Effects of intramuscular olanzapine vs. haloperidol and placebo on QTc intervals in acutely agitated patients

Prolongation of the QTc interval has been reported during treatment with oral antipsychotic agents and may be more pronounced during parenteral administration. Pooled QTc interval data from acutely agitated patients across four double-blind trials were compared. Databases included: placebo-controlled [two schizophrenia, one bipolar mania trials (n=565)]; haloperidol-controlled [two schizophrenia trials (n=482)]; geriatric placebo-controlled [1 dementia trial (n=204)]. Patients received 1-3 injections of intramuscular (IM) olanzapine (2.5-10 mg/injection), IM haloperidol (7.5 mg/injection), or IM placebo. At 2 and 24 h after IM olanzapine treatment, the mean QTc interval decreased approximately 3 ms from baseline in the placebo- and haloperidol-controlled databases. When there was a statistically significant difference between IM olanzapine and IM placebo, QTc intervals decreased during treatment with IM olanzapine and increased with IM placebo. The incidences of prolonged (endpoint >/=99th percentile of healthy adults or >/=500 ms) or lengthened (increase >/=60 ms) QTc intervals during treatment with IM olanzapine (<3% placebo- and haloperidol-controlled databases, <12% geriatric placebo-controlled database) were never significantly greater than with comparators. These data suggest that IM olanzapine has a favorable QTc interval profile in acutely agitated patients with schizophrenia, bipolar mania, or dementia.     

A retrospective study of the safety of intramuscular ziprasidone in agitated elderly patients

OBJECTIVE: Authors evaluated the safety of intramuscular ziprasidone for use in acute agitation in an elderly population. METHOD: Medical records were reviewed retrospectively to identify consecutive patients who were admitted to our neuropsychiatry service with the presenting complaint of dementia (DSM-IV) with agitation and who were given intramuscular ziprasidone and then administered an electrocardiogram (ECG) (N = 23). Some patients also had a baseline ECG (N = 14). QTc intervals were recorded, and significance was defined as a QTc of > or =450 ms or a 10% prolongation from baseline. A paired-samples t test was performed to compare the baseline and postmedication QTc intervals. Confounding factors were examined, and cardiac events (torsades de pointes, cardiac arrest) were recorded. RESULTS: There was no significant difference in the QTc interval between the baseline and the post-ziprasidone values. One patient had a QTc greater than 500 ms and 25% over baseline, and therefore the medication was discontinued. The mean prolongation of the QTc interval was only 0.5 ms. There were no episodes of torsades de pointes. Other medications that the patients were taking did not appear to affect the QTc interval in an expected manner. CONCLUSION: Larger studies need to be done to evaluate the safety of intramuscular ziprasidone in agitated elderly patients, a population with an increased risk of QT prolongation and torsades de pointes because of their age, comorbid conditions, and concomitant use of multiple medications.     

Pediatric case report of quetiapine overdose and QTc prolongation.

BACKGROUND: Consideration of the risk of QTc interval prolongation associated with atypical antipsychotic administration is mounting, as this can lead to sudden cardiac death. METHODS: This is a case report of a 14-year-old boy with a history of major depressive disorder with psychotic features, post-traumatic stress disorder, oppositional defiant disorder, and polysubstance abuse who ingested 1900 mg of quetiapine. RESULTS: One and one half hours after ingestion, the QTc interval lengthened from 453 msec to 618 msec on the printout (manual calculation was 444 msec to 500 msec, respectively). On the baseline EKG, the QTc interval was 411 msec (manual calculation of 416 msec). CONCLUSION: This report presents an association between higher doses of quetiapine, resulting in higher serum levels and QTc interval prolongation. Also, this report demonstrates the importance of manually calculating the QTc interval to ensure accuracy of the measurement. A review of the literature revealed two case reports and a study where quetiapine was associated with an increase in QTc interval. Further studies are necessary to understand the relationship between higher doses of quetiapine, resulting in higher serum levels, and the propensity for QTc interval prolongation to ensure safe clinical use of this medication.     

Possible association of QTc interval prolongation with co-administration of quetiapine and lovastatin.

