, can acutely induce fasting insulin resistance, but we do not know whether it is able to modulate the meal-induced insulin sensitization (MIS). Two main experimental groups (control and olanzapine-treated) were created with two subgroups (fasted and re-fed) within each. After oral vehicle/olanzapine administration, the first meal size and duration and the total amount of consumed food was recorded in conscious rats. Then, under anaesthesia, the carotid artery and jugular vein was prepared and cannulated to obtain samples for blood glucose and hormone determination as well as for insulin/glucose infusion, respectively. Basal insulin sensitivity and MIS was determined by homeostasis model assessment (HOMA) calculation and by rapid insulin sensitivity test, respectively. In fasted animals, olanzapine increased blood glucose and plasma insulin and reduced basal insulin sensitivity, but it failed to modify other hormone levels. Postprandial leptin and glucose-dependent insulinotropic polypeptide (GIP) levels increased, and ghrelin level decreased significantly (p < 0.05) both in vehicle- and olanzapine-treated groups, but plasma insulin increased only in vehicle-treated animals. Furthermore, decrement in ghrelin level was attenuated in olanzapine-treated animals compared to controls. There was no significant change in the first meal size and duration or in the total amount of food consumed. Olanzapine had no effect on the MIS. We demonstrated that olanzapine can induce insulin resistance without weight gain in healthy rats. Furthermore, the MIS was preserved after acute olanzapine treatment. The blunted postprandial ghrelin and insulin response could contribute to the effect of olanzapine on feeding behaviour. Pharmacological induction of MIS may improve the olanzapine-induced insulin resistance.

Topics: Animals; Benzodiazepines; Blood Glucose; Body Weight; Energy Intake; Fasting; Feeding Behavior; Female; Ghrelin; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Olanzapine; Postprandial Period; Rats, Sprague-Dawley

Treatment with second-generation antipsychotic agents such as olanzapine frequently results in metabolic adverse effects, e.g. hyperphagia, weight gain and dyslipidaemia in patients of both genders. The molecular mechanisms underlying metabolic adverse effects are still largely unknown, and studies in rodents represent an important approach in their exploration. However, the validity of the rodent model is hampered by the fact that antipsychotics induce weight gain in female, but not male, rats. When administered orally, the short half-life of olanzapine in rats prevents stable plasma concentrations of the drug. We recently showed that a single intramuscular injection of long-acting olanzapine formulation yields clinically relevant plasma concentrations accompanied by several dysmetabolic features in the female rat. In the current study, we show that depot injections of 100-250 mg/kg olanzapine yielded clinically relevant plasma olanzapine concentrations also in male rats. In spite of transient hyperphagia, however, olanzapine resulted in weight loss rather than weight gain. The resultant negative feed efficiency was accompanied by a slight elevation of thermogenesis markers in brown adipose tissue for the highest olanzapine dose, but the olanzapine-related reduction in weight gain remains to be explained. In spite of the absence of weight gain, an olanzapine dose of 200mg/kg or above induced significantly elevated plasma cholesterol levels and pronounced activation of lipogenic gene expression in the liver. These results confirm that olanzapine stimulates lipogenic effects, independent of weight gain, and raise the possibility that endocrine factors may influence gender specificity of metabolic effects of antipsychotics in the rat.

Topics: Adipocytes; Alanine Transaminase; Animals; Antiemetics; Aspartate Aminotransferases; Benzodiazepines; Blood Glucose; Body Weight; Delayed-Action Preparations; Dose-Response Relationship, Drug; Fasting; Female; Lipids; Lipogenesis; Liver; Male; Olanzapine; Rats; Rats, Sprague-Dawley; Thermogenesis; Transcription Factors

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

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

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

Topics: Adamantane; Adult; Aged; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Diabetes Mellitus; Humans; Male; Nitriles; Olanzapine; Pyrrolidines; Schizophrenia; Vildagliptin

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

Binge-eating disorder is a common psychiatric disorder affecting ~2% of adults. Binge-eating was initiated in freely-fed, lean, adult, female rats by giving unpredictable, intermittent access to ground, milk chocolate over four weeks. The rats avidly consumed chocolate during 2 hr binge sessions, with compensatory reductions of normal chow intake in these sessions and the days thereafter. Bodyweights of binge-eating rats were normal. The model's predictive validity was explored using nalmefene (0.1-1.0mg/kg), R-baclofen (1.0-10mg/kg) and SB-334867 (3.0-30 mg/kg) (orexin-1 antagonist), which all selectively decreased chocolate bingeing without reducing chow intake. Sibutramine (0.3-5.0mg/kg) non-selectively reduced chocolate and chow consumption. Olanzapine (0.3-3.0mg/kg) was without effect and rolipram (1.0-10mg/kg) abolished all ingestive behaviour. The pro-drug, lisdexamfetamine (LDX; 0.1-1.5mg/kg), dose-dependently reduced chocolate bingeing by ⩽ 71% without significantly decreasing normal chow intake. Its metabolite, D-amphetamine (0.1-1.0mg/kg), dose-dependently and preferentially decreased chocolate bingeing ⩽ 56%. Using selective antagonists to characterize LDX's actions revealed the reduction of chocolate bingeing was partially blocked by prazosin (α1-adrenoceptor; 0.3 and 1.0mg/kg) and possibly by SCH-23390 (D1; 0.1mg/kg). RX821002 (α2-adrenoceptor; 0.1 and 0.3mg/kg) and raclopride (D2; 0.3 and 0.5mg/kg) were without effect. The results indicate that LDX, via its metabolite, d-amphetamine, reduces chocolate bingeing, partly by indirect activation of α1-adrenoceptors and perhaps D1 receptors.

Topics: Animals; Baclofen; Behavior, Animal; Benzazepines; Benzodiazepines; Body Weight; Bulimia; Disease Models, Animal; Eating; Feeding Behavior; Female; Idazoxan; Lisdexamfetamine Dimesylate; Naltrexone; Olanzapine; Prazosin; Prodrugs; Raclopride; Rats; Rats, Wistar; Rolipram

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

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

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

Olanzapine is a second generation antipsychotic. A common side effect in humans is weight gain, but the mechanisms are mostly unknown.. To study the effects of subchronic olanzapine treatment on body weight, fasting plasma glucose (FPG), fasting insulin (FINS), C-peptide, insulin sensitivity index (ISI), and expression of glucose transporter 2 (GLUT2) in rat pancreatic β cells.. Female Sprague-Dawley rats were randomly divided into two groups: the olanzapine-treated group and the control group (each n = 8). Rats in the olanzapine-treated group intragastrically received olanzapine 5 mg/kg/day for 28 days; the rats in the control group received the same volume of vehicle. FPG and body weight were measured on the 1st, 7th, 14th and 28th day. FINS and C-peptide were measured using immunoradiometric assays at baseline and on the 28th day. GLUT2 mRNA and protein expressions in pancreatic β cells were analyzed by RT-PCR and western blot.. Olanzapine-treated rats had higher body weight (227.4 ± 8.9 vs. 211.0 ± 9.9 g), FPG (5.86 ± 0.42 vs. 4.24 ± 0.29 mmol/L), FINS (17.34 ± 3.64 vs. 10.20 ± 1.50 µIU/mL), and C-peptide (0.154 ± 0.027 vs. 0.096 ± 0.009 ng/mL) than those in controls (all P < 0.05) at the 28th day. Pancreatic β cells of the olanzapine-treated group showed lower ISI (-4.60 ± 0.23 vs. -3.76 ± 0.20) and GLUT2 levels (mRNA: 1.12 ± 0.02 vs. 2.00 ± 0.03; protein: 0.884 ± 0.134 vs. 1.118 ± 0.221) than those in controls (all P < 0.05).. Subchronic olanzapine treatment inhibited expression of GLUT2 in rat pancreatic β cells. Therefore, it may disturb glucose metabolism via the insulin resistance of β cells, but confirmation in humans is needed.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Fasting; Female; Glucose Transporter Type 2; Insulin; Insulin Resistance; Insulin-Secreting Cells; Olanzapine; Rats; Rats, Sprague-Dawley

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

The metabolic side-effects of olanzapine have undermined drug compliance and increased concern for this otherwise-effective treatment for schizophrenia. As obesity and type 2 diabetes are associated with low-grade inflammation, and olanzapine-induced weight gain has three typical stages, the current study investigated the inflammatory effects of olanzapine in three treatment stages. Female Sprague-Dawley rats were treated orally with olanzapine (1 mg/kg three times daily) or vehicle for one week, two weeks, and five weeks. Olanzapine significantly increased body weight and white visceral fat deposition in all three treatment stages compared to control. Olanzapine enhanced average adipocyte size and level of macrophage infiltration in white adipose tissue (WAT) compared to control, with levels of macrophage infiltration increased over time. There was a high correlation between adipocyte size and macrophage infiltration rate. Olanzapine also caused increased macrophage infiltration in brown adipose tissue (BAT), but not liver. Additionally, pro-inflammatory cytokines tumor necrosis factor α (TNFα), interleukin (IL)-1β, and IL-6 were upregulated by olanzapine in the hypothalamus, WAT, and BAT compared to control, but not the liver. Finally, plasma triglycerides were elevated by olanzapine compared to control, but not total cholesterol, high density lipoprotein (HDL) or low density lipoprotein (LDL). These findings indicate that olanzapine-induced inflammation and adiposity are closely related, and that peripheral low-grade inflammation develops during olanzapine treatment.

Topics: Adipocytes; Adipose Tissue; Adiposity; Animals; Benzodiazepines; Body Weight; Cell Movement; Cell Size; Cytokines; Female; Hypothalamus; Inflammation; Intra-Abdominal Fat; Lipoproteins; Liver; Macrophages; Olanzapine; Rats; Triglycerides

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

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

Olanzapine is an atypical antipsychotic drug that has been increasingly used in acute treatment of, and therapeutic support for, schizophrenia, bipolar disorder and other psychoses. Considering that olanzapine acts on the dopaminergic receptor and this receptor is detected in germ cells, the present study aims to investigate the effects of treatment with different doses of olanzapine on spermatogenesis, plasma testosterone and weight of androgen-dependent organs in rats. Results showed reduced plasma testosterone levels, and reduced testis, epididymis and prostate weights. Histopathologic and histomorphometric analysis of spermatogenesis indicated testicular degeneration. Furthermore, germ cell desquamation, syncytial multinucleated cells, Sertoli cell vacuolization and presence of necrotic and apoptotic germ cells wwew observed. Olanzapine treatment in rats promoted endocrinological changes and lesions in the testis, leading to a disturbance in spermatogenesis.

Topics: Animals; Antipsychotic Agents; Apoptosis; Benzodiazepines; Body Weight; Cell Count; Epididymis; Genital Diseases, Male; Lethargy; Male; Necrosis; Olanzapine; Organ Size; Prostate; Rats; Rats, Wistar; Sertoli Cells; Spermatocytes; Spermatogenesis; Testis; Testosterone

Schizophrenia is a chronic, severe and highly complex mental illness. Current treatments manage the positive symptoms, yet have minimal effects on the negative and cognitive symptoms, two prominent features of the disease with critical impact on the long-term morbidity. In addition, antipsychotic treatments trigger serious side effects that precipitate treatment discontinuation. Here, we show that activation of the trace amine-associated receptor 1 (TAAR1), a modulator of monoaminergic neurotransmission, represents a novel therapeutic option. In rodents, activation of TAAR1 by two novel and pharmacologically distinct compounds, the full agonist RO5256390 and the partial agonist RO5263397, blocks psychostimulant-induced hyperactivity and produces a brain activation pattern reminiscent of the antipsychotic drug olanzapine, suggesting antipsychotic-like properties. TAAR1 agonists do not induce catalepsy or weight gain; RO5263397 even reduced haloperidol-induced catalepsy and prevented olanzapine from increasing body weight and fat accumulation. Finally, TAAR1 activation promotes vigilance in rats and shows pro-cognitive and antidepressant-like properties in rodent and primate models. These data suggest that TAAR1 agonists may provide a novel and differentiated treatment of schizophrenia as compared with current medication standards: TAAR1 agonists may improve not only the positive symptoms but also the negative symptoms and cognitive deficits, without causing adverse effects such as motor impairments or weight gain.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Attention; Benzodiazepines; Body Weight; Cocaine; Conditioning, Operant; Depression; Disease Models, Animal; Dopamine Uptake Inhibitors; Electroencephalography; Hallucinogens; Haloperidol; Humans; Macaca fascicularis; Magnetic Resonance Imaging; Male; Mental Recall; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microinjections; Motor Activity; Mutation; Olanzapine; Oocytes; Oxazoles; Phencyclidine; Phenethylamines; Protein Binding; Pyrrolidinones; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Reinforcement, Psychology; Schizophrenia; Swimming; Telemetry; Tritium; Xenopus

