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Joseph Biederman, Thomas Spencer, Timothy Wilens: Chapter 4. Attention-Deficit/Hyperactivity Disorder, in Gabbard’s
Treatments of Psychiatric Disorders, 4th Edition. Edited by Glen O. Gabbard. Copyright ©2009 American Psychiatric
Publishing, Inc. DOI: 10.1176/appi.books.9781585622986.250836. Printed 5/10/2009 from www.psychiatryonline.com
Gabbard’s Treatments of Psychiatric Disorders > Part I. Disorders Usually First Diagnosed in Infancy, Childhood, or
Adolescence >
Chapter 4. Attention-Deficit/Hyperactivity Disorder
INTRODUCTION
Attention-deficit/hyperactivity disorder (ADHD) is defined in DSM-IV-TR (American Psychiatric
Association 2000) as a behavioral disorder of childhood onset (by the age of 7 years) characterized
by symptoms of inattentiveness and impulsivity/hyperactivity. Based on the type of symptoms that
predominate, DSM-IV-TR recognizes a combined type in which both inattention and
hyperactivity/impulsivity symptoms are present, a predominantly inattentive subtype, and a
predominantly hyperactive/impulsive subtype. In addition, DSM-IV-TR also recognizes the category
of ADHD not otherwise specified (NOS) for individuals presenting with atypical features.
ADHD is one of the major clinical and public health problems in the United States in terms of
morbidity and disability in children and adolescents. It is estimated to affect at least 5% of
school-age children. Its impact on society is enormous in terms of financial cost, the stress to
families, the impact on schools, and the damaging effects on self-esteem.
PATHOPHYSIOLOGY OF ADHD
ADHD is a heterogeneous disorder of unknown etiology. An emerging neuropsychological and
neuroimaging literature suggests that abnormalities in frontal networks or frontostriatal
dysfunction is the disorder’s underlying neural substrate and that catecholamine dysregulation is
its underlying pathophysiological substrate. The pattern of neuropsychological deficits found in
ADHD children implicates executive functions and working memory; this pattern is similar to what
has been found among adults with frontal lobe damage, which suggests that the frontal cortex or
regions projecting to the frontal cortex are dysfunctional in at least some individuals with ADHD.
Early studies using magnetic resonance imaging (MRI) of the brain indicated subtle anomalies in
caudate and corpus callosum size and shape or possible reductions in the right frontal area in ADHD
(Castellanos et al. 1996). A recent large MRI study demonstrated smaller brain volumes that did
not normalize with maturity (Castellanos et al. 2002). These data are consistent with findings from
a positron emission tomography (PET) study that identified abnormalities of cerebral metabolism in
the prefrontal and premotor areas of the frontal lobe in ADHD adults who had children with ADHD
(Zametkin et al. 1990). Thus, the emerging neuroimaging literature points to abnormalities in
frontal networks in ADHD (frontostriatal dysfunction), and it is these networks that control
attention and motor intentional behavior. Zametkin postulated that “inhibitory influences of frontal
cortical activity, predominantly noradrenergic, acting on lower (striatal) structures are driven
by . . . dopamine agonists” (Zametkin and Rapoport 1987, p. 684). The fronto-subcortical pathways
are rich in catecholamines, and catecholamines also are implicated in ADHD because of the
mechanism of action of stimulants. Yet human studies of the catecholamine hypothesis of ADHD
have produced conflicting results, perhaps due to the insensitivity of peripheral measures.
Data from family genetic, twin, and adoption studies, as well as segregation analysis, suggest a
genetic origin for some forms of the disorder (Biederman et al. 1992). Although their results are
still tentative, molecular genetic studies suggest that some genes may increase the susceptibility to
ADHD: the D4 dopamine receptor gene, the dopamine transporter gene, and the D2 dopamine
receptor gene (Faraone 2000). Studies of environmental adversity have found associations with
pregnancy and delivery complications, marital distress, family dysfunction, and low social class
(Biederman et al. 1994; Milberger et al. 1997a).Print: Chapter 4. Attention-Deficit/Hyperactivity Disorder http://www.psychiatryonline.com/popup.aspx?aID=250840&print=yes…
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Data from follow-up studies indicate that children with ADHD are at risk for maintaining and
developing new psychiatric disorders in adolescence and adulthood, including antisocial and
substance use disorders (tobacco, alcohol, and drugs). Follow-up data also document that the
disorder persists into adulthood in a substantial number of children and that it may be a common
adult diagnosis (Spencer et al. 1998c).
ADULT ADHD
Although it was originally thought that individuals with ADHD inevitably outgrew the disorder,
converging evidence has revealed that the majority of children with ADHD continue to have
significant ADHD-associated impairment as adults. Because disruptive outward manifestations of
ADHD-like hyperactivity decrease with age, adult ADHD remained somewhat hidden and
underdiagnosed. However, with systematic investigation, adults have been shown to have the “look
and feel” of ADHD children. In addition, the subthreshold diagnosis in adults has been
demonstrated to correlate with considerable functional impairment. Like child ADHD, adult ADHD
runs in families and manifests neuropsychological deficits and neuroimaging abnormalities
consistent with the idea that catecholaminergic hypoactivity in frontal subcortical circuits underlies
the disorder. Notably, in both childhood and adulthood, ADHD symptoms respond favorably to drugs
that block either the dopamine transporter or the norepinephrine transporter.
