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P S Y C H O P H A R M A C O L O G Y P E R S P E C T I V E S Review of ADHD Pharmacotherapies: Advantages, JOAN M. DAUGHTON, M.D., AND CHRISTOPHER J. KRATOCHVIL, M.D.
Pharmacotherapy for the treatment of attention-deficit/ hyperactivity disorder (ADHD) originally consisted Advantages: The stimulant medications have an primarily of stimulant medications in immediate-release extensive database supporting their safety, robust preparations dosed multiple times per day. Data dem- efficacy, and rapid onset of action. Studies of the onstrating the efficacy of these stimulant medications for stimulant medications have consistently shown that the treatment of ADHD and their role in treating approximately two of every three patients treated with children was well established by the 1970s. Multiple stimulants respond, with an effect size generally cited at formulations of the stimulant medications have subse- around 1.0.3 Their absorption is rapid, with clinical quently been developed during the past 40 years.
effects noticeable as early as 30 minutes after ingestion.
Recent studies, including the NIMH Collaborative Disadvantages: The shorter duration of action limits Multisite Multimodal Treatment Study of Children consistent efficacy as well as compliance because these With Attention-Deficit/Hyperactivity Disorder and medications must be taken two to three times daily.
the Preschool ADHD Treatment Study, have helpedto clarify the role of stimulant medications in the treatment of ADHD.1Y5 Significant data supporting • In medications containing only the methylphenidate the use of nonstimulant pharmacotherapy have also d-enantiomer (e.g., d-methylphenidate [Focalin]), a emerged in the last decade.1 This review summarizes 50% reduction in dose may be needed compared with the recent advances in ADHD treatment, providing methylphenidate products containing both the d- and advantages, disadvantages, and clinical pearls for the use l-isomers (methylphenidate [Ritalin]). Adderall con- tains d-amphetamine and l-amphetamine salts in theratio of 3:1; however, no recommendations are madefor converting the dosing of Adderall to a productcontaining only d-amphetamine (d-amphetamine Psychopharmacology Perspectives aims to discuss practical approaches to everyday issues in pediatric pharmacotherapy. The discussions may address aspects • One immediate-release methylphenidate product of clinical care related to psychopharmacology for which we do not have ade-quate applicable controlled trials, and includes discussions that are "off-label" (Methylin) is available as chewable tablets as well as from the perspective of the U.S. Food and Drug Administration. Although we an oral solution, for children who have difficulty fully appreciate that for virtually all disorders, medication is only one aspect of comprehensive care, this column focuses primarily on psychopharmacologicalmanagement. These are not meant to be practice guidelines, but rather examples • Growth should be regularly monitored during of the thought process that may go into pharmacotherapy decision making.
treatment with stimulants because data from several studies suggest that, as a group, consistently med- Drs. Daughton and Kratochvil are with the University of Nebraska Medical icated children have a temporary modest slowing in Correspondence to Joan Daughton, M.D., 985584 Nebraska Medical Center, growth rate while taking stimulant medication.1Y4,6 Omaha, NE 68198-5584; e-mail: [email protected].
• Blood pressure and heart rate should be monitored 0890-8567/09/4803-0240Ó2009 by the American Academy of Child and before and during stimulant treatment for every patient. In addition to an individual and family health J. AM. ACAD. CHIL D AD OLE SC. P SYCHIATRY, 48: 3, MARCH 2009 Copyright @ 2009 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
history, inquiries should be made regarding a history Advantages: The longer acting stimulants are equally of severe heart palpitations, fainting, exercise intoler- as efficacious as the short-acting stimulants and provide ance, chest pain, or family history of sudden death. A a longer effective response that limits the need for physical examination focused on signs of cardiovas- multiple daily doses. This also decreases the stigma of cular disease should be performed before initiating having to receive medications within the school setting.
