Does Antidepressant Augmentation Need to be Continued?

ABSTRACT & COMMENTARY

Source: Bauer M, et al. Double-blind, placebo-controlled trial of the use of lithium to augment antidepressant medication in continuation treatment of unipolar major depression. Am J Psych 2000;157:(9)1429-1435.

More over 30% of patients with depression fail to respond to treatment with an antidepressant medication, and more have only a partial response. There are a variety of clinical interventions for patients who have not benefited adequately from an initial antidepressant, including switching to a different monotherapy or adding a second agent (augmenting). Lithium is the classic augmenting strategy for antidepressant resistance. As Bauer and colleagues point out, the scientific evidence for the efficacy of this treatment strategy is unambiguous, yet a deficit exists in our knowledge about the optimal duration of lithium augmentation. To be eligible for the acute treatment phase of the study, a patient had to satisfy the following criteria: 1) a current major depressive episode that met DSM-III-R criteria; 2) a score of at least 15 points on the 21-item Hamilton Depression Rating Scale; 3) a score of 4 ("moderately ill") or more on the Clinical Global Impression (CGI) scale for severity of illness; 4) no acute suicidal ideation; 5) failure to respond to an adequate trial of either a nonselective antidepressant or an SSRI; 6) not more than four lifetime depressive episodes and not more than two depressive episodes in the five years before the index episode; 7) no history of hypomanic or manic episode; 8) no other DSM-III-R axis I diagnosis; and 9) no medical exclusions for any condition incompatible with lithium therapy. To be eligible for the continuation treatment phase, patients had to satisfy criteria for remission during a six-week period after initiation of lithium augmentation. After a 2- to 4-week stabilization period following remission, patients were randomly assigned to receive either lithium or placebo for a four-month period. Thirty patients (18 women and 12 men) with a major depressive episode (13 single episode, 17 recurrent; 25 inpatients, 5 outpatients) who had responded to treatment with the addition of lithium to ongoing antidepressant medication participated in the study. Antidepressant medication was continued throughout the study. There was no statistically significant difference in the distribution of the antidepressants between groups during the continuation phase (lithium group: amitriptyline, n = 9, clomipramine, n = 3, and nortriptyline, trazodone, or paroxetine, each n = 1; placebo group: amitriptyline, n = 7, nortriptyline or dibenzepin, each n = 2, and clomipramine, imipramine, maprotiline, or venlafaxine, each n = 1). There were no significant differences in the doses or blood levels of tricyclics or tetracyclics between groups during the continuation phase. Relapse occurred in seven (47%) of the 15 patients who received antidepressants plus placebo. None (0%) of the 14 patients who continued to receive lithium-antidepressant combination treatment suffered a relapse. The relapses occurred an average of 27 days (SD = 35, range = 7-103) after beginning double-blind treatment. Fisher’s exact test revealed a significant group difference in the relapse rate (P = 0.006). Of the seven relapses in the placebo group, five were depressive relapses and two were manic relapses. The two patients with a manic relapse had never before experienced a manic episode, and both patients subsequently received a diagnosis of bipolar disorder.

COMMENT BY LAUREN B. MARANGELL, MD

Despite the common use of augmenting strategies with antidepressants, this is the first controlled evaluation of efficacy in the continuation phase of treatment. The current results clearly indicate that acute response to lithium augmentation warrants continuation for an additional four months (as opposed to continuation of the antidepressant alone). Although similar data are required for other common augmenting strategies (e.g., thyroid hormone, buspirone, etc) in the absence of data to the contrary, it may be wisest to continue augmentation strategies and then consider tapering only after a sustained period of remission.