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

Atypical antipsychotics are associated with increased risk of weight gain, and researchers have turned to rodent models to better understand underlying mechanisms. Weight gain has been inconsistent in these studies though, possibly related to the rapid metabolism of antipsychotics in rodents. This study investigates olanzapine, an atypical antipsychotic with high liability for weight gain in humans, administered to rats by continuous infusion via osmotic minipump versus daily subcutaneous (s.c.) or intraperitoneal (i.p.) injections. We examined body weight, food intake and body composition for olanzapine (7.5mg/kg/day) versus placebo (n=8/group) in female Sprague-Dawley rats using the 3 routes of administration over 14 days. For olanzapine treated animals, weight gain was significantly greater in the minipump sample compared to both s.c. and i.p. injections. Twice as many animals (i.e. 75%) gained ≥ 7% body weight compared to either daily s.c. or i.p. injections. Olanzapine treated animals consumed more kilocalories than vehicle, and the minipump group consumed more than either daily injection group, although the difference with the s.c. sample was nonsignificant. Significantly more visceral fat was amassed in olanzapine treated animals versus vehicle, again greatest in the minipump sample, although differences between groups did not reach significance. The magnitude of increase across all groups fits with other evidence suggesting change in body composition may represent a more sensitive measure than body weight in assessing antipsychotic related changes. We conclude that the rodent model is tenable in evaluating the effects of antipsychotics on weight/body composition.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Body Composition; Body Weight; Eating; Female; Infusion Pumps; Injections, Intraperitoneal; Injections, Subcutaneous; Olanzapine; Random Allocation; Rats; Rats, Sprague-Dawley; Treatment Outcome

Antipsychotic drugs are increasingly used in children and adolescents to treat a variety of psychiatric disorders. However, little is known about the long-term effects of early life antipsychotic drug (APD) treatment. Most APDs are potent antagonists or partial agonists of dopamine (DA) D₂ receptors; atypical APDs also have multiple serotonergic activities. DA and serotonin regulate many neurodevelopmental processes. Thus, early life APD treatment can, potentially, perturb these processes, causing long-term behavioural and neurobiological sequelae. We treated adolescent, male rats with olanzapine (Ola) on post-natal days 28-49, under dosing conditions that approximate those employed therapeutically in humans. As adults, they exhibited enhanced conditioned place preference for amphetamine, as compared to vehicle-treated rats. In the nucleus accumbens core, DA D₁ receptor binding was reduced, D₂ binding was increased and DA release evoked by electrical stimulation of the ventral tegmental area was reduced. Thus, adolescent Ola treatment enduringly alters a key behavioural response to rewarding stimuli and modifies DAergic neurotransmission in the nucleus accumbens. The persistence of these changes suggests that even limited periods of early life Ola treatment may induce enduring changes in other reward-related behaviours and in behavioural and neurobiological responses to therapeutic and illicit psychotropic drugs. These results underscore the importance of improved understanding of the enduring sequelae of paediatric APD treatment as a basis for weighing the benefits and risks of adolescent APD therapy, especially prophylactic treatment in high-risk, asymptomatic patients.

Topics: Age Factors; Animals; Animals, Newborn; Benzamides; Benzazepines; Benzodiazepines; Body Weight; Conditioning, Operant; Dopamine; Dopamine Antagonists; Follow-Up Studies; Male; Nucleus Accumbens; Olanzapine; Protein Binding; Rats; Rats, Long-Evans; Reward; Selective Serotonin Reuptake Inhibitors; Tritium

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

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

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

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

Atypical antipsychotic drugs (AAPDs) such as olanzapine have a serious side effect profile including weight gain and metabolic dysfunction, and a number of studies have suggested a role for gender in the susceptibility to these effects. In recent times, the gut microbiota has been recognised as a major contributor to the regulation of body weight and metabolism. Thus, we investigated the effects of olanzapine on body weight, behaviour, gut microbiota and inflammatory and metabolic markers in both male and female rats.. Male and female rats received olanzapine (2 or 4 mg/kg/day) or vehicle for 3 weeks. Body weight, food and water intake were monitored daily. The faecal microbial content was assessed by 454 pyrosequencing. Plasma cytokines (tumour necrosis alpha, interleukin 8 (IL-8), interleuin-6 and interleukin 1-beta (IL-1β)) as well as expression of genes including sterol-regulatory element binding protein-1c and CD68 were analysed.. Olanzapine induced significant body weight gain in the female rats only. Only female rats treated with olanzapine (2 mg/kg) had elevated plasma levels of IL-8 and IL-1β, while both males and females had olanzapine-induced increases in adiposity and evidence of macrophage infiltration into adipose tissue. Furthermore, an altered microbiota profile was observed following olanzapine treatment in both genders.. This study furthers the theory that gender may impact on the nature of, and susceptibility to, certain side effects of antipsychotics. In addition, we demonstrate, what is to our knowledge the first time, an altered microbiota associated with chronic olanzapine treatment.

Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antipsychotic Agents; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Benzodiazepines; Biomarkers; Body Weight; Brain; Drinking; Eating; Female; Gene Expression; Ghrelin; Inflammation Mediators; Leptin; Liver; Locomotion; Male; Metagenome; Nuclear Proteins; Olanzapine; Rats; Rats, Sprague-Dawley; Sex Characteristics; Sterol Regulatory Element Binding Protein 1; Transcription Factors

Anorexia nervosa (AN) is an eating disorder characterized by extreme hypophagia, hyperactivity, and fear of weight gain. No approved pharmacological treatments exist for AN despite high mortality rates. The activity-based anorexia (ABA) phenomenon models aspects of AN in rodents, including progressive weight loss, reduced food intake, and hyperactivity. First, we optimized the ABA paradigm for mice. We compared mouse strains (Balb/cJ, A/J) for susceptibility with ABA, and evaluated the effects of different food access durations (2, 4, 6, 8, and 10 h) on ABA parameters. Balb/cJ mice exhibited significantly shorter survival time (days until 25% bodyweight loss) in the ABA paradigm compared with A/J mice. Furthermore, 6 h of food access reduced survival in mice housed with wheels without reducing survival in mice housed without wheels. We then evaluated the effects of chronic treatment with fluoxetine (4 weeks) or subchronic treatment with olanzapine (OLZ) (1 week) on ABA in BALB/cJ mice. OLZ (12 mg/kg/day) significantly increased survival and reduced food anticipatory activity (FAA). However, OLZ did not alter food intake or running wheel activity during ad-lib feeding (baseline) or restriction conditions, or in mice housed without wheels. Fluoxetine (18 mg/kg/day) increased food intake and reduced FAA, but did not alter survival. Here, we report for the first time that OLZ, but not fluoxetine, reduces ABA in mice. Our findings indicate further need for clinical investigations into the effects of OLZ, but not selective serotonin reuptake inhibitors, on core features of AN.

Topics: Animals; Anorexia; Benzodiazepines; Body Weight; Disease Models, Animal; Dose-Response Relationship, Drug; Eating; Female; Fluoxetine; Mice; Motor Activity; Olanzapine; Running; Selective Serotonin Reuptake Inhibitors; Survival Rate

This study aims to assess the proportion of patients with schizophrenia or bipolar disorder who discontinued treatment with one of two oral formulations of olanzapine within 12 months in outpatient settings in Germany, Greece, and France.. This 1-year, prospective, observational study included patients who had recently initiated treatment with olanzapine-coated tablets (OC) or the orodispersible (OD) formulation. Primary endpoint was olanzapine discontinuation for any reason. Clinical and functional status were also evaluated.. Out of 927 enrolled patients, 903 were included in the analyses (612 patients with schizophrenia, 291 with bipolar disorder). Within 12 months, 46 of 903 patients discontinued olanzapine. Most (95%) patients remained on olanzapine for 12 months with similar rates for patients with either diagnosis (94.5% for schizophrenia, 94.9% for bipolar disorder) and for both formulations (93.7% with OC, 95.3% with OD). The only factor significantly associated with time to discontinuation was baseline disease severity. Patients with more severe disease at baseline had a lower discontinuation risk. There were significant improvements in functioning and well-being and non-significant improvements in therapeutic alliance and compliance.. No significant difference was seen between discontinuation rates of the two formulations. Higher baseline severity was associated with a lower discontinuation rate.

Topics: Administration, Oral; Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Body Weight; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; Europe; Female; Follow-Up Studies; Hospitalization; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Observation; Olanzapine; Outpatients; Patient Compliance; Prospective Studies; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Suicide, Attempted; Treatment Outcome

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

Although weight gain is one of the most widely studied adverse effects of second-generation antipsychotics, only relatively few studies have specifically evaluated the long-term effect of switching antipsychotic medication on body weight. We aimed to evaluate the impact of switching antipsychotics on body mass index (BMI) during a 6-month follow-up period in a large cohort of patients with schizophrenia.. Data came from a 6-month prospective naturalistic survey in 6007 patients with schizophrenia.. We prospectively studied the effect on BMI of initiating or switching antipsychotic medication after 6 months of treatment among 3801 patients with schizophrenia in a real-life setting. Patients who were being treated with clozapine or olanzapine at baseline were more likely to experience a decrease in BMI during the follow-up period than the patients who were being treated with a conventional antipsychotic (odds ratio, 2.25 and 1.68, respectively). Patients treated with aripiprazole and, to a lesser extent, those treated with risperidone were more likely to experience a decrease in BMI during follow-up than patients treated with conventional antipsychotics (odds ratio, 2.96 and 2.06, respectively).. Our findings suggest that switching antipsychotics could be an effective strategy for reducing or preventing weight gain.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Body Mass Index; Body Weight; Clozapine; Cohort Studies; Female; Follow-Up Studies; Humans; Male; Middle Aged; Olanzapine; Piperazines; Prospective Studies; Quinolones; Risperidone; Schizophrenia; Weight Loss

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

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

Clinical use of olanzapine has been suggested to be associated with weight gain and adiposity in schizophrenic patients. While studies in experimental animals have noted weight gain in olanzapine-treated female rats, these findings have yet to be replicated in males. This study investigated the effect of chronic subcutaneous infusion of olanzapine in male rats via a recently developed electrical microinfusion pump.. An electrical microinfusion pump was subcutaneously implanted in male Sprague-Dawley rats who were then chronically administered olanzapine. Plasma olanzapine concentration and body weight were monitored, and fat pads were weighed after six weeks' olanzapine treatment.. Plasma olanzapine concentration plateaued within 4h of commencement of chronic olanzapine 1.5mg/animal/day infusion and remained constant until day 21. Six-week infusion of olanzapine at 1.5 but not 1mg/animal/day induced significant adiposity in subcutaneous, epididymal, and retroperitoneal fat. Body weight and food intake values did not differ between olanzapine- and vehicle-treated rats throughout the experiment.. The present study demonstrated that chronic infusion of olanzapine induced adiposity in male rats without inducing weight gain or hyperphagia, even with sufficient plasma concentration. This report is the first to provide information about adiposity-inducible plasma concentration of olanzapine in male rats.

Topics: Adipose Tissue; Animals; Antipsychotic Agents; Benzodiazepines; Body Weight; Eating; Infusion Pumps, Implantable; Infusions, Subcutaneous; Male; Olanzapine; Rats; Rats, Sprague-Dawley

Bipolar disorder (BPD) is a devastating long-term disease for which a significant symptom is mania. Rodent models for mania include psychostimulant-induced hyperactivity and single gene alterations, such as in the Clock or DAT genes, but there is still a pressing need for additional models. Recently, our lab isolated a line of mice, termed Madison (MSN), that exhibit behavioral characteristics that may be analogous to symptoms of mania. In this study we quantified possible traits for mania and tested the response to common anti-BPD drugs in altering the behavioral profiles observed in this strain. Relative to other mouse lines, MSN mice showed significant elevations of in-cage hyperactivity levels, significant decreases in daytime sleep, and significant increases in time swimming in the forced swim test. In terms of sexual behavior, the MSN mice showed significantly higher number of mounts and a trend toward higher time mounting. In separate studies, olanzapine and lithium (or respective controls) were administered to MSN mice for at least 2weeks and response to treatments was evaluated. Olanzapine (1mg/kg/day) significantly decreased in-cage hyperactivity and significantly increased time sleeping. Lithium (0.2-0.4% in food) significantly decreased in-cage hyperactivity. Given the behavioral phenotypes and the response to anti-BPD treatments, we propose that MSN mice may provide a possible new model for understanding the neural and genetic basis of phenotypes related to mania and for developing pharmaceutical treatments.

Topics: Animals; Antimanic Agents; Behavior, Animal; Benzodiazepines; Bipolar Disorder; Body Weight; Dark Adaptation; Disease Models, Animal; Exploratory Behavior; Lithium Chloride; Mice; Olanzapine; Sexual Behavior, Animal; Sleep; Swimming

To examine assessment and treatment profiles of adolescent patients with anorexia nervosa and eating disorder not otherwise specified who received olanzapine as compared with an untreated matched sample.. A retrospective, matched-groups comparison study was completed. Medical files of 86 female patients treated in the eating disorder program at the Children's Hospital of Eastern Ontario were examined. Patients treated with olanzapine were initially identified through chart review and then matched to a diagnosis, age, and, when possible, treatment group that served as the active comparator. Weight gain was examined in a sample of 22 inpatients.. Patients treated with olanzapine displayed greater evidence of psychopathology and medical compromise at the time of first assessment compared with those not treated. Rate of weight gain was not statistically different between groups when olanzapine was started during inpatient admissions. Medication effect on eating disorder cognitions could not be assessed given the presence of multiple confounders relating to treatment. Notable side effects included sedation and dyslipidemia in 56% of patients.. Despite our best attempts at matching olanzapine-treated subjects with a control sample, analysis revealed significant differences between groups, suggesting greater illness severity in those augmented with olanzapine. Given these inherent differences, we were unable to draw any firm conclusions regarding the potential efficacy of olanzapine. Factors associated with the prescription of adjunctive pharmacotherapy in this cohort appear to be linked to illness severity, acuity, and associated comorbidity. The observed side-effect profile indicates the need for more consistent predrug screening and for closer monitoring during treatment.