Disadvantages: Because of their longer duration of • Consultation with a cardiologist is recommended if action, if side effects do emerge, they may extend later stimulants are considered a clinically necessary in- into the day. Cost is an important consideration when tervention in patients with cardiomyopathy, serious choosing a medication, and many of the extended- heart rhythm abnormalities, or other serious cardiac release medications are more expensive. A cost compar- problems because sudden death has been reported ison between all FDA-approved ADHD medications in patients with these conditions. The recent joint advisory of the American Academy of Pediatricsand the American Heart Association recommends obtaining an electrocardiogram as part of the eval-uation of patients with serious cardiac problems who • One of the differences between the various long- are being considered for ADHD pharmacotherapy.6 acting stimulant medications is the duration of action(Table 2), which can be helpful in tailoring treatment • Short-acting stimulants may be used as initial treat- • The long-acting stimulant medications require the ment in children weighing less than 16 kg, for whom same caution as short-acting stimulants in regard to sufficiently low doses do not exist in a long-acting • A short-acting medication can be useful as an additional treatment when used in conjunction with • The long-acting stimulant preparations are consid- a long-acting stimulant. For example, early afternoon ered first-line treatments for ADHD. Either the is often when a long-acting medication’s effects are methylphenidate or the amphetamine class may be starting to wear off, and a short-acting medication can used because they have equal efficacy and similar be given to resolve ADHD symptoms during home- work time or other after-school activities that requirefocus and concentration. Similarly, a short-acting medication can be given upon awakening to help Single-pulse sustained-release methylphenidate products include Ritalin SR, Metadate ER, and routine and allow the long-acting medication to be given before leaving for school to increase thelikelihood of its duration of action lasting throughout • These wax-matrix products must be swallowed whole • Inexpensive generic formulations of the immediate- to retain the long-acting properties.
release stimulants are available (Fig. 1).7 Table 1summarizes the short-acting methylphenidate and These bead-filled capsules generally contain half the dose as immediate-release beads and half as enteric-coated delayed-release beads. This mimics the use of two LONG-ACTING STIMULANT PREPARATIONS: PULSE, doses of immediate-release medication dosed 4 hours apart. Products using this general type of technology Table 2 summarizes the long-acting methylpheni- include Dexedrine Spansule, Ritalin LA, Focalin XR, date and amphetamine FDA-approved treatments for Adderall XR, and Metadate CD. Metadate CD is slightly different from the other beaded formulations in J. AM . ACAD . CHILD ADOLESC. PSYCH IAT RY, 48:3, MARCH 2 009 Copyright @ 2009 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
that 30% of the beads are immediately released, and applesauce, yogurt, or other soft foods. The beads The osmotic-release oral system methylphenidate • The beaded formulations may be helpful for children capsule (Concerta) uses an osmotic delivery system in who have difficulty swallowing pills because the which the tablet is coated with a 22% immediate-release capsules may be opened and the beads sprinkled into methylphenidate for initial dosing. The long-duration Fig. 1 Cost comparison of Food and Drug AdministrationYapproved medications for attention-deficit/hyperactivity disorder.
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component is delivered by an osmotic pump (osmotic- release oral system) that gradually releases methylphe- nidate producing an ascending serum concentration curve to approximate a three-times-daily dosingschedule.
• This capsule should not be opened or chewed.
• Clinicians should notify parents and youths that the capsule is passed through the gastrointestinal tract • Children with reduced gastrointestinal absorption or intestinal resections may not receive the full benefit from this medication because of decreased absorption The transdermal delivery system for methylphenidate (Daytrana) contains methylphenidate in a multipoly- meric adhesive layer attached to a transparent backing.
Methylphenidate is steadily absorbed after application of the patch, but levels do not peak until 7 to 9 hours later, with a noticeable reduction of symptoms by the end ofthe first 2 hours. Mild skin reactions to the patch are common, and insomnia is often reported when worn • The patch may be particularly useful for those who cannot swallow pills and are unable to tolerate the oral form or for those requiring more flexible duration • More methylphenidate is bioavailable because the drug does not go through first-pass metabolism.
