Stimulant side effects and inverted-U: Implications for ADHD guidelines

Objective: To review literature relevant to a possible prediction of stimulant side effects in attention deficit hyperactivity disorder (ADHD), with implications for guidelines. Method: Recent literature on inverted-U effects of dopamine in the prefrontal cortex (PFC), default mode processing, and motor circuits relevant to stimulant side effects is reviewed. Results: The literature on inverted-U effects in the PFC suggests that catechol-O-methyltransferase (COMT) Met versus Val polymorphisms may predict excess dopaminergic effects, including headache and introversion in Met/Met subjects, but therapeutic effects in Val/Val subjects, while dopamine transporter polymorphisms may predict motor side effects. In particular, an understanding of 'inverted-U' effects helps to explain why some children may experience side effects while others show improvements at similar dose ranges. Conclusion: Genetic prediction of stimulant side effects should be investigated, particularly given recent controversies in relation to National Health and Medical Research Council guidelines for stimulant use. A better understanding of treatment-emergent effects will also provide a better understanding of therapeutic effects.