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Tryptophan hydroxylase 2 (TPH2) is a key enzyme in the biosynthesis of serotonin in the brain. This study aims to investigate the role of a functional variant in TPH2 (rs17110747) in the pathophysiology of ADHD. This variant has been implicated in mood disorders in recent meta-analysis. This study uses a comprehensive approach that combines association testing and pharmaco-dynamic evaluation of behaviour, in a large sample of children with ADHD (n = 570). The association between various ADHD relevant traits and rs17110747 was analyzed using family-based association tests (FBAT). Children were assessed by parents, teachers and research staff under three experimental conditions (EC): baseline, placebo, and methylphenidate using a double-blind placebo-controlled crossover trial. FBAT analysis conducted in a sample stratified based on sex of the proband, showed that there was a highly significant overtransmission of the G allele from parents to affected girls. In addition, significant association with several behavioral and cognitive dimensions of ADHD was observed only when the proband was female. Further, girls with the G/G genotype (rs17110747) had greater response to placebo when evaluated by parents. These results suggest that there may be a complex association of TPH2 in the etiology of ADHD, with a sex-specific effect. • Family-based association tests show specific findings with TPH2 and girls with ADHD. • Sex-specific effect is observed with behaviour and cognitive dimensions. • Differential association also observed with treatment response in girls. • Appears that there may be different etiological pathways in girls with ADHD. • Results may inform sex-specific pharmacological interventions. [ABSTRACT FROM AUTHOR]

This exploratory study aims to determine whether the change in systolic blood pressure (sBP) after acute methylphenidate (MPH) administration (ΔBP MPH) is associated with the neurocognitive response to MPH in the Conners Continuous Performance Test (CPT) in 513 children with ADHD (aged 6 to 12 years old). We noted that higher increases in sBP were associated with larger improvement in CPT performance with MPH. In the univariate regression model, the ΔBP MPH accounted for an additional 2% of the variance in the change in CPT-Overall Index (OI) after controlling for covariates (p <.001). Linear regression analysis also indicated that ΔBP MPH significantly contributed to predict a change in omission errors, reaction time, and reaction time variability (p <.001, p <.01, p =.001, respectively), but not in commission errors or detectability index (d'). Participants with a clinically meaningful sBP increase of at least 5 mmHg (n = 191) improved by 4.8 points on the CPT-OI score (p <.001), compared to an improvement of only 0.6 points for participants whose sBP declined by at least 5 mmHg (n = 121). In conclusion, larger sBP increases after MPH administration were associated with greater enhancement in CPT performance. These results could be useful in informing MPH dosing in clinical practice. • Examined response to methylphenidate (MPH) treatment in children with ADHD. • Change in systolic blood pressure (sBP) noted after MPH treatment. • Higher increases in sBP were associated with larger improvement in attention. • Higher increases in sBP were also associated with better clinical response. [ABSTRACT FROM AUTHOR]