Topics: Adolescent; Anorexia Nervosa; Antipsychotic Agents; Benzodiazepines; Body Weight; Child; Cohort Studies; Female; Humans; Olanzapine; Research Design; Retrospective Studies; Severity of Illness Index; Treatment Outcome

Olanzapine has been recently tried to relieve anxiety and hyperactivity in adolescents with eating disorders (EDs). Presently, the side effects of the drug have been evaluated.. Forty-seven adolescents with EDs were followed up by repeated blood sampling before, during, and at 3 months after medication with olanzapine.. Olanzapine medication was discontinued in three patients because of galactorrhea, seizures, and raised liver enzyme activities, respectively. There was a normalization of glucose, insulin, and lipid profiles during treatment, which was related to weight gain and resumption of menstruations but not to medication. Increases in thyroid-stimulating hormone and prolactin were related to olanzapine medication and comedication with selective serotonine reuptake inhibitors. Three months after discontinuing medication, there were no persisting biochemical effects.. The side effects observed were those previously described for olanzapine. Most biochemical changes were related to weight (change) and amenorrhea and not to medication. Placebo-controlled studies are needed to investigate the efficacy of olanzapine in adolescents with EDs.

Topics: Adolescent; Amenorrhea; Antipsychotic Agents; Benzodiazepines; Body Weight; Child; Feeding and Eating Disorders; Female; Follow-Up Studies; Humans; Male; Olanzapine

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

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

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

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

The atypical antipsychotic, olanzapine (OLZ), is used to treat bipolar disorder, but its therapeutic mechanism of action is not clear. Arachidonic acid (AA, 20:4n-6) plays a critical role in brain signaling and an up-regulated AA metabolic cascade was reported in postmortem brains from bipolar disorder patients. In this study, we tested whether, similar to the action of the mood stabilizers lithium, carbamazepine and valproate, chronic OLZ treatment would reduce AA turnover in rat brain. We administered OLZ (6 mg/kg/day) or vehicle i.p. to male rats once daily for 21 days. A washout group received 21 days of OLZ followed by vehicle on day 22. Two hours after the last injection, [1-¹⁴C]AA was infused intravenously for 5 min, and timed arterial blood samples were taken. After the rat was killed at 5 min, its brain was microwaved, removed and analyzed. Chronic OLZ decreased plasma unesterified AA concentration, AA incorporation rates and AA turnover in brain phospholipids. These effects were absent after washout. Consistent with reduced AA turnover, OLZ decreased brain cyclooxygenase activity and the brain concentration of the proinflammatory AA-derived metabolite, prostaglandin E₂, In view of up-regulated brain AA metabolic markers in bipolar disorder, the abilities of OLZ and the mood stabilizers to commonly decrease prostaglandin E₂, and AA turnover in rat brain phospholipids, albeit by different mechanisms, may be related to their efficacy against the disease.

Topics: Acyl Coenzyme A; Algorithms; Animals; Antipsychotic Agents; Arachidonic Acid; Benzodiazepines; Blood Pressure; Blotting, Western; Body Weight; Brain Chemistry; Choline; Chromatography, Gas; Cytosol; Dinoprostone; Half-Life; Heart Rate; Kinetics; Lipid Metabolism; Male; Olanzapine; Phospholipases A2; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Inbred F344; Reverse Transcriptase Polymerase Chain Reaction

To measure the changes in subcutaneous and intra-abdominal fat and other metabolic parameters in patients with psychotic disorders, who were newly started on olanzapine treatment and in drug-free controls. The correlation between changes in visceral fat and other metabolic parameters were also studied.. Using a longitudinal open-label design, the 2 studied groups included patients with psychoses (n = 23) [diagnosed as per the 10th edition of the International Classification of Diseases criteria] and drug-free controls (n = 11). Fasting sugar, lipid profile and glycosylated haemoglobin levels were collected at baseline and follow-up. Computed tomographic scans were used to determine changes in the various abdominal fat parameters.. The patients were significantly younger than the controls, and the former had higher mean subcutaneous fat at baseline. There were statistically significant increases in the subcutaneous fat, intraabdominal fat, weight, waist circumference, hip circumference and body mass index in patients but not in controls. The mean dose of olanzapine (mg/day) correlated significantly with change of intraabdominal fat at follow-up. The change in intra-abdominal fat did not correlate significantly with any of the metabolic parameters studied.. Olanzapine produced significant increase in weight and fat parameters. This increase correlated with the dose of olanzapine.

Topics: Abdominal Fat; Adolescent; Adult; Aged; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Body Weight; Dose-Response Relationship, Drug; Follow-Up Studies; Glycated Hemoglobin; Humans; India; Intra-Abdominal Fat; Lipids; Longitudinal Studies; Middle Aged; Olanzapine; Psychotic Disorders; Tomography, X-Ray Computed; Waist Circumference; Waist-Hip Ratio; Young Adult

Topics: Adolescent; Analysis of Variance; Antipsychotic Agents; Aripiprazole; Attention Deficit and Disruptive Behavior Disorders; Benzodiazepines; Bipolar Disorder; Body Mass Index; Body Weight; Child; Dibenzothiazepines; Female; Follow-Up Studies; Humans; Male; Mental Disorders; Olanzapine; Piperazines; Quetiapine Fumarate; Quinolones; Risperidone; Schizophrenia; Spain; Time Factors

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

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

Atypical antipsychotic drugs (AAPDs) induce hyperphagia and body weight gain as a deleterious side effect. However, the mechanism whereby these drugs affect the neuronal pathways regulating energy balance has yet to be fully elucidated. The present study was conducted to investigate the respective and interaction effects of olanzapine and agonism of the melanin-concentrating hormone (MCH) receptor (MCHR1) on body weight, food intake, adiposity and expressions of genes liable of being involved in the anabolic action of AAPDs and MCH agonism. MCH is a hypothalamic neuropeptide, which exerts stimulating effects on food intake and body weight gain. Male Wistar rats received olanzapine (1 mg/kg of rat/day per os) and/or an intracerebroventricular (ICV) infusion of a MCHR1 agonist (30 microg/rat/day) during 13 days. Food intake and body weight were recorded daily, whereas adipose tissue depots were weighed at day 13. At the end of the experiment, we also measured brain levels of the messengers RNAs (mRNAs) encoding for MCH, MCHR1, neuropeptides-Y (NPY) and agouti-related peptide (AgRP) using in situ hybridization. The 13-day treatments combining olanzapine and the MCHR1 agonist exerted additive effects in enhancing food intake and adiposity. Consistently, each treatment differently affected brain expression of genes influencing energy balance. While the MCHR1 agonist treatment increased NPY mRNA expression in the hypothalamic arcuate nucleus, olanzapine treatment specifically increased MCHR1 mRNA expression in the nucleus accumbens shell (NAcSh). AAPDs and MCH agonism exert additive effects on energy balance and selective effects on the brain expression of energy balance-related genes.

Topics: Adiposity; Agouti-Related Protein; Analysis of Variance; Animals; Antipsychotic Agents; Arcuate Nucleus of Hypothalamus; Benzodiazepines; Body Weight; Eating; Energy Metabolism; Hypothalamic Hormones; In Situ Hybridization; Infusion Pumps, Implantable; Male; Melanins; Neuropeptide Y; Nucleus Accumbens; Olanzapine; Pituitary Hormones; Rats; Rats, Wistar; Receptors, Pituitary Hormone; RNA, Messenger; Time Factors

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

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

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

The impact of the UGT1A4, CYP1A2, and MDR1 genetic variants on olanzapine plasma levels, in relation to those of other individual factors, such as gender, smoking status, body weight, and age, was investigated in patients with schizophrenia.. A total of 121 patients were recruited from psychosis-specialized outpatient departments in Stockholm County. Olanzapine plasma concentrations were determined by high-performance liquid chromatography. Genotyping was carried out by PCR-restriction fragment length polymorphism or minisequencing, and haplotypes were analyzed using specialized computer software on population genetics. Multiple regression analysis was performed to investigate the combined effect of patient characteristics and genotypes/haplotypes on daily dose-corrected plasma concentrations of olanzapine.. In addition to , the results indicate that inter-patient differences in olanzapine exposure were explained by the known factor of time of sampling from last dose intake and by the following individual factors in order of relative impact: (1) male gender, (2) carrier of the UGT1A4 142T>G single nucleotide polymorphism (SNP), and (3) smoking. Each of these three factors predicted a decrease in daily dose-corrected plasma concentrations of 35, 25, and 21%, respectively. In contrast, age, body weight, and MDR1 or CYP1A2 haplotype did not have a significant impact.. At 12 h after dose intake, the regression model predicted a 5.1-fold higher olanzapine plasma level in a non-smoking female patient who did not carry the UGT1A4 142T>G SNP compared to a smoking man treated with the same dose but heterozygous for UGT1A4 142T>G SNP. Whether these combined genetic and environmental factors influence the risk of therapeutic failure remains to be established.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Antipsychotic Agents; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzodiazepines; Body Weight; Cytochrome P-450 CYP1A2; Female; Glucuronosyltransferase; Humans; Male; Middle Aged; Olanzapine; Polymorphism, Single Nucleotide; Schizophrenia; Sex Characteristics; Smoking

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

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

The second generation antipsychotic drugs (SGAs) are effective in treating patients with schizophrenia and have been considered as the first line therapy. Recently, increasing attention has been drawn to the potential diabetogenic effect of these novel antipsychotics. The goal of this study was to evaluate the time-dependent effects of olanzapine treatment on pancreatic beta cell function in SGA-naïve schizophrenic patients. Forty-two schizophrenic subjects received olanzapine therapy for 8 weeks and thirty-three of them completed the trial. Of whom 33 completers (21 male, mean+/-SD age: 37.6+/-8.0 years) were inpatients and unexposed to SGA. The metabolic parameters were quantitatively assessed at weeks 0, 2, 4, and 8 by the intravenous glucose tolerance test. After 56-day olanzapine treatment, subjects had significant increases in body weight and as well as in the levels of triglyceride, total cholesterol, and low-density lipoprotein. Insulin secretion significantly decreased at week 2, returned to baseline at week 4, and significantly increased at week 8. Of the total samples, 18.2% and 33.3% of them met the criteria for significant weight gain and metabolic syndrome after 8-week olanzapine treatment, respectively. This study indicates that olanzapine-treated schizophrenic patients displayed biphasic changes in insulin secretion to a hyperglycemic challenge. The results of this study support that olanzapine might directly influence pancreatic beta cell function.

Topics: Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Olanzapine; Prospective Studies; Schizophrenia; Time Factors

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

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

The prevalence of smoking is high in persons with serious mental illness (SMI) despite associated health risks. Persons with SMI die on average 25 years earlier than the general population and an increased focus on wellness, including smoking cessation, has been a goal of federal, state, and municipal governments.. The primary objective of this study was to evaluate the effects of smoking cessation on symptom severity in psychiatric inpatients at a New York State psychiatric facility 1 year after a smoke-free policy had been implemented. The secondary objective of this study was to evaluate cardiometabolic risk factors.. A retrospective chart review of 26 adult psychiatric inpatients receiving either clozapine, olanzapine, or both at any time between January 2006 and December 2007 was conducted. In addition to Brief Psychiatric Rating Scale (BPRS) scores and cardiometabolic measures (body weight, body mass index [BMI], and blood pressures before and after implementation of the smoke-free policy), other information collected included age, gender, diagnosis, the frequency of psychiatric medications used on an as-needed (p.r.n.) basis, immediate-need (stat) medication use, medication dosing, number of psychiatric emergencies, Global Assessment of Functioning (GAF) scores, privilege status, and time in special observation. Patients were compared on their own pre- and post-smoking cessation parameters and data were analyzed using a dependent t-test with p < 0.01 chosen as indicating significance.. Data analysis revealed a small but statistically significant decrease in GAF scores (p < 0.01), but no other significant difference between values pre- and post-smoking cessation.. Analysis demonstrated no change in psychiatric symptomatology or cardiometabolic factors 1 year post-smoking cessation in individuals with schizophrenia taking clozapine, olanzapine, or both. Further investigation is needed before concluding that smoking cessation has no impact on symptoms or on cardiometabolic risk factors. Despite a slight but statistically significant worsening in GAF scores, the health benefits of smoking cessation should continue to form the basis of encouraging smoking cessation in persons with SMI while longer term and methodologically more rigorous assessments on psychiatric and general health status are undertaken.