BACKGROUND: QTc interval prolongation can occur as a result of treatment with both conventional and novel antipsychotic medications and is of clinical concern because of its association with the potentially fatal ventricular arrhythmia, torsade de pointes. METHODS: One case is described in which a patient with schizophrenia, who was being treated for dyslipidemia, developed a prolonged QTc interval while taking quetiapine and lovastatin. RESULTS: QTc returned to baseline when the lovastatin dose was reduced. CONCLUSIONS: QTc prolongation associated with antipsychotic medication occurs in a dose-dependent manner. We therefore hypothesize that the addition of lovastatin caused an increase in plasma quetiapine levels through competitive inhibition of the cytochrome P(450) (CYP) isoenzyme 3A4. Our case highlights the potential for a drug interaction between quetiapine and lovastatin leading to QTc prolongation during the management of dysipidemia in patients with schizophrenia.     

Cardiac safety parameters of olanzapine: comparison with other atypical and typical antipsychotics

Alterations of electrocardiogram results and cases of sudden cardiac death have been reported since the beginning of neuroleptic treatment. In particular, a temporal association exists between some antipsychotics and prolongation of the heart rate-corrected QT interval (QTc), an event that may increase the risk for developing a potentially fatal ventricular tachycardia arrhythmia known as torsades de pointes if it significantly exceeds normal intraindividual and interindividual variation. Although the incidence of serious adverse cardiac events in response to antipsychotic medications is relatively low, any possibility for the occurrence of cardiotoxicity warrants continued study. The present article reviews important differences among antipsychotic drugs in the potential for, and occurrence of, serious adverse cardiac outcomes and suggests that olanzapine, as therapeutically administered to patients with schizophrenia and related psychoses, does not contribute significantly to a QTc prolongation that could result in potentially fatal ventricular arrhythmias.     

Electrocardiographic changes in children and adolescents treated with ziprasidone: a prospective study

OBJECTIVE: To assess the electrocardiographic safety profile of low-dose ziprasidone (< or =40 mg/day) among pediatric outpatients treated for up to 6 months. METHOD: This was a prospective, open-label trial involving 20 subjects with a mean age of 13.2 +/- 3.0 years. Subjects received a mean ziprasidone dose of 30 +/- 13 mg/day and were followed for 4.6 +/- 2.0 months, receiving a median of nine electrocardiograms each (range 2-11; total, 176). RESULTS: There were statistically significant changes from baseline to peak values in heart rate, PR, and QTc intervals, but not in QRS complex width. The mean QTc prolongation was 28 +/- 26 milliseconds and not related to dose (r = 0.16, p = .07). The peak QTc of three subjects reached or exceeded 450 milliseconds; one subject experienced a 114-millisecond prolongation. There was poor agreement (kappa = 0.25) between automated and manual identification of long QTc intervals (> or =440 milliseconds). CONCLUSIONS: These preliminary findings, occurring at doses low by current treatment standards, suggest that close electrocardiographic monitoring is warranted when prescribing ziprasidone to children, particularly at higher doses or when combined with other QTc-prolonging agents.     

No significant QTc interval changes with high-dose ziprasidone: a case series

This study examined the effects of high-dose ziprasidone on the electrocardiograms (ECGs) of adult inpatients. This was done in an effort to assess the incremental risk of QTc interval prolongation when using ziprasidone in doses above the maximum dose of 160 mg/day approved by the Food and Drug Administration. We retrospectively examined pre- and post-treatment QTc intervals in 15 subjects at the James A. Haley Veterans Affairs Medical Center who had received high doses of ziprasidone, ranging from 240 to 320 mg/day, due to intractable psychotic symptoms. Pure baseline ECGs were not always attainable, since the majority of the subjects were taking concomitant medications at the time that ziprasidone was initiated. Analysis yielded an average increase of 3.4 msec from pre- to post-treatment, with a maximum post-treatment interval of 452 msec and no cases having a pre- to post- treatment QTc interval increase > 20 msec. These findings are statistically insignificant and do not approach the 500 msec threshold of concern. This study suggests that high-dose ziprasidone does not have a significant incremental effect on QTc interval prolongation in certain subsets of patients. However, it does not rule out the possibility that ziprasidone could have deleterious effects in higher risk populations or that ziprasidone could have rare, idiosyncratic cardiogenic effects. Limitations of the study are identified and recommendations for future research are presented.     