• Although this methylphenidate preparation is re- commended to be worn for 9 hours, a recent study suggests that the duration of the effect on ADHD symptoms is related to the amount of time the patchis worn such that early removal of the patch allows for a controlled duration, ending approximately 2 to3 hours after the patch is removed.
Lisdexamfetamine dimesylate (Vyvanse) is a thera- peutically inactive prodrug in which d-amphetamine is pharmacologically activated after oral ingestion. Thismedication has been shown in two recent studies to be well tolerated, effective, and long-lasting (10 hours).
J. AM . ACAD . CHILD ADOLESC. PSYCH IAT RY, 48:3, MARCH 2 009 Copyright @ 2009 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
J. AM. ACAD. CHIL D AD OLE SC. P SYCHIATRY, 48: 3, MARCH 2009 Copyright @ 2009 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
about this risk, and patients should be monitored closely • It is hypothesized that this medication may be for suicidality during the first few months of treatment associated with diminished risk for abuse because of and during any dose changes. There is another bolded its decreased and/or delayed release after intravenous or FDA warning stating atomoxetine should be discon- intranasal administration and delayed blood level spike tinued if a patient develops jaundice or laboratory evi- after ingestion, decreasing any immediate effects.
dence of liver injury develops. Although no reports ofliver injury occurred during clinical trials with atomo- xetine, liver injury recurred on rechallenge in one One overall advantage of nonstimulant medications is patient and is likely a rare side effect of the drug.
the decreased substance abuse liability.
Studies show acute growth effects but limited long- term effects on growth parameters with atomoxetine.1Y3 Atomoxetine (Strattera) is a nonstimulant approved by the FDA for the treatment of ADHD (Table 3). It • Taking atomoxetine with food may help to avoid the works by blocking presynaptic uptake at noradrenergic common side effects of nausea or upset stomach.
neurons. Atomoxetine is well absorbed after oral ad- • Dosing may be started as a split dose or initially given ministration and is metabolized primarily through the near bedtime to diminish the effects of tiredness or cytochrome P450 2D6 (CYP2D6) pathway.
drowsiness, which is more apt to be present during Advantages: Possible advantages of atomoxetine over initiation and titration of the medication.
stimulants include a lower potential for abuse, long- • Doses of atomoxetine should initially be reduced if lasting therapeutic effects, and the fact that it is not a administered with agents that inhibit the cytochrome P450 2D6,(CYP2D6) enzyme, such as paroxetine or Disadvantages: The efficacy of atomoxetine seems fluoxetine, because of the potential for significant to be less than that of the stimulants. In one meta- increases in atomoxetine blood levels.
analysis,8 atomoxetine’s effect size was 0.62, in com- parison to 0.91 for immediate-release stimulants and0.95 for sustained-release stimulants. Furthermore, the • In general, atomoxetine is considered after trials of initial therapeutic effects of atomoxetine are gradual, methylphenidate and amphetamine have been inef- developing a peak efficacy during 2 to 6 weeks. Ato- moxetine holds a bolded warning for increased poten- • Atomoxetine may be first-line treatment in children tial for suicidal ideation, at a rate of 3.7 cases per 1,000 with a history of substance abuse or dependence and children compared with none in placebo-treated chil- with significant anxiety symptoms or based on family dren. Patients and their families should be educated FDA-Approved Nonstimulant ADHD Pharmacotherapy Note: ADHD = attention-deficit/hyperactivity disorder; FDA = Food and Drug Administration; q.d. = medication delivered once per day.
J. AM . ACAD . CHILD ADOLESC. PSYCH IAT RY, 48:3, MARCH 2 009 Copyright @ 2009 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
J. AM. ACAD. CHIL D AD OLE SC. P SYCHIATRY, 48: 3, MARCH 2009 Copyright @ 2009 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
See Table 4 for all nonYFDA-approved medications. See • An extended-release guanfacine preparation has Figure 2 for a cost comparison for all nonYFDA- recently received a letter of approvability by the FDA.
approved medications summarized below.
