Effects of lithium on circadian rhythm and cognitive function in patients with bipolar disorder

Bipolar disorder (BD) is a highly prevalent group of chronic, debilitating mental disorders. Although lithium has been widely used as the gold-standard treatment for BD, its mechanism of action remains unclear. Additionally, no robust lithium response predictors exist to avoid lengthy and ineffective treatment trials. Therefore, there is a need to investigate the mechanism of action of lithium and to develop biomarkers of lithium response in patients with BD. Circadian rhythm disruption is one of the hallmarks of BD. However, the effect of lithium on circadian rhythm in clinical cohorts of patients with BD is unclear. The first objective of this thesis was to examine whether lithium has a direct effect on reversing circadian rhythm abnormalities commonly reported among patients with bipolar disorder. A systematic review was conducted to examine whether lithium has an impact on circadian rhythm in patients with bipolar disorder. The meta-analysis suggested lithium treatment was associated with greater morningness in patients with BD. The effect of lithium on circadian rhythm was examined further using finer-grained actigraphy data from a double-blind, randomised, placebo-controlled experimental medicine study (Oxford Lithium Trial). No robust evidence supported the hypothesis that lithium might increase the levels of circadian rest-activity, advance the phase of the circadian rest-activity, or reduce the variability of the circadian rest-activity. However, there was some tentative evidence that lithium reduced daytime activity, suggesting that it may have a stabilising effect. In addition, lithium reduced the onset time of daytime activity as well as the variability of circadian rest-activity. The second objective of this thesis was to examine whether lithium has an adverse impact on cognitive function in patients with bipolar disorder. The subjective cognitive dullness reported by patients with BD treated with lithium has been shown to be a major reason for nonadherence to lithium. Cognitive impairment has also been commonly reported in patients with BD. The methodological limitations of previous studies made it difficult to determine the extent to which cognitive impairments often reported in patients with BD were the result of lithium treatment. In the Oxford Lithium Trial, a modified mobile-based contextual cueing task was applied in patients with BD to monitor daily attentional performance, implicit learning, and memory function after six weeks of treatment. No significant difference between lithium and placebo was found on attention, implicit learning, and memory, suggesting short-term lithium treatment does not impair these cognitive domains in patients with BD. Overall, these findings provide new insights not only into the effects of lithium on circadian rhythm and cognitive function in patients with BD, but also into the development of novel experimental models for the treatment of BD. Moreover, this thesis demonstrates the potential of real-time, high-frequency mobile assessment techniques to characterise bipolar phenotypes with greater resolution and accuracy, which may provide new insights into the pathogenesis of BD.