Stimulants and other non-stimulants for attention-deficit/hyperactivity disorder (ADHD)

Abstract

Methylphenidate, amphetamines, and atomoxetine are established agents used to treat children, adolescents, and adults with attention-deficit/hyperactivity disorder (ADHD). Methylphenidate remains the commonly prescribed drug for ADHD throughout the world. The dosage formulations for the majority of methylphenidate preparations contain a racemic mixture (50:50) of d - And l -isomers. The d -isomer is the therapeutically active compound. Amphetamine formulations are marketed as mixtures of d - and l -isomers, or the d -isomer only, where in the d -isomer is about three to five times more potent than the l -isomer. A variety of sustained or extended-release products have been developed to provide patients with either once or twice-daily dosing regimens for methylphenidate and amphetamine. Methylphenidate is almost exclusively metabolized by the hepatic enzyme carboxylesterase 1 (CES1) in a stereoselective manner. A single nucleotide polymorphism (SNP) encoding for CES1 variant p.Gly143Glu was found in various populations resulting in impairment of methylphenidate metabolism and clearance. Amphetamine is mainly metabolized by oxidative deamination and a minor route via CYP2D6. Atomoxetine was the first non-stimulant agent developed for ADHD pharmacotherapy. The CYP2D6 system primarily metabolizes atomoxetine, and it was found that poor metabolizers have about a ten-fold decrease in oral drug clearance. The pharmacodynamic benefits and adverse effects of methylphenidate, amphetamines, and atomoxetine may be linked to their pharmacokinetic profiles. Guanfacine and clonidine are more recent additions to the ADHD armamentarium but are not considered first-line treatments.