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

Abstract

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.

Figures

Figure 1

Regression scatterplot of mean change in weight at endpoint (LOCF) by dose. Figure 1 shows the scatterplot, regression line, and resulting equation for the relationship between endpoint weight change and dose. In the equation, "dose" refers to the calculated oral equivalent daily dose (10.7, 14.5, or 21.4 mg/day), not the actual injected dose. Abbreviations: OLZ LAI = olanzapine long-acting injection; OLZ LAI 150 = group receiving low-dose olanzapine LAI, 150 mg/2 weeks, approximate oral equivalent 10 mg/day (N = 140); OLZ LAI 405 = group receiving medium-dose olanzapine LAI, 405 mg/4 weeks, approximate oral equivalent 15 mg/day (N = 318); and OLZ LAI 300 = group receiving high-dose olanzapine LAI, 300 mg/2 weeks, approximate oral equivalent 20 mg/day (N = 141).

Figure 2

Regression scatterplots of mean change in prolactin at endpoint (LOCF) by dose and gender. Figure 2 shows the scatterplots, regression lines, and resulting equations for the relationship between endpoint prolactin change and dose, by gender. In the equation, "dose" refers to the calculated oral equivalent daily dose (10.7, 14.5, or 21.4 mg/day), not the actual injected dose. Abbreviations: OLZ LAI = olanzapine long-acting injection; OLZ LAI 150 = group receiving low-dose olanzapine LAI, 150 mg/2 weeks, approximate oral equivalent 10 mg/day (N = 140); OLZ LAI 405 = group receiving medium-dose olanzapine LAI, 405 mg/4 weeks, approximate oral equivalent 15 mg/day (N = 318); and OLZ LAI 300 = group receiving high-dose olanzapine LAI, 300 mg/2 weeks, approximate oral equivalent 20 mg/day (N = 141).

Figure 3

Kaplan-Meier survival analysis of time to relapse by dose group. Figure 3 illustrates the survival curves for time to relapse by dose group. Relapse or "psychotic exacerbation" was defined as 1) an increase of any BPRS positive symptom item to a score >4, with an absolute increase ≥2 for the specific item since randomization, 2) an increase of any BPRS positive symptom item to a score >4, with an absolute increase ≥4 on the positive symptom subscale since randomization; or 3) hospitalization as the result of worsening of positive psychotic symptoms. Median time to relapse not reported because no group had >50% rate of relapse. Abbreviations: OLZ LAI = olanzapine long-acting injection; OLZ LAI 150 = group receiving low-dose olanzapine LAI, 150 mg every 2 weeks, approximate oral equivalent 10 mg/day (N = 140); OLZ LAI 405 = group receiving medium-dose olanzapine LAI, 405 mg every 4 weeks, approximate oral equivalent 15 mg/day (N = 318); and OLZ LAI 300 = group receiving high-dose olanzapine LAI, 300 mg every 2 weeks, approximate oral equivalent 20 mg/day (N = 141).

Figure 4

Regression scatterplot of mean change in PANSS total score (LOCF) by dose. Figure 4 shows the scatterplot, regression line, and resulting equation for the relationship between endpoint PANSS total score change and dose (R2 = 0.0133). In the equation, "dose" refers to the calculated oral equivalent daily dose (10.7, 14.5, or 21.4 mg/day), not the actual injected dose. Abbreviations: OLZ LAI = olanzapine long-acting injection; OLZ LAI 150 = group receiving low-dose olanzapine LAI, 150 mg every 2 weeks, approximate oral equivalent 10 mg/day (N = 140); OLZ LAI 405 = group receiving medium-dose olanzapine LAI, 405 mg every 4 weeks, approximate oral equivalent 15 mg/day (N = 318); and OLZ LAI 300 = group receiving high-dose olanzapine LAI, 300 mg every 2 weeks, approximate oral equivalent 20 mg/day (N = 141).

Figure 5

Rates of overall discontinuation and discontinuation due to efficacy-related reasons by dose group. Figure 5 illustrates the rates of overall discontinuation (NNT = 9 high vs. low dose) and discontinuation for efficacy-related reasons (NNT = 8 high vs. low dose; NNT = 13 high vs. medium dose) by dose group. Efficacy-related reasons includes lack of efficacy and/or any psychiatric adverse event (e.g., "schizophrenia", "paranoid disorder," etc.). Abbreviations: OLZ LAI = olanzapine long-acting injection; OLZ LAI 150 = group receiving low-dose olanzapine LAI, 150 mg every 2 weeks, approximate oral equivalent 10 mg/day (N = 140); OLZ LAI 405 = group receiving medium-dose olanzapine LAI, 405 mg every 4 weeks, approximate oral equivalent 15 mg/day (N = 318); and OLZ LAI 300 = group receiving high-dose olanzapine LAI, 300 mg every 2 weeks, approximate oral equivalent 20 mg/day (N = 141).

Figure 6

Kaplan-Meier survival analysis of time to all-cause discontinuation by dose group. Figure 6 shows the survival curves for time to all-cause discontinuation by dose group. Abbreviations: OLZ LAI = olanzapine long-acting injection; OLZ LAI 150 = group receiving low-dose olanzapine LAI, 150 mg every 2 weeks, approximate oral equivalent 10 mg/day (N = 140); OLZ LAI 405 = group receiving medium-dose olanzapine LAI, 405 mg every 4 weeks, approximate oral equivalent 15 mg/day (N = 318); and OLZ LAI 300 = group receiving high-dose olanzapine LAI, 300 mg every 2 weeks, approximate oral equivalent 20 mg/day (N = 141).