COMT x DRD4 Epistasis Impacts Prefrontal Cortex Function Underlying Response Control

The prefrontal cortex plays a major role in cognitive control, but it is unclear how single genes and gene-gene interactions (genetic epistasis) impact neural and behavioral phenotypes. Both dopamine (DA) availability ("inverted U-model") and excitatory versus inhibitory DA receptor stimulation ("dual-state theory") have been linked to important principles of prefrontal processing. Catechol-O-methyltransferase (COMT; Val158Met) and DA D4-receptor (DRD4; 48 bp VNTR) genotypes were analyzed for effects on behavioral and neural correlates of prefrontal response control (NoGo-anteriorization, NGA) using a Go-NoGo task and electroencephalography (114 controls and 181 patients with attention-deficit/hyperactivity disorder). ?DRD4 and COMT epistatically interacted on the NGA, whereas single genes and diagnosis showed no significant impact. Subjects with presumably relatively increased D4-receptor function (DRD4: no 7R-alleles) displayed an inverted U-relationship between the NGA and increasing COMT-dependent DA levels, whereas subjects with decreased D4-sensitivity (7R) showed a U-relationship. This interaction was supported by 7R-allele dose effects and mirrored by reaction time variability (non-significant after multiple testing correction). Combining previous theories of prefrontal DA functioning, neural stability at intermediate DA levels may be accompanied by the risk of overly decreased neural flexibility if inhibitory DA receptor function is additionally decreased. Our findings might help to disentangle the genetic basis of dopaminergic mechanisms underlying prefrontal (dys)function

COMT x DRD4 Epistasis Impacts Prefrontal Cortex Function Underlying Response Control

The prefrontal cortex plays a major role in cognitive control, but it is unclear how single genes and gene-gene interactions (genetic epistasis) impact neural and behavioral phenotypes. Both dopamine (DA) availability ("inverted U-model") and excitatory versus inhibitory DA receptor stimulation ("dual-state theory") have been linked to important principles of prefrontal processing. Catechol-O-methyltransferase (COMT; Val158Met) and DA D4-receptor (DRD4; 48 bp VNTR) genotypes were analyzed for effects on behavioral and neural correlates of prefrontal response control (NoGo-anteriorization, NGA) using a Go-NoGo task and electroencephalography (114 controls and 181 patients with attention-deficit/hyperactivity disorder). ?DRD4 and COMT epistatically interacted on the NGA, whereas single genes and diagnosis showed no significant impact. Subjects with presumably relatively increased D4-receptor function (DRD4: no 7R-alleles) displayed an inverted U-relationship between the NGA and increasing COMT-dependent DA levels, whereas subjects with decreased D4-sensitivity (7R) showed a U-relationship. This interaction was supported by 7R-allele dose effects and mirrored by reaction time variability (non-significant after multiple testing correction). Combining previous theories of prefrontal DA functioning, neural stability at intermediate DA levels may be accompanied by the risk of overly decreased neural flexibility if inhibitory DA receptor function is additionally decreased. Our findings might help to disentangle the genetic basis of dopaminergic mechanisms underlying prefrontal (dys)function

Dopamine Transporter (SLC6A3) Genotype Impacts Neurophysiological Correlates of Cognitive Response Control in an Adult Sample of Patients with ADHD

Studies provide ample evidence for a dysfunction in dopaminergic neurotransmission in Attention-Deficit/Hyperactivity Disorder (ADHD). In that respect, a common variable number of tandem repeats (VNTR) polymorphism in the 3′ untranslated region (UTR) of the dopamine transporter gene (SLC6A3) has been repeatedly associated with the disorder. Here, we examined the influence of the common 9- and 10-repeat alleles of SLC6A3 on prefrontal brain functioning and cognitive response control in a large sample of adult ADHD patients (n=161) and healthy controls (n=109). To this end, we inspected a neurophysiological marker of cognitive response control (NoGo anteriorization, NGA) elicited by means of a Go-NoGo task (continuous performance test, CPT). Within the group of ADHD patients, nine-repeat allele carriers showed significantly reduced NGA, whereas no influence of SLC6A3 genotype was observed in the control group. In contrast to previous association studies of children, the nine-repeat—not the 10-repeat—allele was associated with functional impairments in our sample of adult ADHD patients. Our findings confirm a significant effect of the SLC6A3 genotype on the neurophysiological correlates of cognitive response control in ADHD, and indicate that still to-be-identified age-related factors are important variables modulating the effect of genetic factors on endophenotypes

