Dose-associated changes in safety and efficacy parameters observed in a 24-week maintenance trial of olanzapine long-acting injection in patients with schizophrenia.

BACKGROUND: In a recently published 24-week maintenance study of olanzapine long-acting injection (LAI) in schizophrenia (Kane et al., 2010), apparent dose-associated changes were noted in both efficacy and safety parameters. To help clinicians balance safety and efficacy when choosing a dose of olanzapine LAI, we further studied these changes. METHODS: Outpatients with schizophrenia who had maintained stability on open-label oral olanzapine for 4 to 8 weeks were randomly assigned to "low" (150 mg/2 weeks; N = 140), "medium" (405 mg/4 weeks; N = 318), or "high" (300 mg/2 weeks; N = 141) dosages of olanzapine LAI for 24 weeks. Potential relationships between dose and several safety or efficacy measures were examined via regression analysis, the Jonckheere-Terpstra test (continuous data), or the Cochran-Armitage test (categorical data). RESULTS: Safety parameters statistically significantly related to dose were mean weight change (low: +0.67 [SD = 4.38], medium: +0.89 [SD = 3.87], high: +1.70 [SD = 4.14] kg, p = .024; effect size [ES] = 0.264 high vs. low dose), mean change in prolactin (low: -5.61 [SD = 12.49], medium: -2.76 [SD = 19.02]), high: +3.58 [SD = 33.78] µg/L, p = .001; ES = 0.410 high vs. low dose), fasting triglycerides change from normal at baseline to high (low: 3.2%, medium: 6.0%, high: 18.9%, p = .001; NNT = 7 high vs. low dose) and fasting high-density lipoprotein cholesterol change from normal at baseline to low (low: 13.8%, medium: 19.6%, high: 30.7%, p = .019; NNT = 6 high vs. low dose). Efficacy measures significantly related to dose included Positive and Negative Syndrome Scale total score mean change (low: +2.66 [SD = 14.95], medium: -0.09 [SD = 13.47], high: -2.19 [SD = 13.11], p <.01; ES = 0.356 high vs. low dose), relapse rate (low: 16%, medium: 10%, high: 5%, p = .003; NNT = 9 high vs. low dose), all-cause discontinuation rate (low: 36%, medium: 30%, high: 24%, p = .037; NNT = 9 high vs. low dose), and rate of discontinuation due to efficacy-related reasons (low: 20%, medium: 14%, high: 6%, p <.001). Time to all-cause discontinuation (p = .035) and time to relapse (p = .005) were also significantly related to dose. CONCLUSIONS: Analyses of several safety and efficacy parameters revealed significant associations with dose of olanzapine LAI, with the highest dose generally showing greater efficacy as well as greater adverse changes in metabolic safety measures. When considering olanzapine LAI, as with all antipsychotics, it is important to carefully consider the potential benefits and risks for an individual patient. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00088491.

Number needed to treat or harm analyses of olanzapine for maintenance treatment of bipolar disorder.

The number-needed-to-treat (NNT) or the number-needed-to-harm (NNH) analysis was performed on olanzapine and comparators for all known controlled clinical studies of olanzapine for bipolar maintenance treatment or relapse prevention to assess safety and efficacy. Studies compared olanzapine (n = 225) and placebo (n = 136) for 12 months, olanzapine (n = 217) and lithium (n = 214) for 12 months, and olanzapine plus lithium or valproate (n = 72) and placebo plus lithium or valproate (n = 64) for 18 months. For prevention of all-cause treatment discontinuation, the NNT was 7 to 8. For 9 of 11 efficacy and disposition measures examined, beneficial outcomes were more common with olanzapine than placebo. Beneficial outcomes were more common with olanzapine than lithium for 7 measures and more common for olanzapine plus lithium or valproate than placebo plus lithium or valproate for 1 measure. The NNHs of 5 to 8 for a weight gain of 7% or higher and 10 to 11 for the increase in body mass index category to overweight or obese during maintenance treatment indicated that these outcomes were more common for olanzapine or olanzapine plus mood stabilizers than for the comparators. All efficacy and disposition measures showing significant differences between groups for 12 to 18 months have NNTs favoring olanzapine or olanzapine plus lithium or valproate over placebo, lithium, or placebo plus lithium or valproate. However, the NNHs favor these comparators for avoidance of weight gain and of increase in body mass index category to overweight or obese. Clinicians should consider these and other potential benefits and risks in using maintenance treatments for patients with a bipolar disorder.

