Factors influencing acute weight change in patients with schizophrenia treated with olanzapine, haloperidol, or risperidone

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSION: 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.     

Olanzapine versus placebo in the treatment of adolescents with bipolar mania

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

A comparison of the efficacy,safety, and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder

BACKGROUND: This study compared the efficacy, safety, and tolerability of divalproex and olanzapine in the treatment of acute mania associated with bipolar disorder. METHOD: This randomized, 12-week, double-blind, parallel-group, multicenter study included DSM-IV-defined bipolar disorder type I patients hospitalized for acute mania and randomly assigned to treatment with divalproex or olanzapine. After an inpatient period of up to 21 days, subjects were followed as outpatients. Dose adjustment was permitted during the inpatient period. Efficacy was assessed using change from baseline in Mania Rating Scale (MRS) score to day 21; other efficacy measures included the Brief Psychiatric Rating Scale, the Hamilton Rating Scale for Depression, and the Clinical Global Impressions-Part I, Severity of Illness scale. The primary safety endpoint was change from baseline in weight. Other safety and tolerability endpoints included spontaneous adverse event reporting and changes from baseline in laboratory measures and vital signs. RESULTS: 120 subjects (N = 63 divalproex, N = 57 olanzapine) were randomly assigned to treatment. No significant differences between groups were found for any efficacy variable for change from baseline to day 21. Mean MRS score changes from baseline to day 21 were -14.8 for divalproex and -17.2 for olanzapine (p =.210). A significantly (p <.05) greater proportion of olanzapine-treated subjects experienced somnolence, weight gain, edema, rhinitis, and speech disorder (slurred speech); no adverse events were significantly greater in the divalproex group. A number of laboratory measures also demonstrated significant treatment differences, but the clinical significance of many of these is uncertain. Mean body weight changes were significantly greater in the olanzapine group (+ 8.8 lb [+ 4.0 kg]) than the divalproex group (+ 5.5 lb [+ 2.5 kg], p <.050). One death occurred during the study (olanzapine group, diabetic ketoacidosis). CONCLUSION: No significant difference in efficacy was found between treatment groups. Divalproex was associated with a more favorable adverse event profile and significantly less weight gain than olanzapine.     

Olanzapine increases weight and serum triglyceride levels

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

Weight gain and antipsychotic medication: differences between antipsychotic-free and treatment periods.

BACKGROUND: We performed a retrospective analysis of data involving 121 inpatients to examine the rate of weight gain during antipsychotic-free periods and during treatment with various antipsychotic drugs. METHOD: Data were analyzed to determine differences in weekly weight change during antipsychotic-free (N = 65), typical antipsychotic (N = 51), or atypical antipsychotic (N = 130) treatment periods. Atypical antipsychotic treatment periods were further subdivided into olanzapine (N = 45), clozapine (N = 47), or risperidone (N = 36) treatment periods. A paired comparison was conducted on 65 patients who had an antipsychotic-free treatment period preceding or following a neuroleptic drug treatment period. In addition, patients were classified as either non-obese (with a body mass index [BMI] < or = 29.9 kg/ml) or obese (BMI > or = 30.0 kg/m2) to test whether the rate of weight gain during treatment periods was related to initial BMI. RESULTS: Across all treatment periods, weekly weight gain was as follows: 0.89 lb/wk (0.40 kg/wk) on atypical antipsychotic medication, 0.61 lb/wk (0.27 kg/wk) on typical antipsychotic medication, and 0.21 lb/wk (0.09 kg/wk) on no antipsychotic medications. The atypical antipsychotic versus antipsychotic-free comparison was significant (F = 3.51; df = 2,231; p = .031), while the typical antipsychotic versus antipsychotic-free comparison was not. Among the individual atypical antipsychotic medications, significantly more weight gain occurred during olanzapine treatment (1.70 lb/wk) (0.76 kg/wk) than with either clozapine (0.50 lb/wk) (0.22 kg/wk) or risperidone (0.34 lb/wk) (0.15 kg/wk) treatments (F = 7.77; df = 2,117; p = .001). In the paired analysis with patients serving as their own controls, the difference between weekly weight gain during atypical antipsychotic treatment and antipsychotic-free treatment was significant (t = -3.91; df = 44; p = .001), while the difference between weight gain during typical antipsychotic treatment and antipsychotic-free treatment was not significant. With the individual drugs. treatment with both olanzapine and clozapine caused significantly higher weekly weight gain than antipsychotic-free treatment (p = .001 and p = .036, respectively). while treatment with risperidone did not. Non-obese patients (BMI < 29.9 kg/m2) and obese patients (BMI > 30.0 kg/m2) did not differ significantly in their weight gain during typical or atypical antipsychotic treatment. CONCLUSION: Treatment with atypical antipsychotics was associated with more weight gain than treatment with typical antipsychotics. Among the atypical drugs, olanzapine was associated with more weight gain than either clozapine or risperidone. The patient's admission BMI was not associated with the amount of weight gained during subsequent antipsychotic treatment.     