Antipsychotic drugs and QT interval prolongation

The QTc prolongation by antipsychotic drugs is of major concern, especially in light of the data indicating an increased risk of sudden death in psychiatric patients taking these drugs. Sudden death in psychiatric patients could be partially attributed to drug-induced torsades de pointes and for this reason careful evaluation of QTc prolonging properties of antipsychotic drugs is needed. Antipsychotic drugs prolong QT interval usually by blocking the potassium I_Kr current. Improved understanding of ion channel structure and kinetics and its role in repolarization has tremendous impact on understanding of the mechanisms of drug-induced QT prolongation and torsades de pointes. Proarrhythmia caused by a QT-prolonging drug occurs infrequently, and usually multiple factors need to operate to precipitate such an event including a combination of two or more drugs affecting the same pathway, hypokalemia, and possibly genetic predisposition. Currently prescribed antipsychotics might cause QT prolongation ranging from 4–6 ms for haloperidol and olanzapine to 35 ms for thioridazine. The response of a patient to a drug is very individual and therefore an individualized system of drug administration and monitoring needs to be developed which takes into account baseline QTc duration and its changes after a drug was introduced. A systematic approach while stratifying psychiatric patients as those with short QTc (QTc 0.41 sec), borderline QTc (QTC = 0.42–0.44 sec), and prolonged QTc ( 0.45 sec) is being proposed to improve the safety of administering antipsychotic drugs and to decrease the risk of drug-related sudden death in psychiatric patients.     

抗精神病药致首发精神疾病QTc 间期变化的相关 因素分析

目的 调查抗精神病药致首发精神疾病QTc间期延长的影响因素.方法 对服用稳定剂量抗精神病药治疗1月的309例首发精神疾病患者进行回顾性调查,收集人口学资料、空腹血糖、血压、血脂等生化指标、心电图资料,以QTc≥440ms作为QTc间期延长的标准,分析QTc间期延长的状况及其相关因素.结果 QTc间期延长的发生率为10.6%.药物治疗组QTc间期均值大于基线期,差异有统计学意义(P<0.05);药物联合电休克治疗组以及药物联合脑电治疗组QTc间期与基线期相比,差异无统计学意义(P>0.05).单一抗精神病药治疗组QTc间期与基线期差异无统计学意义(P>0.05);而抗精神病药联用以及抗精神病药联用抗抑郁药/心境稳定剂组QTc间期均值大于基线期,差异有统计学意义(P<0.05).抗精神病药等效氯丙嗪剂量<1000mg/d组别QTc间期与基线期相比差异有统计学意义(P<0.05).抗精神病药剂量与QTc间期没有相关性.女性是QTc间期延长的风险因素(OR=3.26,95%CI=1.050~10.094),其他因素未进入回归方程.结论 首发精神疾病患者抗精神病药治疗期间QTc间期延长存在性别差异,女性发生QTc间期延长的风险是男性的3.26倍.药物联用延长的QTc间期并未达到异常值.抗精神病药剂量与QTc间期没有相关性.除了性别因素外,其他指标不是QTc间期延长的风险因素.     

Antidepressant efficacy of olanzapine as monotherapy in major depressive disorder, without psychosis: a pilot study

In this pilot study we assessed the efficacy of olanzapine as monotherapy in the treatment of major depressive disorder, without psychosis. We also demonstrated the in vivo 5-HT2A receptor occupancy of olanzapine using positron emission tomography. An open-label prospective 6-week study design with 14 patients who met the inclusion and exclusion criteria for the study were enrolled from the general community of the St. Louis metropolitan area. All patients met DSM-IV criteria for major depressive disorder without psychosis, had a Hamilton Depression Rating Scale (HAMD17) score >18 and were between the ages of 18 and 65. The primary measure of efficacy was the change in HAMD 17 total score from baseline to endpoint. The data were collected between 1998 and 2004. There was a significant reduction in the HAMD17 scores from baseline to endpoint. Half the patients (n=6) showed > or =50% reduction in their HAMD17 scores. This study points to the potential of olanzapine as a therapeutic agent for the treatment of major depressive disorder without psychosis.     

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.     

