The impact of COMT inhibition on behaviour and neural activity, and its modulation by genotype and acute stress.

Dopamine is a chemical messenger important for many brain functions, including memory, emotion and motivation. It needs to be maintained at the right level for these functions to be optimal, and either too much or too little is harmful, as seen in various brain diseases. COMT is an enzyme, a biological catalyst, which destroys dopamine. As a result, dopamine levels are influenced by the activity of COMT. Some people have a genetic variant that gives them low COMT activity, whilst others have a variant that leads to high activity. COMT's activity can also be reduced by drugs which prevent it working (a 'COMT inhibitor'). We and others have shown that both of these influences on COMT activity (from the gene, and from the drug) can affect memory and how people take risks, because of COMT's effects on dopamine. Other studies suggest that COMT also affects people's emotional state. This grant aims to help us understand better the potential of COMT inhibitor drugs for treating psychiatric disorders, many of which include problems with memory, risk taking, and controlling emotion. First, we will measure how the drug and the genetic variant interact to affect people's emotions and how they deal with risk and reward. Second, there is evidence that the genetic variation in COMT affects how well people cope with stress, and stress can have negative effects on memory and emotional state. We will therefore study how this relationship is affected by the COMT inhibitor and what exactly is going on in the brain during and after a stressful situation. The results of these studies will help us understand much better the potential of COMT inhibitors as useful drugs for psychiatric disorders, and whether a person's genetic make-up affects how they respond to them. The research will also provide information of wider value about how COMT regulates dopamine and its abnormal function in brain diseases.

COMT metabolises catechols, notably dopamine, and is an attractive neuropsychiatric drug target. Variation in COMT activity, as influenced by the Val158Met polymorphism, or by COMT inhibition, impacts on cortical dopamine-modulated behaviours, especially working memory, and their neural correlates. The effects are consistent with an inverted-U, whereby either low or high dopamine signalling impairs performance. Indeed, the inverted-U model predicts that the effects of COMT inhibition will differ according to Val158Met genotype; our recent study using the COMT inhibitor tolcapone showed this convincingly for working memory and, unexpectedly, for risk aversion. The present proposal will extend these findings in two experimental medicine studies of Val158Met homozygote men, given tolcapone or placebo, in a randomised double-blind design. The first study examines tolcapone's impact on validated tests of reward and emotional processing, and investigates whether these effects are genotype-dependent; we predict that tolcapone will have opposing effects in the two homozygote groups. Stress interacts with Val158Met to affect cognition and neural activity, but it is not known if this interaction is affected by COMT inhibition. Thus, in the second study, we will examine how an acute stressor (a traumatic film) affects working memory and emotional processing, and the neural correlates using fMRI. We predict that acute stress will differentially affect responses to tolcapone vs. placebo, dependent on genotype. Tolcapone is used in Parkinson's disease and being trialled for several other disorders. A full understanding of the range of phenotypes impacted by COMT inhibitors is critical to advance their therapeutic candidacy; it is also essential to understand how these effects are altered by stress, given the key role of stress in psychiatric conditions. The work will provide a powerful examination of the potential of pharmacogenetics for stratified treatments in psychiat

In addition to the academic benefits noted elsewhere, the proposed research will have significant direct and indirect impacts for drug development in the field, of value to industry and ultimately to the public.

(1) COMT inhibitors are under investigation by several pharmaceutical companies for use in a range of psychiatric and neurological disorders. However, for most of these applications there is a notable lack of supporting preclinical data. The current project is directly relevant in this respect, since it will clarify the range of emotional and cognitive processes that are affected by COMT inhibition, and the extent to which these effects are modulated by genotype, and by stress. The work will not only provide behavioural and performance outcomes, which are clearly of primary therapeutic interest, but also, via the fMRI component, information about the mechanisms and circuits underlying the effects.

(2) If we do demonstrate the predicted marked interactions between COMT inhibition and genotype, it will have two important impacts: first, it may explain equivocal results of previous clinical trials of COMT inhibitors which have not taken genotype into account, since opposing effects in different COMT genotype groups may cancel each other out. By extension, there would be a compelling case to include genotype in all future trials of COMT inhibitors. Second, demonstration of clear drug by genotype interactions would have broader implications for stratified medicine and encourage pharmacogenetic studies of other novel drug treatments in psychiatry.

(3) Our focus on measuring effects under stressed as well as baseline conditions is relevant when evaluating the likely 'real world' benefits (or otherwise) of medication, given that stress is an important component of most disorders and indications for which COMT inhibitors are being pursued. If we confirm interactions between drug effects and arousal state, it would also encourage the use of similar designs in future experimental medicine studies.