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Year Medication
1990-1995 Increased prescription of stimulants
2000-present Oral ER MPH formulations introduced
2000 OROS MPH (Concerta)
2001 Mixed amphetamine salts (Adderall XR)
MPH MR (Metadate CD)
2002 Atomoxetine (Strattera)
SODAS MPH (Ritalin LA)
2005 d-MPH-XR (Focalin XR)
Future Transdermal MPH
Modafinil (Provigil)

Development of Pharmacologic Treatments for ADHD

Adapted from Wolraich and Doffing.[12]

Advances in Drug Delivery Systems for Attention-Deficit/Hyperactivity Disorder: US Food and Drug Administration (FDA)-Approved Stimulant and Nonstimulant Medications for ADHD


US Food and Drug Administration (FDA)-Approved Stimulant and Nonstimulant Medications for ADHD

Of the pharmacologic treatments for ADHD, methylphenidate (MPH) has been the most widely studied and used. A central nervous system stimulant, MPH exists as either a racemic mixture of d- and l-threo MPH or as d-threo MPH alone. Only the d-threo enantiomer is thought to have clinical benefit. Although both short-acting MPH and short-acting dextro-(D)-amphetamine and D,L-amphetamine have a rapid onset of action, these formulations may result in fluctuations in plasma levels that can affect efficacy and tolerability, in addition to adding the inconvenience of having to take multiple doses during the day.[12] Extended-release (ER) stimulant formulations now allow the potential for extended delivery with less variability throughout the day, improved tolerability, and less frequent administration, which in turn allows added convenience and possibly increased adherence. Controversies surrounding the use of all stimulants include the potential for growth suppression, the development of tics, diversion/misuse, and cardiovascular and psychiatric adverse events including suicidality.

OROS (osmotically controlled-release oral delivery system) MPH (Concerta) has a duration of effect of about 12 hours. After ingestion of OROS MPH, an immediate release of MPH occurs in the outer covering of the tablet, followed by a progressive 8-hour release through the action of the osmotic pump.[13,14] Absorption following a fatty meal is not affected by food, and the design of the tablet does not lend itself easily to abuse.

Diffucaps MPH (Metadate CD) has a biphasic release of MPH with 30% immediate release (IR) and 70% ER beads included in a capsule. It is designed to provide efficacy throughout the school day and does not necessarily extend coverage to the after-school hours.[15] The design produces higher plasma concentrations than OROS MPH over the first 6 hours, followed by a more rapid decline.[16] It can also be sprinkled over food.

SODAS (spheroidal oral drug absorption system) MPH (Ritalin LA) contains 50% IR beads and 50% ER beads covered by polymer overcoat. The first peak in its bimodal plasma concentration profile occurs after 1 to 3 hours, and the second peak is approximately 6 hours postdosage. SODAS MPH is also designed to be effective throughout the school day but not into the evening hours.

d-MPH-XR (Focalin XR) employs the SODAS release system. Each capsule contains 50% IR d-MPH beads and 50% ER d-MPH beads covered by a polymer overcoat that can be sprinkled on food. Its single-isomer technology uses only the active d-MPH stereoisomer (dexmethylphenidate). The clinical differences between d-MPH and d, l-MPH are not clear, and whether those differences result in a more effective, safer, and more tolerable profile has yet to be established.

The mixed amphetamine salts (MAS) XR (Adderall XR) capsule has a 50:50 ratio of IR and delayed-release beads. This once-daily formulation has a similar pharmacokinetic profile to that of IR Adderall given twice a day. Its long duration of action has proven benefit.

Atomoxetine (ATMX) (Strattera) is the only nonstimulant medication approved for use in children, adolescents, and adults with ADHD. It is a specific noradrenergic reuptake inhibitor; however, increased dopamine levels in the prefrontal cortex are also seen. It is unscheduled, renewable, and has little if any abuse liability. Rare reports of hepatitis and a slight increase in suicidal ideation without any completed suicides have been reported.[17,18]

Clinicians should take into account the following considerations when selecting a medication to treat ADHD. First, a thorough history can help guide the clinician, including a family history of medical issues such as heart disease (early myocardial infarction, sudden death) as well as ADHD and other mental health disorders such as bipolar disorder. Second, a detailed account of the child's core symptoms and associated symptoms, including temperamental, developmental, academic, and social adjustment symptoms, is needed. Third, the clinician's own clinical experience will certainly determine the choice of treatment to a large degree, and the family may express a preference as well. Fourth, factors such as efficacy, duration of action, potency, and drug absorption in the presence of food are important.[19] Finally, safety considerations are paramount.