Olanzapine plus carbamazepine v. carbamazepine alone in treating manic episodes

BACKGROUND: Combinations of olanzapine and carbamazepine are often used in clinical practice in the management of mania. AIMS: To assess the efficacy and safety of olanzapine plus carbamazepine in mixed and manic bipolar episodes. METHOD: Randomised, double-blind, 6-week trial of olanzapine (10-30 mg/day) plus carbamazepine (400-1200 mg/day; n=58) v. placebo plus carbamazepine (n=60) followed by open-label, 20-week olanzapine (10-30 mg/day) plus carbamazepine (400-1200 mg/day, n=86), with change in manic symptoms as main outcome measure. Safety and pharmacokinetics were also evaluated. RESULTS: There were no significant differences (baseline to endpoint) in efficacy measures between treatment groups, but at 6 weeks triglyceride levels were significantly higher (P=0.008) and potentially clinically significant weight gain (>or=7%) occurred more frequently (24.6% v. 3.4%, P=0.002) in the combined olanzapine and carbamazepine group. Carbamazepine reduced olanzapine concentrations but olanzapine had no effect on carbamazepine concentrations. CONCLUSIONS: The combination of olanzapine and carbamazepine did not have superior efficacy to carbamazepine alone. The increases in weight and triglycerides observed during combination treatment are a matter of concern.     

Olanzapine/fluoxetine combination for treatment-resistant depression: a controlled study of SSRI and nortriptyline resistance

BACKGROUND: This 8-week, double-blind, multicenter study was undertaken to replicate, in a larger sample of patients with treatment-resistant major depressive disorder (MDD; DSM-IV criteria), the results of a pilot study of the olanzapine/fluoxetine combination. METHOD: The study was begun in August 1999. The primary entry criterion was a history of failure to respond to a selective serotonin reuptake inhibitor (SSRI). Patients (N = 500) who subsequently failed to respond to nortriptyline during an open-label lead-in phase were randomly assigned to 1 of 4 treatment groups: olanzapine (6-12 mg/day) plus fluoxetine (25-50 mg/day) combination, olanzapine (6-12 mg/day), fluoxetine (25-50 mg/day), or nortriptyline (25-175 mg/day). The primary outcome measure was baseline-to-endpoint mean change in score on the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: At the 8-week study endpoint, MADRS total scores decreased by a mean 8.7 points from baseline (28.5) with the olanzapine/fluoxetine combination, 7.0 points from baseline (28.4) with olanzapine (p = .08), 8.5 points from baseline (28.4) with fluoxetine (p = .84), and 7.5 points from baseline (28.8) with nortriptyline (p = .30), with no significant differences among the therapies. The olanzapine/fluoxetine combination was associated with significantly (p < or = .05) greater improvement (decrease) in MADRS scores than olanzapine at weeks 2, 4, 6, and 7; than fluoxetine at weeks 2 through 5; and than nortriptyline at weeks 1 through 4. A post hoc analysis of a subgroup of patients who had an SSRI treatment failure during their current MDD episode (N = 314) revealed that the olanzapine/fluoxetine combination group had a significantly (p = .005) greater decrease in MADRS scores than the olanzapine group at endpoint. Safety data for the olanzapine/fluoxetine combination were similar to those for its component monotherapies. CONCLUSIONS: The olanzapine/fluoxetine combination did not differ significantly from the other therapies at endpoint, although it demonstrated a more rapid response that was sustained until the end of treatment. The results raised several methodological questions, and recommendations are made regarding the criteria for study entry and randomization.     

Long-term olanzapine treatment: weight change and weight-related health factors in schizophrenia

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

Effectiveness and safety of olanzapine in the treatment of schizophrenia among Asian patients switching from conventional antipsychotics

