Predictors of lithium response in bipolar disorder

Abstract

While lithium is generally regarded as the first-line agent for patients with bipolar disorder, it does not work for everyone, which raises the question: can we predict who will be most likely to respond? In this paper, we review the most compelling clinical, biologic, and genetic predictors of lithium response in bipolar disorder. Among clinical factors, the strongest predictors of good response are fewer hospitalizations preceding treatment, an episodic course characterized by an illness pattern of mania followed by depression, and a later age at onset of bipolar disorder. While several biologic predictors have been studied, the results are preliminary and require replication with studies of larger patient samples over longer observation periods. Neuroimaging is a particularly promising method given that it might concurrently illuminate pathophysiologic underpinnings of bipolar disorder, the mechanism of action of lithium, and potential predictors of lithium response. The first genome-wide association study of lithium response was recently completed. No definitive results emerged, perhaps because the study was underpowered. With major new initiatives in progress aiming to identify genes and genetic variations associated with lithium response, there is much reason to be hopeful that clinically useful information might be generated within the next several years. This could ultimately translate into tests that could guide the choice of mood-stabilizing medication for patients. In addition, it might facilitate pharmacologic research aimed at developing newer, more effective medications that might act more quickly and yield fewer side effects.

Keywords: bipolar disorder; genetics; lithium; neuroimaging; predicting response.

Figure 1.

Correlation between clinical predictors and response to lithium treatment. Shown is the meta-analytic effect size (r) for the clinical predictors by descending order of strength. A positive r value indicates a positive correlation between the clinical predictor and a positive response to lithium. A negative r value indicates a negative correlation between the clinical predictor and a positive response to lithium. Meta-analysis performed under a random effects model as described by Kleindienst and colleagues [Kleindienst et al. 2005]. The result for age at onset has been updated to include three additional papers examining this relationship. DMI, depression-mania-free interval; MDI, mania-depression-free interval.

Figure 2.

Genome-wide association study of lithium response. This figure, called a Manhattan plot, shows the results of testing hundreds of thousands of genetic variations across the genome in patients taking lithium. The x axis shows the location of each on one of the 23 chromosomes. A test was performed to determine whether each variant was associated with the time to recurrence of a mood episode while on medication. The y axis shows the strength of association, with the -log₁₀ p value of 8–9 being the range where findings are considered definitive. Each dot represents one genetic variant, and most of them are clustered in the y-axis range of 0-3, so that they are depicted as coalesced into solid bars. The strongest finding reaches just over 6, on chromosome 7. [Reproduced with permission from Perlis et al. 2009].