The role of COMT gene variants in depression: Bridging neuropsychological, behavioral and clinical phenotypes

Depression is a common and disabling psychiatric disorder with a complex etiology, which includes predisposing risk genes and environmental stressors. Variation in the Catechol-O-Methyltransferase (COMT) gene, the Val158Met polymorphism in particular, has been extensively investigated in relation to clinical phenotypes of depression and, in parallel, neurocognitive processes. In this review, we bridge evidence from neuroimaging, behavioral and clinical studies that have examined the role of COMT variants on depression-relevant phenotypes. We observed that clinical phenotypes such as depression severity and diagnosis, or behavioral endophenotypes, are less reliably associated with COMT genetic variation. On the other hand, genetic effects are more discernible on brain systems of emotional processing. Specifically, the Met allele is associated with increased activity in limbic areas and prefrontal cortex, but is also more likely to have a better response to antidepressant treatment, compared to the Val allele. Gender and stress are important modulators of COMT genetic effects. On the basis of current evidence, we propose a tentative pathway through which the COMT gene may influence cognitive vulnerability to depression.