Augmentation Strategies in Treatment-Resistant Depression

The treatment of unipolar major depression presents a substantial challenge for the clinician. Major depression is a common disorder¹ with a high propensity for relapse and recurrence.² In addition, it is increasingly evident that antidepressant treatment offers moderate benefits and that sequential treatments are invariably required to obtain a satisfactory therapeutic effect.

Recent research findings confirm earlier observations that about 50% of patients with major depression respond to an adequate antidepressant trial, and far fewer, about one third, will achieve full remission.^3,4 Moreover, if a patient fails to respond to 2 sequential antidepressant trials, remission rates are alarmingly low, approximately 10% to 15% with yet a third antidepressant.⁵ Remission is the goal of antidepressant therapy, yet it is estimated that first antidepressant trials (usually with an SSRI) fail in more than one half to two thirds of patients, requiring further therapeutic intervention. There are several options available for such patients; these are outlined in Table 1.

While there is limited clinical trial evidence for the efficacy of these options, few have undergone rigorous randomized, controlled trials. Furthermore, there are few data on the comparable efficacy of these various options. For example, a recent report from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial showed no significant difference in remission rates when either bupropion or buspirone was given to patients who failed to respond to or could not tolerate a trial of the SSRI citalopram.⁶

Nonetheless, a recent survey of a large Veterans Administration (VA) mental health population found that when an antidepressant produced an incomplete response, a second antidepressant or a second-generation antipsychotic were the most common drugs added to the regimen.⁷ Given the extremely limited data on the efficacy of both of those options, the findings are surprising and they underscore the need for a critical evaluation of the current clinical approach to treatment-resistant depression.

In the VA study, only one half of one percent of subjects received lithium augmentation despite the general acknowledgement that lithium has the strongest evidence to support its efficacy as an antidepressant augmentation agent.⁷ This article will focus narrowly on augmentation strategies and their utility as treatment options for refractory depression.

AUGMENTATION STRATEGIES

"Augmentation strategies" refers specifically to the addition of compounds that are not usually considered to have clinically substantial antidepressant properties when used alone. The early focus was on lithium and thyroid hormone but recently, other augmentation agents, such as buspirone, pindolol, and second-generation antipsychotics have received increasing attention. There is now a vast array of compounds that have been documented, mostly in case reports or small case series, as effective augmenting agents. Few have been subjected to rigorous clinical evaluation, so the focus here will be on those that have solid documentation or that are in common clinical use.

Lithium

The addition of lithium to a drug regimen is the best substantiated of the augmentation strategies. There have been numerous open-label studies that document the efficacy of lithium augmentation.⁸ Several double-blind controlled trials generally support the superiority of lithium to placebo in augmenting response to both tricyclic antidepressants and SSRIs (Table 2). These studies were limited by small sample sizes and short durations of treatment. However, a meta-analysis confirmed the superiority of lithium augmentation over placebo with a therapeutic advantage for treatment beyond 2 weeks with dosages of lithium carbonate in excess of 750 mg/d.⁸

Thyroid hormone

Thyroid hormone, particularly triiodothyronine (T₃) has also received considerable attention as an augmentation strategy (Table 3). Although most studies have been open-label and involve tricyclics, a meta-analysis confirmed the superiority of T₃ over placebo²⁰ and found evidence of the clinical utility of T₃ for both tricyclic and SSRI augmentation.^21-33 In the only study to directly compare T₃ and lithium augmentation, the 2 agents were found to be comparable in efficacy, and both were superior to placebo.¹⁴

Like the lithium studies, the T₃ studies have several limitations. In particular, the duration of treatment--as short as 6 to 14 days for several T₃ studies and 2 days in some lithium studies--appears to be a major shortcoming. However, given the documented response rates of more than 50% for each strategy and the positive findings of clinical efficacy,^8,20 one could argue that these findings are highly encouraging. Results might be even more impressive in a trial of adequate duration--about 4 to 6 weeks.

Most studies have focused on the use of T₃ as an augmentation strategy; the clinical utility of thyroxine (T₄) remains unresolved.³⁴ To reduce the risk of thyrotoxic symptoms, T₃ should be administered in modest dosages of about 25 µg/d and certainly at dosages well below those required for replacement therapy. No dose-response relationship has been demonstrated for the antidepressant augmenting effect of T₃, and at lower doses adverse effects are minimal.

Buspirone

Augmentation with 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 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 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-resistant depression.³⁸

Atypical 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, aripiprazole, olanzapine, and 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 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.^44,45

SUMMARY AND CONCLUSIONS

Of the various augmentation strategies, 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.

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