Also of interest is the observed reduction in anxiety observed in mice with a mutation of the Clock gene. For example, Clock mutant animals are much more likely to spend time in open spaces, which normal mice avoid.63 However, as these mice also showed behaviors associated with mania, it is unclear how to best classify this phenotype. Bipolar disorder Sleep disturbances have been observed in BPD and often precede relapses into depression or mania.46,64-67 Insomnia or hypersomnia, early-morning awakenings, reduced Inhibitors,research,lifescience,medical sleep efficiency, and reduced RL are the most consistently reported changes.

Irregularities in the sleep-wake cycle and daily activities can be important contributing factors in mood disruption.68 The relationship between the sleep-wake cycle and changes in mood appears to be important in patients with frequent Inhibitors,research,lifescience,medical and rapid changes in mood state, so-called “rapid cyclers,” with the switch from mania/hypomania to depression/euthymia occurring during or after sleep, while positive changes in mood from depression to hypomania/mania are more likely to occur after a period of wakefulness.69,70 Circadian disturbances have

been Inhibitors,research,lifescience,medical reported in BPD that suggest a phase advance of the master clock, including a phase advance of the diurnal rhythm of plasma Inhibitors,research,lifescience,medical Cortisol,71 although negative results have

been reported.72 Much of the work attempting to link BPD to clock genes has focused on the 3111T/C polymorphism of the human CLOCK gene.73-76 The C/C allele of CLOCK has been associated with greater severity of insomnia during antidepressant treatment76 and a higher recurrence rate of bipolar Inhibitors,research,lifescience,medical episodes,74 and reduced need for sleep.75 Support for a role of Clock mutation in BPD has recently come from the animal literature, where behavioral studies using CLOCK mutant mice suggest a phenotype similar to mania, with an increase in the reward value Endonuclease of appetitive stimuli and reduced depressive and anxiety-like behaviors.63 An analysis of 46 single nucleotide polymorphisms (SNP) in eight clock genes (BMAL1, CLOCK, PER 1, 2, 3 CRY 1,2, TIMELESS) using family-based samples with BPD or schizophrenia has been reported.77 A Mendelian transmission distortion analysis chemical structure revealed association of BMAL1 (ARNTL) and TIMELESS with BPD. However, these were modest associations found using a very liberal analysis. Interestingly, an independent study using haplotype analysis seems to confirm the association with BMAL1 (ARNTL) and also finds one with PER3 (TIMELESS was not studied).