Cochrane for Clinicians

Putting Evidence into Practice

Antidepressants Plus Benzodiazepines for Adults with Major Depression


Am Fam Physician. 2020 May 1;101(9):527-528.

Author disclosure: No relevant financial affiliations.

Clinical Question

Is treatment with antidepressants plus benzodiazepines more effective than antidepressants alone for adults with major depression?

Evidence-Based Answer

A combination of tricyclic antidepressants and benzodiazepines is more effective for major depression in adults than tricyclic antidepressants alone in the first four weeks of treatment (standardized mean difference [SMD] = −0.25; 95% CI, −0.46 to −0.03). This effect is not sustained beyond four weeks of therapy. Use of benzodiazepines must be balanced against the risk of adverse effects, including dependence, tolerance, accident proneness, teratogenicity, and increased costs.1 (Strength of Recommendation: B, based on inconsistent or limited-quality patient-oriented evidence.)

Practice Pointers

In the United States, 17.3 million adults had at least one major depressive episode in 2017.2 Although initiating benzodiazepine therapy with antidepressants is a common choice for managing major depression globally, most treatment guidelines recommend antidepressant monotherapy as a first-line approach. The authors of this Cochrane review updated previously published reviews from 2001 and 2005 that assessed the effects of a combination of antidepressants and benzodiazepines vs. antidepressants alone to treat major depression in adults.

This updated Cochrane review included nine randomized controlled trials published between 1978 and 2002 and one reanalysis of a 1998 study that was published in 2010.1 The review involved 731 ambulatory patients and inpatients 18 years and older with depression (diagnosed using the second, third, or fourth edition of the Diagnostic and Statistical Manual of Mental Disorders depending on the year of the study) in the United States (six studies), Netherlands, Spain, Norway, and Japan. Trials were excluded for not being randomized, relying on self-reported patient data alone, lacking outcomes, or having a high risk of bias. Seven studies used tricyclic antidepressants, two used

Author disclosure: No relevant financial affiliations.


show all references

1. Ogawa Y, Takeshima N, Hayasaka Y, et al. Antidepressants plus benzodiazepines for adults with major depression. Cochrane Database Syst Rev. 2019;(6):CD001026....

2. Substance Abuse and Mental Health Services Administration. National Survey on Drug Use and Health (NSDUH) 2018 annual report. Accessed October 12, 2019.

3. U.S. Preventive Services Task Force. Final recommendation statement: depression in adults: screening. May 2019. Accessed October 12, 2019.

4. American Psychiatric Association. American Psychiatric Association Practice Guideline for the Treatment of Major Depressive Disorder. American Psychiatric Publishing; 2010.

5. National Institute for Health and Care Excellence. Depression in adults with a chronic physical health problem: recognition and management. Clinical guideline [CG91]. October 2009. Accessed March 26, 2020.

These are summaries of reviews from the Cochrane Library.

This series is coordinated by Corey D. Fogleman, MD, assistant medical editor.

A collection of Cochrane for Clinicians published in AFP is available at



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