When to Use: Their current role in the treatment of ADHD is primarily as adjunctive medication in those Alpha Agonists (Not FDA Approved for ADHD) patients who do not respond to and/or those who Clonidine (Catapres) and guanfacine (Tenex) are cannot tolerate the FDA-approved treatments.
alpha agonists, which seem to stimulate inhibitory presynaptic autoreceptors in the central nervous system Bupropion (Wellbutrin, Wellbutrin SR, and Well- at lower doses. They have demonstrated use alone or butrin XL) is an antidepressant that acts via dopamine Advantages: The alpha agonists may be useful for core Advantages: Although its therapeutic effect seems to be symptoms of ADHD, as well as associated sleep and tic less than that of stimulants or atomoxetine, it does have demonstrated efficacy in the treatment of ADHD.3 Disadvantages: Their half-lives may necessitate multi- Disadvantages: Common side effects include ir- ple daily doses. Because of their antihypertensive proper- ritability, anorexia, insomnia, and, less commonly, ties, use of these medications may lead to hypotension development of tics. The risk for drug-induced and orthostasis. There have been several case reports of seizures increases 10-fold at dosages greater than unexpected sudden death in children taking the com- bination of clonidine and methylphenidate, although a controlled study of the combination of these twomedications found no evidence of cardiac toxicity.
• It is also approved for smoking cessation (Zyban).
• Clonidine is available in a patch, allowing once-daily • This is another medication that is primarily adjunc- tive treatment or after first-line treatments have failed.
Fig. 2 Cost comparison of nonYFood and Drug AdministrationYapproved medications.
J. AM . ACAD . CHILD ADOLESC. PSYCH IAT RY, 48:3, MARCH 2 009 Copyright @ 2009 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
• It may have a role in patients with co-occurring mood 2. Differences between long-acting stimulant prepara- disorders, substance abuse, or smoking.
tions that influence treatment planning include du-ration of action, cost, ability for children to swallow Modafinil (Provigil) is an antinarcoleptic stimulant 3. Nonstimulant medications are effective as primary as agent that is believed to produce a wakeful effect by well as adjunctive treatments for ADHD.
activating the cortex and may be useful for enhancing 4. NonYFDA-approved medications can be used effec- general arousal, attention, and motivation.
tively and safely as adjunctive treatments for ADHD Advantages: Modafinil demonstrated efficacy in three or when first-line treatments have failed.
double-blind placebo-controlled studies of ADHD in 5. Awareness of the various characteristics of each medication that has been studied in the treatment of Disadvantages: Commonly reported side effects in- ADHD allows for optimal care for each individual clude insomnia, decreased appetite, and headache. This medication was not approved by the FDA for thetreatment of ADHD because, at least in part, of safetyconcerns about a rare but serious rash (e.g., erythema Disclosure: Dr. Kratochvil receives research funding from NIMH multiforme) characteristic of Stevens-Johnson syn- Grant 5K23MH06612701A1. He receives grant support from Eli drome.1 Lastly, the cost of this medication often li- Lilly, McNeil, Shire, Abbott, Somerset, and Cephalon; is a consultantfor Eli Lilly, AstraZeneca, Abbott, and Pfizer. He is the editor of the Brown University Child & Adolescent Psychopharmacology Update, a member of the REACH Institute Primary Pediatric Psycho-pharmacology Steering Committee, a member of the American Profes- • Studies have shown increased efficacy doses in the sional Society for ADHD and Related Disorders Board of Directors,and on the CME Outfitters Professional Advisory Board. He receives study drugs for an NIMH-funded study from Eli Lilly. The otherauthor reports no conflicts of interest.
• This medication, if used at all, should be used with great caution because of the risk for Stevens-JohnsonYlike rash.
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