Since the 1960s, the positive response rates to antipsychotic medications have been dropping steadily, according to a meta-analysis published in JAMA Psychiatry by Columbia University and New York State Psychiatric Institute researchers. At the same time, the positive response rates to placebos have been increasing, and antipsychotic medications are therefore appearing less effective in comparison. This situation necessitates re-thinking how clinical trials are done, wrote the researchers, in order to overcome this appearance of ineffectiveness of antipsychotics.
In their study, the researchers wrote that slim drug-placebo differences in drug trials have been increasing the numbers of “failed antipsychotic trials,” which in turn have been increasing “the cost of drug development” and also causing some pharmaceutical companies to reduce their psychiatric research. “Thus, it is imperative to determine what is causing these increased placebo response rates in antipsychotic trials.”
The researchers examined randomized controlled trials (RCT) published between 1960 and July 2013 that compared antipsychotics to placebos or to other comparable medications in adults with schizophrenia or schizoaffective disorder, and that lasted between 4 and 24 weeks.
“(T)he placebo response was shown to be significantly increasing from 1960 to the present,” they wrote. They found that the average placebo-treated patient in an RCT of antipsychotic drugs during the 1960s worsened by 3.5 Brief Psychiatric Rating Scale (BPRS) points. Yet in the 2000s, the average placebo-treated patient improved by 3.2 BPRS points.
Over the same time span, antipsychotic effectiveness dropped significantly. “The average RCT participant receiving an effective dose of medication in the 1960s improved by 13.8 BPRS points, whereas this difference diminished to 9.7 BPRS points by the 2000s.”
“The consequence of these divergent trends,” the researchers noted, “was a significant decrease in drug-placebo differences from 1960 to the present.”
The researchers found that one factor accounting for this trend seemed to be that people with less severe symptoms — who also responded less well to treatment — were being enrolled in clinical trials in more recent years. They also found that when patients and physicians both knew that patients had higher odds of receiving a drug instead of a placebo in drug comparison trials, response rates improved across the board, possibly due to either heightened patient expectation or clinician “rater bias” or both. In addition, they found that the longer clinical trials lasted, the less effective antipsychotics appeared.
In their conclusion, the researchers suggested that efforts could be made to improve “signal detection,” or the appearance of drug effectiveness. Among such advisable changes, they suggested, “would be to recruit more severely ill patients” and “limit study duration to no longer than 8 to 12 weeks.”
The researchers also concluded that clinical trial designs should “dispense with single-blind placebo lead-in periods.” The study did not go into detail on alternative trial designs; however, a 2012 webinar by UNC at Chapel Hill biostatistician Anastasia Ivanova made the same argument. Discussing many of the same antipsychotic drug trials as were later identified in the JAMA Psychiatry study, Ivanova explained that, “The fact that an increasing number of medications are unable to beat sugar pills has thrown the industry into crisis. The placebo effect has become the elephant in the boardroom.” Ivanova then described in detail how the single-blind placebo lead-in design was an effort to remove people who responded to placebos from clinical trials that did not succeed, and should be replaced by a multi-stage trial design that was much more effective at strategically eliminating people who responded to placebos.
(Abstract) Placebo Response in Antipsychotic Clinical Trials (Rutherford, Bret R. et al. JAMA Psychiatry. Published online October 08, 2014. doi:10.1001/jamapsychiatry.2014.1319)
Changing placebo response dilutes antipsychotic trial power (medwire News, October 16, 2014)
Comparing Strategies for Trials with High Placebo Response (Ivanova, Anastasia. ASA Biopharm Section Webinars Archive. August 27, 2012.)