Augmentation Strategies in Treatment-Resistant Depression

"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(Drug information on lithium) and thyroid hormone but recently, other augmentation agents, such as buspirone(Drug information on buspirone), pindolol(Drug information on 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.

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, 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.