Influence and interaction of genetic polymorphisms in the serotonin system and life stress on antidepressant drug response

Abstract

Variation in genes implicated in serotonin neurotransmission may interact with environmental factors to influence antidepressant response. We aimed to determine how a range of polymorphisms in serotonergic genes determine this response to treatment and how they interact with childhood trauma and recent life stress in a Chinese sample. In total, 14 single nucleotide polymorphisms (SNPs) in coding regions of 10 serotonergic genes (HTR1A, HTR1B, HTR1D, HTR2A, HTR3A, HTR3C, HTR3D, HTR3E, HTR5A and TPH2) were genotyped in 308 Chinese Han patients with major depressive disorder. Response to 6 weeks' antidepressant treatment was determined by change in the 17-item Hamilton Depression Rating Scale (HDRS-17) score, and previous stressful events were evaluated by the Life Events Scale (LES) and Childhood Trauma Questionnaire-Short Form (CTQ-SF). Two 5-HT1B receptor SNPs (rs6296 and rs6298) and one tryptophan hydroxylase2 (rs7305115) SNP were significantly associated with antidepressant response in this Chinese sample, as was a haplotype in TPH2 (rs7305115 and rs4290270). A gene-gene interaction on antidepressant response was found between SNPs in HTR1B, HTR3A and HTR5A in female subjects. The HTR1B SNPs demonstrated interaction with recent stress, while that for TPH2 interacted with childhood trauma to influence antidepressant response.

Influence of 5-HTR2A genetic polymorphisms on the efficacy of antidepressants in the treatment of major depressive disorder: A meta-analysis

“…The Z test was used to estimate the statistical significance of pooled ORs. Heterogeneity among studies was estimated by Cochran's Q-statistic and I 2 tests (Xu et al, 2012). If the Q-test showed a Po0.05 or the I 2 test exhibited450%, indicating significant heterogeneity, the random-effects model was conducted, otherwise, the fixed-effects model was used (Yoshida et al, 2004).…”

Early stress evokes temporally distinct consequences on the hippocampal transcriptome, anxiety and cognitive behaviour

“…Further, altered expression of the MAP kinase signalling pathway in young adult ES animals may also contribute to improved cognitive function noted at this age (Valjent et al, 2001;Xia and Storm, 2012). Concomitant with the enhanced anxiety behaviour observed at this age we also find the regulation of several genes implicated in pathogenesis of psychiatric disorders, such as Prkacb, Htr5a, Htr2a and Slc6a9 (Jokela et al, 2007;Shelton, 2007;Javitt, 2009;Xu et al, 2012). In this regard the Htr2a receptor upregulation is particularly interesting, given we have previously reported enhanced cortical 5-HT 2 receptor function in ES animals (Benekareddy et al, 2010) and shown that postnatal pharmacological blockade of the 5-HT 2 receptor prevents the emergence of anxiety in ES animals (Benekareddy et al, 2011).…”

A patient-centered model of the action of psychotropic drugs

“…Such interactions have been reported between stressful life events and genes involved in serotonergic [70,71] and glutamatergic transmission [72] and adrenal axis regulation [73], and between childhood trauma and genes involved in serotonin metabolism [71]. Similarly, a variant in the angiotensin I-converting enzyme (ACE) gene was found to influence antidepressant response in women, but not in men [74].…”