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Symposium on Developmental and Behavioral Disorders - II

Pharmacologic Treatment of Attention-deficit


Hyperactivity Disorder
Donald E. Greydanus
Pediatrics and Human Development, Kalamazoo Center for Medical Studies, Kalamazoo, Michigan, USA

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

Attention-deficit hyperactivity disorder (ADHD) is noted


in 3% to 9% of children and adolescents, three times more
commonly in males than females. 1-10 The precise diagnosis
depends on which diagnostic criteria the clinician refers
to, and the reader is referred to the classification used by
the The International Classification of Diseases, 10th ed (ICD10)11 , World Health Organization (1993); the American
Psychiatric Associations Diagnostic and Statistical Manual
of Mental Disorders (DSM-IV-TR, 4th ed., 2000);12 and the
American Academy of Pediatrics The Classification of Child
and Adolescent Mental Diagnoses in Primary Care: Diagnostic
and Statistical Manual for Primary Care (DSM-PC): Child
and Adolescent Version.13
The DSM-IV-TR (2000) presents detailed lists of
symptoms and criteria for arriving at a diagnosis; the
DSM-PC is used in the United States in primary care
offices and is based on the DMR-IV-TR. 12,13 The ICD-10 is
typically used by insurance companies, provides
flexibility in the diagnosis, and identifies ADHD as
attention-deficit/hyperkinetic disorder. 11 Other ADHD
classifications may be used depending on the training and
location of the clinician in the world. The approach to
ADHD in this article is based on the concept that ADHD
is a neurobiological condition that involves the presence
of attention span dysfunction along with variable degrees
of hyperactivity and impulsivity. Table 1 lists criteria for
good and poor outcomes in youth with ADHD.
Children and adolescents who have problems with
attention and self-control may develop considerable

Correspondence and Reprint requests : Dr. Donald E. Greydanus,


Pediatrics and Human Development, Michigan State University,
Kalamazoo Center for Medical Studies Kalamazoo, Michigan, USA.

Indian Journal of Pediatrics, Volume 72November, 2005

TABLE 1. Prognostic Factors in ADHD


Good Prognosis
1. High intellectual functioning
2. Strong family supports
3. Good friends
4. Accepted by their peers
5. Nurtured by their teachers
Poor Prognosis
1. Low average to borderline intellectual functioning
2. Minimal family supports
3. Few friends
4. Not accepted by their peers
5. Not nurtured by their teachers
6. Have one or more comorbid psychiatric disorders

impairments in academic skills, social skills attainment,


and emotional/psychological stability. If the youth cannot
focus sufficiently in school to learn basic information for
success as a student, adolescent growth and development
may be impaired, complicating the ability to succeed in
adult life as well. Such individuals may not mature
appropriately in various important dimensions
intellectual, social, and emotional. Table 2 provides a list
of conditions that must be considered when a diagnosis of
ADHD arises. A careful assessment is necessary to be sure
TABLE 2. Differential Diagnosis for ADHD
Anxiety disorders (Generalized Anxiety Disorder, Separation
Anxiety)
Conduct disorder
Impulse-control disorders
Mental retardation
Mood disorders
Oppositional defiant disorder
Pervasive developmental disorders; Autism
Psychotic disorders: Schizophrenia or other dissociative disorders
Personality disorders: Avoidant personality disorder
Substance abuse: Cocaine phencyclidine, stimulants

953

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

assessment should look at presenting problems of the


child or the adolescent, differential diagnoses, and
potential co-morbid disorders. 1-3 A careful physical
examination is also important along with selective
laboratory tests based on findings from the medical
history and examination. Records from other providers
and teachers can also be very useful in the evaluation
process. The youth should be screened for depression,
anxiety disorders, and other mental health conditions.
The clinician should work with appropriate consultants in
psychology, psychiatry, neurology and other fields,
depending on the presenting findings.
PSYCHOLOGICAL MANAGEMENT

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

Various psychological treatments are available to the


trained clinician to improve ADHD in the adolescent, as
outlined in table 4.17-19 There is very little research support
for the efficacy of these psychological treatments except
for Cognitive Behavioral Therapy.2 In the United States,
most ADHD youths are treated with medication. It is the
recommendation of this author that youths receiving a
diagnosis of ADHD receive management involving both
psychological and psychopharmacological interventions
if possible. Critics of an approach only using medication
as treatment note that drugs result in positive changes in
only a few functional areas, side effects may be

TABLE 5. Medications Used in Attention Disorders


Medication

Daily dose schedule (mg/kg)

