Adjunctive Atypical Antipsychotic Treatment for Major Depressive Disorder: A Meta-Analysis of Depression, Quality of Life, and Safety Outcomes
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BACKGROUND: Atypical antipsychotic medications are widely prescribed for the adjunctive treatment of depression, yet their total risk-benefit profile is not well understood. We thus conducted a systematic review of the efficacy and safety profiles of atypical antipsychotic medications used for the adjunctive treatment of depression. METHODS AND FINDINGS: We included randomized trials comparing adjunctive antipsychotic medication to placebo for treatment-resistant depression in adults. Our literature search (conducted in December 2011 and updated on December 14, 2012) identified 14 short-term trials of aripiprazole, olanzapine/fluoxetine combination (OFC), quetiapine, and risperidone. When possible, we supplemented published literature with data from manufacturers' clinical trial registries and US Food and Drug Administration New Drug Applications. Study duration ranged from 4 to 12 wk. All four drugs had statistically significant effects on remission, as follows: aripiprazole (odds ratio [OR], 2.01; 95% CI, 1.48-2.73), OFC (OR, 1.42; 95% CI, 1.01-2.0), quetiapine (OR, 1.79; 95% CI, 1.33-2.42), and risperidone (OR, 2.37; 95% CI, 1.31-4.30). The number needed to treat (NNT) was 19 for OFC and nine for each other drug. All drugs with the exception of OFC also had statistically significant effects on response rates, as follows: aripiprazole (OR, 2.07; 95% CI, 1.58-2.72; NNT, 7), OFC (OR, 1.30, 95% CI, 0.87-1.93), quetiapine (OR, 1.53, 95% CI, 1.17-2.0; NNT, 10), and risperidone (OR, 1.83, 95% CI, 1.16-2.88; NNT, 8). All four drugs showed statistically significant effects on clinician-rated depression severity measures (Hedges' g ranged from 0.26 to 0.48; mean difference of 2.69 points on the Montgomery-Asberg Depression Rating Scale across drugs). On measures of functioning and quality of life, these medications produced either no benefit or a very small benefit, except for risperidone, which had a small-to-moderate effect on quality of life (g = 0.49). Treatment was linked to several adverse events, including akathisia (aripiprazole), sedation (quetiapine, OFC, and aripiprazole), abnormal metabolic laboratory results (quetiapine and OFC), and weight gain (all four drugs, especially OFC). Shortcomings in study design and data reporting, as well as use of post hoc analyses, may have inflated the apparent benefits of treatment and reduced the apparent incidence of adverse events. CONCLUSIONS: Atypical antipsychotic medications for the adjunctive treatment of depression are efficacious in reducing observer-rated depressive symptoms, but clinicians should interpret these findings cautiously in light of (1) the small-to-moderate-sized benefits, (2) the lack of benefit with regards to quality of life or functional impairment, and (3) the abundant evidence of potential treatment-related harm. Please see later in the article for the Editors' Summary.
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There is now increasingly evidence that supervised exercise training, a key component of the DPP, can improve psychiatric symptoms, cognition and functioning across a range of mental disorders.
“Furthermore, there is now increasingly evidence that supervised exercise training (a key component of the DPP) can improve psychiatric symptoms, cognition and functioning across a range of mental disorders 237-239”
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- Authors
- Spielmans, G. I., Berman, M. I., Linardatos, E., Rosenlicht, N. Z., Perry, A., & Tsai, A. C.
- Affiliations
- Metropolitan State University (US)
- San Francisco VA Medical Center (US)
- Harvard University (US)
- Corresponding author
- Spielmans, Glen I.
- Venue
- PLoS Medicine
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-03-12
- Volume
- 10
- Issue
- 3
- Pages
- e1001403
- ISSN
- 1549-1277 (ISSN-L)
- 1549-1676
- PMC
- PMC3595214
- OpenAlex
- W2340538438
- Cited by
- 275
- References
- 84
- Citations by year
- 2026: 11 · 2025: 14 · 2024: 16 · 2023: 21 · 2022: 15 · 2021: 17 · 2020: 21 · 2019: 20 · 2018: 16 · 2017: 30 · 2016: 36 · 2015: 26 · 2014: 19 · 2013: 13
- FWCI
- 3.93
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Veterans Affairs
- National Institute of Mental Health (MH096620, K23MH096620)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Keywords
- adjunctive antipsychotic therapy, treatment-resistant depression, major depressive disorder, aripiprazole, olanzapine-fluoxetine combination, quetiapine, risperidone, remission, response rate, quality of life, adverse drug reactions, risk-benefit profile, antipsychotic safety, number needed to treat
- MeSH terms
- Depression, Major Depressive Disorder, Humans, Quality of Life, Antipsychotic Agents, Treatment Outcome, Publication Bias
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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