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GSK-3β and BDNF genes may not be associated with venlafaxine treatment response in Chinese of Han ethnicity

Purpose Venlafaxine is one of the commonly prescribed antidepressants for major depressive disorder (MDD). Accumulated evidence revealed the involvement of glutamatergic system in the pathophysiology of MDD and antidepressant treatment. Methods We recruited 193 MDD patients who have been taking venlafaxine for 6 weeks, and investigated whether single nucleotide polymorphisms (SNPs) in GSK-3β and BDNF were associated with treatment response. Nine SNPs were selected randomly depending on association studies. Efficacy of treatment was determined by 17-item Hamilton Rating Scale. Allele and genotype frequencies were compared between responders and nonresponders. Results After adjusting the false discovery rate, no significant difference was observed between response and nonresponse groups in allele or genotype distributions after venlafaxine treatment for 6 weeks. Conclusion Our results indicated that genetic variants in the GSK-3β and BDNF may not be associated with treatment response in MDD patients treated with venlafaxine.


Introduction
Major depressive disorder (MDD) is a common, debilitating psychiatric disorder. 1 Venlafaxine, as a serotonin and norepinephrine reuptake inhibitor, is one of the major prescribed medications for MDD. 2 Previous studies implicate glutamate system genes, the glycogen synthase kinase-3β (GSK-3β) and brain-derived neurotrophic factor (BDNF), are involved in both pathophysiology of MDD and antidepressant treatment. 3 Furthermore, BDNF gene promotes the growth of neurons in vitro mediated by GSK-3β. 4 However, pharmacogenetic studies of GSK-3β and BDNF genes with antidepressant response are controversial in the literature. [5][6][7][8] Therefore, we attempted to investigate whether GSK-3β and BDNF gene polymorphisms are associated with venlafaxine treatment in the Han population.
For pharmacogenetics association study, 193 MDD patients in Chinese Han population (aged 18-65 years, no blood relationship) were recruited. All subjects recruited were of Han Chinese origin. Participants were first-onset patients. They did not receive any antidepressant treatment for at least 2 weeks and had no electroconvulsive therapy. Efficacy of treatment was determined by 17-item Hamilton Rating Scale, and all MDD patients had a minimum baseline Hamilton Rating Scale for Depression (HAMD) score of 18 points. Clinical interviews were performed by board-certified and experienced psychiatrists. The study was approved by the Ethics Committee of the Human Genetics Center in Shanghai and conducted

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Sun et al in accordance with the Declaration of Helsinki. All subjects signed the informed consent form.
All MDD patients received a continuous antidepressant treatment for .6 weeks. A total venlafaxine dose of 75-375 mg/day was used based on patients' conditions. Patients were evaluated at the end of weeks 1, 2, 4, and 6. Patients who have .50% reduction of HAMD score were assigned to response group, and ,50% were assigned to nonresponse group at the end of week 6. 9 Other psychotropic medications were not allowed during the study except an eligible dose of benzodiazepine for insomnia at bedtime.
Demographic differences between responders and nonresponders were calculated by the Student's t-test (age, age of onset, body mass index, and HAMD score) or Pearson's chi-squared test (gender, marital status, education, and family history). The SPSS Statistics Version 22 and R software (Lucent Technologies, Morris Plains, NJ, USA) were used to carry out the above analyses. Interrater reliability was evaluated by Kappa coefficients (Kappa value =0.85). 12 The online software SHEsis (http://202.120.31.177/myanalysis.php) 13 and R (version 3.2.2) were used to analyze allelic and genotypic distributions. HaploView version 4.2 was used to estimate linkage disequilibrium of all pairs of SNPs with D′, which is the standard measurement. 14 Hardy-Weinberg equilibrium (HWE) was calculated by using SHEsis. For all analyses, P-values were shown as two-tailed, and P,0.05 was considered statistically significant.
In our study, 175 MDD patients completed the 6-week venlafaxine treatment, in which 146 (83%) patients were responders and the remaining 29 (27%) participants who gave no response at the end of week 6 were termed as nonresponders. The endpoint values for responders and nonresponders of HAMD were 16.24±5.49 and 6.04±3.57, respectively. We found no significant difference between responders and nonresponders in age, BMI, number of episodes, HAMD baseline score, family history, marital status, education years, and gender except for 6-week HAMD score (P,0.05). Thus, it is reasonable to conclude that no systematic differences can potentially affect clinical outcomes between the responders and nonresponders.
None of the SNPs showed significantly deviated HWE (P,0.05). Genotypes of response group vs nonresponse group were distributed as follows: There is no significant difference observed between response and nonresponse groups in allele or genotype distributions (P.0.05), which is shown in Table S1. We also calculated D′ and r 2 for all combinations of the four SNPs (data not shown). The haplotype distributions showed no significant association between all combinations of these SNPs with antidepressant efficacy in MDD patients.
The association between polymorphism rs6265 of BDNF gene and antidepressant treatment outcome has always been inconsistent. 15 The polymorphism has been proven to be not associated with venlafaxine treatment response in our generalized anxiety disorder population. 16 Our result indicated that the polymorphism was negative in MDD samples. Additionally, the other three common SNPs in BDNF gene and GSK-3β gene were not associated with venlafaxine treatment in our Chinese MDD patients. However, there are some limitations in our study. Replicated studies with larger sample sizes and more common or rare variants are necessary to verify this association. A placebo control would offer a convincing estimation of the response rate and validate the association between the gene and venlafaxine treatment. Whereas, we did not use it due to high suicide rate in MDD patients. Furthermore, the phenotype of venlafaxine responses can be revealed with detailed genotypes. 17 Despite these, the current study may shed new light on predicting venlafaxine responses in MDD treatment.