Second-generation antipsychotics for major depressive disorder and dysthymia

Cochrane Database Syst Rev. 2010 Dec 8:(12):CD008121. doi: 10.1002/14651858.CD008121.pub2.


Background: Major depressive disorder (MDD) is a common condition with a lifetime prevalence of 15% to 18%, which leads to considerable suffering and disability. Some antipsychotics have been reported to induce remission in major depression, when added to an antidepressant.

Objectives: To evaluate the effects of second-generation antipsychotic (SGA) drugs (alone or augmentation) compared with placebo or antidepressants for people with MDD or dysthymia.

Search strategy: The Cochrane Depression, Anxiety and Neurosis Group's controlled trial registers (CCDANCTR-Studies and CCDANCTR-References) were searched up to 21 July 2010. The author team ran complementary searches on and contacted key authors and drug companies.

Selection criteria: We included all randomised, double-blind trials comparing oral SGA treatment (alone or augmentation) with other forms of pharmaceutical treatment or placebo in people with MDD or dysthymia.

Data collection and analysis: We extracted data independently. For dichotomous data we calculated the odds ratio (OR) and 95% confidence interval (CI) on an intention-to-treat basis, and for continuous data the mean difference (MD), based on a random-effects model. We presented each comparison separately; we did not perform a pooled data analysis.

Main results: We included 28 trials with 8487 participants on five SGAs: amisulpride, aripiprazole, olanzapine, quetiapine and risperidone.Three studies (1092 participants) provided data on aripiprazole augmentation in MDD. All efficacy data (response n = 1092, three RCTs, OR 0.48; 95% CI 0.37 to 0.63), (MADRS n = 1077, three RCTs, MD -3.04; 95% CI -4.09 to -2) indicated a benefit for aripiprazole but more side effects (weight gain, EPS) .Seven trials (1754 participants) reported data on olanzapine. Compared to placebo fewer people discontinued treatment due to inefficacy; compared to antidepressants there were no efficacy differences, olanzapine augmentation showed symptom reduction (MADRS n = 808, five RCTs, MD -2.84; 95% CI -5.48 to -0.20), but also more weight or prolactin increase.Quetiapine data are based on seven trials (3414 participants). Compared to placebo, quetiapine monotherapy (response n = 1342, three RCTs, OR 0.52; 95% CI 0.41 to 0.66) and quetiapine augmentation (response n = 937, two RCTs, OR 0.68; 95% CI 0.52 to 0.90) showed symptom reduction, but quetiapine induced more sedation.Four trials (637 participants) presented data on risperidone augmentation, response data were better for risperidone (n = 371, two RCTs, OR 0.57; 95% CI 0.36 to 0.89) but augmentation showed more prolactin increase and weight gain.Five studies (1313 participants) presented data on amisulpride treatment for dysthymia. There were some beneficial effects compared to placebo or antidepressants but tolerability was worse.

Authors' conclusions: Quetiapine was more effective than placebo treatment. Aripiprazole and quetiapine and partly also olanzapine and risperidone augmentation showed beneficial effects compared to placebo. Some evidence indicated beneficial effects of low-dose amisulpride for dysthymic people. Most SGAs showed worse tolerability.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Amisulpride
  • Antidepressive Agents / therapeutic use
  • Antipsychotic Agents / therapeutic use*
  • Aripiprazole
  • Benzodiazepines / therapeutic use
  • Depressive Disorder, Major / drug therapy*
  • Dibenzothiazepines / therapeutic use
  • Dysthymic Disorder / drug therapy*
  • Humans
  • Olanzapine
  • Piperazines / therapeutic use
  • Quetiapine Fumarate
  • Quinolones / therapeutic use
  • Randomized Controlled Trials as Topic
  • Risperidone / therapeutic use
  • Sulpiride / analogs & derivatives
  • Sulpiride / therapeutic use


  • Antidepressive Agents
  • Antipsychotic Agents
  • Dibenzothiazepines
  • Piperazines
  • Quinolones
  • Benzodiazepines
  • Quetiapine Fumarate
  • Sulpiride
  • Amisulpride
  • Aripiprazole
  • Risperidone
  • Olanzapine