Purpose:

Attention deficit hyperactivity disorder (ADHD) affects children and adults and is treated with both pharmacologic and nonpharmacologic interventions. Multiple drugs are used to treat ADHD. This review evaluates the evidence on how these drugs compare to each other in benefits and harms.

Data Sources:

To identify published studies, we searched MEDLINE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, and reference lists of included studies. We also searched the US Food and Drug Administration Center for Drug Evaluation and Research website for additional unpublished data and requested information from pharmaceutical manufacturers.

Review Methods:

Study selection, data abstraction, validity assessment, grading the strength of the evidence, and data synthesis were all carried out according to our standard review methods.

Results and Conclusions:

Evidence on the comparative effectiveness of drugs to treat ADHD was insufficient. Evidence on the comparative efficacy in children and adolescents was moderate to low strength and indicated very few differences among the drugs in improving symptoms or in adverse event rates. Sustained-release formulations of stimulants showed benefit over comparators at specific times of day depending on the pharmacokinetics of the specific formulation, but overall differences were not found. Atomoxetine (a nonstimulant) was not found superior to some extended-release stimulant products. Atomoxetine resulted in higher rates of vomiting and somnolence, similar rates of nausea and anorexia, and lower rates of insomnia than stimulants. Extended-release formulations of other nonstimulant drugs (clonidine, guanfacine) have no comparative evidence to date. Immediate-release clonidine was similar to immediate-release methylphenidate.

Comparative evidence in adults provided low-strength evidence of no significant differences in efficacy between switching to methylphenidate OROS compared with continuing with immediate-release methylphenidate or between immediate-release guanfacine or modafinil compared with immediate-release dextroamphetamine. Low-strength evidence found no significant differences between immediate-release guanfacine or modafinil compared with immediate-release dextroamphetamine.

Evidence on the risk of serious harms was primarily indirect, and indicated atomoxetine has increased risk of suicidal behavior compared with placebo. Differences in risk for sudden death was unclear, cardiac adverse events were not different between stimulants, and cerebrovascular adverse events in adults did not differ between stimulants and atomoxetine. Dextroamphetamine immediate-release caused more inhibition of growth than other stimulants, but the difference was influenced by dose and resolved after 2 years of treatment. Atomoxetine caused similar inhibition of weight gain that lasted up to 5 years. Evidence on abuse, misuse, and diversion was limited, but indicated that stimulant use during childhood is not associated with increased risk of substance use later. Misuse and diversion rates varied by age and were highest among college students, and rates of diversion were highest with amphetamine-based products but similar among methylphenidate products. Evidence of effects in important subgroups of patients with ADHD (e.g. comorbid anxiety) was not comparative.