1. ¹Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
2. ²Division of Psychiatry, School of Medicine, National Yang-Ming University, Taipei, Taiwan
3. ³Department of Psychiatry, Yuli Veterans Hospital, Hualien, Taiwan
4. ⁴Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
5. ⁵Division of Mental Health and Substance Abuse Research, National Health Research Institutes, Miaoli, Taiwan
6. ⁶Yu's Psychiatric Clinic, Kaohsiung, Taiwan
7. ⁷Department of Psychiatry, E-DA Hospital and I-Shou University, Kaohsiung, Taiwan

Correspondence: Dr S-J Tsai, Department of Psychiatry, Taipei Veterans General Hospital and National Yang-Ming University, No. 201, Shih-Pai Road, Sec. 2, Taipei 11217, Taiwan. E-mail: sjtsai@vghtpe.gov.tw

⁸These authors contributed equally to this work.

Received 19 February 2007; Revised 6 November 2007; Accepted 15 November 2007; Published online 15 January 2008.

Abstract

Evidence suggests that glycogen synthase kinase-3 (GSK3B) activity is increased significantly in the brain of patients with major depressive disorders (MDD). Inhibition of GSK3B is thought to be a key feature in the therapeutic mechanism of antidepressants. To investigate whether common genetic variants in the GSK3B gene are associated with MDD and the therapeutic response to antidepressants, four polymorphisms (rs334558 (-50 T>C), rs13321783 (IVS7+9227 A>G), rs2319398 (IVS7+11660 G>T) and rs6808874 (IVS11+4251 T>A)) of the GSK3B gene were genotyped in 230 Chinese MDD patients and 415 controls. Among the MDD patients, 168 accepted selective serotonin reuptake inhibitor (SSRI) (fluoxetine or citalopram) antidepressant treatment and therapeutic evaluation for 4 weeks and 117 for 8 weeks. Significant association with MDD was not shown in the alleles and genotypes of single loci or four-locus haplotypes. However, three of the four polymorphisms investigated were significantly associated with 4-week antidepressant therapeutic effect (P=0.002–0.011). Of the four-locus haplotype analysis, the GSK3B TAGT carriers showed a poorer response to antidepressants in 4-week (P<0.0001) and 8-week (P=0.015) evaluation compared with other haplotype groups and would quite likely be the non-remitter to 8-week antidepressant treatment (P=0.006). Our findings show, for the first time, that GSK3B genetic variants play a role in the SSRI antidepressant therapeutic response and support the hypothesis that drugs regulating GSK3B activity may represent a novel treatment strategy for MDD.