Clinical trials for antipsychotic drugs: design conventions, dilemmas and innovations

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More than 50 years after the introduction of modern pharmacotherapies for schizophrenia, there remains a tremendous need for therapeutic advances. A second generation of antipsychotic drugs, introduced over the past 15 years, has provided uncertain advantages over the first-generation drugs. This paper reviews the designs of studies that evaluate the effectiveness of putative antipsychotic drugs. Data from the trials needed to achieve regulatory approval do not meet all the needs of clinicians and policy makers. Practical and large, simple trials that evaluate the comparative effectiveness of antipsychotic drugs in real-world settings can help to meet these needs once a drug has reached the market.

Key Points

  • Schizophrenia is a severe and complex illness for which current treatments are only partially effective. The development of antipsychotic drugs that are used to treat schizophrenia follows usual drug development paradigms, but these studies have illness-specific challenges.

  • The complex nature of schizophrenia means there are many clinically relevant outcomes worthy of study. Typical studies attempt to address many outcomes, leading to a multiple comparisons problem and the risk of false-positive research findings. Non-compliance with treatment regimens, study drop-out rates and missing data pose major problems in schizophrenia trials.

  • Most available data regarding antipsychotic drug effectiveness come from industry-sponsored studies that were intended to meet regulatory requirements efficiently. Available data are not adequately informative for clinicians and policy-makers, who face difficult, 'real-world' decisions.

  • Large, simple trials attempt to answer important clinical questions by enrolling large numbers of subjects in randomized trials in typical treatment settings that collect minimal data regarding only crucial outcomes.

  • Practical clinical trials attempt to aid clinical and policy decision-makers by addressing a broad range of relevant questions regarding existing treatments in settings and conditions that are representative of 'real-world' conditions.

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Figure 1: Drug treatments for features of schizophrenia.
Figure 2: The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial: an example of a practical trial.


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The authors' research was supported in part by a research grant from the National Institutes of Health, USA, and funded by the National Institute of Mental Health (NIMH), the Office of the Director, Office of Behavioral and Social Research (OD/OBSSR) and the Clinical Antipsychotic Trials of Intervention Effectiveness project, which, in turn, is supported by the NIMH. The authors thank D. Healy for his suggestions regarding the timeline.

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Correspondence to T. Scott Stroup.

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Competing interests

W.M.A. has no competing interests relevant to this paper.

T.S.S. has consulted for Pfizer, Lilly and GlaxoSmithKline.

J.A.L. has received research funding and speaking and consultancy fees from Bristol-Myers Squibb, Pfizer, Lilly and AstraZeneca.

R.M.H. has consulted for Janssen, Lilly, Somerset, Forest, Corcept Therapeutics and Xcel Pharmaceuticals. He also serves on Data Safety Monitoring Boards for the National Institute of Neurological Disorders and Stroke, Schwartz Pharma, Johnson &Johnson, Pfizer, Solvay and Duke University. He is a principal investigator (PI) on a contract between the University of North Carolina and Lilly for the analysis of data from a clinical trial on which J.A.L. was PI comparing two antipsychotics (olanzapine and haloperidol). He has served on multiple NIMH study sections and, from 1998 to 2001, on the FDA Psychopharmacologic Drugs Advisory Committee.

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