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Abstract. Attention-deficit hyperactivity disorder (ADHD) is highly prevalent in children and adolescents. Highly effective
pharmacological treatments are available that allow the child and the adolescent to function at his/her full potential. Various
preparations of methylphenidate and amphetamines have been used for a long time in the treatment of ADHD. This article
reviews these and some of the newer drugs used in the treatment of ADHD, including atomoxetine and bupropion.
[Indian J Pediatr 2005; 72 (11) : 953-960] E-mail: Greydanus@kcms.msu.edu
Key words : Attention deficit hyperactivity disorder; Methylphenidate; Amphetamines; Atomoxetine; Bupropion
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Donald E. Greydanus
the core ADHD symptoms are not due to other mental
health disorders. Also, comorbid conditions may be
present and the youth can present with both ADHD and
additional diagnosis (Table 3). Psychiatric disorders may
be found in 44% of youth having ADHD; 32% have at
least two psychiatric disorders, and 11% have three or
more.14,15
TABLE 3. ADHD Comorbid Disorders
Table 2 disorders
Communication disorders
Reading disorders
Mathematic disorders
Written expression disorders
Tourettes disorder
Miscellaneous medical conditions
EVALUATION
ADHD diagnosis is based on careful assessments of the
functioning of the child or the adolescent in various
environments as school, home, and work (if
appropriate).7,8,16 Information is also helpful regarding
peer relations, family mental health history, family
conflict history, and history of psychological trauma in
the adolescent. There is no definitive test(s) for ADHD,
but a comprehensive evaluation is helpful, include
behavioral, psychological, and neurological testing. The
Methylphenidate
Magnesium pemoline
Stimulants
Dextroamphetamine
Antidepressants
Tricyclic antidepressants
Imipramine, desipramine
Nortriptyline
Bupropion
Alpha2-agonists
Clonidine
Guanfacine
Norepinephrine reuptake inhibitors
Atomoxetine
15
Anticholinergic effects, others. See text
15
0.53
36 (50300 mg/day) in 23 divided doses Insomnia, irritability, drug-induced seizures (with
doses >6 mg/kg): contraindicated in bulimic
patients
310 g/kg (0.050.4 mg/day) in 24
divided doses
Source: Modified with permission from: Greydanus DE, Pratt HD et al. Psychopharmacology of ADHD in adolescents. Adolesc Med 2002;13:600.
954
PSYCHOPHARMACOLOGIC MANAGEMENT
There is over 60 years of research noting that medication
can ameliorate ADHD symptoms in children, adolescents,
The
beneficial
role
of
and
adults. 1-3,20-25
psychopharmacology is due to its effects on the central
nervous system noradrenergic and dopaminergic
pathways. Table 5 lists the medications that have been
proven to benefit ADHD: stimulants, antidepressants, alpha2
agonists, and norepinephrine reuptake inhibitors. Principles of
ADHD psychopharmacology are listed in table 6.
Stimulant Medication
Hundreds of research studies on patients with ADHD
have noted the beneficial effects of stimulant medication
(methylphenidate, amphetamine, and pemoline (Table
5).1-3,20 Since the late 1930s, it has been seen that stimulants
improve attention span impairment, and sometimes,
hyperactivity and impulsivity. 1-3,20 Approximately 75% or
more of those with ADHD note some benefit, and the use
of medication has become a standard part of management
for these patients by many clinicians. The most
comprehensive study today was arranged by the National
Institute of Mental Health (NIHM) in the United States;
this research was named the NIMH Collaborative
Multisite Multimodal Treatment Study of Children with
Attention-Deficit/Hyperactivity Disorder (or the MTA
study).4-6, 26 It involved almost 600 children aged 7-9 years
of age and documented the efficacy of methylphenidate
(MPH) for these children above that of psychological
therapies; the second best management strategy was the
combination of MPH plus cognitive behavioral therapy.5,26
This discussion now considers methylphenidate (MPH),
amphetamine, and pemoline.
Methylphenidate
Methylphenidate (MPH) is the stimulant most commonly
Indian Journal of Pediatrics, Volume 72November, 2005
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
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Donald E. Greydanus
include enhanced concentration, reduced hyperarousal,
reduced impulsivity, reduced motor restlessness (ie., less
gross/fine motor movement and/or work performance),
and less aggressive and/or antisocial behavior.
