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Proposal 1457

Title of the Proposed Research

Initial severity and efficacy of antipsychotics for schizophrenia and bipolar mania: Individual participant level analyses of placebo-controlled studies.

Lead Researcher

Stefan Leucht


Department of Psychiatry and Psychotherapy TU-München

Funding Source


Potential Conflicts of Interest

Prof Leucht has received honoraria for lectures from Abbvie, AstraZeneca, Bristol-Myers Squibb, ICON, Eli Lilly and Co, Janssen, Johnson & Johnson, Roche, Sanofi-Aventis, Lundbeck, and Pfizer and for consulting or advisory boards from Roche, Eli Lilly and Co, MedAvante, Bristol-Myers Squibb,Alkermes, Janssen, Johnson & Johnson, and Lundbeck, and Eli Lilly and Co has provided medication for a study with him as primary investigator.

Data Sharing Agreement Date

8 June 2016

Lay Summary

Background: Schizophrenia and bipolar disorder are the most serious and debilitating psychiatric diseases affecting each approximately 1% of the population. Antipsychotic drugs are used for the treatment of both schizophrenia and bipolar mania, either in the acute phase for symptoms’ control or in the long term for relapse prevention. Nevertheless, the efficacy of many psychotropic agents has been recently called into question leading to a general mistrust towards psychiatry and the efficacy of its treatments. The impact on patients’ adherence is still unknown but, given the extensive media coverage of the topic, this is a major issue of public health importance. Our research group has recently published an individual participant data meta-analysis in the acute treatment of schizophrenia examining the influence of baseline severity on the efficacy of antipsychotic drugs. We found that benefits from antipsychotic drugs are expected for all patients with acute schizophrenia and for highly symptomatic patients with predominant negative symptoms. However, antipsychotic efficacy compared to placebo was lessened in less ill patients.

Objectives: Our primary hypothesis is that antipsychotic drugs have greater efficacy compared to placebo for all patients suffering from acute schizophrenia or bipolar mania, irrespectively of their baseline symptom severity, but also that more severely ill patients do benefit more. Our objective is either to confirm or refute this hypothesis by replicating our previous findings in a larger sample of patients, including more antipsychotic drugs and extending the analysis to patients suffering from bipolar mania as well.

Study design: We plan to perform meta-analyses of individual participant data to investigate the relationship between baseline symptom severity and subsequent symptom change comparing antipsychotics versus placebo. Patients with schizophrenia and bipolar mania, in the acute phase of their illness, will be included in two separate analyses. To enhance the clinical interpretation of the results, a linking analysis between different scales will be conducted as well as a psychometric analysis that could identify a network of central symptoms and a short symptom rating scale if possible. Interpretation and communication of findings: The results of our planned study could have a major impact on future guidelines and everyday clinical practice. Thus, any interpretation will be very careful. Clinicians need to take into account that when patients benefit less in terms of symptom improvement, they may still experience full side-effects of antipsychotics. On the other hand, antipsychotic action is not limited in the treatment of active symptoms but also includes relapse prevention. We will communicate our findings to scientists by publishing in major medical journals, giving lectures in symposia at international psychiatric conferences, and implementing them in national and international treatment guidelines.

Study Data Provided

Study LILLY-F1D-MC-HGJZ: A Double-Blind Randomized Study Comparing Intramuscular Olanzapine Depot With Placebo in the Treatment of Patients With Schizophrenia
Study LILLY-F1D-MC-HGEH: Olanzapine Versus Placebo in the Treatment of Mania Associated with Bipolar I Disorder
Study LILLY-F1D-JE-BMAC: Placebo- and Haloperidol-Controlled Double-Blind Trial of Olanzapine in Patients with Manic or Mixed Episode of Bipolar I Disorder
Study LILLY-F1D-MC-HGGW: Olanzapine Versus Placebo in the Treatment of Bipolar Disorder, Manic or Mixed
StudyLILLY-F1D-MC-HGIN: - Olanzapine Versus Placebo in the Treatment of Adolescents With Schizophrenia
StudyLILLY-F1D-MC-HGIU: - Olanzapine Versus Placebo in the Treatment of Mania in Adolescents With Bipolar I Disorder
Study LILLY-F1D-MC-HGKQ: Olanzapine Versus Divalproex and Placebo in the Treatment of Mild to Moderate Mania Associated With Bipolar I Disorder

Statistical Analysis Plan

The statistical analysis plan will be added after the research is published.

Publication Citation

The publication citation will be added after the research is published.

Summary Results

Results summary or link will be posted when available.