Relationship between adverse effects of antipsychotic treatment and dopamine D(2) receptor polymorphisms in patients with schizophrenia.

Extrapyramidal adverse symptoms (EPS) represent a major type of adverse events in treatment with typical antipsychotic drugs which share high affinity to the dopamine D(2) receptor (DRD2). Genetic variants of this receptor may modulate the therapeutic response and the severity of adverse symptoms of antipsychotics. We analyzed nine known polymorphisms of the DRD2 in 665 schizophrenic patients with European Caucasian ethnic background and compared the intensity of acute dystonia, extrapyramidal symptoms, akathisia, and tardive dyskinesia between carriers of different DRD2 genotypes. In a subgroup of 40 patients with most severe extrapyramidal symptoms we sequenced the coding region including the exon-intron junctions of the DRD2 gene. Functionally relevant DRD2 amino acid variants (Ser(310), Cys(311)) were rare or were not found at all (Ala(96)). Complete sequence analysis of sufferers from the most severe adverse effects revealed two new intronic polymorphisms and a silent polymorphism in exon 7, but no new amino acid variants beyond those which are already known. We found no significant association between these polymorphisms and the intensity of the different types of adverse neurologic effects of the antipsychotics. These results were obtained by correlating adverse events with each of the nine single nucleotide polymorphisms and by correlation with the estimated haplotypes. In conclusion, genetic variations in the DRD2 gene were no major predictors of the individually variable adverse effects from antipsychotic treatment in Caucasian schizophrenic patients.