PSYCHOPHARMACOLOGICAL TREATMENT OF ADHD
Stimulant Drugs
Stimulant drugs were the first class of compounds reported as being effective in treating the
behavioral disturbances that are evident in children with ADHD (Table 4–1). Stimulants are
sympathomimetic drugs structurally similar to endogenous catecholamines. The most commonly
used compounds in this class are methylphenidate (Ritalin), D-methylphenidate (Focalin),
D-amphetamine (Dexedrine), and a mixed amphetamine product (Adderall). These drugs have been
shown to enhance dopaminergic and noradrenergic neurotransmission (Bymaster et al. 2002;
Volkow et al. 2001). Because the various stimulants have somewhat different mechanisms of
action, some patients may respond preferentially to one or another agent (Greenhill et al. 1998).
Table 4–1. Stimulants used in the pharmacotherapy of attention-deficit/hyperactivity disorder
Drug Daily
dosage
(mg/kg)
Daily
dosage
schedule
Main indications Common adverse effects and
comments
First-generation stimulants
Dextroamphetamine
Dexedrine
0.3–1.0 Twice or
three times
ADHD
Mental retardation
+ ADHD
Insomnia, decreased appetite,
weight loss
Depression, psychosis (rare,
with very high doses)
Increase in heart rate and blood
pressure (mild)
Possible reduction in growth
velocity with long-term use
Withdrawal effects and rebound
phenomena
Mixed salts of levo- and
dextro-amphetamine
Adderall
0.5–1.5 Once or
twice
Adjunctive
treatment in
refractory
depression
Duration of behavioral effect: 6
hours
Methylphenidate
Ritalin
Methylin
1.0–2.0
1.0–2.0
Twice or
three times
ADHD Rare potential cardiovascular
risk with preexisting
cardiovascular abnormalitiesPrint: Chapter 4. Attention-Deficit/Hyperactivity Disorder http://www.psychiatryonline.com/popup.aspx?aID=250840&print=yes…
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Drug Daily
dosage
(mg/kg)
Daily
dosage
schedule
Main indications Common adverse effects and
comments
Focalin 0.5–1.0
Drug Daily
dosage
(mg/kg)
Daily
dosage
schedule
Duration of
behavioral effects
Comments
New long-acting stimulants
Methylphenidate
Concerta
Ritalin LA
Metadate CD
Focalin XR
1.0–2.0 Once or
twice
10–12 hours
8–9 hours
8–9 hours
10–12 hours
Ascending profile, OROS
osmotic technology
Capsules with
immediate-release (IR) and
delayed-release (DR) beads
50:50 ratio (IR:DR)
30:70 ratio (IR:DR)
50:50 ratio (IR:DR)
Mixed salts of levo- and
dextro-amphetamine
Adderall XR
0.5–1.5 Once or
twice
10–12 hours
Capsule with immediate-release
(IR) and delayed-release (DR)
beads
50:50 ratio (IR:DR)
Note. Doses are general guidelines. All doses must be individualized with appropriate monitoring.
Weight-corrected doses are less appropriate for obese children. ADHD = attention-deficit/hyperactivity
disorder.
Source. Adapted from Biederman J, Spencer T, Wilens T: “Evidence-Based Pharmacotherapy for Attention
Deficit Hyperactivity Disorder.” International Journal of Neuropsychopharmacology 7:77–97, 2004. Used with
the permission of Cambridge University Press.
Usual daily dosages range from 0.3 mg/kg/day to 2 mg/kg/day for methylphenidate and
approximately half that for amphetamine compounds (given that they are roughly twice as potent
as methylphenidate). Because of their short half-life, the short-acting stimulants (methylphenidate
and dextroamphetamine) are given in divided doses throughout the day, typically 4 hours apart.
The starting dosage is generally 2.5–5.0 mg/day, taken in the morning, with the dose being
increased as necessary every few days by 2.5–5.0 mg in a divided-dose schedule. Given the
anorexogenic effects of the stimulants, it may be beneficial to administer the medication after
meals. Similarly, Adderall (a mixed amphetamine salt), with its longer half-life, lasts throughout
most or all of the school day but for full coverage is typically given twice daily (such as 8:00 A.M.
and 2:00 P.M.) in dosages ranging from 1.0 to 1.5 mg/kg/day. Typically, stimulants have a rapid
onset of action, so that clinical response will be evident when a therapeutic dose has been
obtained.
An extensive literature has clearly documented the short-term efficacy of methylphenidate
treatment, mostly in latency-age white males (Spencer et al. 1997). A much more limited literature
exists for stimulants in children of other ages, in females, and in ethnic minorities. Despite small
numbers, the few studies of stimulants in adolescents have reported rates of response highly
consistent with those seen in latency-age children. By contrast, the few studies in preschoolers
appear to indicate that young children respond less well to stimulant therapy, suggesting that
ADHD in preschoolers may be more refractory to treatment. The literature clearly documents that
treatment with stimulants improves not only the abnormal behaviors of ADHD but also self-esteem
and cognitive, social, and family functioning, supporting the importance of treating ADHD patients
beyond school or work hours (including evenings, weekends, and vacations). Controlled clinical
trials, such as Spencer’s double-blind crossover comparison of methlyphenidate and placebo in
adults (Spencer et al. 1995; Wilens et al. 1999a), also have documented the efficacy ofPrint: Chapter 4. Attention-Deficit/Hyperactivity Disorder http://www.psychiatryonline.com/popup.aspx?aID=250840&print=yes…
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methylphenidate and amphetamine in adults with ADHD.
Treatment with stimulants improves a wide variety of cognitive abilities (Barkley 1977;
Gittelman-Klein 1987; Rapport et al. 1988; Wilson 2006) and increases school-based productivity
(Schachar and Tannock 1993). However, despite these beneficial cognitive effects, it is important to
be aware that patients with ADHD can manifest additional learning disabilities that are not
responsive to pharmacotherapy (Bergman et al. 1991; Faraone et al. (1993) but that may respond
to educational remediation.
