ABSTRACT
BACKGROUND: Many strategies have been used to manage patients with treatment-resistant major depression. Few controlled trials have prospectively addressed the effects of switching between classes of antidepressant medication. This investigation measured the effects of switching patients with treatment-resistant chronic depression from one class of medication to another.
POPULATION STUDIED: Eligible subjects included 207 outpatients referred from primary care physicians and mental health professionals or who responded to advertising or word of mouth. The patients were between the ages of 21 and 65 years and were diagnosed with chronic major depression according to the DSM-III-R criteria, based on a structured clinical interview. All patients were initially treated and did not respond to 12 weeks of double-blind treatment with either sertraline (at least 50 mg daily) or imipramine (at least 150 mg daily). The authors did not enroll patients with mood and anxiety disorders, psychotic disorders, personality and somatoform disorders, or substance abuse disorders. They also excluded patients who had not responded previously to low doses of sertraline or imipramine (ie, at least 4 weeks of at least 50 mg sertraline or 150 mg imipramine daily).
STUDY DESIGN AND VALIDITY: The study was randomized and double-blinded. Of the 207 nonresponders, 168 (81%) were enrolled and switched to the alternate antidepressant for an additional 12 weeks of follow-up. Psychotherapy was continued during the study only if it had been ongoing for at least 3 months before intake. In both phases of the study, imipramine was increased to a maximum of 300 mg daily and sertraline was increased to a maximum of 200 mg daily if tolerated. Drug doses were gradually increased so that the maximum dosage of either drug could be reached by the 6th week.
OUTCOMES MEASURED: Outcomes measured included the 24-item Hamilton Rating Scale for Depression and the Clinical Global Impressions Severity and Improvement scales. Other outcomes related to chronic depression such as absence from work, physician visits, acute and chronic hospitalizations. Other social and economic issues were not measured in this study.
RESULTS: Switching from sertraline to imipramine (mean dosage, 221 mg/day) and from imipramine to sertraline (mean dosage, 163 mg/day) resulted in clinically and statistically significant improvements. Using intention-to-treat analysis, switching medications resulted in a higher response rate in the sertraline group (60% in the sertraline group vs 44% in the imipramine group, P = .03). More patients whose depression did not improve with imipramine subsequently responded favorably to sertraline as compared with the converse. Attrition related to side effects was higher in patients treated with imipramine (41% vs 30%, P = .045) and was similar to the dropout rate of other studies (number needed to treat = 9). Although the initial antidepressant response rate was favorable, after the switch of medications only 32% of patients in the sertraline group and 23% in the imipramine group achieved full remission. About half of the initial responders had significant residual depressive symptoms after 12 weeks of pharmacotherapy.
About half the patients who do not respond to an initial trial of either a selective serotonin reuptake inhibitor (SSRI) or a tricyclic antidepressant will respond to some degree when switched to a medication from the other class. Ultimately, however, only about 20% to 30% of these patients will achieve full remission after 16 weeks of therapy with the new agent. Initial nonresponders to a tricyclic antidepressant were more likely to respond to the SSRI than nonresponders to the SSRI who were switched to a tricyclic agent. Switching across classes is an option but not a requirement in treating patients with resistant major depression.