Executive Functioning in adult Attention Deficit Hyperactivity Disorder (ADHD): From basic mechanisms to functional outcome

<p><strong>Background</strong>  Attention deficit hyperactivity disorder (ADHD) is characterized by age inappropriate levels of hyperactivity, inattention and impulsivity. A large proportion of children with ADHD have persisting symptoms into adulthood. However, the pathways from genetic susceptibility to symptoms and functional outcomes of ADHD are still not well understood. Some researchers argue that impairment of executive function (EF) is an essential part of the disorder. The present thesis was motivated by the need of more research to understand the genetics of EF, how to measure EF, the heterogenetiy of EF and the functional outcomes of deficit of EF (EFD) in ADHD. In the first study included in this thesis, we used a dimensional approach to investigate COMT haplotypes and symptoms of ADHD, in addition to investigate genetic heterogeneity through the identification of potential subgroups within the disorder. The COMT gene has been shown to be important for the regulation of dopamine levels in prefrontal cortex, and has been associated with several asptects of EF, such as set shifting and inhibition. In the second study, we investigated these functions in ADHD, with the aim to obtain “pure” measures of EF. In the third study, these functions, in addition to other important EFs were included, and we investigated the heterogeneity of ADHD through characterizing functional impairment in the group with ADHD and psychometrically defined EFD.</p><p><strong>Materials and methods</strong> The thesis is based on three different papers. In the first paper, 435 participants with a clinical diagnosis of ADHD and 383 controls were included. The second paper included 60 participants with ADHD and 60 controls, while 79 participants with ADHD and 77 controls were included in the third paper. All participants filled in self-report questionnaires and supplied blood or saliva samples for genetic analysis. The questionnaires included items to assess demographical and clinical data, in addition to levels of ADHD-symptoms in adulthood and childhood. Participants included in the two last papers also went through a neuropsychological examination and a psychiatric interview. The neuropsychological assessment included tests from the Delis-Kaplan Executive Function System (D-KEFS), Wechsler Abbreviated Scale of Intelligence (WASI) and Paced Auditory Serial Addition Task (PASAT).</p><p><strong>Results</strong> We found that COMT haplotypes were significantly associated with dimensional hyperactivity/impulsivity symptoms with a stepwise decreased score associated with the mid and low activity haplotypes. When stratifying for use of medication, the significance was only kept for hyperactivity in the subgroup of medicated ADHD patients. There was no significant association between COMT and measures of impulsivity. In the second paper, we found that participants with ADHD scored significantly lower than the control group on set shifting as measured with a subtest from the Colour-Word Interference Test (CWIT) from D-KEFS, also after control for basic functions, working memory and IQ. In the third paper, we found that the participants with ADHD and neuropsychologically defined EFD were characterized by a higher degree of functional impairment than those without EFD, including more reading and writing problems, lower IQ, more ADHD symptoms in childhood and lower work participation.</p><p><strong>Conclusions</strong> Our data show that examining COMT haplotypes may be useful to understand basic  mechanisms in ADHD and the heterogeneity of the disorder. The second study indicates that set shifting as measured with the CWIT from D-KEFS may act as a potential endophenotype for ADHD. The third study, in line with the first one, supported that ADHD is a heterogeneous condition by showing that the group with ADHD and EFD combined may be a distinct subgroup characterized by a high level of functional impairment. </p><p>The results in the present thesis suggest that set shifting measures from D-KEFS should be included in the definition of EFD. Future studies should examine groups with and without psychometrically defined EFD, both at a genetic and psychosocial level, as the identification of such subgroups could lead to more targeted and effective treatment.</p