Augmentation Strategies in Treatment-Resistant Depression
By Russell Joffe, MD |
October 30, 2006
Augmentation with buspirone(Drug information on buspirone) produced encouraging results in open studies of serotonergic antidepressants, but 2 placebo-controlled trials failed to separate buspirone from placebo.35,36 In these 2 studies, buspirone was efficacious in more than half of the subjects, but placebo was comparably efficacious. The findings are difficult to interpret: subjects who were treatment-resistant would not be expected to have high placebo response rates in an augmentation study.35,36 The recent observation that buspirone and bupropion produced comparable clinical benefits following citalopram(Drug information on citalopram) failure6 should rekindle interest in buspirone as an augmentation strategy given its favorable side-effect profile (although bupropion performed better on some secondary outcome measures and was better tolerated).Pindolol
Pindolol, a serotonin 5HT1A receptor antagonist, initially generated much optimism regarding its use as an augmentation agent, but in controlled trials, it produced disappointing results. A recent meta-analysis concluded that pindolol(Drug information on pindolol) is not a clinically effective augmentation strategy, although this may be explained by the inadequate doses employed in the included studies; at higher doses, the clinical utility of pindolol remains uncertain.37 A small placebo-controlled trial found that a single daily dose of 7.5 mg of pindolol was effective for paroxetine(Drug information on paroxetine)-resistant depression.38Atypical antipsychotics
In the VA study mentioned above, the atypical antipsychotics were the second most common augmentation strategy used.7 Compounds that have been shown to augment antidepressant response in open-label studies include risperidone(Drug information on risperidone), aripiprazole(Drug information on aripiprazole), olanzapine, and ziprasidone(Drug information on ziprasidone).39-41 However, the limited number of controlled trials of antipsychotic antidepressant augmentation have produced inconclusive, largely negative data on their clinical efficacy.42 Since the use of this class of drug for this indication may be broadening, adequately designed and powered studies are required to evaluate their effectiveness for treatment-refractory depression.Other augmentation strategies
Other common augmentation strategies include psychostimulants, for which there is very limited empiric support, and anticonvulsants. The latter are commonly used in bipolar disorder, but their role in unipolar treatment-resistant depression has been studied less and is, therefore, less understood. In particular, lamotrigine(Drug information on lamotrigine) would be of interest as an antidepressant augmentation agent, given its antidepressant efficacy in bipolar illness. However, to date, the results of studies on the antidepressant augmenting effect of lamotrigine are mixed; there has been 1 small study with positive results43 and 2 studies with negative results.44,45SUMMARY AND CONCLUSIONS
Of the various augmentation strategies, lithium(Drug information on lithium) and T3 show considerable promise as effective augmentation agents; the effectiveness of busprirone requires further consideration given the results of the STAR*D trial. These compounds, however, seem to have limited use and one could reasonably conclude that they have fallen out of favor with clinicians as useful treatments for depression.7
The problems with lithium are obvious: its high side-effect burden, the need for continual monitoring, and the potential long-term effects on organs, such as the thyroid and kidney. In light of its well-established efficacy, however, and the limited successes of other antidepressant options,4-6 it still may be underused.7
The perception of T3 is that it is not as effective as lithium or that it will not work with SSRIs. Although the literature is limited, there is some evidence of the comparable efficacy of T3 and lithium, and 3 studies confirm the efficacy of T3 when it is added to an SSRI.31-33
Notwithstanding the need for proof of the clinical efficacy of T3 and bu-spirone, on the basis of the evidence to date, these compounds appear safe and effective, with limited need for patient monitoring, and they have no documented long-term adverse effects. Although most augmentation studies have been of short duration, it is possible that an augmentation agent, once effective, should be maintained for the period of antidepressant therapy and even during maintenance treatment which may extend over months or years. T3 and buspirone would be ideal for such long-term use, although there would be greater concern about long-term lithium treatment. The second-generation antipsychotics appear to be increasingly popular as augmentation agents; however, the risk of the metabolic syndrome, the adverse cardiac sequelae, and the need for regular monitoring should raise concern over their potential for long-term use.
Augmentation strategies represent a viable alternative for patients with major depressive illness who do not respond to initial antidepressant therapy. The early augmentation agents have been largely overlooked despite their often better-established efficacy and, as is certainly the case with T3, a favorable side-effect profile. These compounds need a careful reappraisal as viable treatment options because refractory depression is a disorder with a high nonresponse rate and a high risk of recurrence and chronicity.
Lithium also needs a favorable reappraisal given its well-documented efficacy and because commonly used second-generation antipsychotics appear to have little, if any, advantage over lithium in terms of monitoring and short- and long-term adverse sequelae. Ultimately, given the limited efficacy of the various options for sequential treatment,4-6 no viable treatment can be ignored. It may not be so much a factor of whether one agent is better than another, but rather that all should be considered and used appropriately to effect the best treatment result.
Dr Joffe is a professor in the department of psychiatry at the New Jersey Medical School in Newark. He reports no conflicts of interest concerning the subject matter of this article.
Drugs Mentioned in this article
Triiodothyronine (Liothyronine, Cytomel)
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