Recent studies showed that a polymorphism (T to C nucleotide substitution) in the 3' flanking region of the human CLOCK gene is associated with diurnal preferences of human healthy subjects, with higher "eveningness" in subjects carrying at least one copy of the C allele. We investigated the possible role of CLOCK gene polymorphism in the regulation of diurnal mood fluctuations during a major depressive episode. Sample (n = 101) was collected, in the context of previously reported trials, among patients affected by bipolar disorder type I, depressive episode without psychotic features, free of psychotropic medications. Perceived mood levels were assessed three times a day with self-administered visual analogue scales. Genotype groups showed no significant difference in diurnal mood fluctuations. When stratifying the sample by including only patients with an adequate period of observation (duration of illness higher than 5 years, n = 69), we post-hoc observed a significantly higher recurrence rate in homozygotes for the C variant, which was almost double than that of the other genotype groups. This preliminary observation leads to hypothesize a role for the CLOCK gene polymorphism in the regulation of long-term illness recurrence in bipolar disorder. Given the post-hoc nature of the finding, replication in independent samples is necessary to confirm it.
We investigated the possible effect of the 3111T/C CLOCK gene polymorphism on sleep disorders in a sample of 620 patients affected by major depressive disorder (MDD) and bipolar disorder (BP). We detected a significantly higher recurrence of initial (P = 0.0001), middle (P = 0.0009), and early (P = 0.0008) insomnia in homozygotes for the C variant and a similar trend concerning decreased need of sleep in BP (P = 0.0074). Other demographic and clinical features were found not related with CLOCK polymorphisms. This preliminary observation leads to hypothesize a possible involvement of the CLOCK gene polymorphism in the sleep disregulations in MDD and BP.
The available data from preclinical and pharmacological studies on the role of the C-O-methyl transferase (COMT) support the hypothesis that abnormal catecholamine transmission has been implicated in the pathogenesis of mood disorders (MD). We examined the relationship of a common functional polymorphism (Val108/158Met) in the COMT gene, which accounts for four-fold variation in enzyme activity, with 'early-onset' (EO) forms (less than or equal to 25 years) of MD, including patients with major depressive disorder (EO-MDD) and bipolar patients (EO-BPD), in a European multicenter case-control sample. Our sample includes 378 MDD (120 EO-MDD), 506 BPD (222 EO-BPD) and 628 controls. An association was found between the high-activity COMT Val allele, particularly the COMT Val/Val genotype and EO-MDD. These findings suggest that the COMT Val/Val genotype may be involved in EO-MDD or may be in linkage disequilibrium with a different causative polymorphism in the vicinity. The COMT gene may have complex and pleiotropic effects on susceptibility and symptomatology of neuropsychiatric disorders. Molecular Psychiatry (2005) 10, 598-605.
Depressive insomnia and diurnal fluctuations of mood and activity are core clinical features of mood disorders. Here we studied the effect of CLOCK 3111 T/C SNP (rs1801260) on the actimetric recorded diurnal activity and nocturnal sleep of 39 bipolar depressed inpatients. Compared to T/T homozygotes, carriers of the C allele had a similar degree of severity of depression, but showed higher activity levels in the evening, a delayed sleep onset (mean 79 min later), and a reduced amount of sleep during the night (mean 75 min less). Ongoing lithium treatment significantly interacted with rs1801260 by enhancing activity levels in the evening and reducing the differences among genotype groups. Individual characteristics of the molecular clock can influence sleep symptoms in mood disorders.
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