Although lithium does not have an FDA approved indication for augmentation of an antidepressant in major depressive disorder, it has been prescribed for this purpose for decades. While a wide variety of medications have been used historically in this capacity, lithium is one of the few agents that has demonstrated efficacy in multiple randomized controlled trials. Although the ideal role for lithium augmentation has yet to be established, there is currently ample evidence to support the clinical practice of adding lithium to conventional antidepressants in pursuit of major depressive disorder remission.

Results from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies suggest that only 30% of depressed patients will achieve remission after treatment with an initial antidepressant, and the remainder of the population will require substantial changes in their antidepressant regimens to recover.1 One of the more popular therapeutic strategies employed to improve depression outcomes is to add a second agent to the original antidepressant, a practice commonly referred to as augmentation. Although lithium does not have an FDA approved indication for augmentation of an antidepressant in major depressive disorder (MDD), it has been prescribed for this purpose for decades. Lithium has been used in psychiatric medicine since the 1940's and was first described as an augmentation agent for major depressive disorder in the 1980's. Despite the decades of experience using lithium, the mechanism of action for depression remains largely unknown. One of the proposed mechanisms of action is derived from animal studies, which demonstrated that lithium enhanced serotonin synthesis and release.2–3 Lithium remains the augmentation strategy for MDD with the most supporting evidence in randomized controlled trials. The intent of this article is to review current evidence for lithium augmentation in major depressive disorder.

The American Psychiatric Association (APA) recommends considering augmentation of an antidepressant in patients that have experienced significant side effects to the antidepressant or have exhibited a minimal or partial response to the current antidepressant.4 While a wide variety of augmentation strategies have been endorsed, there is little evidence to suggest one psychotropic is clearly superior in efficacy and tolerability for this indication. At the present time, the choice of augmentation agents is largely based on clinical judgment or experience, though evidence-based recommendations from comprehensive treatment guidelines may be instructive. In 2010, for instance, the APA concluded that level II evidence existed to support lithium augmentation, a rating which corresponds to ‘moderate clinical confidence.4 In 2009, the Canadian Network for Mood and Anxiety Treatments recommended lithium for augmentation with level I evidence.5 Never-the-less, there is a general perception that lithium augmentation is an underutilized strategy due, perhaps, to a lack of familiarity with supporting evidence or cumbersome therapeutic monitoring requirements.

Evidence describing lithium augmentation was detailed in a meta-analysis by Bauer et al. The 1999 meta-analysis of 9 randomized, placebo-controlled trials (n=234) evaluated the efficacy of lithium augmentation in acutely depressed subjects who had not adequately responded to at least one antidepressant alone. The augmented antidepressant in the majority of the studies was a tricyclic antidepressant, with a few studies including a selective serotonin reuptake inhibitor or monoamine oxidase inhibitor. Lithium dosing ranged from 250mg to 1,200mg per day and duration of lithium augmentation ranged from 48 hours to 6 weeks. Lithium serum levels were reported in eight of the nine studies and ranged from 0.5 to 1.1mEq/L. The median response rate in the lithium group was 50% and ranged from 12.5% to 62.5%. Treatment with lithium resulted in a significantly higher response rate compared to placebo (p<0.001) and an associated odds ratio of 3.31 (95% confidence interval, 1.46 – 7.53). The effect of lithium became significant at doses of at least 600 to 800mg per day and at least 7 days of treatment.6 A 2002 update by Bauer et al. included a review of prospective, open-label, and comparator studies. The review of open-label trials found the median response rate was 56% and ranged from 23.5% to 100%. In addition, 10 of the 17 open-label studies found lithium response rates of 50% or greater.7 

The long-term efficacy of lithium augmentation was demonstrated in a continuation study with 29 subjects that had responded to lithium augmentation and were randomized to continue on lithium (N=14) or placebo (N=15) for another 4 months. No subjects in the lithium treatment group relapsed while 7 subjects in the placebo group relapsed.8 Although these findings were limited by the small sample size, the results suggested lithium therapy should be continued past the acute phase of depression in order to prevent relapse.

Not all lithium augmentation studies were superior to placebo, five of which were included in the 1999 meta-analysis performed by Bauer et al. Some of these results may be explained by short treatment durations and sub-therapeutic dosing. Two of the studies had lithium treatment durations of only 48 hours.9–10 Another study used lithium doses of 250mg per day, lower than the dose found to be effective in the Bauer et al 1999 meta-analysis.11 

The efficacy of lithium for augmentation was investigated more recently during Phase III of STAR*D trials. The 142 subjects enrolled in this study had failed treatment with an SSRI (citalopram) in phase I, as well as either an antidepressant switch or augmentation trial (bupropion SR or buspirone) in phase II. During phase III, subjects were randomized to antidepressant augmentation with either lithium or triidothyronine (T3). Lithium was started at 450mg/day and increased based on clinical judgment to a maximum of 900mg/day. At the end of the trial, the mean daily dose of lithium was 859.8mg (SD=373.1) and the median lithium blood level was 0.6 mEq/liter. The remission rates of lithium and T3 did not significantly differ after 12–14 weeks of treatment (15.9% and 24.7% respectively). Lithium was associated with higher treatment discontinuation rates in comparison to T3.12 This study demonstrated that augmentation with T3 or lithium may be efficacious in this treatment-resistant population, and suggests that either agent may be appropriate for first-line augmentation.

Depression is widely viewed as a heterogeneous disorder, with various subtypes manifesting in different patient populations. With thyroid augmentation, for instance, response rates appear to be substantially higher in women suffering from depression than their male counterparts. With lithium treatment, neither age, gender, concurrent antidepressant class nor depressive subtype has been consistently associated with distinct outcomes. There is conflicting evidence regarding higher response rates in subjects with lower baseline depression scores.7 One study found a significant association between treatment response and subjects with higher cortisol/adrenocorticotropic hormone peak ratio prior to lithium augmentation.13 However, further studies are needed to identify how these findings can be applied to clinical practice.

Notably, lithium is one of the few agents with long-term data showing a reduction in suicide among patients with a mental illness. A systematic review of 32 randomized controlled trials of lithium for suicidality and all-cause mortality in mood disorders found that subjects that received lithium were less likely to die from suicide compared to subjects taking other psychotropic medications (odds ratio=0.26; 95% CI=0.09–0.77). This review was not specific for major depressive disorder and included subjects with bipolar depression, schizoaffective disorder, dysthymia and rapid cycling. Never-the-less, the authors stated that these positive findings were consistent between mood disorders.14 

In summary, current evidence supports the efficacy of lithium as an augmentation agent for major depressive disorder. While a wide variety of medications have been used historically in this capacity, lithium is one of the few agents that has demonstrated efficacy in multiple randomized controlled trials. Although the ideal role for lithium augmentation has yet to be established (i.e. – dosing recommendations, suitable patient populations remain unknown), and the side effect burden should not be overlooked, there is currently ample evidence to support the clinical practice of adding lithium to conventional antidepressants in pursuit of major depressive disorder remission.

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