A common method of prescription is to have the youth
take MPH in the early morning, noon, and, if necessary,
late afternoon.1-3 The youth and clinician can decide
together the schedule that works best for the patient. A
low dose (as 2.5 to 5 mg) can be started at first, with
gradual titration upwards, finding the optimal dose for
each individual patient. The dosage range is 0.3 to 2.0
mg/kg/day with single doses usually not exceeding 20
mg and daily doses not exceeding 60-80 mg. There is no
correlation between weight of the youth and optimal
MPH dose, and plasma levels of MPH are not useful. A
number of tools are used to verify effectiveness, such as
patient/family interviews, parent ratings, school grades
or reports, and others. Reasons for failure of MPH to be
effective are listed in table 7.
TABLE 7. Reasons for Failure of Methylphenidate
Inaccurate diagnosis
Comorbid disorders that overshadow the ADHD
Medication doses that are too high or not high enough
Medication is diverted to others in or outside the family
Intolerable medication side effects
Medication is used as a drug of abuse for its euphoric effects
Patient and/or family not accepting of medication
Patient does not respond to MPH but does to other stimulants or
alternative medications
Patient does not respond to medications of any kind
Source: Modified with permission from: Greydanus DE, Pratt HD et
al. Psychopharmacology of ADHD in adolescents. Adolesc Med 2002;
13 : 604.
Stimulant Side-effects
Stimulant (including MPH) side-effects are listed in table
8, some of which are transient, and can be reduced if the
patient starts with a low dose and slowly increases the
dosage to maximize benefit with reduced side effects. 1-3
Contraindications to MPH and stimulants include drug
dependence, uncontrolled hypertension, glaucoma,
symptomatic cardiovascular disorder, psychosis, and
hyperthyroidism; stimulants should not be combined
with monoamine oxidase inhibitors, because this mixture
may lead to a hypertensive crisis. Mixing a stimulant with
a tricyclic antidepressant may lead to sudden death from
cardiac arrhythmia in rare cases.28,29 MPH can interfere
with the metabolism of some anticonvulsant drugs, such
as ethosuximide, phenytoin, and phenobarbital. Stimulant
effectiveness can be reduced by mixing stimulants with
antihistamine drugs.
Nausea or emesis that may occur on stimulants often
improves if the medication is taken with meals. If the
cardiovascular system is normal, the mild rise in heart
rate and blood pressure noted with stimulants is not a
problem. Dizziness occurs in some patients, worse with
956
MPH Preparations
A.
B.
C.
Short-acting (36 h)
Ritalin (methylphenidate)
Methylin (methylphenidate)
Dexedrine
Dextrostat (dexedrine)
Focalin (isomer of methylphenidate)
Intermediate-acting (68 h)
Ritalin-SR
Methylin ER
Adderall (mixed salt of amphetamines)
Metadate ER
Once-daily (8+ h)
Dexedrine Spansules
Concerta (methylphenidate)
Adderall XR
Metadate CD
Ritalin LA
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Donald E. Greydanus
Dexedrine Spansule is given once a day and produces
anti-ADHD effects for 8 to 10 hours. Amphetamines may
induce more depression than MPH and the abuse
potential of amphetamine is well-known. Amphetamine
and MPH are not combined. Adderall and Adderall XR
are long-acting amphetamine products that last up to 10
and 12 hours respectively.
Pemoline
Pemoline (magnesium pemoline; Cylert) is a stimulant
medication taken once daily with a dosage range of 0.5 to
3.0 mg/kg/day, with a maximum dose of 112.5 to 131.25
mg per day. A movement disorder can be noted in some
patients on this medication. Chemical hepatitis develops
in approximately 3% after several months. In the United
States, the Federal Drug Administration (Washington,
DC) has given a black box warning for pemoline
because of rare irreversible liver failure that may occur.
Patients should be informed of this side-effect and have
their liver function tests closely monitored. Unfortunately,
even close monitoring cannot prevent death from liver
failure. Because of this problem, pemoline is now
uncommonly used as an anti-ADHD drug in the United
States. Its production in the U.S. has been stopped.