Long-term Effects of Multimodal Treatment on Adult Attention-Deficit/Hyperactivity Disorder Symptoms Follow-up Analysis of the COMPAS Trial

IMPORTANCE Knowledge about the long-term effects of multimodal treatment in adult attention-deficit/hyperactivity disorder (ADHD) is much needed. OBJECTIVE To evaluate the long-term efficacy of multimodal treatment for adult ADHD. DESIGN, SETTING, AND PARTICIPANTS This observer-masked, 1.5-year follow-up of the Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS), a prospective, multicenter randomized clinical trial, compared cognitive behavioral group psychotherapy (GPT) with individual clinical management (CM) and methylphenidate (MPH) with placebo (2 x 2 factorial design). Recruitment started January 2007 and ended August 2010, and treatments were finalized in August 2011 with follow-up through March 2013. Overall, 433 adults with ADHD participated in the trial, and 256 (59.1%) participated in the follow-up assessment. Analysis began in November 2013 and was completed in February 2018. INTERVENTIONS After 1-year treatment with GPT or CM and MPH or placebo, no further treatment restrictions were imposed. MAIN OUTCOMES AND MEASURES The primary outcome was change in the observer-masked ADHD Index of Conners Adult ADHD Rating Scale score from baseline to follow-up. Secondary outcomes included further ADHD rating scale scores, observer-masked ratings of the Clinical Global Impression scale, and self-ratings of depression on the Beck Depression Inventory. RESULTS At follow-up, 256 of 433 randomized patients (baseline measured in 419 individuals) participated. Of the 256 patients participating in follow-up, the observer-masked ADHD Index of Conners Adult ADHD Rating Scale score was assessed for 251; the mean (SD) baseline age was 36.3 (10.1) years; 125 patients (49.8%) were men; and the sample was well-balanced with respect to prior randomization (GPT and MPH: 64 of 107; GPT and placebo: 67 of 109; CM and MPH: 70 of 110; and CM and placebo: 55 of 107). At baseline, the all-group mean ADHD Index of Conners Adult ADHD Rating Scale score was 20.6, which improved to adjusted means of 14.2 for the GPT arm and 14.7 for the CM arm at follow-up with no significant difference between groups (difference, -0.5; 95% CI, -1.9 to 0.9; P=.48). The adjusted mean decreased to 13.8 for the MPH arm and 15.2 for the placebo arm (difference, -1.4; 95% CI, -2.8 to -0.1; P=.04). As in the core study, MPH was associated with a larger reduction in symptoms than placebo at follow-up. These results remained unchanged when accounting for MPH intake at follow-up. Compared with participants in the CM arm, patients who participated in group psychotherapy were associated with less severe symptoms as measured by the self-reported ADHD Symptoms Total Score according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) of Conners Adult ADHD Rating Scale (AMD, -2.1; 95% CI, -4.2 to -0.1; P=.04) and in the subscale of reducing pure hyperactive symptoms, measured via the Diagnostic Checklist for the diagnosis of ADHD in adults (AMD, -1.3; 95% CI, -2.8 to 0.1; P=.08). Regarding the Clinical Global Impression scale assessment of effectiveness, the difference between GPT and CM remained significant at follow-up (odds ratio, 1.63; 95% CI, 1.03-2.59; P=.04). No differences were found for any comparison concerning depression as measured with the Beck Depression Inventory. CONCLUSIONS AND RELEVANCE Results from COMPAS demonstrate a maintained improvement in ADHD symptoms for adults 1.5 years after the end of a 52-week controlled multimodal treatment period. The results indicate that MPH treatment combined with GPT or CM provides a benefit lasting 1.5 years. Confirming the results of the core study, GPT was not associated with better results regarding the primary outcome compared with CM. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN5409620