Overview and Comparison of Drug Classes

Historically the treatment of ADHD relied on agents affecting monoaminergic neurotransmission, and largely consisted of the stimulants, antidepressants, and antihypertensive agents (Table 1).1'65 The primary pharmacological treatment for ADHD continues to be the use of stimulants, particularly methylphenidate and amphetamines. Methylphenidate has long been the leading treatment for ADHD; however it has a short duration of action and a midday dose is required. In schoolchildren, this necessitates dosing during the school day and contributes to poor compliance and social stigma. The importance of avoiding this midday dose is underscored by the success of Concerta (J & J), a novel formulation of methylphenidate designed to provide both rapid and sustained release, and Adderall XR (Shire), a QD formulation of mixed amphetamine salts.

The first nonstimulant therapy designed for ADHD, Strattera (atomoxetine, Lilly), was introduced in January 2003 and has rapidly gained acceptance. Atomoxetine is not a scheduled drug, has a low risk for abuse and dependency, has a nonstimulant side-effect profile (although sleep and growth disturbances are shared with stimulants), and is the first indicated product for adults with ADHD. Unlike stimulants, for example, atomoxetine lacks methylphenidate-like drug reinforcement properties in monkeys,77 leading to the conclusion of reduced likelihood for abuse potential in human patients. On the other hand, there is no consensus that patients with ADHD abuse prescribed stimulants.46 The efficacy of atomoxetine is not better, and perhaps less, than methylphenidate. In one clinical report,78 atomoxetine was reported to have better effects on inattentive symptoms compared to the hyperactive/impulsive symptoms consistent with the proposed role for norepinephrine in measures of distractibility. Atomoxetine use is associated with a number of adverse events that are an extension of its pharmacology (e.g., elevated blood pressure, urinary dysfunction), or to those of the primary metabolite (4-OH-atomoxetine) that shows modest affinity79 for several opioid receptors (e.g., constipation or other gastrointestinal disturbances).

Table 1 Comparison of the main agents currently used for the treatment of ADHD



Mechanism of action




Norepinephrine reuptake inhibitor

First non-controlled agent. Indicated for adults and children. Once or twice a day dosing allowed. Nausea and appetite suppression as major limitations. Sexual dysfunction is problematic for adults

Adderall XR


Amphetamine salts

Provides more sustained effects compared to unformulated MPH



MPH controlled release

1st QD MPH formulation. Clinical data demonstrate efficacy for ~ 12 h equivalent to MPH



MPH immediate release

Has 1-4-h duration of action. Multiple generics exist

Medadate CD


MPH controlled release

Combines immediate and sustained release like Concerta



Dexmethylphenidate MPH (d-isomer)

Lower dosing, longer duration and better side effect profile than MPH

Dexedrine SR



9-h duration. Subject to greater


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