The lack of association between 5HT2A and 5HT2C receptor gene polymorphisms and clinical response to olanzapine or risperidone therapy in male schizophrenic patients

M Mustapic1, M Zivkovic2, N Pivac1, A Mihaljevic-Peles3, M Sagud3, D Mück-Seler1. 1Rudjer Boskovic Institute, Division of Molecular Medicine HR-10000, Croatia, 2Neuropsychiatric Hospital Dr. Ivan Barbot, HR-44317, Croatia, 3University Hospital Center Zagreb, School of Medicine, University of Zagreb, Department of Psychiatry HR-10000, Croatia

Schizophrenia is a severe psychiatric disorder, where the first line of treatment includes atypical antipsychotic drugs. Antipsychotics block central dopaminergic and serotonergic receptors, thus treatment response could reflect the function of polymorphisms in serotonergic type 2A (5-HT2A) and type 2C (5-HT2C) receptors. Beside in clinical response, 5-HT2A and 5-HT2C receptors were implicated in the metabolic adverse effects and weight gain induced by atypical antipsychotics. The aim of this study was to determine the association between 5-HT2A and 5-HT2C receptor gene polymorphisms and the clinical response to treatment with two antipsychotic drugs olanzapine or risperidone in male schizophrenics.

The study included 114 male schizophrenic patients (mean age ± SD, 37.1± 9.6 yeras, range 20-60 years) treated with atypical antipsychotics olanzapine (mean dose 17.4 ± 3.1 ranging from 10-20 mg/day), risperidone (mean dose 4.6 ± 1.0, ranging from 4-6 mg/day) or long acting risperidone (mean dose 38.2 ± 7.4 ranging 7.5-50mg/day). Diagnosis of schizophrenia was made according to Structured Clinical Interview for DSM-IV. The severity of symptoms and treatment response was assessed using Positive and Negative Syndrome Scale (PANSS). Severity of symptoms was recorded at baseline and every two weeks till week 12 and afterwards every 6 weeks in a period of 36 weeks total. Symptomatic improvement was considered positive and patient as a responder if there was more than 30% decrease in total PANSS score between baseline and after 8 weeks of treatment. Remission was defined as the score reduction to 3 or less on the PANSS items defined by the Remission in Schizophrenia working group 2005. Genotyping was performed with Applied Biosystems SNP genotyping assays on ABI 7300 real-time system. All the results were analysed with chi square and logistic regression tests. Our results did not show the association of 5-HT2A (T102C, rs6313) (χ2=1.04, df=2, p=0.595) or 5HT-2C (-759CT, rs3813929) (χ2=0.001, df=1, p=0.995) gene polymorphism with late response to antipsychotic treatment. There was no significant change in 5-HT2A genotype frequencies compared to positive (χ2=4.47, df=2, p=0.107), negative (χ2=0.61, df=2, p=0.738) or general PANSS score (χ2=1.34, df=2, p=0.511). The lack of significance was also observed between 5-HT2C genotypes and positive (χ2=0.51, df=2, p=0.476) negative (χ2=2.28, df=2, p=0.131) and general (χ2=0.06, df=2, p=0.813) PANSS score . Investigated polymorphisms 5-HT2A (χ2=3.86, df=2, p=0.145) and 5-HT2C (χ2=1.48, df=1, p=0.223) did not reach significance regarding remission.

In conclusion our results suggest that 5-HT2A and 5-HT2C gene polymorphisms are not associated with treatment response in male schizophrenic patients, nor are associated with changes in positive, negative and general items score on PANSS scale. Investigated polymorphisms did not show the association with remission in those patients as well. Our negative results might show lack of associaton with serotonergic receptor genes but due to small number of patients replication of the study with larger number of subjects is warranted.