Genes of neurotrophic factors and responsiveness to antidepressive psychopharmacotherapy in patients with depressive disorders

Abstract

Major depressive disorder (MDD) is a clinically and biologically heterogeneous disorder with a heavy personal and socio-economic burden [1]. The neurotrophic theory of the development of depression most fully explains the morphological changes that occur in the brain of patients [2,3]. Among the various neurotrophic factors brain-derived neurotrophic factor (BDNF) and prolactin play an important role in pathogenesis of depression [4]. Objective of the study was to investigate the association of genes polymorphisms of BDNF and prolactin with responsiveness to therapy in patients with MDD. Methods The study group included 185 MDD patients (F32,F33,ICD-10) and 134 healthy persons. Severity of depressive symptoms on the baseline and on the 14th and 28th day of therapy was assessed using Hamilton Depression Scale (HDRS-17) and Clinical Global Impression – Severity scale (CGI-S). Antidepressive therapy response on the 14th and 28th day of therapy was evaluated using Clinical Global Impression – Improvement scale (CGI-I). Genotyping was carried out on polymorphic variants of BDNF genes (rs6265, rs7124442, rs11030104) and PRL gene (rs1341239). The SPSS software was used for statistical analysis. The Hardy-Weinberg equilibrium (HWE) of genotypic frequencies was tested by the chi-square test. Results The study found no deviation of genotype frequencies from HWE (р > 0.05), except for the SNP rs11030104 in the group of patients (χ2 = 37.540; p = 0.001). Important differences in frequency of genotypes and alleles of SNPs rs11030104 of BDNF and rs1341239 of PRL genes between patients and healthy persons at entry have been found. The final multivariate binary logistic regression analysis shows that the A/A genotype of SNP rs11030104 has a more than 6 times higher risk of developing depression than G/G or G/A genotype (p = 0.009). Allele G of SNP rs1341239 gene was more common in patients (63%) compared to control (59%) (p <0.001). We studied the association between the scores on the HDRS-17, CGI-S and CGI-I scales and gene polymorphisms. A statistically significant reduction in scores on all scales during therapy was observed (p <0.01). A decreased scores on the HDRS-17 is associated with G/G genotype of SNP rs6265 (p = 0.049), C/C genotype of SNP rs7124442 (р = 0.009) and A/A genotype of SNP rs11030104 (p = 0.07), patients with these genotypes are characterized by mild depressive disorder on the 14th day of therapy. We showed a relationship between the carriage of the C allele of SNP rs7124442 (p = 0.014) and the G/G genotype of SNP rs6265 (p = 0.078) and a reduced CGI-S score indicating a good response to therapy in this patients. There was a correlation between the presence of the T allele of SNP rs1341239 and the absence of remission according to the CGI-S scale (p = 0.004) and the worst response to antidepressant therapy. Conclusions Our results suggest that SNPs rs11030104 of BDNF gene and rs1341239 of PRL gene are associated with higher risk of developing depression, SNPs rs6265 and rs7124442 of BDNF gene are probably related to the clinical characteristics of the disorder and the response to pharmacotherapy. Disclosure statement: This study was supported by the Russian Foundation Basic Research, grant No. 17-29-02205 “Development of a molecular-genetic panel of depressive disorders based on polymorphisms of the genes of neuronal kinases, neurotrophic proteins and genes of the serotonergic system”