Abstract: New models of interaction between genetic and environmental factors have been proposed to explain the pathogenesis of schizophrenia. The Val158Met polymorphism of the COMT (Catechol-O-Methyltransferase) gene, involved in dopamine regulation and related to negative symptoms, has been previously thought to interact with cannabis use in the modulation of risk of psychosis. The aim of the study was to explore the existence of an interaction between COMT genotype and cannabis use in early stages of psychosis and its effects on the age of onset in a representative group of first-episode psychosis patients. Age of onset, DUP (Duration of Untreated Psychosis) and cannabis use (regular user versus sporadic or non-user) were assessed in 169 Caucasian patients with a first-episode schizophrenia spectrum disorder. COMT polymorphism was typed using PCR of the relevant region followed by digestion with NlaIII and electrophoresis. A multivariate ANCOVA was performed with DUP and age of onset as dependent variables, cannabis and the COMT genotype as fixed factors, and gender as a covariate. The MANCOVA was significant for age of onset and DUP. Cannabis users had a significant earlier age of onset. Age of onset was later in the Met homozygote group (non-significant). The cannabis?COMT interaction showed a significant effect on both DUP and age of onset. Post hoc analyses showed that differences between genotypes were only present in the non-users' group. Based on these results, the use of cannabis could exert a modulator effect on the genotype, suppressing the delay effect for the age of onset in the case of the Met allele patients.

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