Topics: Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Benzodiazepines; Blood Pressure; Body Weight; Brief Psychiatric Rating Scale; Clozapine; Comorbidity; Cross-Sectional Studies; Female; Hospitalization; Humans; Male; Middle Aged; Olanzapine; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Smoking; Smoking Cessation

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

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

Weight gain is increasingly recognized as an unwanted side effect of atypical antipsychotic drugs. To explore the mechanisms underlying this side effect, we examined the effects of olanzapine, an atypical antipsychotic drug, on cellular proliferation and differentiation in the adult mouse hypothalamus. A 6-week treatment with olanzapine resulted in a significant increase in body weight. The sizes and numbers of olanzapine-treated mouse adipocytes were significantly larger than those of control mice. No significant differences were observed in the levels of blood insulin, cholesterol, triglyceride, leptin, and ghrelin among olanzapine-, haloperidol-treated and control mice with an exception that adiponectin was significantly higher in olanzapine group than control group. Body temperature and the level of uncoupling protein 2 were also comparable between the olanzapine-treated and control groups. We found that the treatment increased BrdU-incorporating cell numbers in the hypothalamus, while the same regimen with haloperidol or control had little effect on cellular proliferation. Double-labeling immunohistochemistry revealed that the majority of the BrdU-positive cells were also Olig2- or APC-positive, indicating that oligodendrocyte-lineage cells were generated in response to olanzapine treatment. Enhancement of hypothalamic cellular proliferation after intracerebroventricular infusion of cytosine arabinoside coincided with elevated food intake and weight gain. These findings suggest a possible link between gliogenesis in the hypothalamus and weight gain following olanzapine treatment.

Topics: Adipocytes; Animals; Antimetabolites; Antipsychotic Agents; Benzodiazepines; Biomarkers; Body Temperature; Body Weight; Bromodeoxyuridine; Cell Lineage; Cell Proliferation; Cell Size; Eating; Energy Metabolism; Female; Haloperidol; Hypothalamus; Immunohistochemistry; Mice; Mice, Inbred C57BL; Mitosis; Motor Activity; Olanzapine; Oligodendroglia

Numerous reports have linked atypical antipsychotics, especially clozapine and olanzapine, to the development of cardiovascular risk factors. In this retrospective chart review study, we investigated the blood pressure changes in Korean schizophrenic inpatients treated with clozapine or olanzapine.. We reviewed the medical record of schizophrenic patients treated with clozapine or olanzapine for 8 weeks. A total of 167 patients were included in the study; 70 patients in clozapine group and 97 patients in olanzapine group. Systolic and diastolic blood pressures prior to medication and at post-treatment (8-week) were assessed, and changes in blood pressure were analyzed. The prevalence of hypertension at the time of study period was assessed and compared between the two groups.. There was a significant difference in hypertension prevalence in comparisons between the clozapine and olanzapine group. The systolic and diastolic blood pressures in the clozapine group were significantly increased after treatment, but systolic and diastolic blood pressures in olanzapine group did not change significantly.. Our findings suggest that clozapine treatment may be associated with increased blood pressure and higher prevalence of hypertension, which may have a significant impact on medical morbidity and mortality.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Pressure; Body Weight; Cardiovascular Diseases; Clozapine; Cross-Sectional Studies; Female; Humans; Hypertension; Male; Middle Aged; Olanzapine; Republic of Korea; Retrospective Studies; Risk Factors; Schizophrenia

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

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

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

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

Progression of metabolic illness in a patient with schizophrenia who was stabilized on an atypical antipsychotic is described using a case study framework. Risks and benefits of staying on current treatment versus switching to another agent and switching strategies are described.. Switching an antipsychotic with more favorable side effects may improve metabolic parameters if other weight loss strategies have failed. Switching or stopping medications too quickly may exacerbate psychiatric symptoms. There is little evidence to support which is the best switching strategy.. The psychiatric mental health nurse practitioner carries a significant responsibility of discussing risks and benefits of switching and closely monitoring the patient during a switch of medications. Ensuring that the patient decides and agrees upon the treatment plan will improve the overall outcome.

Topics: Antipsychotic Agents; Benzodiazepines; Body Weight; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Follow-Up Studies; Humans; Hypercholesterolemia; Hypertriglyceridemia; Long-Term Care; Male; Middle Aged; Olanzapine; Paroxetine; Psychotic Disorders; Risk Assessment; Schizophrenia; Thioridazine

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

A 15 year old patient suffering from psychiatric disturbances looked for psychiatric help but refused hospital admission. Following an ambulatory treatment, the patient was diagnosed with Anorexia nervosa. The patient, a girl, was 175 centimeters tall, weighting only 39 kilos. Within the clinical picture, there were few dominant disorders present; anxiety, depression, low self-esteem, fear of feminization, with recurrent psychotic episodes. By the implementation of an intensive psychotherapeutic treatment, without the use of psychopharmacs, the weight was kept stable. In accordance with the girl's mother, a psychopharmacotherapy was commenced, a combination of olanzapine and paroxetine (the choice of psychopharmacs was lead by the side effects known). At the end of a 24-month period of a psychological treatment which was combined with psychopharmacotherapy, the patient exhibited no symptomatology and a stable clinical remission of the illness was achieved.

Topics: Adolescent; Ambulatory Care; Anorexia Nervosa; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Benzodiazepines; Body Weight; Combined Modality Therapy; Defense Mechanisms; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; MMPI; Olanzapine; Paroxetine; Psychotherapy

SOHO is a 3-year, prospective, observational study of schizophrenia patients who started a new antipsychotic in 10 European countries. Cohorts of patients were defined according to the antipsychotic started at baseline: olanzapine, risperidone, quetiapine, amisulpride, clozapine, oral typical and depot typical antipsychotics. Tolerability in terms of rates of extrapyramidal symptoms (EPS), tardive dyskinesia (TD), anticholinergic use, loss of libido/impotence, amenorrhoea/galactorrhoea/gynaecomastia, and weight change was assessed in 4939 patients who started monotherapy. Logistic regression models related medication initiated at study entry to adverse events over follow-up, adjusting by baseline differences among treatment cohorts. Patients taking typical antipsychotics or risperidone were more likely to experience EPS and TD during follow-up than patients taking olanzapine. Patients taking olanzapine were less likely to have loss of libido/impotence during follow-up than patients in the risperidone, amisulpride, clozapine, oral typical and depot typical cohorts. Weight gain occurred in all groups, but was greater with olanzapine. In conclusion, antipsychotics have different tolerability profiles in terms of the adverse events we monitored. Results should be interpreted conservatively due to the observational study design.

Topics: Administration, Oral; Adult; Antipsychotic Agents; Benzodiazepines; Body Weight; Cohort Studies; Delayed-Action Preparations; Dyskinesia, Drug-Induced; Erectile Dysfunction; Europe; Female; Humans; Libido; Male; Middle Aged; Odds Ratio; Olanzapine; Outpatients; Prolactin; Schizophrenia; Sexual Dysfunction, Physiological; Treatment Outcome

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

The aim of this study was to model in mice the association between metabolic syndrome and the administration of atypical antipsychotic (AAP). Two dosages (4 and 8 mg/kg per day) of olanzapine (OL) were infused in 36 female mice for 30 days by osmotic mini-pumps. This study was also designed to further extend the implications raised in other experiments by our model of AAP-induced metabolic dysregulation. Through the use of the osmotic mini-pumps, this model is aimed to circumvent the shorter (than in humans) half-life of AAPs in rodents and to chronically administer OL by a reliable and less disturbing method. Indirect calorimetry was used to evaluate metabolic rate (MR) and respiratory exchange ratio together with weight and caloric intake. Serum insulin, leptin, and glucose tolerance (oral glucose tolerance test) were assessed. Pancreatic beta cells insulin levels, periuterine and liver fat content were also analyzed. Olanzapine-infused mice exhibited a reduction of overall MR (kilojoule per hour) and resting MR and respiratory exchange ratio, with periuterine fat significantly enlarged. All metabolic alterations were detected at the highest dose, with major effects found on weight gain and hyperphagia. Impaired glucose metabolism, associated with hyperinsulinemia and hyperleptinemia were found. Insulin resistance was evidenced by the raise of HOMA-IR index. Increased insulin and lipid storage were detected at pancreatic and hepatic levels respectively. These findings illustrate the development of a cluster of risk factors (metabolic syndrome) and, for the first time, a decrease of energy expenditure (MR) due to chronic OL infusion.

Topics: Animals; Benzodiazepines; Body Weight; Dyslipidemias; Energy Metabolism; Female; Glucose Intolerance; Infusion Pumps, Implantable; Infusions, Intravenous; Insulin Resistance; Metabolic Syndrome; Mice; Olanzapine; Time Factors

A mouse model of atypical antipsychotic-associated adverse effects was used to compare the liability to induce weight gain, food intake, and metabolic alterations after chronic olanzapine (OL; LY170053, 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-[2,3-b][1,5] benzodiazepine) and ST2472 (ST; 9-piperazin-1-ylpyrrolo[2,1-b][1,3]benzothiazepine) administration. By adding two equipotent doses (3 and 6 mg/kg) of either OL or ST to a high-sweet, high-fat (HS-HF) diet, mice were allowed to self-administer drugs up to 50 days. Body weight and food intake were evaluated daily. Locomotor activity was recorded over 48 h at two different time points. Dyslipidemia was measured by central visceral obesity. Blood serum levels of insulin (IN), glucose (Glu), triglycerides (TGs), nonesterified fatty acids (NEFAs), cholesterol (Ch), and ketone (Ke) bodies were quantified. OL treatment at 3 mg/kg enhanced body weight, whereas at the highest dose, the increase became evident only during the last 10 days of treatment. OL (3 mg/kg) increased HS-HF intake over time, whereas the highest dose reduced intake during the second 10 and final 10 days of administration. Both compounds induced nocturnal hypomotility at the highest dose. In contrast to ST, 3 mg/kg OL elevated serum levels of IN, Glu, TG, NEFA, Ch, and Ke, whereas 6 mg/kg OL elevated those of Glu, TG, and Ch. In contrast, ST did not affect weight gain, food intake, and metabolic markers. Given the similarities between OL-induced obesogenic effects and medical reports, this study further supports the view that ST may represent a new class of agents characterized by a low propensity to induce side effects with promising clinical safety.

Topics: Animals; Benzodiazepines; Body Weight; Hyperphagia; Metabolic Diseases; Mice; Olanzapine; Piperazines; Pyrroles; Thiazepines; Weight Gain

Therapeutic use of atypical antipsychotic agents is often associated with weight gain and impaired glucose tolerance. The once-daily human GLP-1 analog liraglutide improves glycemic control and reduces body weight. We have investigated the ability of liraglutide to improve olanzapine-induced metabolic effects in female rats. Female Sprague-Dawley rats were implanted with subcutaneous osmotic mini pumps for delivery of olanzapine (1.75 mg/24 h) or vehicle for 28 days (n=20). After 14 days, ten animals from each group were given liraglutide (0.2 mg/kg) or vehicle twice daily for the remainder of the study. Compared to vehicle treated animals, olanzapine infusion for 4 weeks significantly increased end point cumulated food intake (667.3+/-7.0 versus 593.2+/-13.2g, p<0.01), body weight (306.6+/-4.2 versus 276.4+/-3.6 g, p<0.001), subcutaneous inguinal fat (3.4+/-0.3 versus 1.9+/-0.1 g, p<0.001), mesenteric fat (3.1+/-0.2 versus 1.7+/-0.2g, p<0.001), retroperitoneal fat (6.2+/-0.6 versus 2.8+/-0.3 g, p<0.001), and impaired glucose tolerance, measured as total area under the glucose curve during an oral glucose tolerance test (1906+/-66 versus 1770+/-28 mMxmin, p<0.05). These olanzapine-induced elevations were significantly reduced by liraglutide (cumulated food intake: 601.8+/-20.4 g, p<0.01; body weight: 280.2+/-5.6 g, p<0.001; subcutaneous inguinal fat: 2.4+/-0.2 g, p<0.001; mesenteric fat: 1.8+/-0.1 g, p<0.001; retroperitoneal fat: 3.5+/-0.4 g, p<0.001; AUC: 1764+/-32 mMxmin, p<0.05). In conclusion, subcutaneous olanzapine infusion in female rats leads to weight gain and metabolic changes of which several are reversed following liraglutide treatment. It may therefore be relevant to study these effects of liraglutide in patients treated with atypically antipsychotics.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Body Composition; Body Weight; Drug Administration Schedule; Eating; Female; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Intra-Abdominal Fat; Liraglutide; Olanzapine; Rats; Rats, Sprague-Dawley; Subcutaneous Fat, Abdominal; Weight Gain

Some atypical antipsychotics have been linked to an increased propensity for weight gain and metabolic disturbances, including type II diabetes. The objective of this study was to investigate an animal model to help understand the mechanisms underlying this phenomenon. Female, Sprague-Dawley rats were treated with olanzapine (2.0 or 7.5 mg/kg, via osmotic mini-pump) for 4 weeks, followed by the hyperinsulinemic/euglycemic and hyperglycemic clamp procedures to assess insulin sensitivity and secretion in vivo. Changes in body weight, visceral fat, food intake and locomotor activity were also assessed. Hepatic glucose production (R(A)) was increased in the hyperinsulinemic/euglycemic clamp for both treatment groups compared to control rats, while the high-dose olanzapine group had decreased peripheral glucose utilization (R(D)). No changes in insulin secretion were detected in the hyperglycemic clamp. Olanzapine did not change body weight or food intake, but did result in significant accumulation of visceral fat and decreases in locomotor activity. Like others, we found that a rodent model for antipsychotic-related weight gain per se is not tenable. However, chronic treatment with olanzapine was found to confer both hepatic and peripheral insulin resistance independent of weight gain, indicating a direct effect on glucose dysregulation.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Experimental; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hyperinsulinism; Insulin Resistance; Locomotion; Olanzapine; Rats; Rats, Sprague-Dawley

Although enhanced appetite and weight gain are potential side effects of treatment with antipsychotic agents, particularly olanzapine and clozapine, the mechanisms underlying these side effects are poorly understood. Leptin and ghrelin were recently identified as hormones that play crucial roles in the regulation of energy balance and glucose metabolism. To elucidate relationships between weight change and plasma levels of ghrelin and leptin, we investigated the circulating ghrelin and leptin levels and body weight during olanzapine treatment. Twenty-four patients with schizophrenia were examined during 6-month administration of olanzapine. Ghrelin, leptin, weight and body mass index (BMI) were measured before and after 2, 4, 8, 12, 16, and 24 weeks of olanzapine treatment. The concentration of glucose and various lipid metabolic parameters were measured at baseline and at 24 weeks. Significant increases in weight, BMI and leptin were observed at week 24. On the other hand, the serum levels of ghrelin decreased significantly after olanzapine treatment. In addition, the level of ghrelin was negatively correlated with the leptin level, BMI and weight. The leptin level was positively correlated with both BMI and weight. Ghrelin is associated with metabolic changes, in combination with leptin, during olanzapine treatment. However, further large-scale and longitudinal studies are warranted to elucidate the metabolic changes involving ghrelin, leptin and insulin during treatment with antipsychotics.