The early concern that optimal clinical efficacy could be attained only at the cost of impaired
learning ability has not been confirmed (Gittelman-Klein 1987). In fact, the majority of studies
indicate that both behavior and cognitive performance improve with stimulant treatment in a
dose-dependent fashion (Douglas et al. 1988; Gittelman-Klein 1987; Kupietz et al. 1988; Pelham et
- 1985; Rapport et al. 1987, 1989a, 1989b; Tannock et al. 1989). The literature examining the
association between clinical benefits in ADHD and plasma levels of stimulants has been equivocal
and is complicated by large inter- and intraindividual variability in plasma levels at constant oral
doses (Gittelman-Klein 1987).
The most commonly reported side effects associated with stimulant medication are appetite
suppression and sleep disturbances. The sleep disturbance most often reported is delay of sleep
onset, which usually accompanies late-afternoon or early-evening administration of the stimulant
medications. Although less commonly reported, mood disturbances—ranging from increased
tearfulness to a full-blown major depression–like syndrome—can be associated with stimulant
treatment (Wilens and Biederman 1992). Other infrequent side effects include headaches,
abdominal discomfort, increased lethargy, and fatigue.
Adverse cardiovascular effects of stimulants have consistently been documented, including mild
increases in pulse and blood pressure of unclear clinical significance (Brown et al. 1984). Recent
concerns about cardiovascular safety led to the temporary removal of Adderall XR from the
Canadian market. The U.S. Food and Drug Administration (FDA) issued the following statement in
regard to this issue:
Health Canada, the Canadian drug regulatory agency, has suspended the sale of Adderall XR in the
Canadian market. . . . The Canadian action was based on U.S. postmarketing reports of sudden deaths in
pediatric patients . . . . When one considers the rate of sudden death in pediatric patients treated with
Adderall products based on the approximately 30 million prescriptions written between 1999 and 2003
(the period of time in which these deaths occurred), it does not appear that the number of deaths
reported is greater than the number of sudden deaths that would be expected to occur in this population
without treatment. For this reason, the FDA has decided not to take any further regulatory action at this
time. However, because it appeared that patients with underlying heart defects might be at increased risk
for sudden death, the labeling for Adderall XR was changed in August 2004 to include a warning that
these patients might be at particular risk, and that these patients should ordinarily not be treated with
Adderall products. (Available at: www.fda.gov/cder/drug/advisory/adderall.htm)
The Canadian health authorities have since reintroduced Adderall XR. Although at present there is
limited concern about the general cardiovascular safety of Adderall or other psychostimulants,
caution should be used in the treatment of patients with a family history of early cardiac death or
arrhythmias or a personal history of structural abnormalities, chest pain, palpitations, or fainting
episodes of unclear etiology either before or during treatment with this compound. In such cases,
consultation with a cardiologist is recommended. Although less of a clinical concern in pediatric
care, potential increases in blood pressure associated with stimulant drugs may be of greater
clinical significance in the treatment of adults with ADHD.
A stimulant-associated toxic psychosis has also been very rarely observed, usually in the context of
either a rapid rise in the dosage or a very high dosage. The reported psychosis in children in
response to stimulant medications resembles a toxic phenomenon (i.e., visual hallucinosis) and
differs from the exacerbation of psychotic symptoms present in schizophrenia. The development ofPrint: Chapter 4. Attention-Deficit/Hyperactivity Disorder http://www.psychiatryonline.com/popup.aspx?aID=250840&print=yes…
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psychotic symptoms in a child exposed to stimulants requires careful evaluation to rule out the
presence of a preexisting psychotic disorder.
Early reports indicated that children with a personal or family history of tic disorders were at
greater risk for developing a tic disorder when exposed to stimulants (Lowe et al. 1982). However,
other work has increasingly challenged this view (Comings and Comings 1988; Gadow et al. 1992,
1995). For example, in a controlled study of 34 children with ADHD and tics, Gadow et al. (1995)
reported that methylphenidate effectively suppressed ADHD symptoms with only a weak effect on
the frequency of tics. In addition, in a study of 128 boys with ADHD, Spencer et al. (1999) reported
no evidence of earlier onset, higher rates, or worsening of tics in the subgroup exposed to
stimulants. Although these findings are reassuring, it is clear that more information is needed in
larger numbers of subjects over longer periods of time to obtain closure on this issue. Until more is
known, it seems prudent to weigh risks and benefits in individual cases, with appropriate
discussion with the child and family about the benefits and pitfalls of the use of stimulants in
children with ADHD and tics.
Similar uncertainties remain about the abuse potential of stimulants in ADHD children. Despite
concerns that ADHD might increase the risk of abuse in adolescents and young adults (or their
associates), to date there is no clear evidence that stimulant-treated ADHD children abuse
prescribed medication when they are appropriately diagnosed and carefully monitored. Moreover,
the most commonly abused substance in adolescents and adults with ADHD has been shown to be
marijuana, not stimulants (Biederman et al. 1995b). Furthermore, an additional report provides
statistical evidence documenting that the use of stimulants and other pharmacological treatments
for ADHD significantly decreased the risk for subsequent substance use disorders in ADHD youth
(Biederman et al. 1999).
Although concerns remain about the effect of long-term administration of stimulants on growth, a
number of studies have begun to question this issue. Stimulants routinely produce anorexia and
weight loss; however, their effect on growth in height is much less certain. While initial reports
suggested a persistent stimulant-associated decrease in growth in height in children (Mattes and
Gittelman 1983; Safer et al. 1972), other reports have failed to substantiate this claim (Gross 1976;
Satterfield et al. 1979). Moreover, several studies showed that ultimate height appears to be
unaffected if stimulant treatment is discontinued in adolescence (Klein and Mannuzza 1988).
