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Nonpharmacological Versus Pharmacological Treatments for Adult Patients With Major Depressive Disorder

Systematic Review ARCHIVED Dec 8, 2015
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Archived: This report is greater than 3 years old. Findings may be used for research purposes, but should not be considered current.


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Structured Abstract


To compare the benefits and harms of second-generation antidepressants (SGAs), psychological, complementary and alternative medicine, and exercise treatment options as first-step interventions for adult outpatients with acute-phase major depressive disorder (MDD), and as second-step interventions for patients with MDD who did not achieve remission after a first treatment attempt with SGAs.

Data sources

MEDLINE® (via PubMed®), Embase®, the Cochrane Library, AMED (Allied and Complementary Medicine Database), PsycINFO®, and CINAHL (Cumulative Index to Nursing and Allied Health Literature) from January 1, 1990, through January 13, 2015.

Review method

Two investigators independently selected, extracted data from, and rated risk of bias of studies. We graded strength of evidence based on established guidance.


Forty-four trials met inclusion criteria. For benefits across all interventions, we graded the strength of evidence as moderate for only one outcome of one comparison: SGAs compared with cognitive behavioral therapy (CBT). Results indicate that SGAs and CBT had similar effectiveness regarding symptomatic relief in patients with mild to severe MDD.

For risk of harms, we graded the strength of evidence as moderate for some outcomes of three comparisons--namely, SGAs compared with CBT, acupuncture, and St. John's wort. Patients treated with SGAs had a higher risk of experiencing adverse events or discontinuing treatment because of adverse events than patients treated with CBT, acupuncture, or St. John's wort.

Our confidence in the benefits and harms of SGAs compared with the remaining treatment options is low or insufficient, indicating that the bodies of evidence had major or unacceptable deficiencies. Nevertheless, for most comparisons, the overall findings indicated no statistically significant differences in benefits but a lower risk of adverse events for nonpharmacological treatment options. Across all comparisons of interventions, major research gaps pertain to information about the comparative risk of harms and patient-relevant outcomes such as functional capacity and quality of life.

For second-step therapies (i.e., therapy for patients with MDD who did not achieve remission after a first treatment attempt with SGAs), comparative evidence is limited. However, available data suggest that switching to another SGA, switching to cognitive therapy, and augmenting with a particular medication or cognitive therapy are all reasonable options.


Overall, the available evidence indicates that SGAs and CBT do not differ significantly in symptomatic relief as first-step treatments for adult outpatients with moderate to severe MDD. SGAs, in general, lead to a higher risk of adverse events than nonpharmacological treatment options. The evidence is insufficient to form conclusions about differences in serious adverse events, such as suicidal ideas and behavior. Given comparable effectiveness, the choice of the initial treatment of MDD should consider results of previous treatments, patient preferences, and feasibility (e.g., costs, likely adherence, and availability) following a discussion of the advantages and disadvantages of each treatment option, including risks of particular adverse effects and potential drug interactions. Such shared and informed decisionmaking might enhance treatment adherence and improve treatment outcomes for patients with MDD, especially because treatment continuity is one of the main challenges in treating such patients.

Journal Publications

Gartlehner G, Gaynes BN, Amick HR, et al. Comparative Benefits and Harms of Antidepressant, Psychological, Complementary, and Exercise Treatments for Major Depression: An Evidence Report for a Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2016;164:331-341. doi:10.7326/M15-1813

Amick HR, Gartlehner G, Gaynes BN, et al. Comparative benefits and harms of second generation antidepressants and cognitive behavioral therapies in initial treatment of major depressive disorder: systematic review and meta-analysis. BMJ 2015;351:h6019

Project Timeline

Nonpharmacological Versus Pharmacological Treatments for Adult Patients With Major Depressive Disorder

Feb 3, 2014
Jun 19, 2014
Dec 8, 2015
Systematic Review Archived
Sep 13, 2016
Sep 13, 2016
Consumer Summary Archived
May 9, 2017
Consumer Summary Archived
Page last reviewed December 2019
Page originally created November 2017

Internet Citation: Systematic Review: Nonpharmacological Versus Pharmacological Treatments for Adult Patients With Major Depressive Disorder. Content last reviewed December 2019. Effective Health Care Program, Agency for Healthcare Research and Quality, Rockville, MD.

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