Evidence for a combined genetic effect of the 5-HT1A receptor and serotonin transporter genes in the clinical outcome of major depressive patients treated with citalopram

Abstract

In the context of a long-term follow-up study, we analysed the possible implication of the 5-HT(1A) receptor gene (HTR1A) -1018C/G polymorphism in the clinical outcome of major depressive patients treated with citalopram. We had previously reported an association between variation on the SERT gene (SLC6A4) and clinical remission after citalopram treatment. In the present 12-week follow-up study, the combined effect of HTR1A and SLC6A4 genes in clinical outcome and response to citalopram was also evaluated. The sample consisted of 130 patients, all of Spanish origin, who were diagnosed as having a current major depressive episode according to DSM-IV criteria. A 21-item Hamilton Depression Rating Scale was used to assess severity of symptoms at the beginning and during the follow-up to determine the outcome and remission status at week 12. Patients were genotyped for HTR1A gene and, in addition, for two polymorphisms at the CYP2C19 gene, which together account for the 87% of the Caucasian poor metabolizer phenotype. Data were analysed adjusting for the effect of poor metabolizers in clinical response. No independent effect was found for the 5-HT(1A) receptor gene in relation to clinical outcome or remission after citalopram treatment. However, a combined genetic effect of HTR1A and SLC6A4 genes was found to influence the clinical outcome of patients [F(4,102) = 2.89, p= 0.02]. When considering the remission status, an increase of patients carrying the risk genotype combination (S/S-G/G) was found among those subjects who did not reach remission (Fisher's exact test = 0.009). Our results suggest that the combined effect of the serotonin transporter and the 5-HT(1A) receptor genes could be related to the clinical outcome of depressive patients treated with citalopram.

Evidence for HTR1A and LHPP as interacting genetic risk factors in major depression

“…8 The À1019G allele or the homozygous À1019GG genotype has been associated with depression, suicide, bipolar disorder, panic disorder with agoraphobia, neuroticism and decreased antidepressant response. [8][9][10][11][12][13][14][15] We tested the hypothesis that the HTR1A À1019G allele increases depression risk in a Utah population. Observed frequencies of À1019G allele (350/688) and À1019GG genotype (89/344) were 1.10-and 1.34-fold higher among unrelated individuals affected with MDD compared to unaffected individuals (312/672 and 65/336; one-tailed Fisher's exact test P = 0.05 and 0.02, respectively).…”

Molecular studies of major depressive disorder: the epigenetic perspective

“…The short allele is generally associated with reduced transporter activity and lower SLC6A4 expression 19 -precisely the functional effect of the SSRIs used to treat depression -although a recent study investigating allelic expression in the serotonin transporter gene found no correlation between expression levels and the promoter polymorphism. 20 Other genes that have been putatively associated with MDD include those encoding tryptophan hydroxylase, 21 brain-derived neurotrophic factor, 22,23 catechol-O-methyl transferase, 24 phospholipase A2, 25 the glucocorticoid receptor 26 and the serotonin receptor 1A, 27 although these findings still await convincing replication in other samples (see Levinson 28 a recent review).…”

Serotonin 1A receptor gene and major depressive disorder: an association study and meta-analysis

“…4,5 In several studies, these variants were associated with responses including the antidepressant response in MDD. [24][25][26][27][28][29] Recently, Kato and Serretti 30 reported a meta-analysis between rs6295 and antidepressant efficacy in MDD. The authors showed that the pooled OR derived from six studies comprising 893 patients was not significant.…”