Effects of the Serotonin Type 2A, 3A and 3B Receptor and the Serotonin Transporter Genes on Paroxetine and Fluvoxamine Efficacy and Adverse Drug Reactions in Depressed Japanese Patients

Abstract

In this study, we tested the influence of the serotonin type 2A, 3A and 3B receptor genes (HTR2A, HTR3A, HTR3B) in addition to a polymorphism in the promoter region of the serotonin transporter (SERTPR), and investigated the different characteristics of clinical responses to paroxetine and fluvoxamine. A total of 100 Japanese patients affected by major recurrent depression were enrolled in a randomized 6-week study. The clinical response was evaluated using the Hamilton Rating Scale for Depression (HAM-D), and adverse drug reactions were assessed at each visit. Patients with the l allele of SERTPR showed a better response to SSRIs than s/s genotype carriers (p = 0.015–0.042), more significantly to fluvoxamine. The –1438G/G genotype of HTR2A was associated with a good response to SSRIs (p = 0.010–0.039), especially to fluvoxamine, and significantly with severe nausea in paroxetine-treated patients (p = 0.013). The 178C/C genotype of the HTR3A was associated with an antidepressant response (p = 0.022–0.042), and more significantly in paroxetine-treated patients (p = 0.002–0.042). These effects were independent of one another. We replicated the finding that the SERPTR polymorphism was associated with a response to SSRIs. We additionally found that HTR2A and HTR3A polymorphisms are associated with the efficacy, and the HTR2A polymorphism is also associated with adverse drug reactions. Furthermore, the effects of these polymorphisms varied from one SSRI to another and thus may depend on the characteristics of each SSRI.

High-frequency HTR3B variant associated with major depression dramatically augments the signaling of the human 5-HT 3AB receptor

“…Considering the importance of the serotonergic system in depression and for the medical treatment of it, this link between a variant serotonin receptor with pronounced augmented signaling characteristics and depression is highly interesting. In a previous study (23), a polymorphism in the regulatory region of HTR3A shown to increase gene expression (24) was found to affect the improvement observed in depressed patients upon paroxetine treatment. In addition, other studies have suggested a link between 5-HT 3 receptor activation and the treatment/ etiology of depression (5,(25)(26)(27).…”

Polymorphisms in GRIK4, HTR2A, and FKBP5 Show Interactive Effects in Predicting Remission to Antidepressant Treatment

“…Although not covering the locus systematically, several previous studies have provided suggestive evidence for an involvement of other HTR2A variants in antidepressant outcome (Minov et al, 2001;Cusin et al, 2002;Peters et al, 2004;Choi et al, 2005;Hong et al, 2006;Kato et al, 2006;McMahon et al, 2006;Paddock et al, 2007;Perlis et al, 2009). Post-mortem (McKeith et al, 1987Lopez-Figueroa et al, 2004) and positron emission tomography (PET) (Yates et al, 1990;Yatham et al, 2000;Mintun et al, 2004) studies have reported both increased and decreased HTR2A receptor number and binding in different brain regions of depressed individuals.…”

Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients

“…Hardy-Weinberg equilibrium was examined in studies where genotype frequencies were included. 9,[15][16][17][18][19][20][21][22][23][24][25] Given the lack of unequivocal data for 5-HTTLPR genotype pooling, we tested both dominant and recessive hypotheses: l/l versus l/s-s/s and l/l-l/s versus s/s. Outcome was defined with three phenotypes: remission rate, response rate, and response rate within 4 weeks.…”