OBJECTIVES: The objectives of this study were: (1) to investigate, in a clinical practice setting, the effectiveness of olanzapine in the treatment of schizophrenia among partially-responding, symptomatic Asian patients who switch from conventional antipsychotic treatment, (2) to assess the safety of olanzapine and (3) to assess the change in quality of life in Asian patients with schizophrenia who switch to olanzapine. METHODS: Effectiveness, safety and quality of life were assessed in outpatients with schizophrenia (n=1267) who lacked symptomatic control with conventional antipsychotics and were switched to olanzapine therapy. Data for this prospective, observational study were collected for 12 months from Asian patients in China, Hong Kong, the Philippines, South Korea and Taiwan. RESULTS: Significant clinical improvements (P<0.05) were observed following 12 months of olanzapine treatment and 87.3% of the subjects responded to treatment at endpoint (i.e. Brief Psychiatric Rating Scale Total score reduced by > or =30% relative to baseline; last observation carried forward). Abnormal involuntary movements (mean change in Abnormal Involuntary Movement Scale: -3.20, P<0.001) and quality of life were significantly improved in patients treated with olanzapine. However, some patients experienced significant weight gain (3.60+/-4.50 kg, P<0.001) with olanzapine treatment, relative to baseline. CONCLUSIONS: This study shows that switching to olanzapine may be effective in improving symptoms, may be well-tolerated and may improve the quality of life in Asian patients who are only partially responsive to treatment with conventional antipsychotics. The pragmatic design and naturalistic setting of this large study make the findings relevant for treating patients from some Asian countries in routine clinical practice.     

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.     

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.     

Comparison of olanzapine and risperidone in the treatment of psychosis and associated behavioral disturbances in patients with dementia.

OBJECTIVE: The authors compared efficacy of olanzapine versus placebo and risperidone as measured by the Neuropsychiatric Inventory and Clinical Global Impression-Severity of Psychosis scale in patients with dementia-related psychosis. METHODS: Patients with moderate-to-severe psychotic symptoms associated with dementia were recruited from outpatient or residential settings and randomly assigned to 10-week, double-blind, flexible-dose treatment with olanzapine (N=204; 2.5 mg-10 mg/day; mean: 5.2 mg/day), risperidone (N=196; 0.5 mg-2 mg/day; mean: 1.0 mg/day) or placebo (N=94). RESULTS: Most measures of neuropsychiatric functioning improved in all treatment groups, including the placebo group, and no significant treatment differences occurred. Overall discontinuation was lowest in the placebo group, and the olanzapine group had a significantly higher incidence of discontinuation due to adverse events (16.2%) relative to placebo (3.2%) and risperidone (8.7%) groups. Treatment-emergent extrapyramidal symptoms were more numerous for risperidone- than placebo- or olanzapine-treated patients. Abnormally high prolactin levels occurred in 78.0% of risperidone patients, compared with 16.7% for olanzapine and 5.0% for placebo. The incidence of weight gain greater than 7% from baseline was higher in the olanzapine group relative to risperidone, but neither active-treatment group showed a statistical difference from placebo (1.1%). No other statistically significant and clinically relevant differences were seen for any other vital sign, electrocardiographic measure, or laboratory hematology and chemistry, including glucose, except for cholesterol, which decreased from baseline to endpoint in both active-treatment groups. CONCLUSIONS: Patients' neuropsychiatric functioning improved with olanzapine, risperidone, and placebo treatment. There was a substantial response in the placebo group, and no significant differences emerged among treatments.     

Extrapyramidal symptom profiles in Japanese patients with schizophrenia treated with olanzapine or haloperidol

Previous clinical trials have clearly shown the superiority of olanzapine to haloperidol in the improvement of extrapyramidal symptoms (EPS) in schizophrenic patients. The primary purpose of this study was to compare EPS profiles in Japanese schizophrenic patients treated with an atypical antipsychotic, olanzapine, or a typical antipsychotic, haloperidol, as measured by the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). The DIEPSS, which consists of eight individual parameters and one global assessment (overall severity), was used to evaluate 182 patients enrolled in this 8-week study. The primary safety analysis was maximum change (that could be either a decrease or increase) from baseline in DIEPSS total score. Secondary analyses included change from baseline to maximum in DIEPSS total score, change from baseline to endpoint (LOCF) in DIEPSS total score, and the rank sum of the maximum change (that could be either a decrease or increase) from baseline in the DIEPSS individual items. Incidence of treatment-emergent EPS adverse events using the DIEPSS scale was also analyzed. The olanzapine group showed statistically significant superiority to the haloperidol group on the primary analysis (p<0.001). Secondary analyses also demonstrated olanzapine's superiority in DIEPSS total, parkinsonism, akathisia and overall severity scores (all p< or =0.014). Categorical analysis of treatment-emergent akathisia and parkinsonism syndromes at endpoint showed improvement in the olanzapine group but worsening in the haloperidol group. The results from this study suggest that olanzapine, as in Caucasian populations, is a safe treatment in Japanese patients chronically ill with schizophrenia.     

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.