Increasing placebo response in antipsychotic trials: a clinical perspective

An increase in placebo response is often cited as rationale for the continuously diminishing drug-placebo differences in randomized controlled trials (RCTs) evaluating antipsychotic and antidepressant drugs. As a consequence, the probability for negative study results in placebo-controlled RCTs grows. This alarming trend conveys the impression that the newer marked psychopharmacological medications are less efficacious compared to the older ones although particularly trial methodological reasons contribute to the mitigation of the drug-placebo contrasts over the last decades. With regard to antipsychotic RCTs, the present article aims to elucidate the magnitude of the raising placebo response, factors contributing to this increase, and potential reasons for this phenomenon. Therefore, we summarize and critically discuss the findings of two recent meta-analyses on this topic. Both research projects revealed that the mean improvement of schizophrenic symptoms in the placebo groups of antipsychotic trials increased considerably over time. Factors that were significantly associated with larger placebo response in antipsychotic trials comprise with respect to participants characteristics younger age and shorter duration of illness. The results in terms of symptom severity at baseline were conflictive. In terms of trial methodology factors, shorter study duration, a larger number of study sites and participants, fewer academic/university sites, and a lower percentage of patients randomized to placebo were identified as potential predictors for high placebo response. The implications of these findings for the interpretation of antipsychotic trial results and meta-analyses are presented.