Common untoward effects

Methylphenidate

0.32.0 (1080 mg/day) in 24


divided doses

Magnesium pemoline

0.53.0 (37.5131.25 mg/day) in 12


divided doses
0.11.5 (580 mg/day) in 24
divided doses

Insomnia, decreased appetite, abdominal pain,


headache, depression, loss of weight, rebound
symptoms, decreased velocity vs growth delay;
see text
Same as MPH + possible liver toxicity (new FDA
black box warning)
Same as MPH but more depression

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

1543 g/kg (0.54.0 mg/day) in 12


divided doses
0.51.4 mg/kg/day in 12 divided doses

Sedation (very frequent), depression, dry mouth,


rebound hypertension, hypotension (rare),
confusion (with high doses), localized irritation
with transdermal preparation
Same as clonidine but much less sedation, less
hypotension
Decreased appetite, dyspepsia, dizziness, fatigue,
sedation, nausea emesis, mood swings, growth
delay

Source: Modified with permission from: Greydanus DE, Pratt HD et al. Psychopharmacology of ADHD in adolescents. Adolesc Med 2002;13:600.

954

Indian Journal of Pediatrics, Volume 72November, 2005

Pharmacologic Treatment of Attention-deficit Hyperactivity Disorder


TABLE 4. Psychological Management of ADHD in Children and
Adolescents
Psychotherapy
Cognitive-behavioral therapy (CBT)
Behavioral therapy (BT)
Psychosocial interventions
Support groups
Social skills training
Biofeedback training
Peer mediation to resolve interpersonal conflicts
Family therapy
Self management training

considerable in some youth placed on medications, and at


least 25% of ADHD youth do not improve with
psychopharmacology. 17,19 The rest of this article now
focuses on the use of medication to improve ADHD in
youth.

prescribed for patients with ADHD since its production


started in 1957.1-3 Its beneficial effect on attention span
dysfunction is based on selective binding of the
presynaptic dopamine transporter in the CNS striatal and
prefrontal areas, leading to rise in extracellular dopamine;
it also causes a blockade of the CNS norepinephrine
transporter in the norepinephrine system.27 MPH (Ritalin
and generic form as well) is taken orally with peak
pharmacologic action in 1-2 hours, disappearing in 4
hours, requiring another dose if attention span benefit is
desired. Beneficial effects of stimulant medication may
TABLE 6. Principles of Psychopharmacologic Management for
ADHD
1.

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.

Educate the patient and parents (family) about the purpose


of these medications; clarify the goals of medications
(improving concentration, decreasing impulsivity, others).
The clinician should avoid focusing only on medication in the
clinical encounter. This implies to families that medication
use alone should be the remedy to all problems. It further
implies that when things are not going well, the problem
must be with the choice or dose of medication. This shifts
responsibility for problems completely to the clinician who
must then urgently find the right medication.
Be sure the patient and parents understand that medications
are not curative.
Correct any myths about medication the family may have.
For example, medication will not correct family problems
(i.e., alcoholism in a parent, contentious custody battles).
Wait for the patient/family to approve of a trial medication
period before embarking on medication management. Do not
force medication on a child or adolescent.
Educate the patient/family about potential side effects of
medications and how you will deal with them; follow these
patients on a regular basis to monitor efficacy and adverse
effects.
Provide a thorough evaluation of the patient and family to
determine possible comorbidities that may benefit from other
medications.
Be supportive of other management tools (i.e.,
psychoeducation strategies, behavioral therapy).
Begin with a low dose and increase slowly until identified
target symptoms are sufficiently improved; stop the
medication(s) if side effects are unacceptable or upper
medication levels are reached without amelioration of target
symptoms.
Specific medications and doses may vary from patient to
patient and are identified by careful trial and error.
Medication(s) that are helpful may change as the child
emerges to adolescence and adulthood.
Adolescents may require a medication dose higher than
needed for adults because of increased renal clearance of
drugs, lower body fat percentage, increased liver metabolism,
or idiosyncratic medication metabolism.
Strive to achieve complete syndrome remission if feasible
(rather than settling for symptom improvement).
Share responsibility explicitly by clearly stating what issues
the family must work on, the school must work on, the child
or adolescent must work on, and the physician must work on.

Source: Modified with permission from: Greydanus DE, Pratt HD et


al. Attention-deficit/hyperactivity disorder in children and
adolescents: Interventions for a complex costly clinical conundrum.
Pediatr Clin North Am 2003; 50 : 10611062.

