Antisocial behaviour in young people with ADHD: Identifying risk pathways

Antisocial behaviour is a major clinical and societal problem. However, there are many different types and causes of antisocial behaviour. One subgroup of children that shows very poor outcomes in adult life consists of children who show antisocial behaviour in childhood accompanied by problems with inattention, hyperactivity and impulsiveness (ADHD). Although inherited, family and social factors all contribute to antisocial behaviour, inherited factors seem to be especially important for this subgroup. Interestingly, a gene variant that affects a brain enzyme called COMT has been found to be associated with antisocial behaviour in this subgroup of children. Usually, there is a need to be cautious about such findings, but this link has now been reported in 5 different samples across the world. It is therefore time to understand how this gene affects this subgroup of antisocial children so we can get clues for better types of treatment. Unfortunately, existing treatments for these children do not seem to work in the longer term. We have some ideas as to how this gene might increase risk, because it has been linked to brain function and emotions in normal individuals. Some exploratory work that we have done suggests that reduced reaction to emotional stimuli might be important. However, to accurately test this we need to ask affected children to come into our laboratory so we can properly measure emotions and brain function by seeing how well these children do on specific tasks. The aim of this proposal is to test 274 male adolescents with ADHD to examine whether the COMT gene variant increases the risk of early onset antisocial behaviour through emotional or affective pathways. We will set the study up in such a way that once we have results, we will also be able to undertake research involving brain imaging to find out in a more direct way what happens in the brains of those affected.

Childhood-onset conduct disorder (CD) problems accompanied by ADHD (Attention Deficit Hyperactivity Disorder) are clinically important because this subgroup shows greater clinical severity and worse outcomes than when either problem presents alone. CD problems are clinically and aetiologically heterogeneous, and influenced by both genetic and environmental risk factors. Family and twin studies show that inherited factors appear to be especially important for this subgroup. Five studies (3 UK, 1 New Zealand, 1 USA) and a pooled analysis have now found association between a gene variant affecting COMT enzyme activity and CD problems in those with ADHD. This relationship is not observed for CD alone or ADHD alone. There is now a need to move beyond simply observing association to testing likely risk mechanisms. Studies of normal individuals, those with CD and our own pilot work suggest that impaired affective response is an important link on the risk pathway, but this needs to be properly tested because executive functioning deficits might also contribute. Why is identifying risk pathways important? Despite ADHD being the most common reason for Child Mental Health Service follow-up, currently used treatment strategies (medication and behavioural treatment) appear to have limited long-term effectiveness on CD outcomes. There is thus a pressing need to identify appropriate targets for new types of psychological and pharmacological treatment. The aim of this proposal is to build on existing genetic and cognitive evidence and identify risk pathways that contribute to conduct problems in ADHD and targets for future intervention strategies. Specifically, we propose to capitalise on an existing sample of 274 clinically well-characterised adolescents with ADHD, who have been genotyped for the COMT risk variant, and to undertake laboratory testing of their cognitive function, affective response and associated psychophysiological reactivity. This is to test the hypothesis that impaired affective response is an intermediate phenotype that mediates the links between the COMT risk genotype and CD problems. Because different genetic and environmental risk factors could impact on similar risk pathways, we will also examine whether this intermediate phenotype distinguishes between those with and without CD problems regardless of genotype. The results of this study will enable us to undertake future research involving brain imaging to better understand how specific neurocognitive vulnerabilities may characterize different subtypes of children with antisocial behaviour.