Polymorphisms in the 5-Hydroxytryptamine 2A Receptor and CytochromeP4502D6 Genes Synergistically Predict Fluvoxamine-Induced Side Effects in Japanese Depressed Patients

Abstract

5-Hydroxytryptamine (5-HT) receptors are thought to be associated with the gastrointestinal side effects induced by selective serotonin reuptake inhibitors. CytochromeP450 (CYP) 2D6 may also be associated with the side effects induced by fluvoxamine, since the plasma fluvoxamine concentration depends on a CYP2D6 gene polymorphism. This study investigated whether 5-HT receptor and CYP2D6 gene polymorphisms could predict the occurrence of the side effects. The effects of 5-HT receptor and CYP2D6 gene polymorphisms on the incidence of gastrointestinal side effects induced by fluvoxamine were investigated in 100 depressed outpatients who gave written consent to participate in the study. The patients visited every 2 weeks until the week 12 end point and the fluvoxamine dose was changed in response to their clinical symptoms. All side effects, including the gastrointestinal side effects, were assessed at each visit. Polymerase chain reaction was used to determine A-1438G of the 5-HT2A receptor, C195T and Pro16Ser of the 5-HT3A receptor, Tyr129Ser of the 5-HT3B receptor, and the *5 and *10 alleles of CYP2D6. Both the A-1438G polymorphism of the 5-HT2A receptor gene and the CYP2D6 gene polymorphism had significant effects on the incidence of gastrointestinal side effects. Cox regression was used to analyze the combination effect of the two polymorphisms on the gastrointestinal side effects. Cox regression analysis showed that lower metabolizers (LMs) of CYP2D6 with the G/G genotype of the 5-HT2A A-1438G polymorphism had a 4.242-fold (P ¼ 0.009) and LMs with the A/G genotype had a 4.147-fold (P ¼ 0.004) higher risk of developing gastrointestinal side effects than normal metabolizers with the A/A genotype. The 5-HT3A and 3B gene polymorphisms had no significant effects on the incidence of gastrointestinal side effects. 5-HT2A receptor and CYP2D6 gene polymorphisms had a synergistic effect for the prediction of fluvoxamine-induced gastrointestinal side effects.

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

“…For example, the receptor is a well established target in the treatment of nausea and emesis. The association between the 5-HT 3B (Y129S) polymorphism and various forms of nausea and/or emesis (induced by selective serotonin-reuptake inhibitors or chemotherapy) has been investigated with divergent results (21,28,29). Future studies are required to determine the possible contributions of the 5-HT 3B (Y129S) polymorphism to the development and/or the treatment efficacy of the nausea and emesis known to be common side effects of radio/chemotherapy, anesthetics, and antidepressants.…”

Pharmacogenetics of antidepressant response

“…256 Three variations within the coding region of 5-HT 2A have been implicated in antidepressant response: 102T>C (rs 6313) 176 and 1438G>A (rs6311) 190,257 and 1420C>T, 153 although results were not unequivocal and some findings not replicated. 52,83,85,116,153,185,258 The variants 102T>C and 1438G>A are 2 of the most investigated polymorphisms of this gene: they are in linkage disequilibrium, and they can be considered together. 259 Several other variants have been reported to predict antidepressant response.…”

“…264 An association with vomiting and nausea, both caused by chemotherapy and paroxetine, was reported with the -100 -102 AAG deletion variant of HTR3B. 265 Conflicting findings were reported for the HTR3A 195C>T (rs62625041) and 178C>T SNPs with respect to the gastrointestinal side effects induced by SSRIs, 52,190,266 whereas the HTR3B polymorphism at position 129 leading to a tyrosine-to-serine substitution (rs1176744) was found to be associated with nausea induced by paroxetine, 266 but conflicting findings have been reported.…”

Could Endogenous Substrates of Drug-Metabolizing Enzymes Influence Constitutive Physiology and Drug Target Responsiveness?

“…Although the number of association studies involving the serotonin system increased annually between 1995 and 2005 (from 14 per annum in 1995, to 150 in 2005 [ Figure 3]), only four studies [45][46][47][48] of a total of 875 reported over the preceding decade evaluated serotonin system-related genes together with genes involved in pharmacokinetics (Table 1). Notably, the established or putative endogenous substrates of respective pharmacokinetic genes were not mentioned or discussed in any of these studies.…”