Another study suggested that deficits in growth in height may be transient maturational delays
associated with ADHD rather than stunting of growth in height in stimulant-treated ADHD children
(Spencer et al. 1998a). If confirmed, this finding would not support the common practice of drug
holidays in ADHD children. However, for children suspected of stimulant-associated growth deficits,
it would seem prudent to provide drug holidays or alternative treatment. This recommendation
should be carefully weighed against the risk for exacerbation of symptoms due to drug
discontinuation. A transient behavioral deterioration can occur upon abrupt discontinuation of
stimulant medications in some children. The prevalence and etiology of this phenomenon are
unclear. Rebound phenomena can also occur in some children between doses, creating an uneven,
often disturbing clinical course. In those cases, consideration should be given to alternative
treatments.
New-Generation Stimulants
A new generation of highly sophisticated, well-developed, safe, and effective long-acting
preparations of stimulant drugs has reached the market, revolutionizing the treatment of ADHD
(see Table 4–1). These compounds employ novel delivery systems to overcome acute tolerance,
termed “tachyphylaxis.” An analogue classroom paradigm has been used to test the fine-grained
pharmacodynamic and pharmacokinetic profiles of some of these medications. Developed by
Swanson et al. (2000), analogue classroom settings simulate the real-life demands and distractions
of a typical classroom. Hour-by-hour ratings are conducted by trained observers recording
frequency counts of behaviors as well as academic production and accuracy. Sequential serum
sampling from catheters allows correlation of medication blood levels with behavioral activity.Print: Chapter 4. Attention-Deficit/Hyperactivity Disorder http://www.psychiatryonline.com/popup.aspx?aID=250840&print=yes…
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Concerta
The first new-generation medication developed was Concerta, which uses an osmotic pump
mechanism to create an ascending profile of methylphenidate in the blood to provide effective
extended treatment. Concerta is available in 18-, 27-, 36-, and 54-mg tablets to approximate 5-,
7.5-, 10-, and 15-mg three-times-a-day dosing of immediate-release methylphenidate (MPH-IR). A
laboratory classroom study of 68 children found that a single morning dose of Concerta was
effective for 12 hours on social and on-task behaviors as well as academic performance (Pelham et
- 2001).
A large multicenter randomized clinical trial was used to determine the safety and efficacy of
Concerta in an outpatient setting (Wolraich et al. 2001). Two hundred and eighty-two children with
ADHD (ages 6–12 years) were randomized to placebo (n = 90), MPH-IR three times a day (n = 97),
or Concerta once a day (n = 95) in a double-blind 28-day trial. Children in the Concerta and MPH-IR
groups showed significantly greater reductions in core ADHD symptoms than did children on
placebo throughout the study. Concerta was well tolerated; there was mild appetite suppression but
no sleep abnormalities. A 1-year follow-up study of 407 children treated with Concerta found no
marked effects on weight, height, blood pressure, pulse, or tic exacerbation (Palumbo 2002;
Spencer 2002; Wilens et al. 2002).
Metadate CD
Metadate CD is a capsule with a mixture of immediate- and delayed-release beads containing
methylphenidate. In Metadate CD, 30% of the beads are immediate release and 70% delayed
release, designed to provide effective methylphenidate treatment for 8–9 hours. The efficacy and
safety of Metadate CD were tested in a multicenter randomized, double-blind, placebo-controlled
trial conducted at 32 sites and involving 316 children with ADHD. The trial consisted of a 1-week
single-blind placebo run-in followed by a 3-week double-blind titration and treatment period.
Improvement versus placebo was equally good morning and afternoon, as measured by teachers on
the Conners Global Index. The medication was well tolerated, with relatively low rates of decreased
appetite (9.7% vs. 2.5%) and insomnia (7.1% vs. 2.5%) in active-treatment versus placebo
groups. Metadate CD is available in 20-mg capsules to approximate 10-mg bid dosing of
methylphenidate IR (Greenhill et al. 2002). Recently, a study documented that the bioavailability
and tolerability of Metadate CD are not altered when the capsule is opened and the beads are
sprinkled on food (Pentikis et al. 2002).
Ritalin LA
A new extended-release form of Ritalin (Ritalin LA) has been developed to provide effective
methylphenidate treatment for 8 hours. Ritalin LA uses a bimodal release system, which produces
pharmacokinetic characteristics that, in single-dose administration, resemble those of two doses of
Ritalin tablets administered 4–5 hours apart. Ritalin LA consists of a mixture of immediate- and
delayed-release beads in a 50:50 ratio. The delayed-release beads are coated with an
absorption-delaying polymer. Ritalin LA is available in 20-, 30-, and 40-mg capsules to approximate
10-, 15-, and 20-mg bid dosing of MPH-IR. Ritalin LA may be used as a sprinkle preparation for
children unable to swallow pills. An initial analogue classroom study evaluated the
pharmacodynamic (efficacy) profile, safety, and tolerability of Ritalin LA (Spencer et al. 2000).
Single doses of all variants of Ritalin LA were effective relative to placebo in improving classroom
behavior and academic productivity over the 9-hour period after dosing. Ritalin LA had a rapid
onset of effect, and the improvement relative to placebo was statistically significant during both the
morning (0–4 hours after dosing) and the afternoon (4–9 hours after dosing) hours.
Ritalin LA was further tested in a multicenter double-blind trial of 160 children (Biederman et al.
