Although randomized placebo-controlled trials represent the gold standard in studies supporting the development of new psychotropic drugs, they are not required for approval by the US Food and Drug Administration.1 The use of placebo-controlled relapse prevention studies (PCRPS) in schizophrenia research has increasingly become a point of debate among experts, some of whom question the necessity and risk of using placebos in these studies, while others defend their use.

A review published in 2013 in Schizophrenia Research examined 12 relapse-prevention placebo-controlled randomized controlled trials (RCTs) involving the use of second-generation psychotics in a total of 2842 patients with schizophrenia.2 In the patients who received placebo (n=968), the relapse rate was 56% compared with 17.4% in the active treatment groups.

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The review also revealed a “lack of well-designed longitudinal studies investigating the psychosocial and biological consequences of exposure to placebo, to treatment discontinuation and to relapse in schizophrenia,” wrote the investigators.2 Thus, it is “risky to assume that patients are not at risk of significant distress and long-term harm, and therefore it is difficult to justify the ongoing use of placebo in relapse-prevention RCTs in schizophrenia.”

In a 2019 review published in Psychotherapy and Psychosomatics, researchers at the University of California, Los Angeles, explored methods used in the discontinuation of psychotropic drugs, as well as justifications for this approach and the acknowledgment of potential withdrawal symptoms across 80 RCTs (N=5757).3 Relapse prevention was the most common focus of these trials (44%), in which the medications were often abruptly or rapidly discontinued.

Only 33% of RCTs provided justification for the discontinuation strategy used and only 14% of trials addressed possible withdrawal confounding of study outcomes. “RCTs use drug discontinuation to study several key issues in psychopharmacology but infrequently justify how they implement it or acknowledge that possible withdrawal symptoms may threaten internal validity,” the researchers concluded.3 “Reappraising the use of drug discontinuation and the recognition of withdrawal symptoms in RCTs is required.”

In a letter to the editor that appeared in October 2019 in Acta Psychiatrica Scandinavica, Dr Marko Ćurković and Dr Ana Borovečki acknowledge the complexity of PCRPS, but cautioned against the abandonment of this research design altogether, suggesting that associated concerns may represent scientific issues.4 They noted that relapse prevention in schizophrenia remains a critical subject to be further examined despite the “ethical unease,” and they described several factors to consider pertaining to the necessity of PCRPS.

The letter pointed to the many questions regarding antipsychotic treatment that warrant additional investigation, such as which patients are disproportionately burdened by long-term antipsychotic use with minimal benefit. “Those individuals come from both ends of [the] schizophrenia continuum, those with good (regardless of treatment intervention) and worst outcomes (certain subgroups of treatment-resistant individuals),” according to the letter.4

“In other words, in [a] certain proportion of users there is no benefit as relapse is not to be expected, while in substantial proportions of others remission will never be achieved, so there is no relapse to be prevented.” In addition, the long-term effects of antipsychotic drugs are still unclear and there is scant evidence to justify the prophylactic use of these medications beyond 2 to 3 years.4 

Another key issue is the lack of consensus on suitable alternatives to PCRPS, and there are shortcomings associated with each possible option. For example, the use of an active comparator study would present uncertainty about which agent should be considered the gold standard, since there are “significant differences between antipsychotics in their long-term risk-benefit profiles, while no single antipsychotic shows clear superiority across multiple outcome domains,” Ćurković and Borovečki stated.4 “This situation promotes the use of placebo as this is the bare definition of clinical equipoise.”

For further discussion regarding the implications of PCRPS in schizophrenia, Psychiatry Advisor interviewed Ryan E. Lawrence, MD, professor of psychiatry at Columbia University Medical Center in New York City, who co-authored a 2019 paper on this topic in JAMA Psychiatry.1

Psychiatry Advisor: What are some of the main points of debate regarding the use of placebo in schizophrenia relapse studies?

Ryan Lawrence, MD: I think the center of the debate is whether we are accurately assessing the risks and benefits of these studies. On the risk side, just how concerning is it for patient to relapse in the context of a clinical trial? How early do clinicians actually identify symptoms of relapse? How frequent are bad outcomes? Does each relapse worsen the prognosis? I think these are important questions and there is very little empirical data to help us answer them.

On the benefits side, there is an epistemologic question about how necessary these trials are. Do they really give us information we did not have before? Are there other study designs that would provide the data we need without exposing patients to such a high relapse risk? These questions present philosophical challenges for the scientific community, as well as practical policy questions for regulatory agencies.

Psychiatry Advisor: How should these issues be addressed?

Dr Lawrence: I think there are opportunities to address these issues on multiple levels. I would applaud regulatory bodies offering more guidance about when a placebo-controlled trial is absolutely necessary and when alternative designs might be acceptable.

I would encourage antipsychotic researchers to prefer active-comparison trials over placebo-controlled trials. Yes, they would be more expensive and take longer than placebo-controlled trials, but active-comparison trials more closely reflect the clinical question patients and prescribers face every day: Prescribers are not deciding between an antipsychotic medication and a placebo for schizophrenia, they are deciding whether to prescribe one antipsychotic over another antipsychotic.

At the patient level, I think there is an opportunity to educate patients about the relapse risks, so they can be especially mindful of whether or not enrolling in a placebo-controlled trial is right for them.

Psychiatry Advisor: What are the treatment implications of this issue for clinicians?

Dr Lawrence: Studies on “the therapeutic misconception” have frequently shown that research participants often misunderstand the purpose or design of a study and incorrectly assume a research trial is intended to benefit them. Clinicians can play a crucial role in helping patients understand the research proposal, weigh the risks and benefits, and make an informed decision about participating in a study.

Psychiatry Advisor: What are remaining research needs in this area?

Dr Lawrence: There are countless unanswered questions in schizophrenia research. Even in the realm of relapse prevention, much remains to be discovered about predicting and preventing relapse, minimizing long-term adverse events of antipsychotic medication, and optimizing drug selection for specific individuals. We have learned an enormous amount from PCRP studies over the years, but I have doubts that this particular study design will address these unanswered questions.

References

1. Lawrence RE, Appelbaum PS, Lieberman JA. Are placebo-controlled, relapse prevention trials in schizophrenia research still necessary or ethical? JAMA Psychiatry. 2019;76(7):673-674.

2. Emsley R, Fleischhacker WW. Is the ongoing use of placebo in relapse-prevention clinical trials in schizophrenia justified? Schizophr Res. 2013;150(2-3):427-433.

3. Cohen D, Recalt A. Discontinuing psychotropic drugs from participants in randomized controlled trials: A systematic review. Psychother Psychosom. 2019;88(2):96-104.

4. Ćurković M, Borovečki A. The use of placebo in schizophrenia relapse prevention studies: scientific or ethical debate? Acta Psychiatr Scand. 2019;140(4):386-387.