Risk of treatment-emergent diabetes mellitus in patients receiving antipsychotics.

BACKGROUND: Type 2 diabetes mellitus has been reported during antipsychotic treatment. OBJECTIVE: To quantify the potential risk of treatment-emergent diabetes mellitus among patients receiving antipsychotic medications. METHODS: The MEDLINE and Psychinfo databases were searched using the key words antipsychotic (including individual drug names), diabetes, risk, and incidence for all English-language articles published between 1966 and 2005. Risk calculations were performed using data obtained from pharmacoepidemiologic studies that met the following criteria: (1) cohort design, (2) determination of preexisting diabetes, (3) inclusion of antipsychotic monotherapy as an exposure variable, and (4) comparison with exposure to first-generation antipsychotics. Studies meeting these criteria were used to calculate incidence, attributable risk between agents, and number needed to harm. RESULTS: A total of 25 observational pharmacoepidemiologic studies were found comparing antipsychotics on the outcome of diabetes mellitus. Sufficient information was provided in 15 of the reports to be able to estimate attributable risk. Attributable risk for individual second-generation antipsychotics relative to first-generation antipsychotics ranged from 53 more to 46 fewer new cases of diabetes per 1000 patients. Little observable difference was noted between the individual second-generation antipsychotics versus first-generation antipsychotics on this outcome. However, few of the studies controlled for body weight, race or ethnicity, or the presence of diabetogenic medications. None adjusted for familial history of diabetes, levels of physical activity, or diet, as this information is not usually available in the databases used in pharmacoepidemiologic studies. CONCLUSIONS: Based on the published pharmacoepidemiologic reports reviewed, the avoidance of diabetes as an outcome cannot be predictably achieved with precision by choice of a second-versus a first-generation antipsychotic. Risk management for new-onset diabetes requires the assessment of established risk factors such as family history, advancing age, non-white ethnicity, diet, central obesity, and level of physical activity.

Weight change by baseline BMI from three-year observational data: findings from the Worldwide Schizophrenia Outpatient Health Outcomes Database.

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

Real-world use patterns of olanzapine long-acting injection in the United States: comparison to the recommended dosing strategy.

OBJECTIVE: Recommended doses for olanzapine long-acting injection (olanzapine LAI) are 150 mg/2 weeks, 210 mg/2 weeks, 300 mg/2 or 4 weeks, and 405 mg/4 weeks. This analysis evaluated the dosing and interval patterns to compare the actual dosing patterns with the recommended dosing strategy. RESEARCH DESIGN AND METHODS: These data, from March 2010 through September 2011, were collected as part of a Risk Evaluation and Mitigation Strategy mandatory patient registry that captures all post-approval olanzapine injections in the US. This registry includes both active and inactive (60 + days since last injection) patients. RESULTS: All patients with at least one olanzapine injection were included (n = 1694). The mean number of injections received was 6.6 (range of 1-40). The most frequent numbers of injections were one (26.3%) and two (12.9%). For the 11,228 olanzapine injections, the most common doses were 300 mg and 405 mg, accounting for 92.9% of injections. Although the most common time intervals between injections was about 14 days for 150 mg, 210 mg, and 300 mg, and about 28 days for 405 mg, the intervals ranged from less than 10 to more than 60 days for all doses. Among active patients (48.2% of registry), 68.2% had >120 days of treatment with any dose, and the number of days since the last injection was around 2 weeks or less for 61.2% of patients, around 3 weeks for 16.5% of patients, and around 4 weeks for 7.1% of patients. Among inactive patients (51.8% of registry), 48.6% had <30 days of treatment. For the pattern of the first five injections, most patients (70.9%) received four subsequent injections of the same dose as their initial injection. CONCLUSIONS: This registry will continue to change. There is a broad range in time between injections. Most patients continue to receive the same initial dose instead of switching to a maintenance dose. This may suggest that some clinicians are not reassessing the dose after the initial starting dose because the patient was stabilized on olanzapine oral before beginning olanzapine long-acting injection. The study is limited by a database that does not include reasons for dose and dosing interval decisions or reasons for delaying or discontinuing treatment.