Topics: Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Ghrelin; Humans; Leptin; Male; Olanzapine; Schizophrenia

Leptin dysregulation has been implicated in the body weight gain and metabolic dysfunction observed with the second generation antipsychotic drugs (SGAD) olanzapine and clozapine.. This study quantified the frequency of subjects with abnormal correlation between leptin and the body mass index controlling for gender (defined as being out of the upper or lower 95% confidence interval in the regression line when combining each group with the drug-free subjects) after prolonged treatment with olanzapine (n=126), clozapine (n=62), first generation antiypsychotics (n=91), other SGAD (n=22), other psychotropic drugs (n=65) and drug-free subjects (n=229).. None of the analysis was significant (p>0.05). In fact, in 17 out of 20 comparisons, the drug-free group had numerically higher frequencies of outliers than the corresponding treatment group. There were 28 outliers (4.7% of the total sample). In agreement with previous studies, cross-sectional analysis did not report gross alterations in serum leptin levels during olanzapine or clozapine administration.. Longitudinal studies should focus on leptin regulation early on treatment, on the frequency of abnormal leptin receptor sensitivity and/or specific polymorphisms in the leptin allele and on several confounding factors in order to design personalized preventive and therapeutic measures.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Body Mass Index; Body Weight; Clozapine; Cross-Sectional Studies; Female; Humans; Insulin Resistance; Leptin; Male; Mental Disorders; Middle Aged; Olanzapine; Outliers, DRG; Receptors, Leptin; Schizophrenia; Sex Factors; Weight Gain

Olanzapine is widely used for the treatment of schizophrenia and is considered a first line medication in India. Along with other factors, the variation in response and side effects to this agent may be accounted for by genetic differences among patients. Olanzapine was administered for 6 weeks to Indian subjects with schizophrenia or schizoaffective disorder (DSM-IV, n=130), as part of an open label study. Intent-to-treat analysis was performed, and 10 polymorphic markers from seven genes (dopamine D1, D2, D3 and D4 receptors, serotonin 2A receptor and the drug-metabolizing enzymes (CYP1A2 and CYP2D6)), together with demographic and clinical variables, were analyzed as potential predictors of response. Olanzapine was efficacious, but significant weight gain was noted. Baseline weight and a 120 bp deletion polymorphism at the dopamine receptor D4 (DRD4) gene were associated with changes in symptom scores. Predictable covariates of treatment response were also noted. These results merit replicate studies.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Weight; Chromosome Deletion; Developing Countries; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; India; Male; Middle Aged; Olanzapine; Polymorphism, Genetic; Psychiatric Status Rating Scales; Risk Factors; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; 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

The ability of clozapine to induce weight gain in female rats was investigated in three studies with progressively lowered doses of clozapine. In an initial preliminary high dose study, clozapine at 6 and 12 mg/kg (i.p., b.i.d.) was found to induce weight loss. In a subsequent intermediate dose study, we obtained no evidence for clozapine-induced weight gain despite using identical procedures and doses of clozapine (1-4 mg/kg, i.p., b.i.d.) with which we have observed olanzapine-induced weight gain, hyperphagia, enhanced adiposity and metabolic changes [Cooper G, Pickavance L, Wilding J, Halford J, Goudie A (2005). A parametric analysis of olanzapine-induced weight gain in female rats. Psychopharmacology; 181: 80-89.]. Instead, clozapine induced weight loss without alteration in food intake and muscle mass or changes in levels of glucose, insulin, leptin and prolactin. However, these intermediate doses of clozapine enhanced visceral adiposity and elevated levels of adiponectin. In a final study, low doses of clozapine (0.25-0.5 mg/kg, i.p, b.i.d.) induced weight loss. These data demonstrate that clozapine-induced weight gain can be much more difficult to observe in female rats than olanzapine-induced weight gain. Moreover, these findings contrast with clinical findings with clozapine, which induces substantial weight gain in humans. Clozapine-induced enhanced adiposity appears to be easier to observe in rats than weight gain. These findings, along with other preclinical studies, suggest that enhanced adiposity can be observed in the absence of antipsychotic-induced weight gain and hyperphagia, possibly reflecting a direct drug effect on adipocyte function independent of drug-induced hyperphagia [e.g. Minet-Ringuet J, Even P, Valet P, Carpene C, Visentin V, Prevot D, Daviaud D, Quignard-Boulange A, Tome D, de Beaurepaire R (2007). Alterations of lipid metabolism and gene expression in rat adipocytes during chronic olanzapine treatment. Molecular Psychiatry; 12: 562-571.]. These and other findings which show that the results of studies of antipsychotic treatment in animals do not always mimic clinical findings have important implications for the use of animal models of antipsychotic-induced weight gain. With regard to weight gain the results obtained appear to depend critically on the experimental procedures used and the specific drugs studied. Thus such models are not without limitations. However, they do consistently demonstrate the ability of various ant

Topics: Adiponectin; Adiposity; Animals; Antipsychotic Agents; Behavior, Animal; Benzodiazepines; Body Mass Index; Body Weight; Clozapine; Dose-Response Relationship, Drug; Eating; Female; Hyperinsulinism; Hyperphagia; Models, Animal; Olanzapine; Rats; Rats, Wistar; Research Design; Sex Factors; Weight Gain; Weight Loss

Atypical antipsychotic medications have largely supplanted their typical counterparts, both for psychosis and for the treatment of aggression and/or self-injurious behaviour (SIB), in persons with intellectual disabilities (ID). However, with the exception of risperidone, little systematic research supports their use in such persons.. A retrospective review of 31 adult residents of a state developmental centre, who were treated for aggression and/or SIB with atypical antipsychotics. Average monthly counts of aggression and SIB for 1 year of treatment with typical antipsychotics, were compared with monthly averages for the next 12 months of treatment with atypical antipsychotics.. Twenty-seven of 31 subjects (87%) completed a full year of atypical antipsychotic treatment. Subjects ranged in age from 24 to 54 years (mean = 39); 18/31 (58%) had profound ID. Twelve of 26 (46%) had typical antipsychotics discontinued within the year of atypical treatment; another 7/26 (27%) had their typical antipsychotic dose decreased. Twenty-three of 31 trials involved risperidone; 7/31 olanzapine; 1/31 quetiapine. Subjects gained an average of 6.6 pounds during the year of atypical treatment, but no significant changes in glucose or cholesterol were found. Subjects with aggression alone (N = 14) had significant decreases in the number of aggressive acts per month during the year of atypical treatment (P = 0.03); those with both aggression and self-injury (N = 12), or those with self-injury alone (N = 5) had no significant improvement.. The findings suggest that atypical antipsychotics can be successfully substituted for typical agents in individuals with ID and decrease the frequency of aggression over one year of treatment. The weight gain seen in our sample reinforces the necessity of regular monitoring of weight and metabolic changes in persons with ID treated with atypical antipsychotics.

Topics: Adult; Aggression; Antipsychotic Agents; Benzodiazepines; Body Weight; Dibenzothiazepines; Dose-Response Relationship, Drug; Female; Humans; Intellectual Disability; Male; Middle Aged; Olanzapine; Quetiapine Fumarate; Retrospective Studies; Risperidone; Self-Injurious Behavior; Treatment Outcome

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

The underlying mechanisms of antipsychotic (AP)-induced weight gain are unknown, but both central and peripheral AP target receptors could potentially be involved. This study used radioligand binding assays to compare the binding affinities of clozapine, olanzapine and haloperidol for candidate receptors potentially involved in AP-induced weight gain. Selected candidates derived from known pathways involved in body weight regulation included receptors classified as anorexigenic (bombesin receptor subtype 3, calcitonin gene-related peptide receptor, cholecystokinin receptor, melanocortin-4 receptor, neurotensin receptor 1) or orexigenic (cannabinoid receptor 1, galanin 1 receptor, melanin-concentrating hormone receptor (MCHR), neuropeptide Y1 receptor) as well as receptors involved in physiological actions related to digestion and fluid homeostasis (angiotensin II type 1 receptor, bradykinin B2 receptor, endothelin receptor, neurokinin 1 receptor, vasoactive intestinal polypeptide receptor 1). Clozapine, olanzapine and haloperidol exhibited negligible affinities to all of these receptors except for the MCHR (Ki=501 nM; haloperidol). With respect to other candidates from (neuro)transmitter systems already suggested to be involved in AP-induced weight gain, the binding profile of olanzapine resembled that of clozapine, with high affinity (Ki<10 nM) for serotonin (5-HT) 5-HT2A, 5-HT2C and 5-HT6, muscarinic M1 and histamine H1 receptors. In contrast, the binding profile of haloperidol was substantially different (high affinity only for the dopamine D1 receptor). In conclusion, we have not identified a novel binding site of the two investigated atypical AP that could contribute to the induced weight gain.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Body Weight; Clozapine; Haloperidol; Humans; Olanzapine; Protein Binding; Radioligand Assay; Receptors, Cell Surface

The study was aimed at the evaluation of weight gain associated with atypical antipsychotics and its clinical risk factors in children and adolescents. Weight and body mass index (BMI) of initially hospitalised patients treated with clozapine (n = 15), olanzapine (n = 15), and risperidone (n = 15) were prospectively monitored on a weekly basis for the first 6 weeks. Different clinical risk factors were tested for their association with weight gain in the three groups. All three groups experienced significant weight gain between baseline and endpoint (p < 0.0001). For all weight measures, planned comparisons were all significant between olanzapine vs. clozapine and risperidone, respectively. Average weight gain was significantly higher for the olanzapine group (mean = 4.6 kg, SD = 1.9) than for the risperidone (mean = 2.8 kg, SD = 1.3) and clozapine (mean = 2.5 kg, SD = 2.9) groups. Olanzapine and risperidone, but not clozapine, caused a disproportionately higher weight gain in children and adolescents in comparison to adults.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Body Weight; Child; Clozapine; Female; Humans; Male; Mental Disorders; Olanzapine; Risperidone; Weight Gain

Treatment with some antipsychotic drugs may result in excessive body weight gain which can have detrimental effects on patient compliance, morbidity and mortality. The aim of the present study was to investigate the effect of atypical antipsychotic drugs on dietary macronutrient selection, body weight, body composition and biochemical parameters related to obesity in female rats.. Forty pair-housed, adult female hooded-Lister rats (250 +/- 5 g) were habituated to three diets containing principally protein, fat, or carbohydrate in a home cage self-selection paradigm. Olanzapine (2 mg/kg), risperidone (0.5 mg/kg), ziprasidone (2.5 mg/kg), or vehicle was injected intraperitoneally once daily for 22 days; food selection, water intake, and body weight were recorded daily, while body composition and plasma hormones (insulin, glucose, nonesterified free fatty acid, total cholesterol, glycerol, triacylglycerol, leptin, and prolactin) were analyzed at the end of the study.. Only olanzapine significantly increased body weight and food intake. Macronutrient selection was significantly altered after olanzapine and risperidone treatment (increased protein and decreased fat preference). Only olanzapine increased carcass fat content. Locomotor activity was significantly reduced in all treatment groups. Both olanzapine and risperidone significantly increased plasma prolactin. Olanzapine was without effect on any other biochemical parameter measured. Ziprasidone significantly reduced plasma leptin and nonsignificantly reduced NEFA, while risperidone significantly reduced fasting plasma glucose.. This study supports our previous work demonstrating weight gain and increased feeding behavior induced by olanzapine and could have important implications for enhancing our understanding of the mechanisms by which olanzapine and other atypical antipsychotics induce weight gain in the clinic.

