Switching Drug Classes Benefits Treatment-Resistant Patients

A large multisite study has looked at the empirical value of switching classes of antidepressants in outpatients with chronic antidepressant-resistant depression. The research data closely follow the anecdotal evidence that most practitioners have known for years—that is, if at first you don’t succeed, try a different drug.

Numerous studies have documented that at least 40 percent of patients treated for depression do not respond to the initial trial of antidepressant medication prescribed for them. For these individuals, several commonly accepted options are available, including switching to another antidepressant—usually a different drug in the same class, augmenting the first drug with a second one, or switching the patient to a different class of antidepressant medication.

Some physicians prefer to switch drugs within a particular class, for example, from one SSRI to another, while some prefer to augment the initial treatment, and others tend to switch these patients to a different class of medication, such as from an SSRI to a tricyclic antidepressant.

Indeed, according to lead author Michael E. Thase, M.D., a professor of psychiatry at the University of Pittsburgh and Western Psychiatric Clinic, one major issue confronting clinicians today is trying to decide which of the “what next” strategies to choose.

The study, which appeared in the March issue of the Archives of General Psychiatry, was funded by Pfizer Inc., maker of the Zoloft brand of sertraline.

Thase and his colleagues followed 635 patients with chronic major depression who were randomly assigned to receive 12 weeks of either sertraline or imipramine. Just over 300 patients completed the 12 weeks as “responders.” About 200 patients did not show any improvement after the initial 12 weeks of drug therapy (145 were given sertraline and 62 imipramine). The number of patients who did not complete the initial 12 weeks of the study was 126.

At the end of the first phase, all nonresponding patients were “crossed over” to the other antidepressant after a tapering of the first antidepressant and at least one week of no antidepressant. All patients were then followed for an additional 12 weeks.

The primary outcome assessments used to monitor depression were the 24-item Hamilton Rating Scale for Depression (Ham-D) and the Clinical Global Impressions-Severity and Improvement Scales (CGI-S/I).

For many nonresponders, the switch resulted in clinically as well as statistically significant improvements. Of the 207 nonresponders at the end of the first 12 weeks, 168 switched medications (51 from imipramine to sertraline and 117 from sertraline to imipramine). The two “switch groups,” according to the authors, “did not differ significantly on any relevant characteristic.” An acceptable response to medication was defined as a final CGI-I score of 1 or 2, a reduction of at least 50 percent on the final Ham-D score resulting in a score of 15 or lower, and a CGI-S score of 3 or lower. Full remission was defined as a final Ham-D of 7 or lower, and a CGI-I score of 2 or lower.

The switch to sertraline was found to be better tolerated, with fewer complaints of adverse effects and significantly fewer dropouts attributed to side effects (10 percent versus 25 percent for imipramine). In addition, sertraline also resulted in significantly higher response rates (60 percent versus 44 percent for imipramine). Among those completing the full study, remission was observed in 35 percent of patients taking sertraline at the end of the study and 30 percent for those ending the study with imipramine.

“This double-blind switch study provides further evidence that chronic depressions are responsive to antidepressant monotherapy after nonresponse,” the authors concluded. The results, they added, are even more noteworthy in that not only did they empirically validate a treatment strategy based upon anecdotal evidence, but in this particular study, the patients had a mean duration of more than six years of continuous major depressive disorder.

The authors note that, compared with augmentation strategies for treating initial antidepressant nonresponders, “switching antidepressant classes has the advantages of simplicity and parsimony (for example, lower cost and little risk of drug-drug interactions.)” They conceded, however, that many clinicians favor augmentation because of quicker implementation, that is, there is no need to wash out the first antidepressant before beginning the next.

The authors cautioned that numerous studies indicate that, overall, simply relying on medication to manage major depression is not wise, confirming that “the combination of psychotherapy and pharmacotherapy also increases the likelihood of remission.”

“The public health importance of treatment-resistant depression provides a strong justification for broader use of the switch design,” which, the authors wrote, could facilitate the study of many promising strategies for antidepressant nonresponders.

An abstract of “Double-Blind Switch Study of Imipramine or Sertraline Treatment of Antidepressant-Resistant Chronic Depression” is posted on the Web at http://archpsyc.ama-assn.org/issues/v59n3/abs/yoa8383.html. ▪

Arch Gen Psychiatry 2002 59 233