Relationship between circadian and social rhythms regulation, chronotype, <i>COMT, CLOCK, GSK3-ß</i> gene polymorphisms and response to valproate treatment in remitted bipolar subjects

Disruption of social and circadian rhythms (SCRs) is linked to the pathophysiology and course of bipolar disorder (BD). Valproate response in BD is variable and may be influenced by SCRs and genetic polymorphisms. This study investigated the relationship of valproate response with <i>COMT</i> (rs4680), <i>CLOCK</i> (rs1801260), <i>GSK3-ß</i> (rs334558) polymorphisms, SCRs, and chronotype. Ninety-four subjects with BD in remission and under valproate treatment were enrolled. Rhythm was evaluated with the Social Rhythm Metric-5 (SRM-5), the Biological Rhythm Interview for Assessment in Neuropsychiatry (BRIAN), and the Morningness Eveningness Questionnaire. Valproate response was measured with the Alda Scale. Genotyping was detected using PCR-RFLP, and serum valproate levels were measured 12 h after the last dose. In <i>GSK3-ß</i>, the C/T genotype showed lower partial response rate <i>(p = 0.02)</i>, and C allele was present in all evening chronotypes <i>(p = 0.06)</i>. In <i>COMT</i>, A allele carriers had greater deviation in first social interaction <i>(p = 0.04)</i>, and the A/A genotype had higher complete response rates than the A/G <i>(p = 0.03)</i>. In <i>CLOCK</i>, C allele carriers had a later age of onset <i>(p = 0.01)</i>, fewer previous depressive <i>(p = 0.05)</i> and manic/hypomanic <i>(p = 0.02)</i> episodes, lower BRIAN total <i>(p = 0.01)</i> and social subscale scores <i>(p = 0.01),</i> and lower SRM-5 weekly mood swing score (MSS) <i>(p = 0.03)</i>. All evening chronotypes were non-C allele carriers <i>(p = 0.06)</i>. Valproate response was predicted by a model including duration of illness, HDRS total score, number of previous manic/hypomanic episodes, SRM-5 weekly MSS, duration of valproate exposure, and presence of the A allele in <i>COMT</i> polymorphism (<i>R</i>^<i>2</i><i> = 0.31, p < 0.001)</i>. These results highlight the value of integrating genetic and SCRs factors into personalized BD treatment.