Brain Volume-Related Polymorphisms of the Glycogen Synthase Kinase-3β Gene and Their Effect on Antidepressant Treatment in Major Depressive Disorder

Neuropsychobiology. 2019;78(3):136-144. doi: 10.1159/000500614. Epub 2019 Jun 12.


Background: Glycogen synthase kinase-3β (GSK-3β) polymorphisms are known to influence hippocampal brain tissue volume in individuals with major depressive disorder (MDD). However, the effects of the GSK-3β gene single nucleotide polymorphisms (SNPs) in those receiving antidepressant therapy are unknown.

Objectives: In the present study, we examined the relationship between brain volume-related SNPs of the GSK-3β gene and antidepressant treatment effects in patients with MDD.

Methods: Paroxetine, fluvoxamine, or milnacipran was administered to 143 Japanese patients with MDD. Two SNPs of the GSK-3β gene (rs6438552 and rs12630592) that influence brain volume in the hippocampus were genotyped. For the primary outcome, the relationship between genetic variations in the SNPs and the percent change in the Hamilton Rating Scale for Depression (HAM-D) score at week 6 was examined. In addition, rs334558, which has been reported repeatedly, was also genotyped.

Results: There was a significant correlation between the two SNPs and the percent change in the HAM-D scores at week 6 (rs6438552 A/A vs. A/G + G/G: p = 0.016; rs12630592 G/G vs. G/T + T/T: p = 0.016). There was high linkage disequilibrium between the rs6438552 and rs12630592 SNPs. The correlation between high therapeutic response over time and the two SNPs were also confirmed (rs6438552 A/A vs. others: p = 0.031; rs12630592 G/G vs. others: p = 0.031).

Conclusions: Our results suggest that two GSK-3β variants that influence brain volume were associated with changes in the HAM-D scores at week 6 in patients with MDD.

Keywords: Antidepressant; Glycogen synthase kinase-3β; Major depressive disorder; Pharmacogenetics; Polymorphism.

MeSH terms

  • Adult
  • Antidepressive Agents / therapeutic use*
  • Depressive Disorder, Major / drug therapy
  • Depressive Disorder, Major / genetics*
  • Depressive Disorder, Major / pathology*
  • Female
  • Fluvoxamine / therapeutic use
  • Genetic Predisposition to Disease
  • Genotype
  • Glycogen Synthase Kinase 3 beta / genetics*
  • Hippocampus / pathology*
  • Humans
  • Linkage Disequilibrium
  • Male
  • Middle Aged
  • Paroxetine / therapeutic use
  • Polymorphism, Single Nucleotide


  • Antidepressive Agents
  • Paroxetine
  • Glycogen Synthase Kinase 3 beta
  • Fluvoxamine