Subject:
Bipolar Disorder

Short Description:
Is Low Dose Lithium Effective in Bipolar Disorder?

Background:
Although it remains one of our oldest and most effective drugs, lithium has become less popular for the treatment of bipolar disorder in the last two decades. The recent LiTMUS trial compared outcomes in bipolar disorder when all subjects took non-lithium mood-stabilizing medication, while half were also randomized to low-dose lithium. The others remained on their existing medications (“optimized personal treatment,” or OPT) alone. LiTMUS involved 283 subjects with bipolar disorder I (77%) or II. All were considered by their psychiatrists to be candidates for lithium treatment. The lithium group (N=141) was given 600 mg/d lithium for the first two months, with further adjustments up or down as necessary, while the rest remained on OPT alone.After six months of follow-up, the authors found no significant advantage to lithium on the CGI-BP-S (clinical global impression for bipolar severity) scale. Scores decreased by only 1.22 points in subjects in the lithium+OPT group, versus 1.48 points in the OPT group. There was also no difference between the groups in the number of medication adjustments required by clinical need.Was this a failure of lithium? Not necessarily. It’s possible that lithium may simply not have been dosed appropriately. Mean lithium levels in the lithium+OPT group ranged between 0.43 and 0.47 mEq/L during the trial (as opposed to the >0.8 mEq/L recommended by most treatment guidelines). And even though the focus of the trial was on low-dose lithium, clinicians were free to increase lithium dose as much as they wished after the first two months. As a single-blind trial, it is also possible that prescribers may have been reluctant to increase lithium dose for fear of causing additional side effects. Finally, higher doses may only have been given to those subjects with more severe illness.Overall, clinical outcomes were disappointing in both groups, with only one quarter of all subjects achieving remission (defined as CGI-BP-S <2 for two months). Symptomatic improvement ranged from 30% to 50% in both groups. The only metric on which the lithium+OPT group differed from OPT alone was in their lower use of atypical antipsychotics, which were prescribed to only 48.3% of the lithium-OPT subjects (vs. 62.5% of the OPT group) (Nierenberg AA et al, Am J Psychiatry 2013;170(1):102–110).

TCPR’s Take:Lithium has a well-deserved position as a workhorse of modern psychiatry, and while this study’s results seem to call that role into question, a “peek under the hood” shows that lithium may simply have been dosed too conservatively in this study. Notably, only a quarter of all subjects in this naturalistic, “real world” trial achieved remission while taking guideline-driven therapy (OPT), with or without lithium. And while it appears that patients on lithium were less likely to use atypical antipsychotics, it remains an open question whether higher doses of lithium may have produced better clinical outcomes than OPT.