Olanzapine induces insulin resistance: results from a prospective study

BACKGROUND: The aim of this study was to compare glucose metabolism in patients with schizophrenia receiving olanzapine with that in control subjects. METHOD: 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. RESULTS: 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. CONCLUSION: 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.     

Weight gain during treatment of bipolar I patients with olanzapine

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

Novel antipsychotics: comparison of weight gain liabilities.

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

Long-term weight gain in patients treated with open-label olanzapine in combination with fluoxetine for major depressive disorder

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

Weight gain associated with olanzapine and risperidone in adolescent patients: a comparative prospective study

OBJECTIVE: To evaluate weight gain associated with olanzapine, risperidone, and haloperidol treatment and its clinical risk factors in adolescent patients. METHOD: The study was conducted at three adolescent psychiatric departments in two mental health centers in the Tel Aviv area. All patients were Jewish Israelis. Weight and body mass index (BMI) of hospitalized adolescents treated with olanzapine (n = 21), risperidone (n = 21), or haloperidol (n = 8) were prospectively monitored on a weekly basis for the first 12 weeks of treatment. Various clinical risk factors were tested for association with weight gain. RESULTS: The olanzapine and risperidone groups experienced significant weight gain between baseline and endpoint (p < .01), whereas the average weight of the haloperidol group did not change. Average weight gain was significantly higher for the olanzapine group (7.2 +/- 6.3 kg, 11.1% +/- 7.8%) than for the risperidone (3.9 +/- 4.8 kg, 6.6% +/- 8.6%) and haloperidol (1.1 +/- 3.3 kg, 1.5% +/- 6.0%) groups. Extreme weight gain (>7%) was recorded in 19 patients (90.5%), 9 patients (42.9%), and 1 (12.5%) patient, respectively Gender (males), low concern about gaining weight (females), low baseline BMI, and paternal BMI were positively correlated with weight gain, whereas previous neuroleptic history, neuroleptic dosage, response to treatment, and illness duration were not. CONCLUSIONS: Olanzapine and risperidone are associated with extreme weight gain in adolescents, much higher than that reported in adults. This side effect should be taken into consideration before prescribing these medications, especially in patients at high risk.     

Atypical antipsychotics and weight gain in Chinese patients: a comparison of olanzapine and risperidone

OBJECTIVE: To compare the effect of olanzapine with that of risperidone on weight change among Chinese patients in Hong Kong. METHOD: The body weight of subjects maintained on olanzapine or risperidone treatment was recorded at the outpatient clinic of a teaching hospital. Pretreatment weight of the subjects was retrieved from case records. Subjects on olanzapine treatment were matched in sex, age, and diagnosis with those on risperidone treatment, and demographic and clinical data were analyzed. The study was conducted in May and June 2002. RESULTS: Twenty-eight olanzapine-risperidone matched pairs were studied. All were diagnosed with DSM-IV schizophrenia. In patients treated with olanzapine and risperidone, respectively, mean +/- SD duration of treatment with atypical neuroleptics was 103.5 +/- 47.4 weeks and 93.2 +/- 50.6 weeks (range, 21-255 weeks), and mean doses were 12.4 +/- 6.7 mg/day and 4.5 +/- 2.8 mg/day. The mean +/- SD weight gain of subjects on treatment with olanzapine and risperidone, respectively, was 8.34 +/- 5.97 kg (18.53 +/- 13.27 lb) and 2.74 +/- 8.09 kg (6.09 +/- 17.98 lb) with a statistically significant difference at p < .005. Lower baseline body weight and body mass index were associated with greater weight gain in both olanzapine- and risperidone-treated subjects. Gender, age, mean daily dose, and duration of treatment had no effect on weight change. CONCLUSION: Treatment with olanzapine was associated with significantly greater weight gain than treatment with risperidone in Chinese schizophrenia patients in Hong Kong. The effect of adjunctive anticonvulsant treatment on weight gain requires further study.     

A retrospective comparison of weight,lipid, and glucose changes between risperidone- and olanzapine-treated inpatients: metabolic outcomes after 1 year

BACKGROUND: 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. METHOD: 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. RESULTS: 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. CONCLUSION: 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.     

Association of olanzapine-induced weight gain with an increase in body fat

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

Weight gain induced by haloperidol, risperidone and olanzapine after 1 year: findings of a randomized clinical trial in a drug-naïve population

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

Effect of Older vs Younger Age on Anthropometric and Metabolic Variables During Treatment of Psychotic Depression With Sertraline Plus Olanzapine: The STOP-PD II Study