2002b). There was an initial 2- to 4-week titration to optimal dose followed by a 1-week placebo
washout period. One hundred thirty-seven subjects with persistent ADHD symptoms during the
washout were randomized to Ritalin LA or placebo. Children on Ritalin LA were rated as greatly
improved over placebo by teachers and parents on the Conners ADHD DSM-IV Scale. ImprovementsPrint: Chapter 4. Attention-Deficit/Hyperactivity Disorder http://www.psychiatryonline.com/popup.aspx?aID=250840&print=yes…
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were equally robust on the Inattention and the Hyperactivity subscales. Significant drug-specific
improvement was also noted by clinicians on the Clinical Global Impression scale. Ritalin LA was
well tolerated, with minimal side effects. Rates of mild appetite suppression and mild insomnia
were both low (3.1%).
Adderall XR
Adderall XR is a capsule with a 50:50 ratio of immediate- to delayed-release beads designed to
release drug content in a time course similar to Adderall given bid (0 and 4 hours). Adderall XR is
available in 5-, 10-, 15-, 20-, 25-, and 30-mg capsules. An analogue classroom study compared
various doses of Adderall XR with Adderall bid and placebo (McCracken et al. 2000). Behavioral and
academic improvement were documented to 12 hours postdose. The efficacy and safety of Adderall
XR were further tested in a multicenter randomized, double-blind, placebo-controlled trial
conducted at 47 sites (Biederman et al. 2002a). Five hundred eighty-four children with ADHD were
randomized to receive single daily A.M. doses of placebo or Adderall XR 10 mg, 20 mg, or 30 mg for
3 weeks. Continuous significant improvement was noted in morning and afternoon assessments by
teachers and in morning, afternoon, and late-afternoon assessments by parents on the Conners
Global Index Scale for Teachers and Parents. All active-treatment groups showed significant
dose-related improvement in behavior from baseline. The medication was well tolerated, with rates
of adverse events similar for active treatments and placebo. A 1-year follow-up of 411 children on
Adderall XR examined long-term safety and efficacy (Chandler et al. 2002). Efficacy was maintained
for 12 months, as measured by the Conners Global Index. The medication was safe and well
tolerated, with a low frequency of mild adverse events and no evidence of untoward cardiovascular
effects.
Adderall XR has also been studied in adults with ADHD (Weisler et al. 2004) in a 6-week
randomized, double-blind, placebo-controlled forced-titration study of fixed preassigned doses (20,
40, or 60 mg) of Adderall XR. Significant reductions in ADHD Rating Scale (ADHD-RS) scores were
observed for all doses. Rates and severity of side effects were consistent with those seen with
Adderall in children. As a result of this study, the FDA approved Adderall XR (up to 20 mg/day) for
the treatment of ADHD in adults. In addition, a 12-month open-label extension reported that
Adderall XR remained efficacious in the treatment of adults with ADHD over 12 months (Biederman
et al. 2005a).
Focalin
Methylphenidate as a secondary amine gives rise to four optical isomers: D-threo, L-threo,
D-erythro, and L-erythro. There is stereoselectivity in receptor-site binding and its relationship to
response. The standard preparation is composed of the threo,D,L racemate, as it appears to be the
central nervous system (CNS) active form. Moreover, recent data suggest that the
D-methylphenidate isomer is the active form. In a PET study, D-threo methylphenidate was found to
bind specifically to the basal ganglia, which are rich in dopamine transporter receptors, whereas
L-threo methylphenidate was widely distributed with only nonspecific binding (Ding et al. 1995).
This finding has led to the development of a purified D-threo methylphenidate compound, Focalin.
Studies have documented similar pharmacokinetic profiles for D-threo methylphenidate and
D,L-threo methylphenidate when given in equimolar doses. Thus, the time to maximum
concentration (Tmax), the maximum concentration (Cmax), and the half-life (t½) were the same for
D-threo and D,L-threo methylphenidate.
The efficacy of Focalin was established in two controlled studies. In the first trial, 132 children and
adolescents were randomized to receive D-threo methylphenidate, D,L-threo methylphenidate, or
placebo at 8 A.M. and noon for 4 weeks. At week 4, teacher ratings on the Swanson, Nolan, and
Pelham (SNAP) ADHD Scale revealed robust improvement for both active treatments. The average
improvement from baseline was equivalent to one standard deviation on the SNAP rating scale, a
magnitude of change that is clinically important. Parent ratings on the SNAP revealed superiority of
both treatments to placebo 3 hours after dosing, but only superiority of D-methylphenidate (notPrint: Chapter 4. Attention-Deficit/Hyperactivity Disorder http://www.psychiatryonline.com/popup.aspx?aID=250840&print=yes…
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D,L-methylphenidate) 6 hours after dosing (C. K. Conners et al. 2001). In a second controlled study,
investigators tested the specificity of response to D-threo methylphenidate (West et al. 2002). One
hundred sixteen patients were treated openly with D-threo methylphenidate to determine the
optimal dosage. At the end of 6 weeks, 75 responders were randomized to blinded treatment with
D-threo methylphenidate or placebo over 2 weeks. Subjects randomized to placebo had a high rate
(62%) of relapse compared with those who continued on D-threo methylphenidate (17%). In
addition, the parent SNAP ratings indicated that effects of D-threo methylphenidate persisted 6
hours after dosing. In both studies, adverse effects seen with D-threo methylphenidate were
consistent with those seen with D,L-threo methylphenidate. These studies have shown Focalin to be
as effective as the racemate at half the dosage. Focalin is available in 2.5-, 5.0-, and 10.0-mg
tablets to approximate 5-, 10-, and 20-mg doses of D,L-methylphenidate.
