Orexin/Hypocretin Type 2 Receptor (HCRTR2) Gene as a Candidate Gene in Sertraline-Associated Insomnia in Depressed Patients

Selective serotonin reuptake inhibitors (SSRIs) are considered as first-line drugs for treating depressive disorders. Among the adverse effects reported with sertraline is sleep disturbances; however, the etiology lying beneath is obscure. Orexin, the most recently discovered neurotransmitter, is involved in the sleep cycle. It exerts its physiological actions through orexin or hypocretin type 1 and 2 receptors (HCRTR1 and HCRTR2). Dysfunction of the orexin system contributes to various psychiatric, neurologic and neuropsychiatric disorders. Thus, our study aimed to assess the possible association of genetic variation of HCRTR2 G1246A with hypersomnia reported with sertraline in a group of major depressive disorder (MDD) patients. Ninety-six newly diagnosed MDD patients were enrolled in our cohort study. MDD was assessed using DSM-V criteria. Insomnia Severity Index (ISI) was used to assess insomnia at baseline (week 0) and week 4. Blood samples were collected for further genotyping of HCRTR2 G1246A (rs2653349) using polymerase chain reaction-restriction fragment length polymorphism. A significant association between G1264A polymorphism of HCRTR2 and insomnia was observed. Insomnia with sertraline happens by 2.5-fold (P=0.022; odds ratio (OR)=2.5; 95% confidence interval (CI): 1.1-5.7) in patients having GG genotype. Patients with G allele experience insomnia by 2.1-fold more than A allele carriers (P=0.022; OR=2.1; 95% CI= 1.1-4.0). Subgroup analysis showed a significant association between GG genotype as well as the G allele and insomnia only in female MDD patients (P=0.011; OR=4.0; 95% CI=1.3-12.0 and P=0.033; OR=2.4; 95% CI=1.02-5.7, respectively). In conclusion, the G1246A variant might be a predictor for insomnia in MDD patients treated with sertraline. Our findings support the idea that some variants of the HCRTR might contribute to inter-individual variability in the sleep pattern of patients receiving antidepressants.