engleski

Serotonergic 5-HT2A and 5-HT2C receptor gene polymorphisms and acute extrapyramidal side effects in haloperidol-treated patients with schizophrenia

Extrapyramidal symptoms (EPS) appear frequently in schizophrenic patients treated with atypical antipsychotics. EPS like akathisia, acute dystonia and dyskinesia make treatment more difficult, induce discontinuation of medication and relapse. Although the antipsychotic-induced EPS are mostly related to the blockade of dopaminergic D2 receptors, pharmacological, electrophysiological and behavioural studies suggest that serotonergic system and its receptors could be also involved in the occurrence of EPS through serotonergic effects on dopaminergic neuronal activity and dopamine release in the nigrostriatal and mesolimbic dopaminergic pathways. The investigations of serotonergic candidate genes, associated with the development of EPS, are focused on the polymorphisms of 5-HT2A receptor gene located on 13q14-q21 and 5-HT2C receptor gene located on Xq24. The few studies with a small number of patients suggest that the C allele of 5-HT2A receptor gene (102T/C polymorphism) and the T allele of 5-HT2C receptor gene (-759C/T polymorphism)could be the risk factors for the development of EPS in schizophrenic patients. Haloperidol is a first generation antipsychotic drug that induces EPS. It has been shown recently, that administration of 5-HT2C but not of 5-HT2A or 5-HT2A/5-HT2C antagonists blocks catalepsy induced by single injection of haloperidol in rats. The aim of the present study was to determine polymorphisms in 5-HT2A and 5-HT2C receptor genes and development of EPS after acute 2 weeks haloperidol (15 mg/day) monotherapy in schizophrenic patients. We test the hypothesis that there is an association between haloperidol-induced EPS and gene variants of 5-HT2 receptors. The study included 140 male (37.6 ± 9.4 years old, mean±SD) patients with schizophrenia (DSM-IV criteria). The severity of EPS was evaluated using SAS (Simpson Angus Rating Scale for Extrapyramidal Side Effects), BARS (Barnes Akathisia Rating Scale) and ESRS (Extrapyramidal Symptom rating Scale). Genomic DNA was extracted from whole blood using a salting out procedure and genotyping of 5-HT2A (102T/C ; rs6313) and 5-HT2C (-759C/T ; rs3813929) receptors was performed using TaqMan based allele-specific polymerase chain reaction assay using commercial kits. After 2 weeks of treatment with haloperidol EPS appeared in 85 (60%), akathisia in 40 (29%), acute dystonia in 29 (21%) and dyskinesia in 62 (44%) of patients. The severity of EPS evaluated by SAS (4.8 ± 5.0, mean ± SD), BARS 1.75 ± 3.0) and ESRS (27.6 ± 24.4) were independent on the genetic variants of 5-HT2A or 5-HT2C receptors. There was no significant (p>0.05) difference in 102C allele and -759C allele frequencies between patients with or without EPS, and with or without symptoms of akathisia, acute dystonia and dyskinesia. The results of the present study did not confirm the hypothesis that 5-HT2A and 5-HT2C gene variants might be the risk factors for haloperidol-induced EPS in schizophrenic patients. Additional genetic studies and haplotype analysis are necessary to evaluate the role of the serotonergic receptors in the prediction of occurrence of EPS in psychiatric patients.

serotonergic receptor 2A (5-HT2A); serotonergic receptor 2C (5-HT2C); acute extrapyramidal side effects; haloperidol; schizophrenia

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