955

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

TABLE 8. Potential Side-effects of Methylphenidate


Headache*
Abdominal pain*
Jitteriness*
Dizziness
Anorexia*
Insomnia (delayed onset of sleep)*
Social withdrawal*
Weight loss (due to decreased appetite)*
Moodiness (irritability)
Nausea
Dry mouth
Constipation
Increase in heart rate, blood pressure, and palpitations
Unmasking of Tourette Syndrome (TS)
Appearance of being dazed or drugged; perseveration and
withdrawal
Rebound phenomenon
Increased hyperactivity
Appearance of psychosis or psychotic features
Personality change
Tolerance
Skin rash (rare)
*Commonly seen side effects
Source: Modified with permission from: Greydanus DE, Pratt HD et
al. Psychopharmacology of ADHD in adolescents. Adolesc Med
2002;13:607.

short-acting stimulants versus long-acting types (see


below under MPH preparations); if this occurs, look for
dehydration or blood pressure changes and treat as
necessary. Headaches may develop while taking
stimulants, sometimes related to peaking MPH plasma
levels, and sometimes related to drug withdrawal;
sometimes a different stimulant relieves the headache.
There is no indication that the use of stimulant medication
increases the risk of substance abuse in youth.
The phenomenon of delayed growth in children or
growing adolescents on stimulants remains controversial
and seems to be, in part, related to appetite suppression
with decreased nutrition; it appears to be a transient
effect, though more research in this area is on-going.1-3
Youth on stimulants who are not growing properly need
careful supervision. If the appetite is blunted while on
stimulants, a number of measures can be taken, including
taking food when the stimulant wears off (as in the
evening), using high-caloric foods, taking the patient off
stimulants when not in school (such as during vacation or
on weekends), and trying other stimulants or anti-ADHD
medications.
Tolerance may develop in some youth on high
stimulant dose and does not indicate any type of
addiction; management involves lowering the stimulant
dose or trying a different anti-ADHD drug. Rebound can
develop in which increased ADHD symptoms (as rage
episodes and irritability) develop as the stimulant effect
wears off, such as late morning or late afternoon for shortacting MPH or late afternoon for the long-acting MPH.
MPH may interfere with sleep and the addition of other
medications causing sedation may be beneficial, such as
Indian Journal of Pediatrics, Volume 72November, 2005

Pharmacologic Treatment of Attention-deficit Hyperactivity Disorder


bupropion, tricyclic antidepressants, alpha2 agonists (as
clonidine), mirtazepine, trazodone, or melatonin.
ADHD is found in 50% to 75% of patients with
Tourette Syndrome (TS) and TS may be officially
diagnosed in some children or adolescents after starting
stimulant drugs. Research does not suggest that stimulant
medications cause TS and the presence of tics is a relative
and not absolute contraindication to stimulant
medication. Youths with both ADHD and TS may be
given both stimulant medications (if effective) and anti-tic
medication (such as risperidone, haloperidol, or
pimozide). If the tics are worsened by the stimulant drugs,
other anti-ADHD medications may be tried that do not
typically worsen tics; these include alpha2 agonists (as
clonidine or guanfacine) or atomoxetine. Bupropion may
improve ADHD but worsens tics.

TABLE 10. Stimulants: Duration of Action

MPH Preparations

Source: Modified with permission from: Greydanus DE, Pratt HD et


al. Attention-deficit/hyperactivity disorder in children and
adolescents: Interventions for a complex costly clinical conundrum.
Pediatr Clin North Am 2003;50:1065.

Ritalin and genetic MPH have been very popular until


recently, when a number of longer acting MPH products
came to be developed. Ritalin-SR is a longer-acting
version of Ritalin, delivering 7 mg of MPH over several
hours. However, its absorption is erratic in half or more of
patients and it is produced only in a 20 mg form.
Pharmaceutical companies have developed a variety of
alternative MPH preparations over the past decade and
these are listed in table 9. There are no unbiased studies
available at this time to help a clinician and patient decide
which of these products are superior; and patients must
simply find out which product is best for them. 1-3 If a
patient has difficulty swallowing pills, some of the longeracting products can be opened and added to food; these
products include Ritalin LA and Metadate CD; longeracting amphetamine products that can be opened and
added to food include Dexedrine Spansule, and Adderall
TABLE 9. Available Methylphenidate Medications
Ritalin (MPH immediate-release; 5, 10, 20 mg tablets) (Novartis)
Ritalin-SR (20 mg MPH tablet, sustained-release) (Novartis)
Generic MPH (both immediate-release and sustained-release; tablet
options same as Ritalin) (Geneva)
Ritalin LA (Ritalin developed for 89 h duration; 20, 30, 40 mg
capsules) (Novartis)

