Acute antipyschotic efficacy and side effects in schizophrenia: Association with serotonin transporter promoter genotypes
ABSTRACT The serotonin transporter (5-HTT) plays an important role in serotonergic neurotransmission. In the present study, we investigated the effects of the 44 bp insertion/deletion polymorphism in the promoter region of 5-HTT gene (5-HTTLPR) on symptomatology of psychosis and clinical response to antipsychotic drugs.
In total 56 patients acutely treated with haloperidol or risperidone either for the first episode of schizophrenia, schizophreniform or schizoaffective disorders, or for the relapse of these psychotic disorders after tapering their maintenance treatment, were genotyped for the 5-HTTLPR L and S alleles and for the new A/G functional variant within the L alelle (La/g). Psychopathological symptoms were assessed with the Brief Psychiatric Rating Scale (BPRS) and with Clinical Global Impression (CGI) twice: at 8-12 days after the first dose of antipsychotic and after 4 weeks. Extrapyramidal side effects were assessed with the Simpson-Angus Extrapyramidal Side Effects Scale (EPS), the Barnes Akathisia Scale (BARS) and the Abnormal Involuntary Movement Scale (AIMS).
Age, body mass index (BMI), illness duration, drug type and dosage were considered as covariates when analysing association with genetic variants as they were associated with baseline or final BPRS and CGI scores and/or extrapyramidal side effects. 5-HTTLPR was not associated with baseline and final BPRS and CGI scores or with the CGI% reduction. However, the 5-HTTLPR S allele was associated with a lower improvement in BPRS scores (P=0.022) and this effect was even stronger after pooling subjects with S or Lg containing alleles (P=0.006). We did not observe any effect of 5-HTTLPR on acute antipsychotics side effects.
Present result supports a contribution of serotonin system to neuroleptics efficacy for the treatment of schizophrenia. The analysis of the La/g functional variant may significantly improve the predictive power of 5-HTTLPR genotyping and represent a step further towards the development of the personalized antipsychotic treatment.
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ABSTRACT: The receptor pharmacology of many antipsychotic drugs includes actions at various serotonin (5-hydroxytryptamine [5-HT]) receptors. The 5-HT neurotransmitter system is thought to be involved in many of the consequences of treatment with antipsychotic drugs, including both symptom response, primarily of negative and depressive symptoms, and adverse effects, notably extrapyramidal side effects and weight gain. There is substantial interindividual variability in these drug effects, to which genetic variability contributes. We review here the influence of functional polymorphisms in genes associated with 5-HT function, including the various processes of neurotransmitter synthesis, receptors, transporters and metabolism, on the clinical response to, and adverse effects of, antipsychotic drugs. The relatively young field of epigenetics also contributes to the variability of 5-HT-related genes in influencing drug response. Several of these findings inform our understanding of the mechanisms of antipsychotic drug action, and also provide the opportunity for the development of genetic testing for personalized medicine.Pharmacogenomics 09/2014; 15(12):1599-609. DOI:10.2217/pgs.14.111 · 3.43 Impact Factor
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