A new extended-release form of Focalin (Focalin XR) has been developed to provide effective
methylphenidate treatment for 10–12 hours. Focalin XR uses the same bimodal release system as
Ritalin LA, producing pharmacokinetic characteristics that, in single-dose administration, resemble
those of two doses of Focalin administered 4–5 hours apart. Similarly, Focalin XR consists of a
mixture of immediate- and delayed-release beads in a 50:50 ratio. The delayed-release beads are
coated with an absorption-delaying polymer. Focalin XR is available in 5-, 10-, and 20-mg capsules.
Focalin XR has been found to be effective in children, adolescents, and adults and is FDA-approved
in all three age groups.
Focalin XR was tested in a multicenter randomized, double-blind study of 103 patients ages 6–17
years (Greenhill et al. 2005). Participants were flexibly dosed to receive 5- to 30-mg capsules or
placebo once daily for 7 weeks. Dosages were gradually increased to optimal levels during the first
5 weeks and were maintained for the final 2 weeks. Efficacy was evaluated weekly at school and at
home using the Conners ADHD DSM-IV Scale. Drug-specific improvement was documented on each
scale. At the final visit, 67.3% of patients receiving Focalin XR and 13.3% receiving placebo were
rated as “very much improved” or “much improved” on the Clinical Global Impression Improvement
scale (CGI-I) (P < 0.001). Focalin XR was well tolerated, with adverse-event rates similar to those
reported with immediate-release D-methylphenidate.
Focalin XR was also evaluated in a multicenter randomized, double-blind, placebo-controlled study
in adults with ADHD (Spencer et al. 2004). Randomized adults with ADHD (n = 221) received
preassigned doses of Focalin XR (20 mg, 30 mg, or 40 mg) or placebo for 5 weeks. All Focalin XR
dosages were significantly superior to placebo in demonstrating improvement on Conners ADHD
DSM-IV Scale total scores as well as on the Inattentive and Hyperactive–Impulsive subscales.
Safety and tolerability were similar to those of racemic methylphenidate in adults and
D-methylphenidate in children. Whereas this study tested a number of doses, the highest
FDA-approved dose is currently 20 mg.
Nonstimulants
Although there is no doubt that the stimulants are effective in the treatment of ADHD, it is
estimated that at least 30% of affected individuals do not adequately respond to or cannot tolerate
stimulant treatment (Barkley 1977; Gittelman 1980; Spencer et al. 1996). In addition, stimulants
are short-acting drugs that require multiple administrations during the day, with an attendant
impact on compliance and need to take treatment during school or work hours. Although this
problem may be offset by the development of an effective long-acting stimulant, this class of drugs
often adversely affects sleep, which means that medication use during the evening hours—a period
when children and adults still need the ability to concentrate so that they can deal with daily
demands and interact with family members and friends—is problematic. In addition to these
problems, the fact that stimulants are controlled substances continues to fuel worries in children,
families, and the treating community that further inhibit these agents’ use. These fears are based
on lingering concerns about the abuse potential of stimulant drugs by the child, a family member,
or his or her associates; the possibility of diversion; and safety concerns regarding the use of a
controlled substance by patients who are impulsive and frequently have antisocial tendenciesPrint: Chapter 4. Attention-Deficit/Hyperactivity Disorder http://www.psychiatryonline.com/popup.aspx?aID=250840&print=yes…
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(Goldman et al. 1998). Similarly, the controlled nature of stimulant drugs poses important
medicolegal concerns for the treating community that further increase barriers to treatment.
Apart from the psychostimulants, noradrenergic- and dopaminergic-active compounds—including
secondary-amine tricyclic antidepressants (TCAs) (Biederman et al. 1989; Donnelly et al. 1986;
Wilens et al. (1993), monoamine oxidase inhibitors (MAOIs) (Zametkin et al. 1985), bupropion
(Barrickman et al. 1995; Casat et al. 1989; C. K. Conners et al. 1996), and atomoxetine (Spencer et
- 2002b)—have been found to be superior to placebo in controlled clinical trials (Table 4–2).
Possible advantages of these compounds over stimulants include a longer duration of action
without symptom rebound or insomnia, greater flexibility in dosage, the option of monitoring
plasma drug levels (for tricyclic antidepressants), minimal risk of abuse or dependence, and the
potential for treating comorbid internalizing symptoms and tics. Although one open case series
reported beneficial effects for the selective serotonin reuptake inhibitor (SSRI) fluoxetine in the
treatment of ADHD (Barrickman et al. 1991), there is little clinical or scientific evidence implicating
serotonergic systems in the pathophysiology of ADHD.
