Some clinicians make a distinction between "combination" and "augmentation" therapies, with the former referring to the use of antidepressants in combination, and the latter referring to the use of drugs that are not antidepressants to augment-approved antidepressants. In our view, this is an artificial distinction, and prefer the term "augmentation" to refer to any combination of medications used to enhance antidepressant response. We recognize that a growing segment of clinical pharmacologists are recommending augmentation therapy at the initiation of treatment, with a rationale that the "best" treatment should be initiated at the start of treatment. This reflects, in part, that primary care providers provide initial pharmacotherapy for depression, and referral to psychiatrists occurs only after monotherapy with antidepressants have failed. The problem with this approach is that there are no augmentation therapies that have superior efficacy.
We recommend augmentation approaches only after monotherapy with two different antidepressants has failed, an opinion based on the observation that at least 50% of out-of-class switches result in treatment response (270-272). In instances of partial responders who have been taking adequate doses for sufficient time, we are inclined to follow an augmentation strategy. Once a decision has been made to augment, a number of options are available. The most common augmentation strategy is to combine antidepressants from different classes. With SSRI, our current practice is to add mirtazapine in doses of 15-30 mg, a strategy that is supported by the somewhat limited literature on the topic (273-275). Alternatively, we employ bupropion augmentation which has a small body of evidence supporting its efficacy in augmentation of SSRIs (276-278) and survey data that indicate it is the most popular SSRI augmentation strategy among clinicians (279). Addition of low doses of a TCA, such as desipramine or nortriptyline, has yielded mixed results (280-283).
Lithium has moderately strong evidence supporting its efficacy as an augmentation agent; however, it is less commonly used than other approaches. The STAR*D study found poor tolerability compared to T3 augmentation. Studies in the early 1980s found that the addition of lithium to TCAs in non-responding patients with unipolar depression resulted in improvement in depression (284, 285) and was comparable to thyroid (T3) supplementation, both of which were better than placebo (286). Other investigators reported similar results, including efficacy in potentiating MAOIs, although lack of efficacy and toxicity has also been reported (287-289). Most but not all studies have found that lithium is also effective in augmentation of SSRIs (281, 290-292). We suspect that the reasons for less frequent use of lithium are its low therapeutic index and the necessity for monitoring serum levels. Typical augmentation doses are 600-1,200 mg daily to produce a target serum level of 0.6-0.9 mEq/L.
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