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Treatment-Resistant Depression: Page 3 of 4

Treatment-Resistant Depression: Page 3 of 4

These findings raise the question of whether combining antidepressants is superior to switching. For example, an open-label, nonrandomized study by Lam and colleagues27 found that when 61 patients who were taking citalopram or bupropion SR for TRD were either switched to the other drug or given the combination, the combination group showed statistically greater rates of response and remission. At a minimum, combination treatments ensure that a partial response to the first agent will not be lost.

Augmentation strategies. If the switching and combination literature is conspicuous by its paucity, the augmentation literature is abundant—but the quality of evidence varies tremendously and the reader must maintain a “buyer beware” approach. One recent review concluded that although studies of augmentation were abundant, many were underpowered and uncontrolled.28 Several comprehensive reviews have been published.28-31

Evaluation strategies have been suggested to assess the quality of evidence.28,32 In general, augmentation strategies are recommended in the event of a partial response to an antidepressant. Switching is preferred in the event of a nonresponse.25 One of the few studies to examine this issue systematically found numerically higher response rates among partial responders compared with nonresponders when lithium or desipramine was added to fluoxetine, but these differences were not statistically significant.33Table 3 presents a summary of agents that may be effective. Although the amount and quality of evidence about the agents in category A is meaningful, the differentiation of groups B and C is somewhat arbitrary.

Click to EnlargeThe presumed mechanism of action of augmentation agents varies tremendously and is generally believed to complement the action of the primary antidepressant in some predictable theoretical manner. Questions remain about the validity of our current classification systems for grouping augmentation agents—an issue of crucial importance for clinicians who need to pair them with antidepressants for maximum benefit.

Lithium, the classic augmentation agent, has been the subject of the greatest number of studies. A recent meta-analysis identified 10 randomized, placebo-controlled trials, all of which were relatively small (the largest included 61 subjects).34 The authors of these studies concluded that lithium was significantly more effective than placebo. The vast majority of the studies with lithium did not include SSRIs but instead used TCAs. Remission rates from level 3 of the STAR*D trial using lithium as an augmentation agent with citalopram were only 13.2% (measured by QIDS-SR), whereas T3 augmentation remission rates at this same step were 24.7%.35 Although these differences were not statistically different, there was a significantly higher dropout rate in the lithium group.

As with lithium, a recent review concluded that the trial data that support the efficacy of T3 augmentation are of better quality with TCAs than with SSRIs.32 Although it has been reported that approximately 50% of patients with unipolar depression given thyroid augmentation show a response, a pooled analysis of 4 randomized double-blind studies of T3 augmentation revealed nonsignificant effects, but the results of 1 of the 4 studies may have accounted for this finding.36,37


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