You can really break down the medication options for ADHD to stimulants or non-stimulants. In deciding what medication is best, prescribers consider side effects, whether it is appropriate to prescribe a controlled substance based on diversion or abuse potential, as well as practical issues such as how complicated the required dosing schedule is.

This review will provide you with a brief overview of current research, treatment options, and recommendations for safe and effective use.

Stimulants

The pharmacologic first-line treatment of ADHD is stimulant medication. Which one to choose is based on prescriber and patient preference. Stimulant agents are subdivided into methylphenidate—such as Ritalin, Concerta, Methylin, Metadate, and Daytrana—or amphetamine-based medications—such as Adderall, Dexedrine, and Vyvanse.

Methylphenidate (MPH) is available in both immediate release (IR) and extended release (ER) and is now also available in a transdermal patch.

Amphetamine salts are available in both IR and ER formulations and are also available as an oral liquid.
The side effects of both methylphenidate and amphetamines are similar. Up to 25% of patients have decreased appetite and gastrointestinal upset that may lead to weight loss. Many patients say this is most common at lunchtime so it is especially important for them to consume a nutritious breakfast and dinner.

Patients may experience insomnia and anxiety that usually lessen with a decreased dose, switching to a non-stimulant, or switching from an ER to an IR formulation. If insomnia persists, some patients can be prescribed short-term medication to treat it.

Data on height suppression indicate that children who used methylphenidate continuously for two years averaged a height gain that was two-fifths of an inch per year less than the children who did not take medication. The children who received medication for only part of the two-year period also had some height suppression, but not as much as the children who used the medication continuously (MTA Cooperative Group, Pediatrics 2004;113(4):762–769). A quantitative analysis of longitudinal studies found delays in height and weight, with evidence of a lessening of growth deficits over time (Faraone SV et al, J Am Acad Child Adolesc Psychiatry 2008;47(9):994–1009). The analysis also suggests that methylphenidate and amphetamine may result in a similar degree of growth deficits, and that these deficits may be dose-dependent. The extent to which growth outcome in adulthood is affected by long-term stimulant use is still unclear, although some data suggest that the deficits may lessen or disappear by adulthood.

Also somewhat unclear is the relationship between stimulant medication and tics. Although there are some data showing an increased likelihood of transient tics among ADHD patients treated with stimulants, research has yet to establish a “definitive and causal” relationship (Pidsosny IC and Virani A, J Can Acad Child Adolesc Psychiatry 2006;15(2):84–86).

All stimulant medications carry a warning about the risk of unexpected sudden death. However, the FDA issued a safety announcement in 2011 highlighting the results of a large study of children and young adults that did not show an association with stimulant treatment and adverse cardiovascular events. Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children, adolescents, and aging adults with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems (Cooper WO et al, N Engl J Med 2011;365(20):1896–1904); FDA safety announcement dated November 1, 2001 at http://1.usa.gov/11yeHvK).

Patients with pre-existing psychotic or anxiety disorders, tic disorders, and/or risk of substance abuse are also candidates for preferred use of non-stimulant medications.

Non-Stimulant Medications

Non-stimulant medications are recommended as second line agents when a patient has either failed a trial of adequate dose and duration of a stimulant agent, experienced an intolerable side effect, or is limited by medication contraindications (Clinical Pharmacology [Internet database]. Tampa, FL: Elsevier/Gold Standard. Updated periodically).

The non-stimulants approved by the FDA for ADHD are atomoxetine (Strattera), as monotherapy; and clonidine XR (Kapvay) and guanfacine XR (Intuniv), as both monotherapy and augmentation therapy with a primary stimulant.

Atomoxetine has become an increasingly popular choice for parents who prefer to not use a stimulant for their child. The most common side effects reported with use are gastrointestinal disturbances, dizziness, and insomnia. Most of these adverse effects can be managed easily by taking doses early in the day and with food. Patients with narrow angle glaucoma should not take atomoxetine, nor should any patient who is taking (or has taken within 14 days) a monoamine oxidase (MAO) inhibitor. There are also rare reported cases of hepatotoxicity (actual frequency of cases is unknown).

The alpha-2 adrenergic agonists approved for use in ADHD include the extended release formulations of guanfacine and clonidine. These agents are excellent choices for patients with tic disorders or insomnia that is unremitting with the use of alternative agents. The most common side effects for both of these agents include sedation, dizziness, and hypotension, which are seen more often at higher doses. The concurrent use of central nervous system depressants can result in additive effects.

Comparative Efficacy

A 2009 meta-analysis of 32 randomized control trials published after 1979, which included stimulant and non-stimulant agents in children, found that the effect size of both FDA-approved and unapproved non-stimulant ADHD medications (atomoxetine, clonidine, guanfacine ER and modafinil (Provigil), bupropion (Wellbutrin)) was significantly smaller compared to stimulant ADHD medications (amphetamine and methylphenidate). All medications, except for clonidine and bupropion, had an effect size that was significantly greater than placebo (although drawing conclusions about the effect of clonidine and bupropion is hampered by a relative paucity of data).

The effect sizes of immediate- and extended-release stimulants were not found to differ from each other. The author concludes that nonstimulants are less efficacious than either immediate-release or extended-release stimulants (Faraone SV, P T 2009;34(12):678–694).

A 2011 meta-analysis of seven randomized control trials (six to 10 weeks in term) that compared atomoxetine to methylphenidate in children six to 18 years-old showed atomoxetine was not inferior to methylphenidate after a minimum of six weeks of therapy. The study did not consider adverse effects or cost (Hazell PL et al, J Atten Disord 2011;15(8):674–683). All of the reviews in this study were supported by Eli Lilly, the manufacturer of atomoxetine. In addition, previous nonresponders to stimulants were excluded, limiting generalizability to patients one might treat in a clinical setting (in other words, those patients more likely to respond).

Finally, there is a lot of attention paid to the potential for abuse of stimulants. A recently published long-term study (up to eight years of follow-up data) found that use of stimulant medication for the treatment of ADHD did not protect from, or contribute to, visible risk of substance use or SUD by adolescence (Molina BS et al, J Am Acad Child Adolesc Psychiatry 2013;52(3):250–263).

TCRBH’s Take: There is strong evidence supporting the effectiveness of several medications for ADHD. There are also many concerns regarding side effects—and a lack of clarity about what some of those side effects are and how serious (or minor) they might be. Discussing these matters with patients (or with the parents of young patients) is an important part of a treatment process that can help build a collaborative clinician-patient relationship that encourages communication and cooperation.