Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder

Abstract

Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patient donors, we measured circadian rhythms in skin fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-Rs were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP 3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD.

Delayed Circadian Rhythms and Pars Tuberalis Dysfunction in Mood Disorders

“…The skin fibroblasts from bipolar patients grown in tissue culture in-vitro had longer free-running circadian periods [2]. Moreover, the subjective chronotype (e.g., degree of delayed sleep phase) of bipolar patients predicted their response to lithium, with the more delayed patients having poorer responses [3]. This corresponds to other evidence from cell cultures that depressed patients have longer intrinsic circadian rhythms in vitro [4].…”

Patient fibroblast circadian rhythms predict lithium sensitivity in bipolar disorder

“…Rather, our observations point to a general mechanistic aberration in these patients' clocks and the chronomodulatory agents driving the clock to an altered equilibrium to overcome these functional deficits. Indeed, the specific observation that lithium exerts differential circadian effects is supported by a recent study [53]. It is unlikely that the longer phenotype is a consequence of long-term medication, as the cells were passaged at least 4-6 times since biopsy, during which time the drugs would have washed out, excluding potential epigenetic changes.…”

Evidence that genes involved in hedgehog signaling are associated with both bipolar disorder and high BMI

“…This gene catalyzes the rate-limiting step in heme (iron-protoporphyrin) biosynthesis, a process which has been shown to be bidirectionally connected with the regulation of the circadian clock 64,65 . Based on a large body of evidence supporting the existence of circadian disturbances in patients with BD 66 as well as the important role of circadian genes in both BD and response to lithium 67–70 , it might be important for future studies to evaluate the role of genes interacting with circadian systems as in the case of ALAS1 .…”