Prefrontal abnormalities, executive dysfunction and symptoms severity are modulated by COMT Val₁₅₈Met polymorphism in...

Core dysfunctions proposed for psychotic disorders include prefrontal cortex (PFC) dopaminergic hypoactivity, executive function (EF) deficits and reduced gray matter in the PFC. The Val variant of COMT Val₁₅₈Met polymorphism is associated with reduced dopaminergic signaling in the PFC. However, it is unclear how COMT Val₁₅₈Met modulates PFC gray matter reduction, EF deficits and symptom severity at the time of the first psychotic episode.

The effect of COMT on both EF performance and prefrontal volume (PFC-VOL) was tested in 158 first episode psychosis (FEP) patients and 141 healthy controls (HC) matched for age (range 9-35 years), sex, ethnicity, handedness and COMT Val₁₅₈Met distribution. EF and PFC-VOL were compared between FEP and HC groups within each polymorphism status (Met/Met versus Val carriers) to assess whether COMT influenced diagnostic differences. Next, correlations between PFC-VOL and EF performance were computed, as well as between both variables and other clinical characteristics of interest (PANSS scores, PAS infancy and premorbid IQ) in the FEP sample.

COMT influenced the diagnostic differences mainly in PFC-VOL, but also in EF performance. FEP-Val carriers showed lower EF scores and reduced PFC-VOL compared to the HC group but also poorer EF performance than FEP Met/Met. Poorer EF performance was associated with smaller PFC-VOL, and both were related to increased severity of negative symptoms, poorer premorbid adjustment, and lower estimated premorbid IQ in FEP patients.

Our findings suggest that COMT Val₁₅₈Met polymorphism might contribute to PFC-VOL reductions, executive dysfunctions and symptom severity in FEP patients.