Topics: Adiposity; Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Composition; Body Weight; Cholesterol; Drinking; Eating; Energy Metabolism; Fatty Acids, Nonesterified; Female; Food Preferences; Glycerol; Insulin; Leptin; Motor Activity; Olanzapine; Piperazines; Prolactin; Rats; Risperidone; Thiazoles; Triglycerides

Schizotypal personality disorder (SPD) has rarely been reported as an eating disorder-related personality trait. A 23-year-old woman was diagnosed as having anorexia nervosa binge eating/purging type. At the age of 53 years, she was admitted to Jikei University Hospital because of excessive bodyweight loss. She was diagnosed as having SPD based on bizarre behavior, ideation and a tendency to seek isolation. She was treated with low-dose antipsychotics, and her impulsive behavior improved. The patient's SPD was considered to have had a psychopathological contribution to her chronic episodes of anorexia nervosa.

Topics: Anorexia Nervosa; Antidepressive Agents, Second-Generation; Benzodiazepines; Body Weight; Bulimia; Chronic Disease; Female; Hospitalization; Humans; Mianserin; Middle Aged; Olanzapine; Paroxetine; Schizotypal Personality Disorder; Selective Serotonin Reuptake Inhibitors

We compared the changes in weight (kg) and body mass index (BMI) (kg/m(2)) in 52 hospitalized adolescents between baseline and after 12 weeks of monotherapy with either (i) olanzapine (OLZ) orally disintegrating tablets (ODT) (N=16; 16.6 mg/day+/-4.4 [SD]), or (ii) OLZ standard oral tablets (SOT) (N=10; 18.0 mg/day+/-4.2), or (iii) risperidone (N=26; 2.8 mg/day+/-1.2). Significantly greater increases in mean weight and BMI were observed in the patients treated with OLZ SOT (8.9+/-5.1 [SD] kg; 1.9+/-0.6 kg/m(2), respectively) than in those with ODT (3.0+/-2.1 kg; 1.1+/-0.8 kg/m(2)). Similarly, OLZ ODT treatment was associated with significantly greater increases in weight and BMI than risperidone (1.0+/-1.8 kg; 0.4+/-0.7 kg/m(2)). These findings suggest that adolescents gain less weight with OLZ ODT than OLZ SOT, possibly because the former formulation shortens the time of interaction with digestive serotonin receptors mediating satiety.

Topics: Administration, Oral; Adolescent; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Drug Administration Routes; Female; Humans; Male; Olanzapine; Risperidone; Schizophrenia; Tablets; Weight Gain

Risperidone and olanzapine are second-generation antipsychotics that are increasingly used in child and adolescent psychiatry. So far, little is known about plasma concentrations and concentration-to-dose (C/D) ratios of these agents in children and adolescents compared to adults.. This study investigated whether age and gender influence risperidone and olanzapine plasma concentration by determining risperidone and olanzapine plasma levels by tandem mass spectrometry in 162 Caucasian patients (98 risperidone and 64 olanzapine).. For risperidone and 9-hydroxyrisperidone, the C(total)/D ratio was almost identical in both age groups (10-18 and 19-45 years, respectively). In the younger age group, females exhibited significantly higher total plasma levels than males while receiving similar doses of risperidone. For olanzapine, in adolescents significantly higher C/D ratios were detected by an average of 43% (after adjustment for weight: 34%) compared to adults.. This study demonstrates an age effect for olanzapine but not for risperidone resulting in higher olanzapine plasma levels in younger patients. For risperidone, we found a gender effect as female adolescent patients had significantly higher risperidone plasma concentrations than male adolescent patients. Future prospective studies are necessary to clarify whether the prescribed dosage should be different in young and older patients.

Topics: Adolescent; Adult; Aging; Antimanic Agents; Antipsychotic Agents; Benzodiazepines; Body Weight; Child; Dose-Response Relationship, Drug; Drug Interactions; Female; Humans; Male; Middle Aged; Olanzapine; Psychotic Disorders; Retrospective Studies; Risperidone; Sex Characteristics; Smoking; Tandem Mass Spectrometry; Valproic Acid

Patients with bipolar disorder (BD) on long-term maintenance treatment represent a clinical population with peculiar characteristics, for which available equations to estimate resting energy expenditure (REE) are not suitable. The aim of this study was to measure REE by means of indirect calorimetry in bipolar patients on maintenance treatment and in controls, and to estimate the agreement between measured and predicted REE in both groups.. Patients diagnosed with BD I and healthy controls were assessed for height, weight and body mass index (BMI). Predicted REE was calculated using Harris-Benedict, Schofield, Recommended Nutrients Assumption Levels (LARN), and OUR equations; measurements of REE were performed using a portable indirect calorimeter.. Results for our sample show the most commonly used formulas give a systematic overestimation of REE with respect to measured basal metabolic rate in the patient group. The mean bias was considerably greater for bipolar subjects than for controls.. These results suggest that patients with severe mental illness on long-term psychopharmacologic treatment may have reduced basal energy expenditure that may be a cause of weight gain.

Topics: Adolescent; Adult; Age Factors; Algorithms; Antipsychotic Agents; Basal Metabolism; Benzodiazepines; Bipolar Disorder; Body Height; Body Weight; Calorimetry, Indirect; Energy Metabolism; Female; Humans; Male; Middle Aged; Models, Biological; Nutritional Status; Olanzapine; Rest; Sex Factors

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

In a putative animal model of antipsychotic drug-induced weight gain, female rats received either vehicle, ziprasidone (2.0, 6.0, 10 mg/kg) or olanzapine (2.0 mg/kg), orally, twice daily, for 7 days. Body weights were assessed daily and prolactin assayed at the end of the regimen. Ziprasidone caused significant weight gain, as did olanzapine, while stimulating distinct patterns of prolactin secretion. Thus, assessment of body weight provides only limited predictive validity in differentiating between weight gain-inducing and weight-neutral drugs.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Body Weight; Female; Olanzapine; Piperazines; Prolactin; Rats; Rats, Sprague-Dawley; Thiazoles; Weight Gain

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

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

Atypical antipsychotics, such as olanzapine, have been associated with clinically significant weight gain. Changes to the hypothalamic pituitary adrenal axis may partially mediate this weight increase. Two experiments were conducted to test the effects of mifepristone on both mitigating and preventing olanzapine-induced weight gain. In the first experiment, adult female Sprague-Dawley rats gained significantly more weight on average when administered olanzapine for 35 days compared to vehicle controls. Subsequently, the olanzapine-treated rats were randomized to three dose levels of mifepristone (20, 60, and 200 mg/kg) in conjunction with olanzapine. Weight measurements were taken for 21 additional days. Rats receiving olanzapine plus mifepristone rapidly lost a significant portion of the weight gained during the olanzapine only phase (p = 0.0001). Rats in the 200 mg/kg dose group had significantly less abdominal fat compared to controls (p < 0.001) at study end. In the second experiment, daily mifepristone (20, 60, 200 mg/kg) initiated concomitantly with olanzapine was compared with olanzapine alone to determine if mifepristone prevented olanzapine-induced weight gain. After 21 days of treatment, mifepristone treated rats gained significantly less weight and had significantly less abdominal fat than rats administered olanzapine alone (p = 0.0002). Results suggest that mifepristone, a potent glucocorticoid antagonist, may both reduce and prevent olanzapine-induced weight gain in rats.

Topics: Abdominal Fat; Analysis of Variance; Animals; Antipsychotic Agents; Benzodiazepines; Body Weight; Dose-Response Relationship, Drug; Drug Interactions; Female; Hormone Antagonists; Mifepristone; Olanzapine; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Glucocorticoid; Receptors, Progesterone; Weight Gain

Weight gain is a common and severe side effect of antipsychotic drugs. A usual tool to study the side effects of psychotropic drugs is animal models. However, attempts to create an animal model of antipsychotic-induced weight gain were not successful so far. Female rodents are sensitive to the effects of antipsychotics, but not males. This does not match the human clinical situation. Antipsychotics have different pharmacokinetic properties in rats and humans, and rats and humans have different spontaneous diets.. In the present study, we tested the hypothesis that the insensitivity of male rats to the weight-promoting effects of antipsychotics could be related to the mode of administration of antipsychotics and to the animals' diet. Antipsychotics were mixed with the food, and rats were fed a diet resembling the human diet. Rats were treated with 0.01, 0.1, 0.5, and 2 mg/kg of olanzapine or with a control solution for 6 weeks. Their weight and food intake were recorded, and their body composition were analyzed. The effects on weight and food intake of olanzapine (1 mg/kg), haloperidol (1 mg/kg), and ziprasidone (10 mg/kg) were also compared in a 3-week treatment experiment.. The results showed that 0.5 and 2 mg of olanzapine, but not lower doses, increase body weight and subcutaneous fat deposition. After the 3-week treatment, olanzapine-treated rats, but not haloperidol- or ziprasidone-treated rats, had significantly increased their weight.. This study shows that a rat model of obesity induced by antipsychotics can be created under specific conditions of drug administration, diet, and dose.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Body Composition; Body Weight; Circadian Rhythm; Diet; Disease Models, Animal; Dose-Response Relationship, Drug; Eating; Feeding Behavior; Haloperidol; Male; Obesity; Olanzapine; Piperazines; Rats; Rats, Sprague-Dawley; Thiazoles; Time Factors; Weight Gain

Risperidone, olanzapine, and clozapine are three atypical antipsychotic medications commonly used in the management of chronic schizophrenia. While they offer advantages with regard to clinical efficacy and side-effect profile, few studies have compared them in a naturalistic prospective observational manner. This study therefore investigated their comparative efficacy over 12 weeks including illness characteristics and adverse effects. One hundred thirty-one patients (76 M, 55 F) with DSMI-V schizophrenia or schizoaffective disorder were treated with risperidone (n = 38), olanzapine (n = 38), or clozapine (n = 55). All patients showed a significant decrease of Positive and Negative Syndrome Scale (PANSS)-positive scores. Decreases in tardive dyskinesia and impulsivity scores were noted with clozapine and olanzapine, respectively. No differences between the medications were noted on depression, anxiety, EPS, or overt aggression scores. Olanzapine and clozapine appeared to be more effective in females. Males showed a decreased sexual performance irrespective of the medication and those treated with risperidone and clozapine showed greater proportional reduction of overt aggression. Clozapine-treated patients showed significant increased weight, increased glucose levels, and lowered sexual performance. Risperidone patients tended to exhibit reduced cholesterol levels. Higher creatine kinase (CK) levels were noted in risperidone-treated patients. While cautious given the nature of the study design, results suggest differences in the response to various atypical antipsychotic medications regarding efficacy and side-effect susceptibility.

Topics: Adolescent; Adult; Aged; Aggression; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Cholesterol; Chronic Disease; Clozapine; Creatine Kinase; Female; Humans; Male; Middle Aged; Olanzapine; Prospective Studies; Risperidone; Schizophrenia; Sex Factors; Triglycerides

Clozapine and olanzapine treatment has been associated with insulin resistance in non-obese schizophrenia patients. Much less is known regarding other agents such as quetiapine. The objective of this study was to compare matched olanzapine- and quetiapine-treated schizophrenia patients and normal controls on measures of glucose metabolism.. A cross-sectional comparison of quetiapine-treated and olanzapine-treated non-obese (body mass index < 30.0 kg/m2) schizophrenia subjects (DSM-IV) with matched normal controls using a frequently sampled intravenous glucose tolerance test and nutritional assessment was conducted from April 2002 to October 2004. Data from 24 subjects were included in the analysis (7 quetiapine, 8 olanzapine, 9 normal controls).. There was a significant difference among groups for fasting baseline plasma glucose concentrations (p = .02), with olanzapine greater than normal controls (p = .01). The insulin sensitivity index (SI) differed significantly among groups (p = .039); olanzapine subjects exhibited significant insulin resistance compared to normal controls (p = .01), but there was no significant difference for quetiapine versus olanzapine (p = .1) or quetiapine versus normal controls (p = .40). SI inversely correlated with quetiapine dose (p = .0001) and waist circumference (p = .03) in quetiapine-treated subjects. Insulin resistance calculated by the homeostasis model assessment of insulin resistance (HOMA-IR) also differed significantly among groups (p = .03). The olanzapine group had a higher HOMA-IR level than normal controls (p = .01). There was a significant difference in glucose effectiveness (SG) among the groups (p = .049). SG was lower in the olanzapine group than in the quetiapine group (p = .03) and in the olanzapine group compared to normal controls (p = .049).. Our findings are consistent with our previous report that nonobese olanzapine-treated subjects showed insulin resistance, measured by both HOMA-IR and SI, and reduction in SG. Studies that include larger samples, unmedicated patients, and varying durations of antipsychotic exposure are necessary to confirm these results.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Body Weight; Cross-Sectional Studies; Dibenzothiazepines; Female; Follow-Up Studies; Glucose; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Male; Metabolic Syndrome; Middle Aged; Nutrition Assessment; Olanzapine; Quetiapine Fumarate; Risk Factors; Schizophrenia

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

This study aimed to examine the impact of ziprasidone and olanzapine on QTc interval, weight and metabolic parameters in adults with schizophrenia and other psychoses. A retrospective cohort chart review was performed of 191 randomly selected patients who were being treated with ziprasidone or olanzapine in an integrated health care system. Significant differences on QTc interval were not observed. A significant weight gain was observed in olanzapine-treated patients (P<0.001) but not in the ziprasidone-treated cohort (P>0.05). Furthermore, adverse metabolic changes associated with olanzapine administration were significant with respect to effects on total cholesterol (P=0.01), triglycerides (P=0.05) and haemoglobin A1C (HbA1C) (P<0.05), whereas significant favourable metabolic effects were observed in ziprasidone-treated patients with regard to total cholesterol (P<0.05), low-density lipoprotein (LDL) (P<0.01), high-density lipoprotein (HDL) (P<0.05) and HbA1c (P<0.05). Our results suggest that these two atypical antipsychotics are safe and well tolerated from a cardiovascular standpoint, with no differences in QTc interval prolongation being observed. Olanzapine-treated patients exhibited significant weight increases, whereas ziprasidone-treated patients exhibited weight loss. Olanzapine treatment was also associated with significant adverse effect on patient's lipid profile and HbA1c. These adverse metabolic effects were not observed in ziprasidone-treated patients although favourable effects were observed with regard to effect on total cholesterol, LDL, HDL and HbA1c.

