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Am Fam Physician. 2020;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 fluoxetine (Prozac), and one used another antidepressant class. A variety of short- and long-acting benzodiazepines were assessed. There was general agreement between study outcomes with no outliers noted.

The studies examined the effect of a combination of antidepressants and benzodiazepines vs. antidepressants alone during three depression treatment phases: early (four weeks or less), acute (five to 12 weeks), and continuous (more than 12 weeks) using the difference in depression severity scores (current score minus baseline score). They used the Hamilton Rating Scale for Depression, a clinician-administered 21-item depression screening questionnaire that evaluates typical depression symptoms (e.g., mood, guilt, agitation, insomnia) at the initiation of therapy and throughout treatment to assess effectiveness and remission of symptoms.

Combination therapy demonstrated a small but significant reduction in symptoms compared with monotherapy in the early phase (SMD = −0.25; 95% CI, −0.46 to −0.03; 10 studies; N = 598; moderate-quality evidence downgraded because of risk of bias). There was likely no difference between treatments in the acute phase (SMD = −0.18; 95% CI, −0.40 to 0.03; seven studies; n = 347; low-quality evidence downgraded because of risk of bias and low number of participants) or the continuous phase (SMD = −0.21; 95% CI, −0.76 to 0.35; one study; n = 50; low-quality evidence downgraded because of risk of bias and low number of participants).

There was no difference in treatment dropout rate for any reason between combined therapy and antidepressants alone. Although specific adverse effects were not reported, benzodiazepine use was associated with potential somnolence and a presumed increased risk of accidents, and in this review patients treated with combined therapy reported experiencing at least one adverse effect more often than those who received antidepressants alone (number needed to harm = 18; 95% CI, 13 to 83; relative risk = 1.12; 95% CI, 1.01 to 1.23; seven studies; n = 510; moderate-quality evidence). This finding was consistent across included studies.

The U.S. Preventive Services Task Force and American Academy of Family Physicians recommend screening for depression in the general adult population. Screening must be implemented with adequate systems in place to ensure accurate diagnosis, effective treatment, and appropriate follow-up.3 Current depression treatment guidelines do not recommend using benzodiazepines for major depression and favor antidepressant monotherapy as the first-line pharmacologic approach.4,5 Most guidelines recommend using selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, mirtazapine (Remeron), and bupropion (Wellbutrin) as first-line agents. The antidepressants used most often in these studies would be considered second-line treatments. There were not enough data to directly compare selective serotonin reuptake inhibitors and tricyclic antidepressants with and without benzodiazepines in this systematic review. Although this review suggests that patients may benefit from combination therapy, there are multiple unanswered questions, including which patients benefit most from combination therapy, how to predict who may be at increased risk of addiction or tolerance, and how to best discontinue benzodiazepine use after four weeks.

The practice recommendations in this activity are available at

Editor's Note: The number needed to harm reported in this Cochrane for Clinicians was calculated by the author based on raw data provided in the original Cochrane review.

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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