Table 4–2. Nonstimulant agents used in the pharmacotherapy of attention-deficit/hyperactivity
disorder
Drug Daily dosage
(mg/kg)
Daily
dosage
schedule
Main indications Common adverse effects and
comments
Noradrenergic-specific reuptake inhibitor (NSRI)
Atomoxetine 0.5–1.4 Once or
twice
ADHD ± comorbidity
?Enuresis
?Tic disorder
?Depression
?Anxiety disorders
Mechanism of action:
noradrenergic-specific reuptake
inhibitor
Mild/moderate appetite decrease
Gastrointestinal symptoms
Mild initial weight loss
Cardiovascular (mild increase)
blood pressure, pulse
No ECG conduction or
repolarization delays
Not abusable
Rare serious hepatotoxicity
Tricyclic antidepressants (TCAs)
Tertiary amines
Imipramine
Amitriptyline
Clomipramine
Secondary
amines
Desipramine
Nortriptyline
2.0–5.0
(1.0–3.0 for
nortriptyline)
Dosage adjusted
according to
serum levels
(therapeutic
window for
nortriptyline)
Once or
twice
ADHD
Enuresis
Tic disorder
?Anxiety disorders
OCD (clomipramine)
Mixed mechanism of action
(noradrenergic–serotonergic)
Secondary amines more
noradrenergic
Clomipramine primarily
serotonergic
Narrow therapeutic index
Overdoses can be fatal
Anticholinergic (dry mouth,
constipation, blurred vision)
Weight loss
Cardiovascular (mild increase)
diastolic blood pressure and ECG
conduction parameters with daily
dosages >3.5 mg/kg
Treatment requires serum levels
and ECG monitoringPrint: Chapter 4. Attention-Deficit/Hyperactivity Disorder http://www.psychiatryonline.com/popup.aspx?aID=250840&print=yes…
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Drug Daily dosage
(mg/kg)
Daily
dosage
schedule
Main indications Common adverse effects and
comments
No known long-term side effects
Withdrawal effects can occur
(severe gastrointestinal symptoms,
malaise)
Risk of seizures
Monoamine oxidase inhibitor (MAOI) antidepressants
Phenelzine
Tranylcypromine
Selegiline
0.5–1.0
0.2–0.4
Twice or
three
times
Atypical depression
Treatment-refractory
depression
Difficult medicines to use in
juveniles
Reserved for refractory cases
Severe dietary restrictions
(high-tyramine foods)
Drug–drug interactions
Hypertensive crisis with dietetic
transgression or with certain drugs
Weight gain
Drowsiness
Changes in blood pressure
Insomnia
Liver toxicity (remote risk)
Norepinephrine-dopamine reuptake inhibitor (NDRI) antidepressant
Bupropion (SR)
Bupropion (XR)
3–6
3–6
Twice
Once
ADHD
Major depressive
disorder
Smoking cessation
?Anti-craving effects
?Bipolar depression
Mixed mechanism of action
(dopaminergic–noradrenergic)
Irritability
Insomnia
Drug-induced seizures (at doses >
6 mg/kg)
Contraindicated in bulimic patients
Selective serotonin reuptake inhibitor (SSRI) antidepressants
Fluoxetine
Paroxetine
Citalopram
Sertraline
Fluvoxamine
0.3–0.9
1.5–3.0
1.5–4.5
Once (in
the A.M.)
Major depression,
dysthymia
OCD
Anxiety disorders
Eating disorders
?PTSD
Mechanism of action is
serotonergic
Large margin of safety
No cardiovascular effects
Irritability
Insomnia
Gastrointestinal symptoms
Headaches
Sexual dysfunction
Withdrawal symptoms more
common in short-acting
Potential drug–drug interactions
(cytochrome P450)
Serotonin–norepinephrine reuptake inhibitor (SNRI) antidepressant
Venlafaxine (XR) 1–3 Once Major depressive
disorder
Anxiety disorders
?ADHD
?OCD
Mixed mechanism of action
(serotonergic–noradrenergic)
Similar to SSRIs
Irritability
InsomniaPrint: Chapter 4. Attention-Deficit/Hyperactivity Disorder http://www.psychiatryonline.com/popup.aspx?aID=250840&print=yes…
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Drug Daily dosage
(mg/kg)
Daily
dosage
schedule
Main indications Common adverse effects and
comments
Gastrointestinal symptoms
Headaches
Potential withdrawal symptoms
Blood pressure changes
Noradrenergic and specific serotonergic antidepressant
Mirtazapine 0.2–0.9 Once (in
the P.M.)
Major depressive
disorder
Anxiety disorders
?Stimulant-induced
insomnia
?Bipolar depression
Mixed mechanism of action
(serotonergic–noradrenergic)
Sedation
Weight gain
Dizziness
?Less manicogenic
Noradrenergic modulators
Alpha-2 agonists
Clonidine
Guanfacine
0.003–0.010
0.015–0.05
Twice or
three
times
Once or
twice
Tourette’s disorder
ADHD
Aggression/self abuse
Severe agitation
Withdrawal syndromes
Sedation (very frequent)
Hypotension (rare)
Dry mouth
Confusion (with high dose)
Depression
Rebound hypertension
Localized irritation with
transdermal preparation
Same as clonidine
Less sedation, hypotension
Noradrenergic modulators
Beta-blockers
Propranolol
1–7
Twice
Aggression/self abuse
Severe agitation
Akathisia
Sedation
Depression
Risk for bradycardia and
hypotension (dose dependent) and
rebound hypertension
Bronchospasm (contraindicated in
asthmatic patients)
Rebound hypertension on abrupt
withdrawal
Other compounds
Modafinil 0.3–1.0 Once (in
the A.M.)
Narcolepsy, obstructive
sleep apnea/hypoapnea
syndrome, shift work
sleep disorder
Insomnia, headache, decreased
appetite
Limited abuse liability
Note. Doses are general guidelines. All doses must be individualized with appropriate monitoring.
Weight-corrected doses are less appropriate for obese children. ADHD = attention-deficit/hyperactivity
disorder; ECG = electrocardiogram; OCD = obsessive-compulsive disorder; PTSD = posttraumatic stress
disorder.
Source. Adapted from Biederman J, Spencer T, Wilens T: “Evidence-Based Pharmacotherapy for Attention
Deficit Hyperactivity Disorder.” International Journal of Neuropsychopharmacology 7:77–97, 2004. Used withPrint: Chapter 4. Attention-Deficit/Hyperactivity Disorder http://www.psychiatryonline.com/popup.aspx?aID=250840&print=yes…
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the permission of Cambridge University Press.
