60 However, recent evidence suggests that the therapeutic action of lithium may be related to direct Paclitaxel CAS effects on the circadian clock. For example, lithium has been shown to lengthen the period of circadian rhythms in rodents,81 and can lengthen the period of neuronal

firing of cultured SCN neurons in a dose-dependent manner.82 A delay of the circadian rhythm of temperature and of REM sleep has also been shown in a BPD patient.83 Inhibitors,research,lifescience,medical This suggests that the therapeutic action of lithium could be due, in part, to correcting a phase advance of the circadian system related to the illness. One proposed molecular mechanism is via the inhibition of GSK3.18,84 Although this enzyme has a number of functions that could potentially mediate the therapeutic effects of lithium,85 one likely possibility is via its function as a central regulator of the circadian clock.60 Numerous lines of evidence support this idea; both lithium and GSK3 knockdown produce a lengthening of mPer2 period in mouse fibroblasts,86 and Inhibitors,research,lifescience,medical GSK3 phosphorylates PER2 and REV-ERBα and regulates their localization and stability, respectively.18’84 Even more interesting are findings that inhibition Inhibitors,research,lifescience,medical of GSK3 may be common to other mood-stabilizing agents such as valproate, and may even be a target of antidepressant therapies, including drugs which

target the serotonergic and dopaminergic systems as well as electroconvusive therapy.60 There is also evidence for effects of allelic frequency of the GSK3/β-50 T/C SNP. Bipolar patients with the T/T allele

Inhibitors,research,lifescience,medical of GSK3β show an earlier age on onset of bipolar disorder and enjoy less improvement from lithium therapy than patients with the T/C or C/C alleles.87,88 Together these results are persuasive, Inhibitors,research,lifescience,medical making GSK3 a promising target for the future development of pharmotherapeutlc agents. Seasonal affective disorder Seasonal affective disorder (SAD) patients frequently have sleep complaints, particularly hypersomnia, with longer polysomnographlcally-recorded non-REM Cilengitide (NREM) sleep and greater slow-wave activity per minute of NREM sleep.89 A chronoblological hypothesis of SAD has been suggested for a while.90,91 The phase shift hypothesis postulates that SAD patients become depressed in winter mostly because there is a season-specific shift in their endogenous circadian system with respect to their sleep-wake cycle.90 Bright light exposure and/or exogenous melatonin have been used successfully to correct this phase shift.92 Recent studies suggest that polymorphisms of PERIOD2, NPAS2, and BMAL1 (ARNTL) could be associated with an increased risk for SAD. These three clock genes were analyzed for SNPs in a sample of 189 SAD patients and an equal number of matched controls.