Effect of lithium on circadian activity level and flexibility in patients with bipolar disorder: results from the Oxford Lithium Trial.

Background: Disruption of circadian rest-activity is prevalent in patients with bipolar disorder (BD). Lithium's impact on circadian rhythms has been documented in cell lines, animal models, and pharmacogenomics studies in patients with BD. However, the causal relationship between such disruption and BD remains unclear.

Methods: We investigated the early effects of lithium on circadian rest-activity in an exploratory analysis of a randomised, placebo-controlled, double-blind six-week study on patients with BD. Participants were assigned to receive either lithium or a placebo in a 1:1 ratio. Circadian activity was monitored using actigraphy, and daily affect was assessed through ecological momentary assessment. A computational model was used to quantify different types of activity variability, and the impact of lithium on activity level, activity onset time and their variability were analysed using linear mixed models.

Findings: Of the thirty-five participants who began treatment, 19 received lithium and 16 received a placebo. Lithium significantly altered circadian rest-activity patterns, including reducing daytime activity levels (after 4 weeks, below as well: Cohen's d = -0.19, p = 0.002, linear mixed model, ibid.), advancing the onset of daytime activity (Cohen's d = -0.14, p = 0.018), and increasing the volatility of both daytime activity level (Cohen's d = 0.10, p = 0.002) and its onset time (Cohen's d = 0.13, p < 0.001), independent of affective symptoms changes.

Interpretation: This study establishes a causal link between lithium treatment and reduced circadian activity with advanced circadian phase, potentially via temporarily increasing their volatility (flexibility). Significant circadian changes were detected within one week of starting lithium, highlighting their potential as an early biomarker for treatment response.

Funding: This research was supported by the Wellcome Trust Strategic Award (CONBRIO: Collaborative Oxford Network for Bipolar Research to Improve Outcomes, reference No. 102,616/Z), NIHR Oxford Health Biomedical Research Centre and the NIHR Oxford cognitive health Clinical Research Facility.