Relationship between regulation of circadian and social rhythm, chronotype, the COMT gene Val158Met (rs4680), CLOCK gene 3111 T/C (rs1801260), GSK3-ß gene -50 T/C (rs334558) polymorphisms and treatment response to valproic acid in bipolar disorder

Aim: Bipolar disorder (BD) is a common and severe mental disorder yielding remarkable disruption in social and circadian rhythms. Treatment response is variable and has been associated with many factors. Circadian rhythm disorder and chronotype are among these factors. The first-line drugs used in the treatment of this disease are mood stabilizers. The most used of these are lithium and valproic acid (VPA). In recent years, studies conducted for both animal and human have shown that VPA influences circadian rhythm. This study aims to investigate whether or not the treatment response of BD cases on the usage of VPA is related to (i) variations in genes previously associated with circadian rhythm [COMT gene Val158Met (rs4680), CLOCK gene 3111T/C (rs1801260), GSK3-ß gene -50 T/C (rs334558) polymorphisms], (ii) regularity of social and biological rhythms and (iii) chronotype. Materials and Methods: 94 patients between the ages of 18 and 65, who were diagnosed with BD and had been using VPA for at least one month, were included in the study. Hamilton Depression Rating Scale (HAM-D), Young Mania Rating Scale (YMRS) and Clinical Global Impressions Scale (CGI), Biological Rhythm Interview for Assessment in Neuropsychiatry (BRIAN), Morningness Eveningness Questionnaire (MEQ), Alda Scale and Unified Parkinson's Disease Rating Scale-Motor Examination (UPDRS-ME) were used in the assessment. Social rhythm pattern was evaluated with the Social Rhythm Metric-5 (SRM-5) scale. Genetic polymorphisms were detected in peripheral blood samples by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RPUP) method. Results: Regarding CLOCK gene 3111T/C (rs1801260) polymorphism, carriers of the C allele had a later age of onset, lower number of previous depressive and manic/hypomanic episodes, more regular social and circadian rhythms and fewer mood swings. It has been demonstrated that A/A genotype of COMT gene Val158Met (rs4680) polymorphism is advantageous in terms of the complete response to VPA maintenance therapy, whereas C/T genotype of GSK3-ß gene -50 T/C (rs334558) polymorphism is disadvantageous in terms of the partial response to VPA maintenance therapy. Moreover regarding COMT gene Val158Met (rs4680) polymorphism, A allele carriage has been associated with social rhythm irregularity. Additionally, a family history of psychiatric disorders is more common in these cases. A negative correlation was found between duration of disease, number of previous manic/hypomanic episodes, HAM-D total score, SRM-5 mood swing score, duration of VPA exposure and Alda Scale A score. Morningness has been associated with more regular biological rhythms and better treatment response. It was determined that the response to VPA treatment was predicted by a model consisting of duration of disease, HAM-D total score, number of previous manic/hypomanic episodes, SRM-5 mood swing score and duration of VPA exposure variables, and no independent variable was excluded from the model [F(5) =9.34, R2=0.32, p<0.001]. Conclusions: These findings suggest that, associated with CLOCK gene 3111T/C (rs1801260) polymorphism, the C allele is protective in terms of number of attacks, regularity of biological rhythm and mood swings. A/A genotype of COMT gene Val158Met (rs4680) polymorphism and C/T genotype of GSK3-ß gene -50 T/C (rs334558) polymorphism are associated with VPA maintenance treatment response. Treatment response is negatively correlated with duration of disease, number of previous manic/hypomanic episodes, HAM-D total score, SRM-5 mood swing score and duration of VPA exposure. Morningness chronotype is associated with more regular biological rhythm and better response to VPA maintenance therapy. A model consisting of the variables duration of disease, HAM-D total score, number of previous manic/hypomanic episodes, SRM-5 mood swing score and duration of VPA exposure predicts treatment response. The effect of the number of previous manic/hypomanic episodes in the past and the duration of VPA exposure on the model is more pronounced than other variables. Keywords: Bipolar disorder, valproic acid, genetic polymorphism, circadian rhythm, chronotype