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.

METHODS

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.

CONCLUSIONS

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.