Initial symptom severity of bipolar I disorder and the efficacy of olanzapine: a meta-analysis of individual participant data from five placebo-controlled studies

Background The efficacy of antipsychotics across the initial severity range in patients with acute mania remains unclear. Therefore, we examined the influence of baseline severity on the efficacy of olanzapine. Methods We did an individual participant data meta-analysis of double-blind, randomised controlled trials that compared olanzapine with placebo, identified through searches of the ClinicalStudyRequest.com database on Feb 2, 2016. We included patients with acute mania associated with bipolar I disorder. We examined the association between baseline and change scores on the Young Mania Rating Scale (YMRS; range 0–60) up to 3 weeks for olanzapine versus placebo groups using eight increasingly complex competing mixed-effects models for repeated measures. Findings We identified 33 reports, five (15%) of which were eligible and contained data for 939 patients (552 received olanzapine; 387 received placebo). The interaction between baseline severity and treatment was significant (β=0·22, 95% CI 0·05–0·39; p=0·013). The greater the baseline severity, the greater the magnitude of the differences between olanzapine and placebo was expected. The mean estimated YMRS scores were reduced at 3 weeks in both groups, but were greater with olazapine than placebo by 2·56 points for patients with a baseline score of 20–25 (9·26 for olanzapine vs 6·70 for placebo; effect size 0·35, 95% CI 0·11–0·60), by 4·74 points for a baseline score of 25–35 (14·25 vs 9·51; 0·58, 0·34–0·86), and by 8·01 points for a baseline score of 35–60 (21·72 vs 13·71; 0·70, 0·31–1·23). Interpretation Benefits of olanzapine can be expected for patients across the full spectrum of symptom severity who are likely to be treated for acute mania. Less severely ill patients seem to benefit less in terms of olanzapine efficacy, but still experience the same side-effects as more severely ill patients. Thus, clinicians and patients should carefully consider the benefit-to-risk ratio of olanzapine and its additional, prophylactic effect against relapse in the long term. The generalisability of these results to other antipsychotics, trial designs, and medical conditions remains to be established. Funding None.