The impact of lithium on circadian rhythms and implications for bipolar disorder pharmacotherapy

•Bipolar disorder is characterized by pervasive disruptions in circadian rhythms.•Lithium has effects on cellular and behavioral rhythms.•The effects of lithium on circadian rhythms are context- and dose-dependent.•Lithium responsive bipolar disorder patients show distinct circadian rhythm characteristics: morning chronotype, less variable behavioral rhythms, and shorter period in cultured cells. Bipolar disorder (BD) is characterized by disrupted circadian rhythms affecting sleep, arousal, and mood. Lithium is among the most effective mood stabilizer treatments for BD, and in addition to improving mood symptoms, stabilizes sleep and activity rhythms in treatment responsive patients. Across a variety of experimental models, lithium has effects on circadian rhythms. However, uncertainty exists as to whether these actions directly pertain to lithium’s therapeutic effects. Here, we consider evidence from mechanistic studies in animals and cells and clinical trials in BD patients that identify associations between circadian rhythms and the therapeutic effects of lithium. Most evidence indicates that lithium has effects on cellular circadian rhythms and increases morningness behaviors in BD patients, changes that may contribute to the therapeutic effects of lithium. However, much of this evidence is limited by cross-sectional analyses and/or imprecise proxy markers of clinical outcomes and circadian rhythms in BD patients, while mechanistic studies rely on inference from animals or small numbers of patients . Further study may clarify the essential mechanisms underlying lithium responsive BD, better characterize the longitudinal changes in circadian rhythms in BD patients, and inform the development of therapeutic interventions targeting circadian rhythms.