Response to antidepressants in major depressive disorder is highly variable and determinants are not well understood. Presentation will provide clinical trial data on time to response and determinants of response to antidepressant treatment. Data is from the Innovative Medicines Initiative funded NEWMEDS collaboration, a large public-private collaboration which assembled the largest dataset of individual patient level information from randomized placebo-controlled trials of antidepressant drugs. Studies were conducted by four large pharmaceutical companies. Dataset includes placebo-controlled trials of citalopram, duloxetine, escitalopram, quetiapine and sertraline 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). While it is conventional for trials to be 6–8 weeks long, data presented will show that drug-placebo differences were observable at week 4 with nearly the same sensitivity and lower dropout rates. Having any of these attributes was significantly associated with greater drug vs. placebo differences on symptom improvement: female, patients being middle aged, increasing proportion of patients on placebo, excluding all patients from centers with high placebo response regardless of active treatment response, using active run in periods and including self-report measures. 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.