Recently, BDNF and its high-affinity receptor, NTRK2, widely expressed in the adult brain, were both reported to be involved in antidepressant response (Blugeot et al., 2011
; Saarelainen et al., 2003
; Squinto et al., 1991
); and mounting data indicated that decreased BDNF levels were likely to develop to TRD (Obergriesser et al., 2003
; Piccinni et al., 2009
; Shah et al., 2002
). Although previous studies have suggested that genetic variants may play a key role in mechanism of TRD (Laje and McMahon, 2007
; O’Reilly et al., 1994
), attempts to identify risk genes for TRD have had limited success thus far.
In the present study, we recruited 948 MDD patients from several multicenter, longitudinal projects to examine the putative association between TRD and polymorphisms in BDNF
(rs6265) and NTRK2
genes (rs1387923, rs2769605, and rs1565445). Statistically significant differences in allele and genotype frequencies were observed between TRD and non-TRD participants for rs1565445 polymorphism in NTRK2
gene. Our analyses revealed a significant allelic association between rs1565445 and TRD with an excess of the T allele in the TRD group, and genotype T/C and C/C of rs1565445 were protective factors for TRD with 0.72-fold and 0.52- fold risk respectively comparing with patients with T/T genotype. Haplotype T-T of rs1565445 and rs1387923 in NTRK2
gene was also found to be associated with 1.41-fold increased risk of the occurrence of TRD in MDD patients. To the best of our knowledge, this is the first study reporting an association between genetic polymorphisms within NTRK2
and TRD occurrence in MDD patients. Previous clinical studies had shown that augmentation or combination with lithium effect TRD patients (Shelton et al., 2010
; Vieta and Colom, 2011
), while polymorphisms (rs1565445 and rs1387923) in the NTRK2
gene had been previously related to lithium response in Caucasian patients with Post-traumatic Stress Disorder (PTSD) (Bremer et al., 2007
Previous clinical and psychopharmacological studies have implicated that BDNF
functional Val66Met polymorphism (rs6265) may play a critical role in the pathophysiology of antidepressant responses. However, results in Asian populations were highly inconsistent. Choi et al. (2006)
and Zou et al. (2010a
found significant associations between the rs6265 variant and response to citalopram and fluoxetine respectively in MDD patients from Asian populations. However, Tsai et al. (2003)
and Kang et al. (2010)
reported no association between the rs6265 variant and response to fluoxetine and mirtazapine respectively. Many factors can contribute to the variability in the study findings above, such as small sample size, varying follow-up duration (4–8 weeks), and different assessment methods. Recently, Anttila et al. (2007)
reported no significant association between BDNF
gene Val66Met polymorphism and risk of TRD in a sample of Caucasian origin, although their study was carried out in samples of TRD patients and healthy controls. In our present multicenter, 12-week, longitudinal prospectively study, there is no significant association with the BDNF
gene functional polymorphism rs6265 (Val66Met) and occurrence of TRD in a cohort of MDD patients, which indicated that BDNF
functional polymorphism Val66Met is unlikely to play a major role in the risk of TRD occurrence in MDD patients in the Han Chinese population.
In addition, we further analyzed the role of interaction of BDNF
(rs6265) and NTRK2
(rs1387923, rs2769605 and rs1565445) gene polymorphisms in development of TRD. Using the MDR method followed by conventional statistical analysis, the best gene-gene interaction model identified was a four-locus model. In this model, one low-risk and three high-risk four-locus genotype combinations were identified. By contrast, the effect sizes (ORs) of our-locus genotype combinations were larger than the effects observed in single marker association analysis, which implies a genetic interaction between these four loci in the susceptibility to TRD. However, the nature of the interaction between these four loci is not clear, as suggested previously when the MDR method was applied to breast cancer (Ritchie et al., 2001
). A consistent trend of high-risk or low-risk genotype combinations would indicate that a particular locus had a main effect. As TRD is most likely caused by interactions among multiple genes and environment factors, the lack of such a trend in our best four-locus model could be regarded as quite natural.
In the present study, a total trial of 12-week (including two 6-week trials using two different classes of antidepressants) at an adequate dose was enough to identify the TRD patients, who were distinguished from “difficult-to-treat” depression (Difficult-to-treat depression included TRD and depression that did not respond satisfactorily to one or more classes of antidepressants for insufficient doses or duration) (Rush et al., 2003
). However, several concerns or limitations still need to be addressed. Firstly, it is noteworthy that our follow-up study used a naturalistic design and patients were treated with different classical antidepressants. Since it was unclear whether such heterogeneity could affect our findings, the potential effects of specific antidepressants should undergo further investigation. Secondly, other critical genes in BDNF/NTRK2 signaling pathway were not examined in our current study. A more recent study suggests that genetic polymorphisms within cyclic adenosine monophosphate response element binding gene (CREB
), a downstream signal in BDNF/NTRK2 signaling pathway, is associated with TRD (Serretti et al., 2011
). Thus, the possible role of other genes in the BDNF/NTRK2 signaling pathway and their interactions on development of TRD should be further examined. Thirdly, the allele frequencies of the four polymorphisms examined in the present study showed significant global variation raising concerns of possible population stratification among case-control studies (The International HapMap Consortium, 2010
). However, the current study utilized participants from the same geographic region and ethnic origin, which should help to reduce the potential effects of stratification, but formal assessments such as genomic control were not performed. Finally, it should be noted that due to the moderate sample size and lack of independent replication, the current results should be interpreted with caution and further studies of independent, largescale, well-characterized clinical samples should be conducted in order to understand the role of these two genes in TRD susceptibility.
In conclusion, we found significant evidence for an association between the NTRK2 gene polymorphism rs1565445 and TRD in MDD patients. Our data suggests a modest but statistically significant role of interaction of BDNF (rs6265) and NTRK2 (rs1387923, rs2769605 and rs1565445) genes polymorphisms in the development of TRD in Chinese Han MDD patients.