engleski

The association between HT1A serothe association between 5-ht1a serotonin receptor gene polymorphism and extrapyramidal side effects in haloperidol-treated patients with schizophrenia

Schizophrenia is a serious chronic psychiatric disorder with etiology and neurobiological basis still insufficiently known. Different studies suggest the involvement of many environmental factors and genes in the development of schizophrenia, as well as interactions between genes and the environment. The disease is treated with so-called typical or first generation antipsychotics (haloperidol, fluphenazine), effective in the treatment of positive symptoms, and atypical or second generation antipsychotics (olanzapine, risperidone, quetiapine), which can reduce both positive and negative symptoms of schizophrenia. Despite various antipsychotic drugs, some schizophrenic patients do not respond satisfactorily, while others develop side-effects that substantially compromise the treatment, leading to discontinuation of therapy and frequent relapse of the disease. The most common adverse effects of typical antipsychotics are acute (dystonia, parkinsonism, akathisia) and chronic (tardive dyskinesia) extrapyramidal motor side effects (EPS). As the role of serotonin receptor genes in the development of antipsychotics side effects is not clear, the aim of the study is to examine the association of polymorphism (rs6295) in serotonin type 1A receptor gene (HTR1A) located on chromosome 5, with the development of acute EPS in schizophrenic patients following haloperidol monotherapy. The study included 233 male patients with schizophrenia of Croatian origin, admitted to the University Clinical Hospital Vrapce, Zagreb and University Hospital Centre Zagreb and diagnosed according to the DSM-IV criteria. The severity of EPS in schizophrenic patients following 2 weeks haloperidol (15 mg/d) monotherapy was evaluated using Simpson Angus Rating Scale for Extrapyramidal Side Effects (SAS), Barnes Akathisia Rating Scale (BARS) and Extrapyramidal Symptom Rating Scale (ESRS). After two weeks treatment with haloperidol patients were grouped according to SAS score in two groups: with (SAS score > 3) and without (SAS score ≤ 3) EPS. The genomic DNA was extracted from the whole blood and a polymorphism (rs6295) located in HTR1A was genotyped using TaqMan Real- Time allelic discrimination. The results were evaluated by hi2 test and the Kruskal-Wallis one way analysis by ranks using GraphPad Prism and Sigma Stat 3.5. statistical package.The acute EPS developed in 48% of patients treated with haloperidol. The most frequent EPS were akathisia, acute dystonia and dyskinesia observed in 22%, 19% and 19% of patients, respectively. The results demonstrated significant differences in the genotype frequencies of HTR1A polymorphism between schizophrenic patients with or without EPS, suggesting potential protective role of HTR1A variant.The results imply that in addition to the dopaminergic system, serotonergic mechanisms might be also involved in the development of EPS, either by the effects on dopamine release or via serotonergic receptors as a molecular targets for antipsychotics. However, further studies are needed to confirm these results and to elucidate biological mechanisms underlying present findings.

schizophrenia; haloperidol; 5-HT1A receptor; serotonin; extrapyramidal side-effects

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