EVIDENCE-BASED ANSWER
YES, LITHIUM, TRIIODOTHYRONINE (T3), AND ATYPICAL ANTIPSYCHOTICS are all effective adjuncts. Lithium (serum levels >0.5 mEq/L) can produce clinical improvement when added to ineffective antidepressant treatment (strength of recommendation [SOR]: A, meta-analysis of randomized controlled trials [RCTs]).
Thyroid supplementation using T3 at doses no higher than 50 mcg per day also increases the effectiveness of antidepressant therapy (SOR: B, meta-analysis of RCT and cohort studies).
Atypical antipsychotic agents are less effective adjuncts for patients with treatment-resistant major depressive disorder (SOR: B, meta-analysis of RCT and cohort studies).
Evidence summary
As many as 30% of patients with major depression fail to respond to treatment with a single antidepressant drug given in adequate dosage for an appropriate period.1 Pharmacologic approaches such as switching antidepressant classes are often attempted first, followed by augmentation with another agent if needed.
The most widely studied medications used for augmentation are lithium and T3.2 An important limitation to their use is that most of the supporting evidence comes from studies of patients who didn’t respond initially to tricyclic antidepressants.
Lithium boosts response to antidepressants
A 2007 meta-analysis of 10 augmentation studies reported that adding lithium to various antidepressant agents increased the chances of clinical response 3-fold relative to placebo (odds ratio [OR]=3.11; 95% confidence interval [CI], 1.80-5.37), yielding a number needed to treat (NNT) of 5.3 The mean response rate was 41.2% in the lithium group and 14.4% in the placebo group (P<.001). The meta-analysis included only RCTs that enrolled subjects with unipolar or bipolar disorder (depressive phase) who were treated with any antidepressant plus lithium in any dose compared with placebo.
A previous meta-analysis published in 1999 concluded that a lithium dose sufficient to produce serum levels of at least 0.5 mEq/L and a minimum treatment duration of 2 weeks resulted in a pooled OR of response to lithium augmentation compared with placebo of 3.31 (95% CI, 1.46-7.53).4 Lithium augmentation is a reasonable alternative for depressed patients who don’t respond to conventional antidepressants.
T3 works well with tricyclics, but what about newer antidepressants?
A 1996 meta-analysis of 8 studies with a total of 292 patients found that patients who received T3 augmentation of tricyclic antidepressant therapy were twice as likely to respond as controls (relative response=2.09; 95% CI, 1.31-3.32).5 The corresponding pooled absolute difference in response rate was 23.2% with a corresponding NNT of 4.3.
T3 dosage in the studies ranged from 25 to 50 mcg/day and duration varied from 7 to 35 days. Analysis of data from RCTs alone produced a lower pooled relative response of 1.53 (95% CI, 0.70-3.35) and an NNT of 12.5. A major drawback of T3 augmentation is that little information is available about its efficacy in combination with newer antidepressant agents.
T3 may have a slight edge over lithium in side effects
As a part of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, lithium and T3 augmentation were compared directly in patients who had failed 2 medication treatments for depression. A total of 142 adult outpatients with nonpsychotic major depressive disorder who had not achieved remission with (or who were intolerant to) citalopram, and who similarly had no luck with either a therapeutic switch or an augmentation trial, were randomly assigned to lithium or T3 augmentation for as long as 14 weeks.
After a mean of 9.6 weeks of treatment, remission rates were 15.9% with lithium and 24.7% with T3, although the difference between the 2 drugs wasn’t statistically significant. Because T3 has fewer side effects and is easier to use, the researchers suggested that it may have a slight advantage over lithium.