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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.
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.
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.
1. Beiderman J, Spencer TJ. Psychopharmacological interventions. Child
Adolesc Psychiatric Clin N Am. 2008;17:439Y458.
2. American Academy of Pediatrics Committee on Quality Improvement
and Subcommittee on Attention-Deficit/Hyperactivity Disorder. Treat-ment of attention deficit/hyperactivity disorder: overview of the evidence.
Pediatrics. 2005;115:e749Ye757 (doi:10.1542/peds.2004<2560).
3. Pliskz S. Practice parameter for the assessment and treatment of children
and adolescents with attention-deficit/hyperactivity disorder. J Am Acad
Child Adolesc Psychiatry. 2007;46:894Y921.
4. Faraone SP, Biederman J, Morley Christopher P et al. Effect of stimu-
lants on height and weight: a review of the literature. J Am Acad Child
http://www.nimh.nih.gov/health/publications/adhd/
Adolesc Psychiatry. 2008;47:994Y1009.
5. Hinshaw SP. Moderators and mediators of treatment outcome for youth
with ADHD: understanding for whom and how interventions work.
http://www.parentsmedguide.com/pmg_adhd.html
6. Towbin K. Paying attention to stimulants: height, weight, and car-
diovascular monitoring in clinical practice. J Am Acad Child Adolesc
http://www.massgeneral.org/schoolpsychiatry/screeningtools_
7. Red Book: Pharmacy_s Fundamental Reference. 2008 ed. Montvale, NJ:
8. Faraone SV, Spencer TJ, Aleadri M et al. Comparing the Efficacy of
Medications Used for ADHD Using Meta-Analysis. Paper Presented at
the 156th Annual Meeting of the American Psychiatric Association. SanFrancisco: May 2003.
9. Pelham WE Jr, Greenslade KE, Vodde-Hamilton M et al. Relative efficacy
1. Short-acting stimulant medications may be useful in
of long-acting stimulants on children with attention deficit-hyperactivity
lower weight children, in conjunction with a long-
disorder: a comparison of standard methylphenidate, sustained-releasemethylphenidate, sustained-release dextroamphetamine, and pemoline.
acting stimulant, and when cost is a limiting factor.
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.
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