Antidepressants plus benzodiazepines for major depression

The reviewers report that a combination of benzodiazepines with antidepressants works in favour for the treatment of depression, because it decreases drop outs from treatment and it increases short-term response up to four weeks. However, there are downsides to this combination therapy because benzodiazepines can induce dependence, which is estimated to occur in one third of patients, as well as a decline in the drug's effect over time. Benzodiazepines have been associated with an increase in accident proneness.

Authors' conclusions: 

The potential benefits of adding a benzodiazepine to an antidepressant must be balanced judiciously against possible harms including development of dependence and accident proneness, on the one hand, and against continued suffering following no response and drop out, on the other.

Read the full abstract...

Anxiety frequently coexists with depression. Adding benzodiazepines to antidepressants is commonly used to treat people with depression, although there has been no convincing evidence to show that such a combination is more effective than antidepressants alone. There are suggestions that benzodiazepines may lose their efficacy with long-term administration and their chronic use carries risks of dependence.


To assess the effects of adding benzodiazepines to antidepressants for adults with major depression.

Search strategy: 

We searched the Cochrane Depression, Anxiety and Neurosis Group Controlled Trials Register (CCDANCTR) (March 1999), The Cochrane Library (issue 3, 1997), MEDLINE (1972 to September 1997), EMBASE (1980 to September 1997), International Pharmaceutical Abstracts (1972 to September 1997), Biological Abstracts (1984 to September 1997), LILACS (1980 to September 1997), PsycLIT (1974 to September 1997), combined with handsearching, reference searching, SciSearch and personal contacts. We did an updating search of the CCDANCTR in December 2004.

Selection criteria: 

All randomised controlled trials that compared combined antidepressant-benzodiazepine treatment with antidepressants alone for adults with major depression. Exclusion criteria were: antidepressant dosage lower than 100 mg of imipramine, or its equivalent daily, and trial duration of less than four weeks.

Data collection and analysis: 

Two reviewers independently extracted the data and assessed the eligibility and quality of the studies. Standardised weighted mean differences and relative risks were estimated with random effects models. The dropouts were assigned the least favourable outcome. Two sensitivity analyses examined the effect of this assumption as well as the effect of including medium quality studies. Three a priori subgroup analyses were performed with regard to the patients with or without comorbid anxiety and with regard to the type of benzodiazepines.

Main results: 

We identified 10 studies involving a total of 731 patients. The standardised mean difference for combined therapy over antidepressants alone was -0.33 (95% confidence interval (CI) -0.51 to -0.15) at one week, and -0.29 (95% CI -0.51 to -0.08) at four weeks, but was no longer statistically significant at six to twelve weeks. If one qualitatively outlying study was excluded, patients on the combination therapy were less likely to drop out than those on antidepressant alone (relative risk (RR) 0.63, 95% CI 0.49 to 0.81). The patients allocated to the combination therapy were less likely to drop out from the treatment due to side effects than those receiving antidepressants alone (RR 0.56, 95% CI 0.34 to 0.91). However, these two groups of patients were equally likely to report at least one side effect (RR 1.05, 95% CI 0.90 to 1.23).