NON-STIMULANT MEDICATIONS
Alpha2 Agonists
Clonidine
Clonidine (Catapres) is a presynaptic, central-acting
alpha2-adrenergic agonist that is used by some clinicians
to manage ADHD symptoms, though it may take weeks
to months to achieve full benefit.1-3 Clonidine is used as an
alternative or adjunctive medication to MPH; it is often
given with MPH and works because its sedative
properties off-set the insomnic effect of MPH. Clonidine is
also used to manage Tourette Syndrome, post-traumatic
stress disorder, and severe aggressiveness with conduct
disorder or oppositional defiant disorder.
Table 12 lists potential adverse effects of clonidine and
its daily dose ranges from 0.05 to 0.4 mg/day; depending
on its use, clonidine is provided 2 to 4 times a day or only
at bedtime. Gradual build-up and withdrawal when
stopping are recommended. Rapid withdrawal may lead
to rebound hypertension. When prescribing this drug,
some baseline data (blood pressure, pulse, blood sugar,
electrocardiogram [EKG]); should be considered this data
should be followed on a regular basis, including a repeat
EKG every 6 months. Tolerance and liver function test
activation is also reported. A few deaths have been
reported in children and adolescents taking both MPH
and clonidine. Clonidine is also available as a patch
lasting 3 to 7 days; this patch may prevent sedation and/
or elevated blood pressure seen with the pill form. As
with any patch, dermatitis may occur at the site of the
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Donald E. Greydanus
including seizure activity0.1% under 300 mg a day and
0.4% over 300 mg a day. Bupropion is contraindicated if
youths have epilepsy or eating disorders (such as bulimia
nervosa). Risks for seizures are reduced if bupropion is not
taken under 8 hours apart, medication is slowly titrated
upward in dose, SR formulation is used, and high doses
of the regular formulation are not used. Drug-to-drug
interactions are minimal with bupropion and it does not
lead to cardiac conduction delays.
Atomoxetine
Atomoxetine (Strattera) is a nonstimulant currently listed
by the United States Federal Drug Administration as an
alternative anti-ADHD drug and is used in those not
wishing to take a stimulant or where stimulant or other
medications are not effective.1-3,9,30 Its actions include the
blockade of the presynaptic norepinephrine transporter in
the prefrontal cortex. It is started at 0.5 mg/kg/day and
gradually raised to 1.0 to 1.4 mg/kg/day to a maximum
of 100 mg per day given once or twice a day. Table 16 lists
potential adverse effects, including drug-to-drug
interactions involving selective serotonin reactive
inhibitors and others metabolized by cytochrome P450
2D6. Atomoxetine has a low affinity for various receptors,
such as alpha 1 -adrenergic, alpha 2-adrenergic,
serotonergic, cholinergic, and histaminic. There is no
increase in drug addiction, drug diversion, cardiovascular
complications, or tics. Table 17 lists treatment options
used by some clinicians but not proven to be of benefit for
children, adolescents, or adults with ADHD.
REFERENCES
1. Greydanus DE, Sloane MA, Rappley MD. Psychopharmacology of ADHD in adolescents. Adolesc Med 2002; 13 : 599-624.
2. Greydanus DE, Pratt HD, Sloane MA et al. Attention-deficit/
hyperactivity disorder in Children and adolescents:
Interventions for a complex costly clinical conundrum. Pediatr
Clin North Am 2003; 50 : 1049-1092.
3. Greydanus DE. Psychopharmacology of ADHD in
adolescents: Quo vadis? Psychiatr Times 2003; 20 : 5-9.
4. National Institute of Mental Health (NIMH). Attention Deficit
Hyperactivity Disorder. NIMH, NIH Publication No. 01-4589,
2001. Available at: http://www.nimh.nih.gov/publicat/
helpchild.cfm.
5. National Institute of Mental Health. NIMH Research on
Treatment for Attention Deficit Hyperactivity Disorder (ADHD):
The Multimodal Treatment StudyQuestions and Answers.
Washington, DC: NIMH, 2000. Available at: http://
www.nimh.nih.gov/events/mtaqa.cfm
6. National Institute of Health (NIH). Diagnosis and Treatment of
Attention Deficit Hyperactivity Disorder. NIH Consensus
Statement Online 1998: Nov 1618; [cited year, month, day];
16(2) : 1-37.
7. Pratt HD. Neurodevelopmental Issues in the assessment and
treatment of deficits in attention, cognition, and learning
during adolescence. Adolesc Med 2002; 13(3): 579-598.
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