Determinants of antidepressant response: Implications for practice and future clinical trials

Background: Response to antidepressants in major depressive disorder is variable and determinants are not well understood or used to design clinical trials. We aimed to understand these determinants. Methods: Supported by Innovative Medicines Initiative, as part of a large public-private collaboration (NEWMEDS), we assembled the largest dataset of individual patient level information from industry sponsored randomized placebo-controlled trials of antidepressant drugs in adults with MDD. We examined patient and trial-design-related determinants of outcome as measured by change on Hamilton Depression Scale or Montgomery–Asberg Depression Rating Scale in 34 placebo-controlled trials (drug, n = 8260; placebo, n = 3957). Results: While it is conventional for trials to be 6–8 weeks long, drug-placebo differences were nearly the same at week 4 as at week 6 and with lower dropout rates. At the multivariate level, having any of these attributes was significantly associated with greater drug vs. placebo differences on symptom improvement: female, increasing proportion of patients on placebo, centers located outside of North America, centers with low placebo response (regardless of active treatment response) and using randomized withdrawal designs. Limitations: Data on compounds that failed were not available to us. Findings may not be relevant for new mechanisms of action. Conclusions: Proof of concept trials can be shorter and efficiency improved by selecting enriched populations based on clinical and demographic variables, ensuring adequate balance of placebo patients, and carefully selecting and monitoring centers. In addition to improving drug discovery, patient exposure to placebo and experimental treatments can be reduced.