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

XR. Table 10 shows the comparison of the relative


duration of action of these compounds. The reader is
referred to recent articles reviewing these newer MPH
preparations.2,9,10,23
Amphetamine Products
A well-known alternative to MPH is dextroamphetamine
(Dexedrine, Dextrostat) and it can be used if MPH is not
acceptable or helpful to the patient with ADHD; however,
the potential adverse effects of MPH are the same as MPH
(Table 8). 1-3 The beneficial effects of amphetamine on
ADHD date back to 1937. Dextroamphetamine is effective
for 3 to 6 hours and its mechanism of action includes
norepinephrine reuptake inhibition and selective binding
to the dopamine transporter with increased dopamine
release; weak effects on the serotonin system are also
noted. Amphetamine products that are available are listed
in table 11. Dextroamphetamine is taken 1 to 3 times a day
with gradual titration to 0.15 to 0.5 mg/kg/day, up to 40
to 50 mg a day. A generic version is also available.
TABLE 11. Available Amphetamine Stimulant Medications

Focalin (dexmethylphenidate [purifed D-methylphenidate] to last 4


6 h at half the usual dose; 2.5, 5, 10 mg tablets) (Novartis)

Dexedrine (dextroamphetamine tablets; short-acting)


(GlaxoSmithKline)
Dexedrine Spansule (long-acting dextroamphetamine)
(GlaxoSmithKline)
Dextroamphetamine generic (Barr)
Dextrostat (dextroamphetamine) (Shire US)
Adderall (mixed-salts amphetamine with extended-release) (Shire
US)
Adderall XR (mixed-salts amphetamine with extended-release)
(Shire US)
Desoxyn (methamphetamine) (Abbott)

Source: Modified with permission from: Greydanus DE, Pratt HD et


al. Attention-deficit/hyperactivity disorder in children and
adolescents: Interventions for a complex costly clinical conundrum.
Pediatr Clin North Am 2003; 50 : 1063.

Source: Modified with permission from: Greydanus DE, Pratt HD et


al. Attention-deficit/hyperactivity disorder in children and
adolescents: Interventions for a complex costly clinical conundrum.
Pediatr Clin North Am 2003; 50 : 1075.

Metadate ER (sustained-release [8 h] MPH; 20 mg tablets) (Celltech)


Methylin ER (sustained-release [8 h] MPH; 10, 20 mg tablets)
(Mallinckrodt)
Concerta (MPH HCl: extended-release tablets: 18, 36, 54 mg; up to 12
h MPH duration) (Alza-McNeil)
Metadate CD (MPH HCl: extended-release 20 mg capsules; 89 h of
MPH duration) (Celltech)

Indian Journal of Pediatrics, Volume 72November, 2005

957

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

TABLE 12. Side Effects of Clonidine


Sedation (50%)
Dry mouth
Headache
Attention impairment
Decreased glucose tolerance
Depression
Dermatitis (from the patch)
Dizziness
Dysphoria
Fatigue
Inconsistent effects
Irritability
Itchy eyes
Postural hypotension
Potentiation of neuroleptic anticholinergic side effects
Rebound phenomenon
Tolerance
Weight gain
Withdrawal effects (rebound tachycardia and severe hypertension
from sudden clonidine cessation)
Worsening of preexisting cardiac arrhythmias
Source: Modified with permission from: Greydanus DE, Pratt HD et
al. Psychopharmacology of ADHD in adolescents. Adolesc Med
2002;13:615.

patch application; changing the patch site and local


application of hydrocortisone usually resolves the local
dermatitis.
Guanfacine

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
958

Guanfacine (Tenex) is an alpha2A-adrenergic agonist


related to clonidine and also not proven to benefit the
attention span problems of ADHD. Its use may result in
less blood pressure problems and sedation than seen with
clonidine. Adverse reactions are similar to clonidine, but
there may be more agitation and headaches. Its daily
dosage range is 0.5 mg to 4.0 mg.
ANTIDEPRESSANTS
Tricyclic Antidepressants
Research studies reveal that tricyclic antidepressants
(TCAs) can be of help to patients with ADHD and is
usually listed as an alternative to stimulant medications if
stimulants are not of help or are contraindicated. Table 13
lists other indications for the use of TCAs. 1-3 These
TABLE 13. Indications for Tricyclic Antidepressants
ADHD
Aggression Disorders
Anxiety Disorders (as panic disorder or obsessive compulsive
disorder)
Depression
Enuresis
Insomnia
Migraine headaches
Tourette syndrome

