Diversity of Human Clock Genotypes and Consequences - Progress in Molecular Biology and Translational Science - page 55

psychosis (mainly schizophrenia), rs1801260 G/G correlates with daytime
sleepiness induced by clozapine treatment, suggesting an interaction
between clozapine and CLOCK rs1801260 polymorphism. 38 Besides the
much studied rs1801260 SNP, two variants in the intronic regions of
CLOCK have also been shown to be associated with sleep duration based
on assessment using Munich ChronoType Questionnaire. 39 Consistently,
mutation in the Clock gene alters sleep homeostasis in mice. 40 Heterozygous
and homozygous Clock mutant mice sleep approximately 1 and 2 h less,
respectively, than wild type. The heterozygous and homozygous mutants
also show 25% and 51% smaller increase of rapid eye movement (REM)
sleep, respectively, during 24 h recovery sleep relative to wild-type mice.
Given the reciprocal connections between circadian rhythms/sleep and
psychiatric disorders, a number of studies searched for association of
CLOCK gene polymorphisms with mood. The much studied rs1801260
G allele exhibits significant association with BP, 41 and in patients with over
5 years of BP history, recurrence rate for bipolar depression is significantly
higher in rs1801260 G/G homozygotes. 42 Two variants downstream of the
CLOCK gene are also significantly linked to BP. 43,44 In BP and unipolar
patients undergoing a depressive episode, rs1801260 is related to neuropsy-
chological performance and neural responses in the cingulate cortex to stim-
uli with moral valence. 31 In addition, the rs1801260 G allele has been shown
to be associated with schizophrenia. 45 Interestingly, the rs1801260 A allele
significantly correlates with attention deficit hyperactivity disorder
(ADHD), implicating a protective role of the G allele in this disorder. 46,47
A synonymous polymorphism in exon 20 of the CLOCK gene is linked to
fluvoxamine therapeutic response in MDD patients as well as remission with
fluvoxamine, 48 implying interaction between the CLOCK polymorphism
and the mechanistic actions of fluvoxamine. Again these findings are con-
sistent with studies in Clock mutant mice. These mice exhibit overall behav-
ioral profile similar to human mania, including hyperactivity, decreased
sleep, reduced depression-like and anxiety-like behaviors, as well as an
increase in the reward value for cocaine, sucrose, and medial forebrain bun-
dle stimulation. 49,50 Chronic administration of the mood stabilizer lithium
can bring many of these behavioral phenotypes back to wild-type levels. 49
The mutant animals exhibit increased dopaminergic activity in the ventral
tegmental area, a key reward region in the brain, which could lead to the
phenotypes. 49,50 Taken together, these findings in mice are in agreement
with the human studies and corroborate the notion that CLOCK is involved
in mood regulation.