Weight change from 3-year observational data: findings from the worldwide schizophrenia outpatient health outcomes database.

BACKGROUND: Weight change data from randomized clinical trials are often of limited duration and trials do not always report a full range of clinically relevant categorical end points. METHOD: We conducted a post hoc analysis of data from the observational Worldwide Schizophrenia Outpatient Health Outcomes database (2000-2005) on weight change in 4,626 patients completing 3 years of antipsychotic monotherapy with amisulpride, clozapine, olanzapine, quetiapine, risperidone, and oral and depot first-generation antipsychotics (FGAs). Reported outcomes included mean and categorical weight changes and the trajectories of different measures of weight change. RESULTS: Mean weight gain was lowest with amisulpride (1.8 kg; 95% CI, 0.2-3.3) and highest with olanzapine (4.2 kg; 95% CI, 3.9-4.5). Weight change for all antipsychotics was most rapid during the first 6 months; subsequent weight change was slower but did not plateau. All drugs showed considerable individual variation in weight change. The proportion losing ≥7% of their baseline bodyweight was highest with quetiapine (10%; 95% CI, 7%-16%) and lowest with depot FGAs (5%; 95% CI, 3%-10%). Between 7% and 15% of patients moved into an overweight or obese body mass index (kg/m2)category (≥25). CONCLUSIONS: The degree of weight gain varied between antipsychotics. All antipsychotics were associated with significant (≥7%) weight loss and gain from baseline. The mean rate of weight gain was maximal during the first 6 months but continued over 3 years without a plateau in this specific cohort. Patients should receive regular monitoring of weight throughout treatment.

Case reports of postmarketing adverse event experiences with olanzapine intramuscular treatment in patients with agitation.

OBJECTIVE: Agitation is a medical emergency with increased risk for poor outcome. Successful treatment often requires intramuscular (IM) psychotropics. Safety data from the first 21 months of olanzapine IM, approved in the United States for the treatment of agitation associated with schizophrenia and bipolar disorder, are presented. METHOD: A Lilly-maintained safety database was searched for all spontaneous adverse events (AEs) reported in temporal association with olanzapine IM treatment. RESULTS: The estimated worldwide patient exposure to olanzapine IM from January 1, 2004, through September 30, 2005, was 539,000; 160 cases containing AEs were reported from patients with schizophrenia (30%), bipolar disorder (21%), unspecified psychosis (10%), dementia (8%), and depression (5%). Many reported concomitant treatment with benzodiazepines (39%) or other antipsychotics (54%). The most frequently reported events involved the following organ systems: central nervous (21%), cardiac (12%), respiratory (6%), vascular (6%), and psychiatric (5%). Eighty-three cases were considered serious, including 29 fatalities. In these fatalities, concomitant benzodiazepines or other antipsychotics were reported in 66% and 76% of cases, respectively. The most frequently reported events in the fatal cases involved the following organ systems: cardiovascular (41%), respiratory (21%), general (17%), and central nervous (10%). The majority of fatal cases (76%) included comorbid conditions and potentially clinically significant risk factors for AEs. CONCLUSIONS: Clinicians should use care when treating agitated patients, especially when they present with concurrent medical conditions and are treated with multiple medications, which may increase the risk of poor or even fatal outcomes. Clinicians should use caution when using olanzapine IM and parenteral benzodiazepines simultaneously.