Scientific, Practical, and Ethical Considerations for Placebo-Controlled, Relapse Prevention Trials in Schizophrenia

In a recent JAMA Psychiatry Viewpoint piece, Columbia Psychiatry’s Ryan E. Lawrence, MD, Paul S. Appelbaum, MD, and Jeffrey A. Lieberman, MD ask the question: “Are Placebo-Controlled, Relapse Prevention Trials in Schizophrenia Research Still Necessary or Ethical?” The authors suggest that researchers, pharmaceutical companies, and the FDA reconsider the scientific, practical, and ethical justification of placebo-controlled, relapse prevention studies in schizophrenia.

“When psychiatrists started doing these trials in the 1960s, antipsychotic medication was still very new, and there were a lot of unanswered questions about whether these drugs reduce the risk of relapse,” says Lawrence. “Now, fifty years later, we know the answer, yet our profession is still running these trials.”

In their paper, Lawrence, Appelbaum, and Lieberman point out that a huge body of data has been generated showing that drugs acting through D2 antagonism improve psychotic symptoms, which would seem to eliminate the need for more studies of drugs that act through the same mechanism. None of the 60 D2 antagonists that has been developed and has shown short-term treatment efficacy has ever been ineffective for relapse prevention.

In terms of practical considerations, Lawrence, Appelbaum, and Lieberman explain that placebo-controlled studies contain cost, reduce study duration, and minimize the number of participants potentially exposed to ineffective treatment. At the same time, placebo-controlled, relapse prevention trials face special challenges inasmuch as different trials have reported markedly different relapse rates.

In an ethical sense, the authors state that patients who participate in placebo-controlled, relapse prevention trials are rolling the dice on the possibility of their illness worsening or incurring other complications to their lives.

Senior author Jeffrey Lieberman, Chairman of Columbia Psychiatry, added, “The FDA clearly states that if effective treatments already exist or if patients will be placed at risk of harm, then active comparators should be used instead of placebo. This standard is applied in drug development for other disease areas and should be for mental disorders like schizophrenia.”

Lawrence, Appelbaum, and Lieberman conclude that the time has come to cease the use of placebo in relapse prevention studies and encourage the use of active comparators that would protect patients from relapse and provide information on the comparative effectiveness of the drugs studied. They recommend that pharmaceutical companies not seek maintenance labeling if it would require placebo-controlled, relapse prevention trials. However, for putative antipsychotics with a novel mechanism of action, placebo-controlled, relapse prevention trials may still be justifiable.