Sleep and Circadian Rhythm Disruption in Social Jetlag and Mental Illness - Progress in Molecular Biology and Translational Science - page 339

phenotype, with a reduction in REM and NREM sleep, reduced sleep bouts
and increased waking. 72 Work on the Afterhours ( Afh ) mutant again shows a
phenotype consistent with mania, reduced anxiety, and depression. More-
over, this study also showed an association between variation in Fbxl3 and
bipolar disorder in three separate human data sets. 73 Remarkably, Clock ,
Myshkin , and Afh mutants all show a long circadian period (27, 25, and
27 h, respectively), suggesting that a long circadian period may be associated
with the mania-related behavior observed in these animal models.
There is now quite compelling genetic evidence for links between bipo-
lar disorder and SCRD. Based on analysis of 46 SNPs of 8 clock genes
( Bmal1 , Clock , Per1-3 , Cry1-2 , Tim ), Bmal1 and Tim were found to be asso-
ciated with bipolar disorder or schizophrenia. 74 The association of Bmal1 has
been confirmed in a separate study. 75 Further evidence comes from patients
carrying the long allele variant of the clock gene Per3 ( PER3 5/ 5 ), which has
been linked to early onset of bipolar disorder. 76
4.3. Where SCRD precedes mental illness
In the few studies undertaken, SCRD appears to be a good predictor of
mental illness in those individuals identified as “at risk” of developing some
form of mental illness. It is worth stressing from the outset, however, that
there are no studies that have undertaken longitudinal tracking of individuals
using high-resolution sleep phenotyping techniques. The problem of falling
asleep, early morning awakenings, and the decreased need for sleep (often
termed insomnia) are the most often reported symptoms preceding the onset
of bipolar disorder. 77,78 Prodromal sleep disturbances have also been
reported in children with childhood-onset schizophrenia. 79 Another study
focused on adolescents at risk of developing psychosis, but lacking mania or
depressive symptoms, and showed that 37% of subjects scored high on sleep
disturbances with females scoring higher than males. 80 A very recent study
examined drug-na¨ve undergraduate students with a hypomania phenotype
(defined by extremely high scores on the Mood Disorder Questionnaire),
and as having a high risk of developing bipolar disorder. In these individuals,
high-resolution sleep/wake analysis was undertaken. The results showed
that during sleep, high-risk individuals compared to low-risk individuals
showed significantly elevated levels of restlessness during the least active
5 h (2-7 a.m.) of sleep. Once again this behavior was more pronounced
in women compared to men. 81 Collectively these few studies suggest that
the structure of sleep/wake timing is beginning to break down before