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Lithium augmentation for treatment-resistant depression


Antidepressants remain the staple treatment of depression, yet some patients treated with them will fail to make a satisfactory improvement, and some of these may develop chronic depression. The use of lithium as an adjunct therapy has been suggested for about a decade, and a new and interesting meta-analysis [1], with some methodological twists, suggests that the strategy is indeed effective.


Searching was extensive, using MEDLINE, the Cochrane Library, and reference lists of reviews and text books. The object was to identify placebo controlled double blind studies involving patients treated with lithium or placebo after not responding to conventional antidepressants. Trials had to use accepted diagnostic criteria for depression, and the use of acceptable measurements of depression improvement as an outcome measure.


Nine randomised double blind studies were found with 234 patients. Patients included had mean ages from 37 years to 54 years, and were predominantly women. Almost all studies used the Hamilton rating scale for depression (HAM-D), and initial scores ranged from ≥12 to >18, after three to six weeks of treatment with an antidepressant drug. Again, most studies required a reduction in the HAM-D score of 50% or more to define a patient as responding.

Lithium doses ranged from 250 mg a day to 1200 mg a day, with some studies allowing titration to a serum lithium level (usually 0.5 mmol/L or more). Duration of therapy was a little as two days to as long as 42 days.

The results from all the trials were fairly consistent (Figure 1). Three studies (Table 1) which had doses of lithium of at least 800 mg or a dose sufficient to reach serum lithium levels of at least 0.5 mmol/L, and a minimum duration of two weeks had a number needed to treat of 3.7 (95% CI 2.3 to 10.6). For all trials the number needed to treat was 3.8 (2.6 to 6.6).

Figure 1: Trials of lithium and placebo in treatment-resistant depression

Table 1: Calculations for both only highly valid trials and all trials

    Improved/Total (%) with    
Trial type Number of trials Lithium Placebo Relative benefit (95% CI) NNT (95% CI)
Minimum dose 800 mg/day AND minimum duration 2 weeks 3 27/54 (50) 13/56 (23) 2.2 (1.3 to 3.7) 3.7 (2.3 to 11)
All trials 9 50/113 (45) 21/121 (18) 2.5 (1.6 to 3.8) 3.8 (2.6 to 6.6)

The authors used cumulative meta-analysis to demonstrate effects of duration of treatment (Figure 2) and dose (Figure 3) on the relative benefit of treatment.

Figure 2: Cumulative meta-analysis according to the duration of lithium augmentation. Bars are 95% confidence interval of relative benefit.

Figure 3: Cumulative meta-analysis according to the dose of lithium. Bars are 95% confidence interval of relative benefit.


There are two main points here. First is that despite a relative paucity of data, from only 234 patients, the authors were able to demonstrate a consistent effect and recommend that lithium augmentation of conventional antidepressants should be for at least seven days and at doses sufficient to reach effective levels of lithium.

Second is that seem to have found a neat way to deal with a common problem in meta-analysis, namely that of performing sensitivity analysis with different doses and durations of treatment. This is a technique that could profitably used elsewhere. Often we exclude information if dose is too low (or high) and duration too short. This method allows us to be more inclusive and for decisions on efficacy to be made on more information.


  1. M Bauer, S Döpfmer. Lithium augmentation in treatment-resistant depression: meta-analysis of placebo-controlled studies. Journal of Clinical Psychopharmacology 1999 19: 427-434.
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