Antidepressant-placebo response-differences (RDs) in controlled trials have been declining, potentially confounding comparisons among older and newer drugs. For clinically employed antidepressants, we carried out a meta-analytic review of placebo-controlled trials in acute, unipolar, major depressive episodes reported over the past three decades to compare efficacy (drug-placebo RDs) of individual antidepressants and classes, and to consider factors associated with year-of-reporting by bivariate and multivariate regression modeling. Observed drug-placebo differences were moderate and generally similar among specific drugs, but larger among older antidepressants, notably tricyclics, than most newer agents. This outcome parallels selective increases in placebo-associated responses as trial-size has increased in recent years. Study findings generally support moderate efficacy of clinically employed antidepressants for acute major depression, but underscore limitations of meta-analyses of controlled trials for ranking drugs by efficacy. We suggest that efficiency and drug-placebo differences may be improved with fewer sites and subjects, and better quality-control of diagnostic and clinical assessments.