ObjectiveTo examine the effect of older versus younger age on change in anthropometric and metabolic measures during extended treatment of psychotic depression with sertraline plus olanzapine.MethodsTwo hundred and sixty-nine men and women aged 18–85 years with an episode of psychotic depression were treated with open-label sertraline plus olanzapine for up to 12 weeks. Participants who remained in remission following an 8-week stabilization phase were eligible to participate in a 36-week randomized controlled trial (RCT) that compared the efficacy and tolerability of sertraline plus olanzapine with sertraline plus placebo. Weight, waist circumference and plasma lipids, glucose, HbA1c, and insulin were measured at regular intervals during the acute, stabilization and randomized phases of the study. Linear mixed models were used to analyze the trajectories of anthropometric and metabolic measures.ResultsParticipants aged 60 years or older experienced less weight gain and less increase in cholesterol during the combined acute and stabilization phases of the study compared with those aged 18–59 years. At the acute-stabilization termination visit, mean weight in older participants was 6.5 lb. less than premorbid weight, whereas it was 17.9 lb. more than premorbid weight in younger participants. In the RCT, there was a significant interaction of treatment and age group for the trajectory of weight, but the post hoc tests that compared age groups within each treatment arm were not statistically significant. There were no clinically significant differences between younger and older participants in glycemic measures.ConclusionOlder patients with psychotic depression experienced less increase in weight and total cholesterol than their younger counterparts during acute and stabilization treatment with sertraline plus olanzapine. In the older group, weight gained during the acute and stabilization phases appeared to be partial restoration of weight lost during the index episode of depression, whereas weight gain in younger participants was not.     

Metformin as an adjunctive treatment to control body weight and metabolic dysfunction during olanzapine administration: a multicentric, double-blind, placebo-controlled trial

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Metformin may safely assist olanzapine-treated patients in body weight and carbohydrate metabolism control.     

Olanzapine versus ziprasidone: results of a 28-week double-blind study in patients with schizophrenia

OBJECTIVE: The efficacy and safety of olanzapine were compared with those of ziprasidone. METHOD: This was a multicenter randomized, double-blind, parallel-group, 28-week study of patients with schizophrenia. Patients were randomly assigned to treatment with 10-20 mg/day of olanzapine or 80-160 mg/day of ziprasidone. The primary efficacy measure was the Positive and Negative Syndrome Scale total score. Secondary efficacy and safety measures included Positive and Negative Syndrome Scale subscales as well as mood, quality of life, and extrapyramidal symptom scales. Safety was evaluated by recording treatment-emergent adverse events and measuring vital signs and weight. RESULTS: The study was completed by significantly more olanzapine-treated patients (165 of 277, 59.6%) than ziprasidone-treated patients (115 of 271, 42.4%). At 28 weeks, the olanzapine-treated patients showed significantly more improvement than the ziprasidone-treated patients on the Positive and Negative Syndrome Scale overall scale and all subscales and on the Clinical Global Impression ratings of severity of illness and improvement. The responder rate was higher for olanzapine than for ziprasidone. Extrapyramidal symptoms were not significantly different between groups in change-to-endpoint analyses, but results favored olanzapine on baseline-to-maximum changes. Weight change was significantly greater with olanzapine (mean=3.06 kg, SD=6.87) than with ziprasidone (mean=-1.12 kg, SD=4.70). Fasting lipid profiles were significantly superior in the ziprasidone group; there was no significant difference in fasting glucose level. CONCLUSIONS: Olanzapine treatment resulted in significantly greater psychopathology improvement and higher response and completion rates than ziprasidone treatment, while ziprasidone was superior for weight change and lipid profile.     

Weight changes during treatment with olanzapine in older adult patients with dementia and behavioral disturbances

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.     

The efficacy of mifepristone in the reduction and prevention of olanzapine-induced weight gain in rats

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.     

Clozapine and hypertension: a chart review of 82 patients

OBJECTIVE: Clozapine has been linked to significant weight gain and increase in serum lipids and appears to negatively impact glucose metabolism. In this retrospective chart review study, we examine changes in systolic and diastolic blood pressure and treatment for hypertension in clozapine-treated patients. METHOD: Data on demographics and systolic and diastolic blood pressure were examined for up to 5 years (September 1987 to September 1992) in 82 patients treated with clozapine. Rates of hypertension treatment in clozapine-treated patients were compared with patients receiving conventional antipsychotics (N = 56) and other atypical antipsychotic agents (N = 102). RESULTS: The mean age of the 82 patients at the time of clozapine initiation was 36.4 +/- 7.8 years, with 22 (27%) female, 75 (91%) white, 3 (4%) black, 3 (4%) Hispanic, and 1 (1%) Asian. The baseline weight was 175.5 +/- 34.0 lb (79.0 +/- 15.3 kg) and baseline body mass index was 26.9 +/- 5.0 kg/m(2). There was a significant increase in systolic blood pressure (p =.0004) and diastolic blood pressure (p =.0001). Overall, 22 patients (27%) received treatment for hypertension following clozapine initiation. Only 2 (4%) of 56 patients in the conventional antipsychotic group and 9 (9%) of 102 patients in the other atypical antipsychotic group (olanzapine, N = 6; risperidone, N = 3) received treatment for hypertension. CONCLUSION: Our findings suggest that long-term clozapine treatment is associated with increased rates of hypertension, which may have a significant impact on medical morbidity and mortality.