Negative symptoms of schizophrenia could explain discrepant data on the association between the 5-HT2A receptor gene and response to antipsychotics.

Pharmacogenetic studies assessing the role of 5-HT(2A) receptor gene in antipsychotic efficacy yielded conflicting data. Phenotypical heterogeneity of schizophrenia might explain such discrepancies. For example, negative symptoms are known to reflect severity of illness and to restrain therapeutic response. On this basis, we re-assessed the possible influence of the -1438A/G polymorphism of the 5-HT(2A) receptor gene on the clinical efficacy of atypical antipsychotics with focus on several relevant dimensions. One hundred and sixteen French schizophrenic subjects treated for at least 1 month by atypical antipsychotics were screened for treatment response according to the May and Dencker scale. Gender, age at onset, duration and severity of illness, intensity of negative and positive symptoms at discharge were investigated. The intensity of negative symptoms at discharge was the only variable explaining May and Dencker score (p < 0.001), and was significantly associated with the AA genotype of the -1438A/G polymorphism of the 5-HT(2A) receptor gene (p = 0.03). However, the A allele was not independently associated with refractoriness to atypical antipsychotics. Accordingly, the score reached in the Scale for the Assessment of Negative Symptoms (SANS) appeared as a confounding factor between therapeutic response and the -1438A/G polymorphism of the 5-HT(2A) receptor gene, at least in our sample. This data indicate that negative symptoms are worth being systematically assessed in pharmacogenetic studies aimed at analysing candidate genes in schizophrenia.