Audrey Morgan

Background: Affecting one to two percent of the population, bipolar disorder (BD) is a psychiatric mood disorder defined by recurrent relapse episodes of depression and mania or hypermania with long euthymic intervals of mild symptoms.⁷ The episodes lead to adverse effects on psychological, social, and occupational outcomes that oscillate over the course of 24-hours and are regulated by the biological or circadian clock. Disrupted circadian rhythms in bipolar patients include sleep quality/duration, arousal, attention, cognition, and appetite.^6,8 Medical treatment for BD involves mood stabilizers with psychological therapies and lifestyle modifications.⁷ Treatments are often ineffective and poorly tolerated due to side effects and burdens which negatively impact patient’s compliance. Lithium is an essential mood stabilizer with clinical efficacy across the clinical spectrum and has been used for seven decades with long term neurotrophic effects.⁵ Lithium’s narrow therapeutic index creates two diverse patient populations: lithium responders and lithium non-responders. Lithium responders present with shorter periods, reach maintenance level therapy for 568.9 days, and represent 30% of the population.^2,4 Non-responders have stabilized moods for 97 days and represent 70% of the population.^2,4 Lithium effects the GSK3 pathway and inositol metabolism, and lithium’s inhibition of the GSK3 has been implicated as a mechanism for circadian rhythm dysruption.¹ Circadian rhythms are generated by the hypothalamic suprachiasmatic nuclear through the rhythmic regulation of clock genes.¹ Circadian rhythm disfunction is prominent in BD.^1-8 The mechanism of lithium and its effects on circadian rhythms are unknown but may have important health implications and therapeutic potential for BD.

Objective: The aim of this review was to summarize relations between circadian rhythm dysfunction and BD. We hypothesis that lithium effects the inositol phosphate pathway by manipulating IP6 providing a novel pathway to regulate circadian rhythms.

Search methods: A review of data sources was performed using PubMed database and was conducted from 2017 to 2023 on MeSH with the following keywords: “lithium,” “bipolar disorder,” and “etiology.”

Results: The studies illustrated a link between disease pathology and circadian rhythm disturbances. BD patients show a late onset of morning activities and intrusion of sleep with a stronger preference for evening activities.² Lithium inhibits IPP (inositol polyphosphatase) and IMP (inositol monophosphate enzymes) increasing IP3 and creating a reversal in reaction to increase IP6.¹ An increase in IP3 is linked to an increase in circadian rhythm period length.¹ An increase in IP6 indicates an increase in rhythm amplitude and shortened period.¹ Lithium is documented to induce period lengthening and amplitude enhancement of the circadian clock.³ Patient-derived fibroblasts exhibited differential drug responses based on circadian rhythm chronotypes.³ With a knock-out of the clock genes in mice, mice do not exhibit typical lithium mediated behavioral responses without a functional clock, suggesting that patients with a dysfunctional circadian clock may not exhibit typical clinical response to lithium therapy.³

Conclusions: These results strongly suggest exploration of chrono-modulation as a novel treatment for mood stability. Further study to identify the mechanism in which lithium effects the interaction between BD and circadian rhythm is necessary. Chrono-modulation of lithium could be a novel route for achieving mood stability.

Works Cited:

1. Wei H, Landgraf D, Wang G, McCarthy MJ. Inositol polyphosphates contribute to cellular circadian rhythms: Implications for understanding lithium’s molecular mechanism.Cell Signal. 2018;44:82-91. doi:10.1016/j.cellsig.2018.01.001
2. McCarthy MJ, Wei H, Nievergelt CM, et al. Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder. Neuropsychopharmacology. 2019;44(3):620-628. doi:10.1038/s41386-018-0273-8
3. Sanghani HR, Jagannath A, Humberstone T, et al. Patient fibroblast circadian rhythms predict lithium sensitivity in bipolar disorder. Mol Psychiatry. 2021;26(9):5252-5265. doi:10.1038/s41380-020-0769-6
4. Cattane N, Courtin C, Mombelli E, et al. Transcriptomics and miRNomics data integration in lymphoblastoid cells highlights the key role of immune-related functions in lithium treatment response in Bipolar disorder. BMC Psychiatry. 2022;22(1):665. Published 2022 Oct 27. doi:10.1186/s12888-022-04286-3
5. Lyoo IK, Dager SR, Kim JE, et al. Lithium-induced gray matter volume increase as a neural correlate of treatment response in bipolar disorder: a longitudinal brain imaging study. Neuropsychopharmacology. 2010;35(8):1743-1750. doi:10.1038/npp.2010.41
6. Porcu A, Gonzalez R, McCarthy MJ. Pharmacological Manipulation of the Circadian Clock: A Possible Approach to the Management of Bipolar Disorder.CNS Drugs. 2019;33(10):981-999. doi:10.1007/s40263-019-00673-9
7. Rohr KE, McCarthy MJ. The impact of lithium on circadian rhythms and implications for bipolar disorder pharmacotherapy.Neurosci Lett. 2022;786:136772. doi:10.1016/j.neulet.2022.136772
8. Takaesu Y. Circadian rhythm in bipolar disorder: A review of the literature.Psychiatry Clin Neurosci. 2018;72(9):673-682. doi:10.1111/pcn.12688