The therapeutic potential of COMT inhibition: cognition and beyond

The catechol-O-methyltransferase (COMT) enzyme regulates dopamine signaling in the prefrontal cortex (PFC). Given the role of PFC dopamine in the regulation of different aspects of executive function, COMT has emerged as a potential modulator of such behaviours. Here, we review the evidence linking COMT with executive function, with a particular focus on human studies using the brain penetrant COMT inhibitor tolcapone. Although small in scale, multiple studies demonstrate improvements in working memory after COMT inhibition in a manner dependent on baseline PFC dopamine signaling, consistent with the well-established inverted-U shaped relationship between PFC dopamine signaling and working memory performance. However, the effects of COMT inhibition extend not only to other cognitive domains but also to other aspects of executive control, notably including the regulation of impulsive or risky behaviours. Findings from rodents are broadly consistent with the human data: animals with lower COMT activity, mediated either genetically or pharmacologically, also show relatively better cognitive performance and reduced impulsive behaviours, compared to wild type/vehicle-treated animals. Taken together, these data are consistent with a model whereby COMT regulates PFC dopamine signaling to modulate top-down control over multiple aspects of behaviour. These findings suggest COMT inhibition as an attractive therapeutic approach in individuals with neuropsychiatric disorders associated with aspects of executive dysfunction.