Association study of serotonergic gene variants with antipsychotic-induced adverse reactions.
BACKGROUND
The products of the serotonin receptor genes are important targets for conventional and atypical antipsychotics, and may be relevant for antipsychotic activity and associated adverse reactions. It has been shown that the high potency at 5-HT2 receptors may also be associated with the production of moderate extrapyramidal side effects (EPS). In addition, serotonin neurotransmitter systems in the central nervous system play an important role in eating behaviours, and are involved in the symptomatology related to the metabolic syndrome, including obesity, diabetes and hyperlipidemia.


METHODS
This study was designed to investigate the hypothesis that serotonin pathway genes play a part in mediating antipsychotic-induced adverse reactions, including EPS, tardive dyskinesia, obesity and diabetes. Polymorphisms in the 5-HT2A (102 (T/C), His452Tyr), 5-HT2C (Cys23Ser, -759 (C/T), -995 (G/A), TPH2 (-366 (C/T), -8933 (A/G) and 5-HTT (LPR, -15370 (A/G)) genes were investigated in a cohort of 427 US Caucasian patients undergoing antipsychotic treatment, using automated genotyping techniques.


RESULTS
5-HTT (LPR) and 5-HT2A (102 (T/C) polymorphisms were found to be associated with BMI (P=0.05 and 0.005, respectively). The genotype distribution of the TPH2-366 (T/C) polymorphism was found to be significantly associated with the presence of diabetes (P=0.01). A trend towards an association (P=0.07) between the 5-HT2C Cys23Ser polymorphism and tardive dyskinesia was found when age, duration of treatment, dose and sex were considered. Genotype distributions of the 5-HT2C -995 (G/A), 5-HT2C -759 (C/T) and 5-HT2A His452Tyr polymorphisms differed among patients presenting EPS and those without (P=0.08, 0.06 and 0.08, respectively). No other statistically significant associations were observed.


CONCLUSIONS
Serotonergic polymorphism may play a moderate role in the development of side effects associated with antipsychotic treatment.
Al-Janabi
Ismail
I
Section of Genomic Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK.
Arranz
Maria J
MJ
Blakemore
Alexandra I F
AI
Saiz
Pilar A
PA
Susce
Margaret T
MT
Glaser
Paul E A
PE
Clark
Daniel
D
de Leon
Jose
J
D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects*; D005260:Female; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D044348:Receptors, Serotonin, 5-HT2 / Q000235:genetics*; D055815:Young Adult
D014150:Antipsychotic Agents; D044348:Receptors, Serotonin, 5-HT2