Topics: Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Electrocardiography; Female; Glycated Hemoglobin; Heart Rate; Humans; Hyperlipidemias; Lipids; Male; Middle Aged; Olanzapine; Piperazines; Retrospective Studies; Schizophrenia; Thiazoles; Triglycerides

Atypical antipsychotics have been linked to weight gain, hyperglycemia, and diabetes. We examined the effects of atypical antipsychotics olanzapine (OLZ) and risperidone (RIS) versus placebo on adiposity, insulin sensitivity (S(I)), and pancreatic beta-cell compensation. Dogs were fed ad libitum and given OLZ (15 mg/day; n = 10), RIS (5 mg/day; n = 10), or gelatin capsules (n = 6) for 4-6 weeks. OLZ resulted in substantial increases in adiposity: increased total body fat (+91 +/- 20%; P = 0.000001) reflecting marked increases in subcutaneous (+106 +/- 24%; P = 0.0001) and visceral (+84 +/- 22%; P = 0.000001) adipose stores. Changes in adiposity with RIS were not different from that observed in the placebo group (P > 0.33). Only OLZ resulted in marked hepatic insulin resistance (hepatic S(I) [pre- versus postdrug]: 6.05 +/- 0.98 vs. 1.53 +/- 0.93 dl . min(-1) . kg(-1)/[microU/ml], respectively; P = 0.009). beta-Cell sensitivity failed to upregulate during OLZ (pre-drug: 1.24 +/- 0.15, post-drug: 1.07 +/- 0.25 microU . ml(-1)/[mg/dl]; P = 0.6). OLZ-induced beta-cell dysfunction was further demonstrated when beta-cell compensation was compared with a group of animals with adiposity and insulin resistance induced by moderate fat feeding alone (+8% of calories from fat; n = 6). These results may explain the diabetogenic effects of atypical antipsychotics and suggest that beta-cell compensation is under neural control.

Topics: Adipose Tissue; Animals; Antipsychotic Agents; Benzodiazepines; Body Weight; Dietary Fats; Dogs; Insulin Resistance; Islets of Langerhans; Male; Olanzapine; Risperidone

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

Prepulse inhibition (PPI) of the acoustic startle reflex is a commonly used measure of preattentive sensorimotor gating. Disrupted PPI in rodents represents an animal model of the sensorimotor gating deficits characteristic of schizophrenia. The neurotensin (NT) system is implicated in the pathophysiology of schizophrenia, and NT has been hypothesized to act as an endogenous antipsychotic. In rats, NT receptor agonists restore PPI disrupted by dopamine receptor agonists and N-methyl-D-aspartate receptor antagonists, and pretreatment with an NT receptor antagonist blocks restoration of isolation rearing induced deficits in PPI by some antipsychotic drugs. The current studies further scrutinized the role of the NT system in the regulation of PPI and in antipsychotic drug-induced restoration of PPI using NT-null mutant mice (NT-/-). NT-/- mice exhibited significantly higher pulse alone startle amplitudes and disrupted PPI compared with NT+/+ mice. Haloperidol (0.1 mg/kg) and quetiapine (0.5 mg/kg) administered 30 min before PPI testing significantly increased PPI in NT+/+ mice but had no effect on PPI in NT-/- mice. In contrast, clozapine (1.0 mg/kg) significantly increased PPI in both NT-/- and NT+/+ mice, whereas olanzapine (0.5 mg/kg) had no effect on PPI in either NT-/- or NT+/+ mice. In a separate experiment, amphetamine (2.0 mg/kg i.p.) significantly disrupted PPI in NT+/+ mice but not NT-/- mice. These results provide evidence that the effects of antipsychotic drugs (APDs) may be differentially affected by the state of NT neurotransmission and, moreover, that APDs differ in their dependence on an intact NT system.

Topics: Amphetamine; Animals; Antipsychotic Agents; Benzodiazepines; Body Weight; Clozapine; Dibenzothiazepines; Female; Haloperidol; Male; Mice; Mice, Inbred C57BL; Neurotensin; Olanzapine; Quetiapine Fumarate; Reflex; Reflex, Startle

Atypical antipsychotic drug (APD)-induced weight gain causes non-compliance, increasing the risk of relapse and medical complications.. In an animal model, we assessed body weights, food intake, body fat/lean body mass contents and blood serum levels of glucose and lipids in female rats treated with olanzapine (Experiment 1). Also, we investigated the effect of aripiprazole vs olanzapine treatment on weight gain (WG) and plasma prolactin secretion in two strains (Wistar and Sprague-Dawley) and in two housing conditions (singly and group housed; Experiment 2).. In Experiment 1, Wistar females received either vehicle or olanzapine (5.0 mg kg(-1), p.o.) twice daily for 14 days. In Experiment 2, female rats (Wistar or Sprague-Dawley), housed singly or in groups, received either vehicle, aripiprazole (2.0-8.0 mg kg(-1), p.o.), or olanzapine (1.0-10 mg kg(-1), p.o.) twice daily for 7 days. Body weights and food intake were assessed daily. Body composition and blood assays were analyzed at the end of the treatment.. WG induced by chronic olanzapine treatment was characterised by hyperphagia, increased body fat, and serum free fatty acid content and reduced lean tissue and serum glucose content. Subchronic aripiprazole treatment resulted in rapid and robust WG similar to those observed with olanzapine. In spite of similar effects on body weight, aripiprazole and olanzapine stimulated markedly different patterns of prolactin secretion. Body weight changes and prolactin secretion induced by these APDs were significantly modulated by housing and by strain.. Assessment of body weight in the present model may not have predictive validity, and other measures may be needed to differentiate between WG-inducing and weight-neutral drugs.

Topics: Animals; Aripiprazole; Benzodiazepines; Body Weight; Cholesterol, HDL; Fatty Acids, Nonesterified; Female; Olanzapine; Piperazines; Prolactin; Quinolones; Rats; Rats, Sprague-Dawley; Rats, Wistar; Weight Gain

New antipsychotic drugs often increase weight and produce metabolic disturbances in treated patients. However, the mechanisms by which neuroleptics induce these undesirable side effects in humans are not known. Studies have shown that antipsychotics can increase body weight in female but not in male rats. However, no studies investigated changes in macronutrient selection during chronic treatments with antipsychotics in male rats, and no studies investigated precisely body composition after such treatments. In the present work, we studied in male rats the effects of long-term administration of two neuroleptics: haloperidol, a classical neuroleptic which has a moderate effect on weight gain in humans, and olanzapine, an atypical neuroleptic which has a more important effect on weight gain. Treatments (both 1 mg/kg) were given orally for 6 weeks, and the animals were allowed to self-select food among carbohydrates, lipids and proteins. Food selection was measured throughout the study, and body composition was measured by dissection and weighing of the main organs and tissues. Circulating leptin, insulin and glucose were also assayed at the end of the study on blood collected at the time of carcass analysis. The results show that none of the neuroleptic treatments modified caloric intake, food selection, body weight, and body composition. Olanzapine produced a statistically non-significant increase in subcutaneous fat tissue. It is concluded that a 6-week olanzapine or haloperidol treatment in male rats under dietary macronutrient selection does not significantly affect energy regulation.

Topics: Adipose Tissue; Animals; Antipsychotic Agents; Behavior, Animal; Benzodiazepines; Blood Glucose; Body Composition; Body Weight; Diet; Dietary Proteins; Eating; Energy Intake; Food Preferences; Haloperidol; Male; Nutritional Status; Olanzapine; Plasma; Rats; Rats, Sprague-Dawley; Time Factors

FMPD [6-fluoro-10-[3-(2-methoxyethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene] is a potential novel antipsychotic with high affinity for dopamine D2 (Ki= 6.3 nM), 5-HT(2A) (Ki= 7.3 nM), and 5-HT6 (Ki= 8.0 nM) human recombinant receptors and lower affinity for histamine H1 (Ki= 30 nM) and 5-HT2C (Ki= 102 nM) human recombinant receptors than olanzapine. Oral administration of FMPD increased rat nucleus accumbens 3,4-dihyroxyphenylacetic acid concentrations (ED200 = 6 mg/kg), blocked 5-HT2A agonist-induced increases in rat serum corticosterone levels (ED50= 1.8 mg/kg), and inhibited the ex vivo binding of [125I]SB-258585 [4-iodo-N-[4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-benzenesulfonamide] to striatal 5-HT6 receptors (ED50= 10 mg/kg) but failed to inhibit ex vivo binding of [3H]pyrilamine to hypothalamic histamine H1 receptors at doses of up to 30 mg/kg. In electrophysiology studies, acute administration of FMPD selectively elevated the number of spontaneously active A10 (versus A9) dopamine neurons and chronic administration selectively decreased the number of spontaneously active A10 (versus A9) dopamine neurons. FMPD did not produce catalepsy at doses lower than 25 mg/kg p.o. In Fos-induction studies, FMPD had an atypical antipsychotic profile in the striatum and nucleus accumbens and increased Fos expression in orexin-containing neurons of the hypothalamus. FMPD produced only a transient elevation of prolactin levels. These data indicate that FMPD is an orally available potent antagonist of dopamine D2, 5-HT2A, and 5-HT6 receptors and a weak antagonist of H1 and 5-HT2C receptors. FMPD has the potential to have efficacy in treating schizophrenia and bipolar mania with a low risk of treatment-emergent extrapyramidal symptoms, prolactin elevation, and weight gain. Clinical trials are needed to test these hypotheses.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Antipsychotic Agents; Benzodiazepines; Body Weight; Catalepsy; Cocaine; Corticosterone; Drug Evaluation, Preclinical; Electrochemistry; Electrophysiology; Fasting; Female; Immunohistochemistry; Male; Molecular Structure; Motor Activity; Nucleus Accumbens; Olanzapine; Piperazines; Prolactin; Quipazine; Radioligand Assay; Rats; Rats, Inbred F344; Rats, Inbred Strains; Rats, Sprague-Dawley; Receptors, Histamine H1; Serotonin Receptor Agonists; Thiophenes; Time Factors

Patients treated with atypical antipsychotic drugs commonly gain excess weight. Because obesity is associated with considerable morbidity and decreased life expectancy, treatment of weight gain in these patients is critical. Topiramate, a fairly new anticonvulsant, promotes bodyweight loss in healthy obese subjects, patients with bipolar disorder, and patients with eating disorder. However, there are very few reports about the efficacy of topiramate for weight management in schizophrenic patients. We present the cases of three Taiwanese patients with schizophrenia whose bodyweight increased as a result of atypical antipsychotics treatment, then was controlled by topiramate without aggravation of their psychotic symptoms.

