In a viewpoint published in JAMA Psychiatry, experts from Columbia University wrote that placebo-controlled, relapse prevention studies for schizophrenia should no longer be conducted; instead, trials should use active comparators that would protect patients from relapse and offer data on the comparative effectiveness of the drugs involved.
The FDA has guidelines on when to use placebo in a trial, according to Ryan E. Lawrence, MD, from the department of psychiatry at New York–Presbyterian Hospital and Columbia University Medical Center, and colleagues. However, when evaluating antipsychotics for schizophrenia, the guidelines are unclear.
“In schizophrenia research, one study design, the placebo-controlled, relapse prevention trial, is especially problematic,” they explained. “These studies, designed to demonstrate prophylactic or maintenance treatment efficacy, enroll stable patients receiving antipsychotic medication and randomize them to placebo or active drug. Participants are followed up for 6 months to 2 years, with return of psychotic symptoms being the primary end point.”
Despite concerns, placebo-controlled, relapse prevention trials are routinely conducted, according to the researchers.
During research examining the efficacy of drugs for relapse prevention, a large body of evidence has shown that D2 antagonists are effective at preventing relapse in schizophrenia. Of the 60 drugs acting through D2 antagonism that have been developed, more than 20 are FDA-approved for treating schizophrenia, which should remove the need for more studies of medications that act through that same mechanism, the investigators explained.
“While it might be true that a new antipsychotic has never been tested against placebo in a relapse prevention trial, 40 years of data have consistently shown that D2 antagonists are superior to placebo for relapse prevention in maintenance treatment,” they wrote.
Furthermore, longitudinal studies have indicated that longer duration of untreated psychosis and experiencing more psychotic episodes may worsen a patient’s outcomes and prognoses. Different placebo-controlled, relapse prevention trials also have reported notably different relapse rates, raising questions of whether there are issues with internal and external validity or applicability, Lawrence and colleagues wrote.
“Given the extent and consistency of these data, and a growing awareness of the potential harms, the scientific value of placebo controls in relapse prevention trials of new antipsychotics with D2 targeted mechanisms of action has decreased, and the risks to patients have increased,” they concluded. “We 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.” – by Savannah Demko
Disclosure: The authors report no relevant financial disclosures.