The Neuropsychopharmacology of Attention-Deficit/Hyperactivity Disorder

doi:10.1016/j.biopsych.2004.08.026

Biological Psychiatry

Volume 57, Issue 11, 1 June 2005, Pages 1385-1390

https://doi.org/10.1016/j.biopsych.2004.08.026 Get rights and content

More than three decades of research has attempted to elucidate the neuropsychopharmacology of attention-deficit/hyperactivity disorder (ADHD). Stimulants, a principle treatment for the disorder, act on the norepinephrine (NE) and dopamine (DA) systems; this has led to a long-standing hypothesis of catecholamine dysfunction in ADHD. Animal studies show a clear role for NE and DA in the modulation of executive functions, which are often disturbed in persons with ADHD. Nonstimulant agents that are effective in the treatment of ADHD tend to affect the NE system, whereas those affecting only DA, or those that affect neither catecholamine, are less potent in reducing ADHD symptoms. Studies of the effects of NE and DA peripheral metabolites by ADHD pharmacotherapies show acute increases in levels of these catecholamines; however, their long-term turnover may be reduced. Imaging studies suggest stimulants increases DA levels in the brain, whereas some animal models of ADHD are more consistent with excessive DA activation in the disorder. Ultimately, ADHD therapy may modify activity in the NE and DA systems to a more optimal level, thus improving responses to environmental stimuli and enhancing working memory and executive function.

Section snippets

Norepinephrine

In preclinical and clinical studies, a number of agents investigated for ADHD have been shown to exert an effect on the noradrenergic system. Stimulants, such as methylphenidate and amphetamine, block the reuptake of both NE and DA at their respective transporters. Amphetamine also enhances the release of these neurotransmitters, even in the absence of neuronal impulse (Seeman and Madras 1998). Both stimulants inhibit monoamine oxidase (MAO), an enzyme that plays a role in metabolizing NE and

Dopamine

Theories regarding the involvement of DA in the pathophysiology of ADHD have focused on whether DA systems show abnormally increased or decreased activity. Plasma and urine measures of DA and its main metabolite HVA have limited relationship to the activity of central DA systems, and studies have shown that stimulant drugs have few effects on urinary HVA (Pliszka et al 1996). Thus, studies of the DA system have focused on the CSF levels of HVA. Shaywitz and colleagues (1977) used the probenecid

Other Neurotransmitter Systems

Smoking by pregnant mothers increases the risk to their offspring for developing ADHD, even after controlling for the much higher risk of having a biologic parent with ADHD (Mick et al 2002). Persons with ADHD are also at much higher risk of initiating smoking and of subsequent nicotine addiction (Milberger et al 1997). Because nicotine influences the central acetylcholine system, which itself modulates arousal and alertness, these data suggest a role for the cholinergic system in ADHD. In

Interactions of NE and DA

The neurotransmitter systems for NE and DA are implicated in the pathophysiology of ADHD. Exactly how these systems are dysfunctional in the disorder is unknown, but it is unlikely that a simple deficiency of either system accounts for the symptomology of ADHD. Like primates, it is likely that humans require an optimal range for NE and DA to enhance executive function (Arnsten 2001). By improving the signal-to-noise ratio within these systems, drugs acting on these neurotransmitter may allow NE