Glycogen synthase kinase-3β gene is associated with antidepressant treatment response in Chinese major depressive disorder

Abstract

Evidence suggests that glycogen synthase kinase-3b (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 (À50 T4C), rs13321783 (IVS7 þ 9227 A4G), rs2319398 (IVS7 þ 11660 G4T) and rs6808874 (IVS11 þ 4251 T4A)) 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 ¼ 0.002-0.011). Of the four-locus haplotype analysis, the GSK3B TAGT carriers showed a poorer response to antidepressants in 4-week (Po0.0001) and 8-week (P ¼ 0.015) evaluation compared with other haplotype groups and would quite likely be the nonremitter to 8-week antidepressant treatment (P ¼ 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.

Pharmacogenetics of antidepressant drugs: An update

“…This polymorphism is likely to be associated with antidepressant response, as suggested by a study in bipolar depressed patients treated with total sleep deprivation where the TT homozygote showed better response [147]. In contrast to these results, other investigations reported that the C allele resulted in favorable variant [148,149].…”

How to Keep the Brain Awake? The Complex Molecular Pharmacogenetics of Wake Promotion

“…Among those, we found Slc7a10 (also known as Asc-1; r ¼ 0.81), which is involved in controlling hyperexcitability (Xie et al, 2005). Almost all significant probe sets were negatively correlated with theta activity and belong to cluster 5, such as Narg1l (r ¼ À0.91), Dnajb14 (Hsp40) (r ¼ À0.82), and Gsk3b (r ¼ À0.81), a cell-proliferation gene associated with antidepressant treatment response (Tsai et al, 2008). It should be noted that the EEG measurements for theta and beta-2 activity were negatively correlated (r ¼ À0.64), and thus probe sets that correlated with one tended to show an opposite correlation with the other.…”

Possible Association of the GSK3β Gene with the Anxiety Symptoms of Major Depressive Disorder and P300 Waveform

“…In a recent study, Tsai et al (2008) recruited 230 Chinese MDD patients and also found no significant association of MDD with the alleles and genotypes of single locus or fourlocus haplotypes (rs334558, rs13321783, rs2319398, and rs6808874). However, three of the four polymorphisms investigated were significantly associated with an antidepressant therapeutic effect ( p = 0.002-0.011).…”

“…Lithium, a mood stabilizer that enhances the action of antidepressants, was found to inhibit GSK3b in vitro, in the mouse brain (Klein and Melton, 1996;Stambolic et al, 1996) and in human peripheral blood mononuclear cells (Li et al, 2007). Furthermore, Tsai et al (2008) have reported an association between genetic variation in GSK3b and response to 4 weeks of selective serotonin reuptake inhibitor antidepressant therapy in Chinese individuals with MDD.…”

“…Thus, identification of MDD susceptibility genes can contribute, not only to understanding the etiology of the disease but also to the development of individualized prevention and treatment strategies. With the development of hypotheses concerning mental illness and neural plasticity, much interest has recently been shown in glycogen synthase kinase-3b (GSK3b), a key regulator of neuronal function (Lachman et al, 2007;Meng et al, 2008;Tsai et al, 2008).…”