Genetic and clinical factors predict lithium’s effects on PER2 gene expression rhythms in cells from bipolar disorder patients

Abstract

Bipolar disorder (BD) is associated with abnormal circadian rhythms. In treatment responsive BD patients, lithium (Li) stabilizes mood and reduces suicide risk. Li also affects circadian rhythms and expression of ‘clock genes' that control them. However, the extent to which BD, Li and the circadian clock share common biological mechanisms is unknown, and there have been few direct measurements of clock gene function in samples from BD patients. Hence, the role of clock genes in BD and Li treatment remains unclear. Skin fibroblasts from BD patients (N=19) or healthy controls (N=19) were transduced with Per2::luc, a rhythmically expressed, bioluminescent circadian clock reporter gene, and rhythms were measured for 5 consecutive days. Rhythm amplitude and period were compared between BD cases and controls with and without Li. Baseline period was longer in BD cases than in controls. Li 1 mM increased amplitude in controls by 36%, but failed to do so in BD cases. Li 10 mM lengthened period in both BD cases and controls. Analysis of clock gene variants revealed that PER3 and RORA genotype predicted period lengthening by Li, whereas GSK3β genotype predicted rhythm effects of Li, specifically among BD cases. Analysis of BD cases by clinical history revealed that cells from past suicide attempters were more likely to show period lengthening with Li 1 mM. Finally, Li enhanced the resynchronization of damped rhythms, suggesting a mechanism by which Li could act therapeutically in BD. Our work suggests that the circadian clock's response to Li may be relevant to molecular pathology of BD.

The mood stabilizer valproic acid opposes the effects of dopamine on circadian rhythms

“…The data from our present study show that high levels of DA lengthen circadian period, possibly explaining a portion of the circadian disturbances observed in BD patients. However, we have shown previously that cultured fibroblasts from BD patients, which lack DA inputs, also display longer period circadian rhythms compared to healthy subjects (McCarthy et al, 2013). Thus, the long period phenotype in BD could have multiple explanations, including heightened DA inputs, but also non-DA inputs or intrinsic aspects of cellular clock function.…”

“…Skin fibroblasts were obtained from BD (type 1) patients and control subjects as described previously (McCarthy et al, 2013). Cells were transduced with a lentiviral vector containing Per2::Luc and grown to 70% confluence in standard culture medium.…”

Disinhibition of the extracellular-signal-regulated kinase restores the amplification of circadian rhythms by lithium in cells from bipolar disorder patients

“…Between mood episodes, euthymic subjects have more variable rhythms, with less daytime activity, more nighttime activity, and reduced sleep compared to controls (Jones et al, 2005;, suggesting that rhythm disturbances are a stable trait marker of BD. The mood stabilizer lithium treats BD symptoms, and has effects on circadian rhythms in cells, including increases in amplitude (Johansson et al, 2011;Li et al, 2012;McCarthy et al, 2013). Because skin fibroblasts contain cell autonomous circadian clocks, they can be used to study rhythms and their molecular mechanisms in clinical samples, including those from BD patients (Liu et al, 2007;McCarthy et al, 2013).…”

“…The mood stabilizer lithium treats BD symptoms, and has effects on circadian rhythms in cells, including increases in amplitude (Johansson et al, 2011;Li et al, 2012;McCarthy et al, 2013). Because skin fibroblasts contain cell autonomous circadian clocks, they can be used to study rhythms and their molecular mechanisms in clinical samples, including those from BD patients (Liu et al, 2007;McCarthy et al, 2013). Based on this fact, we found in previous studies that in fibroblasts from healthy controls, lithium increases amplitude, but generally fails to increase it in cells derived from BD patients (McCarthy et al, 2013), suggesting the bipolar clock may be less responsive to input signals stimulated by this drug.…”

Circadian Rhythm and the Prediction of Relapse in Bipolar Disorder

“…Research in this area has noted that an evening chronotype is associated with rapid mood swings, 24 greater recurrence rates of affective episodes, 24 and an earlier age at illness onset. 24 Rhythmbased phenotyping may also prove to be of importance in defining treatment response, 21 associated variations in the functioning of molecular clocks, 25 genetic variations associated with the illness, [26][27][28][29][30] and heritable features of the disorder. 31 Longitudinal studies are needed to better understand the relationships between chronobiological disturbances and bipolar disorder and to establish potential chronobiologically based phenotypes for the illness.…”