Lithium Stabilises Circadian Activity While Enhancing its 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 the circadian rhythm has been documented in cell lines, animal models, and pharmacogenomics studies in patients with bipolar disorder. However, the causal relationship between such disruption and bipolar disorder remains unclear. Methods: We investigated the early effects of lithium on circadian rest-activity in 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 respectively using linear mixed models. Findings: Of the thirty-five participants who began treatment, nineteen received lithium and sixteen received a placebo. Lithium significantly altered circadian rest-activity patterns, including reducing daytime activity levels, advancing the onset of daytime activity, and increasing the volatility of both daytime activity level and its onset time, independent of affective symptoms changes. Interpretation: This study is the first randomised, placebo-controlled trial to establish a causal link between lithium treatment and changes in circadian rest-activity in BD patients. Our results demonstrate lithium's potential to stabilize circadian activity and advance circadian phase. Notably, significant circadian changes were detected within one week of starting lithium, highlighting their potential as an early biomarker for assessing response to lithium treatment. The increased volatility may reflect greater flexibility of circadian rest-activity, enabling adjustments to the circadian pattern. Trial Registration: Trial registration: ISRCTN91624955. Registered on 22 January 2015. https://www.isrctn.com/ISRCTN91624955 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). The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. KS, JG and MB were supported by the NIHR Oxford Health Biomedical Research Centre and the NIHR Oxford cognitive health Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the UK Department of Health. Declaration of Interest: NX, YY, KS and JG declare no conflict of interests. MB has acted as a consultant for Janssen Research, P1vital Ltd, Boehringer and CHDR, and was previously a paid employee of P1vital Ltd. Ethical Approval: The study protocol was approved on 14 April 2015 by the National Research Ethics Service Committee South Central – Oxford A (reference number 15/SC/0109) and on 10 July 2015 by Oxford Health NHS Foundation Trust. Written consent was obtained from all participants.