Are Antipsychotics or Antidepressants Needed for Psychotic Depression? A Systematic Review and Meta-Analysis of Trials Comparing Antidepressant or Antipsychotic Monotherapy With Combination Treatment

Objective: To perform a meta-analysis of antidepressant-antipsychotic cotreatment versus antidepressant or antipsychotic monotherapy for psychotic depression.

Data Sources: We performed an electronic search (from inception of databases until February 28, 2011) in PubMed/MEDLINE, Cochrane Library, and PsycINFO, without language or time restrictions. Search terms were (psychosis OR psychotic OR hallucinations OR hallucinating OR delusions OR delusional) AND (depression OR depressed OR major depressive disorder) AND (random OR randomized OR randomly).

Study Selection: Eight randomized, placebo-controlled acute-phase studies in adults (N = 762) with standardized criteria-defined psychotic depression (including Research Diagnostic Criteria, DSM-III, DSM-IV, or ICD-10) were meta-analyzed, yielding 10 comparisons. Antidepressant-antipsychotic cotreatment was compared in 5 trials with 6 treatment arms (n = 337) with antidepressant monotherapy and in 4 trials with 4 treatment arms (n = 447) with antipsychotic monotherapy.

Data Extraction: Primary outcome was study-defined inefficacy; secondary outcomes included all-cause discontinuation, specific psychopathology ratings, and side effects. Using random effects models, we calculated relative risk (RR) with 95% confidence intervals (CIs), number-needed-to-treat/harm (NNT/NNH), and effect size (ES).

Results: Antidepressant-antipsychotic cotreatment outperformed antidepressant monotherapy regarding less study-defined inefficacy (no. of comparisons = 6; n = 378; RR = 0.76; 95% CI, 0.59-0.98; P = .03; heterogeneity [I2] = 34%) (NNT = 7; 95% CI, 4-20; P = .009) and Clinical Global Impressions-Severity of Illness scores (no. of comparisons = 4; n = 289; ES = −0.25; 95% CI, −0.49 to −0.02; P = .03; I2 = 0%), with trend-level superiority for depression ratings (no. of comparisons = 5; n = 324; ES = −0.20; 95% CI, −0.44 to 0.03; P = .09; I2 = 10%), but not regarding psychosis ratings (no. of comparisons = 3; n = 161; ES = −0.24; 95% CI, −0.85 to 0.38; P = .45; I2 = 70%). Antidepressant-antipsychotic cotreatment also outperformed antipsychotic monotherapy regarding less study-defined inefficacy (no. of comparisons = 4; n = 447; RR = 0.73; 95% CI, 0.63-0.84; P < .0001; I2 = 0%) (NNT = 5; 95% CI, 4-8; P < .0001) and depression ratings (no. of comparisons = 4; n = 428; ES = −0.49; 95% CI, −0.75 to −0.23; P = .0002; I2 = 27%), while anxiety (P = .11) and psychosis (P = .06) ratings only trended toward favoring cotreatment. All-cause discontinuation and reported side-effect rates were similar, except for more somnolence with antidepressant-antipsychotic cotreatment versus antidepressants (P = .02). Only 1 open-label, 4-month extension study (n = 59) assessed maintenance/relapse-prevention efficacy of antidepressant-antipsychotic cotreatment versus antidepressant monotherapy, without group differences.

Conclusions: Antidepressant-antipsychotic cotreatment was superior to monotherapy with either drug class in the acute treatment of psychotic depression. These results support recent treatment guidelines, but more studies are needed to assess specific combinations and maintenance/relapse-prevention efficacy.

J Clin Psychiatry 2012;73(4):486-496

© Copyright 2012 Physicians Postgraduate Press, Inc.

Submitted: August 10, 2011; accepted December 14, 2011 (doi:10.4088/JCP.11r07324).

Corresponding author: Christoph U. Correll, MD, Division of Psychiatry Research, The Zucker Hillside Hospital, 75-59 263rd St, Glen Oaks, NY 11004 ([email protected]).