Pharmacotherapy for attention-deficit/hyperactivity disorder: from cells to circuits

Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent disorder of childhood and adulthood, with a considerable impact on public health. There is a substantial pharmacopoeia available for safe and effective treatment of ADHD, and newly available agents diversify the treatment options. With the burgeoning scientific literature addressing the genetic, neurochemical, and neural systems basis for this condition, increasing attention is directed at establishing the neural basis for the efficacy of existing treatments. ADHD remains the only highly prevalent, nondegenerative neuropsychiatric disorder for which effective medications remediate the principal cognitive disturbances in concert with clinical efficacy. Therefore, deeper insight into the neural mechanisms of cognitive remediation may serve to advance treatment development not only in ADHD, but across a wide range of neuropsychiatric disorders in which cognitive dysfunction is a cardinal feature and a strong predictor of clinical outcome. To date, all effective medications for ADHD act on 1 or both of the major catecholamine neurotransmitter systems in the brain. These 2 systems, which arise from subcortical nuclei and use norepinephrine (NE) or dopamine (DA) as transmitters, exert strong modulatory effects on widely distributed cortical-subcortical neural circuits, with important effects on cognition, mood, and behavior, in both health and illness. The present review outlines the actions of ADHD medications from subcellular effects to effects on neural systems and cognition in ADHD patients. This is a very active area of investigation at all phases of the translational cycle, and near-term work is poised to firmly link cellular neuropharmacology to large-scale effects, and point the way toward advances in treatment.