COCHRANE FOR CLINICIANS: PUTTING EVIDENCE INTO PRACTICE

Antidepressants for Generalized Anxiety Disorder

CHERYL A. FLYNN, M.D., M.S., and Y.C. CHRISTINE CHEN, M.P.H.
State University of New York Upstate Medical University, Syracuse, New York

The Cochrane Abstract below is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Cheryl A. Flynn, M.D., M.S., and Y.C. Christine Chen, M.P.H., present a clinical scenario and question based on the Cochrane Abstract, along with the evidence-based answer and a full critique of the abstract.

This clinical content conforms to AAFP criteria for evidence-based continuing medical education (EB CME). EB CME is clinical content presented with practice recommendations supported by evidence that has been systematically reviewed by an AAFP-approved source. The practice recommendations in this activity are available at http://www.cochrane.org/cochrane/revabstr/AB003592.htm

Clinical Scenario

A 40-year-old man is in counseling for generalized anxiety disorder (GAD). He asks about pharmacotherapeutic treatment options, expressing a desire to avoid addictive medications.

Clinical Question

Are antidepressants an effective and acceptable treatment for GAD?

Evidence-Based Answer

As a group, antidepressants are an effective short-term treatment for GAD. Compared with placebo, about five to six patients must be treated to get one additional patient who responds to therapy. Side effects occur more frequently with antidepressants than with placebo, but they are not severe enough to require discontinuation of treatment.

Cochrane Abstract Background. Pharmacologic treatments have been used successfully to treat GAD. In past decades, the mainstay of treatment has been the benzodiazepine and nonbenzodiazepine anxiolytics. Data emerging over the past two decades have shown that antidepressants may be equally effective as anxiolytics for treating GAD. The use of antidepressants may be advantageous, because GAD has a high comorbidity ratio with major depressive disorder (62 percent) and dysthymia (37 percent). Objectives. To assess the efficacy and acceptability of antidepressants for treating GAD. Search strategy. The authors1 searched the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (through May 2002), Anxiety Neurosis (through May 2002), and Cochrane Controlled Trials Register (through May 2002), MEDLINE (1966 to May 2002), and LILACS (1982 to May 2002). They also searched references, personal communications, conference abstracts, and book chapters on the treatment of GAD. Selection Criteria. Randomized controlled trials were included. Nonrandomized studies and studies that included patients with GAD and another Axis I comorbidity were excluded. Data Collection and Analysis. The data from studies were extracted independently by two reviewers, and relative risks, weighted mean difference, and number needed to treat (NNT) were estimated. Patients who died or dropped out of the study were regarded as having had no improvement. Main Results. Antidepressants (i.e., imipramine, venlafaxine, and paroxetine) were found to be superior to placebo in treating GAD. The calculated NNT for antidepressants in GAD is 5.5. Dropout rates did not differ between antidepressants. Only one study presented data on imipramine and trazodone. Imipramine was chosen as the reference drug, so data on trazodone could not be included in the meta-analysis. Only one study was conducted among children and adolescents. It showed very promising results with sertraline in children and adolescents with GAD, warranting replication in larger samples. Reviewers' Conclusions. The available evidence suggests that antidepressants are superior to placebo in treating GAD. There is evidence from one trial suggesting that paroxetine and imipramine have similar efficacy and tolerability. There also is evidence from placebo-controlled trials suggesting that these drugs are well tolerated by patients with GAD. Further trials of antidepressants for GAD will help to demonstrate which antidepressants should be used in which patients. These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in The Cochrane Library. Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minor editing changes have been made to the text (www.cochrane.org).

Practice Pointers

Psychotherapy and anxiolytics have been the mainstay of therapy for GAD. Antidepressants also are considered a possible treatment because of the response occurring in patients with comorbid depression. The Cochrane Collaboration has planned a series of reviews on GAD to include antidepressants, 5HT-1 agonists, benzodiazepines, and psychotherapy.

This Cochrane review, the first of the series, finds symptomatic benefit in short-term studies of antidepressants in patients with GAD but without concurrent depressive disorders (relative risk, 0.70; 95 percent confidence interval, 0.60 to 0.82, for nonresponse). Compared with placebo, approximately six patients need to be treated for one additional patient to have a clinical response (NNT = 5.5). Antidepressants were more likely than placebo to cause side effects (e.g., drowsiness, dry mouth, dizziness, constipation, nausea, somnolence, sexual dysfunction), but dropout rates were similar between the groups. The majority of primary care patients with GAD will have some comorbid depressive symptoms; these data would be expected to generalize. Nevertheless, the long-term benefit is unknown.

The small number of studies for any single medication and the limited number of direct comparisons of antidepressants offer little data to guide physicians in choosing an antidepressant. Tricyclic antidepressants and newer selective serotonin reuptake inhibitors were similar in efficacy: the NNT for imipramine was 4.0 compared with 5.0 for venlafaxine and 6.7 for paroxetine. No differences were noted between imipramine and paroxetine in the single study that compared them. Sertraline was shown in one study to be effective in children and adolescents.

Drug interactions, costs, and physician and patient preferences may guide the choice of antidepressant used to treat GAD. Imipramine dosages generally ranged from 50 to 150 mg per day (cost, $10 to $30 per month); paroxetine was given in a dosage of 20 mg per day (cost, $85 per month); and venlafaxine dosages ranged from 75 to 225 mg daily (cost, $50 to $150 per month), with no identifiable differences in response rates by dosage. (Average wholesale costs based on Red book. Montvale, N.J.: Medical Economics Data, 2003.)

This patient likely would benefit from a trial of antidepressant therapy. Because he is young and has no comorbidities, imipramine at a dosage of 50 mg daily would be a reasonable first choice of medication. The dosage should be titrated upward until response is noted, as was done in most of the trials.

REFERENCE

1. Kapczinski F, Lima MS, Souza JS, Schmitt R. Antidepressants for generalized anxiety disorder. Cochrane Database Syst Rev 2003: CD003592. Accessed October 2003 at: http://www.cochrane.org/cochrane/revabstr/AB003592.htm.

Cheryl A. Flynn, M.D., M.S., is assistant professor of family medicine and a researcher in the Center for Evidence Based Practice at State University of New York (SUNY) Upstate Medical University, Syracuse. Y.C. Christine Chen, M.P.H., is a third-year medical student at SUNY Upstate Medical University.

Address correspondence to Cheryl A. Flynn, M.D., M.S., Department of Family Medicine, 475 Irving Ave. #200, Syracuse, NY 13210. Reprints are not available from the authors.