Long-Term Acute-Phase Treatment With Antidepressants, 8 Weeks and Beyond: A Systematic Review and Meta-Analysis of Randomized, Placebo-Controlled Trials

Objective: In clinical practice, acute antidepressant treatment is often applied for several months until remission is achieved. However, data on treatment outcomes beyond 8 weeks are sparse and no systematic review exists to date. This study aims at assessing efficacy and tolerability of antidepressants compared to placebo in acute treatment at and beyond 8 weeks.

Data Sources: MEDLINE, Embase, PsycINFO, and CENTRAL databases were systematically searched through March 2014 using generic terms for depressive and affective disorders combined with generic terms for individual drugs and placebo.

Study Selection: Double-blind, randomized, placebo-controlled studies of 8 weeks or more comparing antidepressant monotherapy to placebo in adult patients with acute depressive disorder.

Data Extraction: Data extraction and synthesis followed guidelines of the Cochrane Collaboration. All data were extracted independently by 2 reviewers. Primary outcome was standardized mean difference (SMD) between antidepressant and placebo; secondary outcomes were response, remission, and dropouts.

Results: Of 6,043 articles screened, we selected 104 studies that met criteria and included 35,052 patients. Active treatment was statistically significantly superior to placebo, with consistent effect sizes (SMD [95% CL]) after 8, 12, 16, 20, and 24 weeks: 0.27 (0.24, 0.30), 0.34 (0.25, 0.43), 0.24 (0.09, 0.40), 0.31 (0.12, 0.51), and 0.34 (0.18, 0.50), respectively. Results remained stable across secondary outcomes and subgroup and sensitivity analyses.

Conclusions: Effect sizes of antidepressant monotherapy compared to placebo seem to be stable over 6 months. These results challenge the assumption that long-term antidepressant effects are due to the natural course of the disorder rather than to a pharmacologic effect.