The Problem

You have a patient with major depression. Symptoms include anxiety and insomnia. You prescribe an antidepressant and consider immediate augmentation with a benzodiazepine, but you are worried about the possibility that benzodiazepines could worsen the depression.

Do benzodiazepines aid antidepressants in treating major depression?

The Analysis

We went to www.cochrane. org/and located a comprehensive review of this topic (Cochrane Database of Syst. Rev. 2001;CD0010 26. [doi: 0.1002/14651858]).

Then we performed a Medline search to update the Cochrane Review by combining "antide-pressant, benzodiazepine, and depressive disorder."

The Evidence

The Cochrane reviewers searched 1,475 articles, which ultimately yielded 25 studies. Of those 25 studies, 10 were considered to be of adequate quality to be included in the review. Study participants had to be 18 years of age or older and diagnosed with major depressive disorder. The studies had to compare any antidepressant combined with a benzodiazepine vs. an antidepressant alone for a minimum of 4 weeks.

Antidepressant dosing had to be 100 mg daily of imipramine equivalents or higher (eight studies used tricyclic antidepressants and two used fluoxetine). Studies also had to be double blinded and randomized. The Cochrane reviewers graded study quality in part based upon clarity of double blinding.

The Cochrane analysis examined the results of 731 patients. For most, their depression was rated using the Hamilton Rating Scale for Depression (HAM-D). Response in depression was defined as a 50% or greater reduction in HAM-D score from baseline. For various statistical reasons, the Cochrane reviewers used relative risk (RR) as a measure of the likelihood of achieving a HAM-D reduction of 50% or more.

For the group that received antidepressant monotherapy, RR was 1.57 at week 1, 1.23 at week 2, 1.13 at week 4 (no longer considered statistically significant), 1.04 at weeks 6-8, and 1.05 at week 12.

For the combination antidepressant-benzo-diazepine group, RR was 1.62 at week 1, 1.37 at week 2, 1.18 at week 4, and 0.95 at weeks 6-8. When the reviewers used only the two highest quality combination studies, the differences were even greater: RR of 2.45 at week 1, 1.58 at week 2, and 1.40 at week 4.

One analysis compared the effects of short-and long-acting benzodiazepines. Two studies using short-acting benzodiazepines were pooled and compared with seven studies using longer-acting benzodiazepines: In the short-acting group, RR was 1.65 at week 1, 1.14 at week 2, and 1.43 at week 4. In the longer-acting group, RR was 1.65 at week 1, 1.48 at week 2, and 1.30 at week 4.

In one study, the investigators factored out the anxiety and insomnia subscale scores from the total HAM-D score and determined that the improvement in scores was not related to these two factors only. Patients randomized to the combination group were just as likely to drop out of the study as the participants from the antidepressant monotherapy group. Those in the combination group, however, were less likely to drop out because of side effects.

In an updated study, investigators evaluated the effectiveness of combining clonazepam 0.5-1 mg/day with fluoxetine 20-40 mg/day in an 18-week double-blind, placebo-controlled study (J. Affect. Disord. 2002;70:251-9). Fifty adult outpatients diagnosed with moderate to marked depression were evaluated using the HAM-D (response defined above) and the Clinical Global Impression of Improvement. The combination therapy group experienced a better response rate at day 7 than the monotherapy group (32% vs. 4%) on the CGI-I.

The authors found no benefit of extended combination therapy except for a more rapid response to increased fluoxetine dosing from 20 to 40 mg/day, which occurred at week 6.

The Conclusion

Patients treated with a combination antide-pressant and benzodiazepine were more likely to show reduction in HAM-D scores at weeks 1-4 than were patients treated with antidepressant monotheraphy.

At 6-8 weeks, the likelihood of response was not significantly greater in the combination group, compared with the monotherapy group, and combination therapy may have actually been worse. Thus, adding a benzodiazepine when beginning antidepressant therapy is logical, but there is little support for continued use.

Results do not include evaluation of newer antidepressants such as mirtazapine, venlafaxine, or duloxetine.

The benefit-to-risk evaluation of prescribing a benzodiazepine with an antidepressant ought to include consideration of potential dependence, accident proneness, teratogenicity, and difficulty in tapering off the benzodiazepine.

One major limitation of this analysis is that medication compliance was not checked.

BY JAN LEARD-HANSSON, M.D.

BY LAURENCE GUTTMACHER, M.D.

DR.LEARD-HANSSON is a forensic psychiatrist who practices in San Diego. DR. GUTTMACHER is chief of psychiatry at the Rochester (N.Y.) Psychiatric Center. They have no financial interest in any product or service discussed in this column. They can be reached at cpnews@elsevier.com.