Indian Journal of Pediatrics, Volume 72November, 2005

Pharmacologic Treatment of Attention-deficit Hyperactivity Disorder


medications include imipramine (Tofranil, others) 50200
mg/day, desipramine (Norpramin, Desipramine) 50200
mg/day, amitriptyline (Elavil) 50200 mg/day, and
nortriptyline (Pamelor) 20100 mg/day. Mechanism of
action includes blockage of norepinephrine and serotonin
reuptake and down regulation of beta-adrenergic
receptors.
Table 14 lists adverse effects of TCAs, including those
that are anticholinergic. Youth placed on TCAs should be
monitored on a periodic basis, with evaluations noting
vital signs, complete blood counts, serum levels of TCAs,
and EKGs; management plans are noted in the literature.29
Plasma TCAs levels correlate with toxity, but not with the
level of benefit. TCAs tend to cause less rebound effect
than stimulants, and tolerance may develop with TCAs.
Sedation can be severe and is worse with imipramine than
with desipramine or notriptyline. TCA-induced tremor
can be helped with careful reduction in TCA dose or
adding propranolol (10-40 mg per day), though this may
lead to depression in some patients.
If agitation develops as a result of the TCA, its dose
should be lowered or a benzodiazepine medication could
be added. Mania may develop if a TCA is added to
someone with latent bipolar disorder; also, psychosis may
develop if a TCA is added to someone with latent
schizophrenia. Rare cases of death are noted in children or
adolescents with TCAs, especially desipramine. Nausea,
emesis, fatigue, or worsening behavior may develop if the
TABLE 14.Tricyclic Antidepressant Side-effects
Blood dyscrasias
Blurred vision (including cycloplegia and mydriasis)
Cholestatic jaundice
Confusion
Constipation
Delirium (in high doses)
Dizziness
Drowsiness and sedation
Drug interactions (as with SSRIs)
Dry mouth (with decreased salivary flow and increased tooth decay)
ECG changes (sinus tachycardia, AV blocks, increased QRS interval,
increased QTc interval)
Exercise-induced tachycardia
Hypotension
Increase in heart rate (1015 bpm) and blood pressure (up to 810
mmHg)
Lowered seizure threshold
Peripheral neuropathy
Priapism
Respiratory failure and death from an overdose
Skin rash
Sudden death
Tachycardia
Tremor
Urinary retention
Weight gain
Source: Modified with permission from: Greydanus DE, Pratt HD et
al. Attention-deficit/hyperactivity disorder in children and
adolescents: Interventions for a complex costly clinical conundrum.
Pediatr Clin North Am 2003;50:1079.

Indian Journal of Pediatrics, Volume 72November, 2005

TCA is stopped too abruptly; this is called the


discontinuation syndrome. Care must be taken when
adding other medications to TCAs. For example, toxic
TCA levels may occur when combining TCAs with
selective serotonin reuptake inhibitors. The combination
of MPH and a TCA may lead to rising TCA levels as well.
Respiratory depression and death may develop after
combining alcohol and TCAs.
Bupropion
Bupropion (Wellbutrin) is an antidepressant medication
with noradrenergic/dopaminergic effects to improve
depression, reduce irritability, and ameliorate attention
dysfunction. 1-3 Venlafaxine (Effexor) is an atypical
antidepressant that is also used by some clinicians for
ADHD. Bupropion is given in a daily dosage range of 50300 mg (3.0 to 6.0 mg/kg/day) as Wellbutrin, 100-150 mg
twice daily as Wellbutrin-SR, and once a day as
Wellbutrin XL (150 mg or 300 mg). In an alternative
formulation of bupropion (Zyban), it is used to manage
tobacco addiction. Table 15 lists side effects of bupropion,
TABLE 15. Bupropion Side-effects
Anorexia
Agitation
Nausea
Restlessness
Drowsiness
Headache
Tics (exacerbation)
Seizures (0.1% under 300 mg/day and 0.4% over 300 mg/day)
TABLE 16. Atomoxetine Side-effects
Anorexia
Nausea
Emesis
Sedation
Fatigue
Dizziness
Mood swings
Dyspepsia
Growth delay
TABLE 17. Non-research-supported ADHD Treatment Options
Antiyeast medications
Chiropractic manipulation
Dietary manipulation
Electroencephalographic-biofeedback training
Herbal treatments
Megavitamin therapy
Sensory integrative training
Herbal products
Acetyl carnitine
DMAE (dimethylaminoethanol [Deaner])
Ginkgo
Phosphatidylserine (CNS phospholipid)
Essential fatty acids (gamma-linolenic acid, docosahexaenoic
acid)

959

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.
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