Attention deficithyperactivity disorder

Attention deficit/hyperactivity disorder (ADHD (see 6.05 Attention Deficit Hyperactivity Disorder)) is one of the most common childhood psychiatric disorders. An estimated 5-10% of children worldwide are afflicted by ADHD. In addition, there is now increasing acceptance that ADHD occurs in adulthood in approximately 4% of the population. DSM-IV-TR diagnostic criteria classify ADHD symptoms under the headings of inattention or hyperactivity-impulsivity. Symptoms of inattention include lack of attention to detail, carelessness, difficulty in sustaining attention, difficulty in organizing and completing tasks, ease of distraction, and forgetfulness. Hyperactivity-impulsivity includes symptoms such as fidgeting or squirming, excessive and inappropriate running or climbing or a feeling of restlessness, excessive talking, difficulty in awaiting turn, and frequent interruption of others. The subjective nature of these criteria has led to the suggestion that ADHD is simply an extreme in normal behavioral variation that is possibly exacerbated by environmental circumstances. However, there is now a wealth of data clearly demonstrating a genetic inheritance of ADHD, albeit a polygenic disorder, with multiple genes each conferring a small risk. Genes associated with ADHD include: the dopamine transporter (DAT), dopamine receptors (D2, D4, and D5) and dopamine ^-hydroxylase (DBH) gene, the a4 neuronal nicotinic receptor subunit, and the synaptosomal-associated protein, SNAP-25.

Current treatment strategies for ADHD involve the use of classical stimulants such as methylphenidate and amphetamine. These compounds act on DAT and norepinephrine transporters (NET) to enhance monoaminergic transmission in these systems. While effective, methylphenidate has a short half-life and must be administered every 4h producing logistical and social stigma issues when dosing school-aged children, leading to low compliance rates. Long-acting formulations of methylphenidate and the development of atomoxetine, a selective NET inhibitor, have addressed this issue although the use of atomoxetine is confounded by potential hepatotoxicity issues. The atypical stimulant, modafinil, is also effective in treating ADHD without the abuse liability seen with classical stimulants.

While current therapies for ADHD have liabilities such as abuse potential, they produce robust effects on the core symptoms of the disorder. As newer generation formulations and novel targets are evaluated, e.g., histamine H3 receptor antagonists, novel nonstimulant agents that would prove efficacious while avoiding the abuse potential of currently available therapeutics should be feasible.

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