Topics: Adult; Anti-Obesity Agents; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Child, Preschool; Clozapine; Dibenzothiazepines; Female; Fructose; Humans; Male; Olanzapine; Psychiatric Status Rating Scales; Quetiapine Fumarate; Risperidone; Schizophrenia; Taiwan; Topiramate; Weight Gain

The results from case-control and retrospective studies revealed that olanzapine might be associated with more increased risks of metabolic dysfunction than risperidone. The crossover design can minimize the influence of individual variation in metabolic profiles and demographic variables, such as age, sex, concomitant medication use and personal life styles.. We design a crossover study to evaluate the metabolic effect of olanzapine and risperidone.. Fifteen schizophrenic patients were shifted from olanzapine and risperidone or from risperidone and olanzapine due to poor treatment response. The body weights, lipid profiles and fasting glucose levels were assessed before medication switch and 3 months after crossover.. In the seven patients taking risperidone at the time of inclusion (risperidone-first group), after shifting to olanzapine, there was a significant increase in triglyceride level (p=0.048) and body weight (p=0.008). In the other eight patients (olanzapine-first group), after shift to risperidone, there was a decrease in triglyceride level (p=0.009), body weight (p=0.049) and body mass index (BMI; p=0.04). When comparing the metabolic profiles in all patients after olanzapine and after risperidone (irrespective of the order of treatment), the mean triglyceride level (p=0.001), body weight (p=0.001) and BMI (p=0.015) were significantly higher in patients receiving olanzapine than in those receiving risperidone. Furthermore, there was a small increase in total cholesterol level (p=0.091) and a small decrease in high-density lipoprotein (HDL) level (p=0.061) in olanzapine group, but the differences did not reach a significant level. There was no significant difference between olanzapine and risperidone in fasting glucose and low-density lipoprotein (LDL).. This study confirms that elevated levels of triglyceride and body weight could be associated with the use of olanzapine as compared with risperidone. The changes in body weights and lipid profiles should be closely monitored in patients during treatment with atypical antipsychotic drugs.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Body Weight; Cross-Over Studies; Female; Humans; Lipids; Male; Middle Aged; Olanzapine; Risperidone; Schizophrenia; Triglycerides

We have established an animal model for olanzapine-induced body weight gain, and used it to explore the relation between this weight gain, excessive food consumption, gross motor activity, and macronutrient choice. Female Sprague-Dawley rats received olanzapine (OLAN) or diluent (1.2mg/kg per day) via gavage for 10 days. Rats receiving OLAN exhibited significant increases in body weight when compared with control rats. Body weight returned to control levels once OLAN treatment was discontinued. Food consumption among the OLAN-treated group was significantly greater than among control rats between 6 and 10 days of treatment. Between 4 and 10 days of treatment, feed efficiency (grams of weight gained/grams of food consumed) was also significantly greater among animals receiving OLAN. In contrast, chronic administration of haloperidol (0.04mg/kg; q.d.; gavage) did not influence body weight or food consumption of treated rats. Gross motor activity was significantly reduced by OLAN between 1 and 10 days of treatment, also returning to control levels when treatment was discontinued. No significant changes were observed in brain DA, DOPAC, HVA or 5-HIAA among animals receiving OLAN daily for 30 days; however, 5-HT levels were significantly elevated. In contrast, acute (1.2mg/kg; 2h; i.p.) administration of OLAN significantly increased brain DOPAC and HVA levels without affecting those of 5-HT or 5-HIAA. OLAN (1.2mg/kg; q.d.; 10 days) administration did not alter macronutrient choice (carbohydrate:protein ratio) of rats. These data show that an animal model of OLAN-induced weight gain is readily generated, and suggest that the weight gain results at least in part from increased food intake, reduced gross motor activity, and enhanced feed efficiency.

Topics: 3,4-Dihydroxyphenylacetic Acid; Analysis of Variance; Animals; Antipsychotic Agents; Behavior, Animal; Benzodiazepines; Body Weight; Brain Chemistry; Chromatography, High Pressure Liquid; Darkness; Dopamine; Eating; Electrochemistry; Female; Food Preferences; Homovanillic Acid; Hydroxyindoleacetic Acid; Models, Animal; Motor Activity; Olanzapine; Photoperiod; Rats; Rats, Sprague-Dawley; Serotonin; Time Factors; Weight Gain

Several clinical reports have demonstrated that most antipsychotics of the new generation, but not the typical antipsychotic haloperidol, induce weight gain in schizophrenic patients. Since weight gain induces serious health complications in humans, it is crucial to test upcoming antipsychotic compounds in an animal model of weight gain. With the aim of evaluating whether the rat can be used as a model for antipsychotic-induced weight gain, we have investigated the effect of chronic treatment (3 weeks) with one antipsychotic drug inducing weight gain in clinic (olanzapine) and one antipsychotic not inducing weight gain in clinic (haloperidol), on food and water intake and body weight gain in rats. We included both female and male rats in this study. To reduce spontaneous high food intake in rats, and to be able to evaluate the treatment effect on a potential increase of food intake or metabolic changes, we allowed animal to receive only low-palatability chow. In male rats, none of the two compounds induced weight gain, but in female rats, both compounds induced weight gain. Consequently, the effect observed in rats does not match the clinical situation, and Wistar rats in this set-up cannot be considered a relevant model for antipsychotic-induced weight gain in humans.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Body Weight; Diet; Disease Models, Animal; Dose-Response Relationship, Drug; Drinking; Eating; Female; Food Preferences; Haloperidol; Humans; Male; Olanzapine; Pirenzepine; Rats; Rats, Wistar; Sex Characteristics; Weight Gain

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

A large number of individuals afflicted with psychiatric disorders, particularly depression with psychotic features, do not respond to conventional drug therapy. An option for this phenomenon is to augment a standard selective serotonin (5-HT) reuptake inhibitor with an atypical antipsychotic agent. In this regard, fluoxetine and olanzapine have been used concomitantly for treatment-resistant depression and bipolar depression. Although highly efficacious in terms of producing superior improvement of symptoms across a variety of psychological measures, the motor patterns, endocrine profiles, and intracellular signaling pathways affected by drug augmentation have not been determined. Here we show that fluoxetine (10 mg/kg) plus olanzapine (5 mg/kg) given to rats for 7 consecutive days (i.e., subchronic treatment) alters motor activity and diminishes spontaneous behaviors as measured by spatial position and angular path analyses. In addition, the same drug combination pattern sensitizes peak adrenal corticosterone secretion without altering serum glucose levels. We also show that subchronic fluoxetine and olanzapine exposure suppresses the induction of two immediate-early gene transcription factors (e.g., pCREB and FOS) that are associated with long-lasting changes in synaptic efficacy and structural modifications in the prefrontal cortex, piriform cortex, and hippocampus. These results suggest that fluoxetine plus olanzapine can interact in a fashion not predicted by the currently accepted model of fluoxetine monotherapy and provide insight into the synergistic actions of drug augmentation in patients with treatment-resistant depression.

Topics: Animals; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Behavior, Animal; Benzodiazepines; Blood Glucose; Blotting, Western; Body Weight; Corticosterone; Cyclic AMP Response Element-Binding Protein; Drug Interactions; Fluoxetine; Gene Expression; Genes, Immediate-Early; Hippocampus; Immunohistochemistry; Male; Mitogen-Activated Protein Kinases; Movement; Olanzapine; Pirenzepine; Proto-Oncogene Proteins c-fos; Rats; Rats, Long-Evans; Time Factors

A potential side-effect in the treatment with olanzapine is hyperglycemia or new onset diabetes mellitus. There are possible mechanisms by which olanzapine could interfere with glucose metabolism but decreased insulin sensitivity due to weight gain is of most relevance.

Topics: Adult; Benzodiazepines; Body Weight; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Dose-Response Relationship, Drug; Genetic Predisposition to Disease; Humans; Male; Olanzapine; Pirenzepine; Risk Factors; Schizophrenia; Schizophrenic Psychology

To provide evidence that olanzapine can cause glucose dysregulation by a mechanism other than weight gain.. I report a case of a diabetic patient who developed glucose dysregulation soon after initiation of olanzapine treatment, occurring in the absence of weight gain. I compare this case to previous case reports.. Our patient developed persistent hyperglycaemia within 3 weeks of initiating treatment with olanzapine. Weight recorded just prior to commencement and soon after discontinuation of olanzapine were not significantly different.. Controlled studies are necessary to elucidate the mechanism by which olanzapine can cause dysregulation of glucose homeostasis, and to develop guidelines for the use of olanzapine in patients with known diabetes as well as in patients with risk factors for diabetes.

Topics: Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Diabetes Complications; Diabetes Mellitus; Female; Humans; Hyperglycemia; Middle Aged; Olanzapine; Pirenzepine; Psychotic Disorders

Metabolic side effects have been increasingly noted during therapy with novel antipsychotics, but there is a dearth of comprehensive comparative data in this area. The goal of this retrospective study was to examine the changes in weight parameters, fasting glucose, and fasting lipids in long-term inpatients treated with either risperidone or olanzapine.. A retrospective study was performed by reviewing charts of patients at Oregon State Hospital, Salem, who were treated during July and August 1999, comparing metabolic outcomes during the first year of therapy with either risperidone or olanzapine. Data were analyzed also by age, sex, and concurrent use of lithium or valproate. Included for analysis were patients at least 18 years old with baseline weights obtained within 3 weeks of drug initiation, and baseline fasting triglycerides, cholesterol, and glucose obtained within 3 months prior to drug initiation and at 1 year of treatment (+/- 4 weeks). The patients meeting these criteria in each drug cohort (risperidone, N = 47; olanzapine, N = 47) included 1 patient with diagnosed diabetes mellitus prior to onset of treatment.. Among those patients under 60 years old, olanzapine patients (N = 37) experienced significantly greater increases at 1 year in all metabolic parameters than the risperidone group (N = 39), except for weight variables: triglycerides +104.8 mg/dL (olanzapine) versus +31.7 mg/dL (risperidone) (p = .037); cholesterol +30.7 mg/dL (olanzapine) versus +7.2 mg/dL (risperidone) (p = .004); glucose +10.8 mg/dL (olanzapine) versus +0.74 mg/dL (risperidone) (p = .030). Patients under 60 years of age with concurrent use of lithium or valproate were associated with greater weight gain in both drug groups, but this difference was statistically significant only for the olanzapine cohort. Neither weight change nor use of lithium or valproate was associated with increases in glucose or lipids among those under 60 years old for either drug.. Olanzapine therapy is associated with significantly greater increases in fasting glucose and lipid levels for nongeriatric adult patients than risperidone, and the increases are not correlated with changes in weight parameters. Appropriate monitoring of fasting glucose and serum lipid levels should be considered during extended treatment with atypical antipsychotics.

Topics: Adult; Aged; Anticonvulsants; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Diabetes Mellitus; Drug Therapy, Combination; Fasting; Female; Glucose Tolerance Test; Hospitalization; Humans; Hyperlipidemias; Lipid Metabolism; Lipids; Lithium; Male; Middle Aged; Olanzapine; Outcome Assessment, Health Care; Pirenzepine; Retrospective Studies; Risperidone; Schizophrenia; Valproic Acid

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Body Weight; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Male; Olanzapine; Pirenzepine

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Weight; Cardiovascular Diseases; Cross-Sectional Studies; Humans; Male; Olanzapine; Pirenzepine; Risk Factors; Risperidone; Schizophrenia

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Weight; Female; Fructose; Humans; Male; Olanzapine; Pirenzepine; Schizophrenia; Topiramate; Weight Gain

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

The aim of this study was to investigate the influence of the antipsychotic agent olanzapine on glucose-insulin homeostasis to explain possible mechanisms behind olanzapine-associated weight gain.. Fourteen patients on treatment with olanzapine (all meeting DSM-IV criteria for schizophrenia or related psychoses) were studied. Fasting blood samples for glucose, insulin, the growth hormone (GH)-dependent insulin-like growth factor I, and the insulin-dependent insulin-like growth factor binding protein-1 (IGFBP-1) were analyzed, as well as GH, leptin, and blood lipid levels and the serum concentrations of olanzapine and its metabolite N-desmethylolanzapine. In addition, body mass index (BMI) was calculated. Moreover, weight change during olanzapine treatment was determined.. Twelve of the 14 patients reported weight gain between 1 and 10 kg during a median olanzapine treatment time of 5 months, whereas data were not available for the other 2 patients. Eight patients (57%) had BMI above the normal limit. Eleven patients were normoglycemic, and 3 showed increased blood glucose values. Most patients (10/14; 71%) had elevated insulin levels (i.e., above the normal limit). Accordingly, the median value of IGFBP-1 was significantly lower for the patients in comparison with healthy subjects. Moreover, 8 (57%) of 14 patients had hyperleptinemia, 62% (8/13) had hypertriglyceridemia, and 85% (11/13) hypercholesterolemia. Weight change correlated positively to blood glucose levels and inversely to the serum concentration level of N-desmethylolanzapine. Additionally, the levels of blood glucose, triglycerides, and cholesterol correlated inversely to the serum concentration of N-desmethylolanzapine.. Olanzapine treatment was associated with weight gain and elevated levels of insulin, leptin, and blood lipids as well as insulin resistance, with 3 patients diagnosed to have diabetes mellitus. Both increased insulin secretion and hyprleptinemia may be mechanisms behind olanzapine-induced weight gain. Moreover, it is suggested that the metabolite N-desmethylolanzapine, but not olanzapine, has a normalizing effect on the metabolic abnormalities.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Chromatography, High Pressure Liquid; Female; Humans; Insulin; Leptin; Lipids; Male; Middle Aged; Olanzapine; Pirenzepine; Psychotic Disorders; Schizophrenia; Triglycerides

Leptin is produced by fat cells and is presumed to signal the size of the adipose tissue to the brain. The authors investigated whether antipsychotic drugs that often induce weight gain affect circulating levels of leptin.. Weight, body mass index, and leptin plasma level were measured weekly over 4 weeks in psychiatric inpatients who received clozapine (N = 11), olanzapine (N = 8), haloperidol (N = 13), or no psychopharmacological treatment (N = 12).. In patients receiving clozapine or olanzapine, significant increases in weight, body mass index, and leptin level were found, whereas these measures remained stable in patients who received haloperidol or no pharmacological treatment.. Weight gain induced by clozapine or olanzapine appears to be associated with an increase in leptin level that cannot be attributed to dietary changes upon hospitalization.

Topics: Adipose Tissue; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Clozapine; Haloperidol; Hospitalization; Humans; Leptin; Mental Disorders; Olanzapine; Pirenzepine; Proteins; Weight Gain