Antidepressants
Tricyclic Antidepressants
Historically, the first nonstimulant treatments for ADHD that were extensively evaluated were the
TCAs (see Table 4–2). Out of 33 studies (21 controlled, 12 open) evaluating TCAs in children,
adolescents (n = 1,139), and adults (n = 78), 91% reported positive effects on ADHD symptoms
(Spencer et al. 1997). Imipramine and desipramine are the most studied TCAs, followed by a
handful of studies on other TCAs. Although most TCA studies (73%) were relatively brief, lasting a
few weeks to several months, nine studies (27%) reported enduring effects for up to 2 years.
Outcomes in both short- and long-term studies were equally positive. Although one study (Quinn
and Rapoport 1975) reported a 50% dropout rate after 1 year, it is noteworthy that among
participants who remained on imipramine, improvement was sustained. Other studies using
aggressive doses of TCAs have reported sustained improvement for up to 1 year with desipramine
(>4 mg/kg) (Biederman et al. 1986; Gastfriend et al. 1985) and nortriptyline (2.0 mg/kg) (Wilens
et al. 1993). Although response was equally positive at all dosage ranges, it was more sustained in
those studies that used higher doses. A high interindividual variability in TCA serum levels has been
consistently reported for imipramine and desipramine, with little relationship between serum level
and daily dosage, response, or side effects. By contrast, nortriptyline appears to have a positive
association between dosage and serum level (Wilens et al. 1993).
In the largest controlled study of a TCA in children, our group reported favorable results with
desipramine in 62 clinically referred ADHD children, most of whom had previously failed to respond
to psychostimulant treatment (Biederman et al. 1989). The study was a randomized,
placebo-controlled, parallel-design 6-week clinical trial. Clinically and statistically significant
differences in behavioral improvement were found for desipramine over placebo, at an average
daily dosage of 5 mg/kg. Although the presence of comorbidity increased the likelihood of a
placebo response, neither comorbidity with conduct disorder, depression, or anxiety nor a family
history of ADHD yielded differential responses to desipramine treatment. In addition,
desipramine-treated ADHD patients showed a substantial reduction in depressive symptoms
compared with placebo-treated patients. Similar results were observed in a similarly designed
controlled clinical trial of desipramine in 41 adults with ADHD (Wilens et al. 1996b). Desipramine,
at an average daily dosage of 150 mg (average serum level: 113 ng/mL), was statistically and
clinically more effective than placebo. Sixty-eight percent of desipramine-treated patients
responded, compared with none of the placebo-treated patients (P < 0.0001). Moreover, at the end
of the study, the average severity of ADHD symptoms was reduced to below the level required to
meet diagnostic criteria in patients receiving desipramine. Importantly, although the full
desipramine dose was achieved at week 2, clinical response improved further over the following 4
weeks, indicating a latency of response. Response was independent of dose, serum desipramine
level, gender, or lifetime psychiatric comorbidity with anxiety or depressive disorders.
In a prospective placebo-controlled discontinuation trial, we demonstrated the efficacy of
nortriptyline at dosages up to 2 mg/kg daily in 35 school-age youth with ADHD (Prince et al. 1999).
In this study, 80% of youth responded by week 6 in the open phase. During the discontinuation
phase, subjects randomized to placebo lost the anti-ADHD effect, whereas those receiving
nortriptyline maintained a robust anti-ADHD effect. ADHD youth receiving nortriptyline also were
found to have more modest but statistically significant reductions in oppositionality and anxiety.
Nortriptyline was well tolerated, with some weight gain. Weight gain is frequently considered to be
a desirable side effect in this population. By contrast, a systematic study in 14 youth with
treatment-refractory ADHD receiving protriptyline (mean dose: 30 mg) yielded less favorable
results. We found that only 45% of ADHD youth responded to or could tolerate protriptyline
(secondary to adverse effects) (Wilens et al. 1996a).
Thirteen of the 33 TCA studies (40%) compared TCAs with stimulants. Five studies each reportedPrint: Chapter 4. Attention-Deficit/Hyperactivity Disorder http://www.psychiatryonline.com/popup.aspx?aID=250840&print=yes…
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that stimulants were superior to TCAs (Garfinkel et al. 1983; Gittelman-Klein 1974; Rapoport et al.
1974) or equal to TCAs (Gross 1973; Huessy and Wright 1970; Kupietz and Balka 1976; Yepes et al.
1977), and three studies reported that TCAs were superior to stimulants (Watter and Dreyfuss
1973; Werry 1980; Winsberg et al. 1972). Analysis of response profiles indicates that TCAs more
consistently improve behavioral symptoms—as rated by clinicians, teachers, and parents—than they
improve cognitive function—as measured via neuropsychological testing (Gualtieri and Evans 1988;
Quinn and Rapoport 1975; Rapport et al. 1993; Werry 1980). As noted earlier, studies of TCAs have
uniformly reported a robust rate of response of ADHD symptoms in ADHD subjects with comorbid
depression or anxiety (Biederman et al. 1993; Cox 1982; Wilens et al. 1993, 1995). In addition,
studies of TCAs have consistently reported a robust rate of response in ADHD subjects with
comorbid tic disorders (Dillon et al. 1985; Hoge and Biederman 1986; Riddle et al. 1988; Singer et
- 1995; Spencer et al. 1993a, 1993b). For example, in a recent controlled study, Spencer et al.
(2002a) replicated data from a retrospective chart review indicating that desipramine had a robust
beneficial effect on ADHD and tic symptoms. The potential benefits of TCAs in the treatment of
ADHD have been clouded by concerns about their safety, stemming from reports of sudden
unexplained death in four ADHD children treated with desipramine (Abramowicz 1990), although
the causal link between desipramine and these deaths remains uncertain.
The mechanism of action of antidepressant drugs appears to be due to various effects on pre- and
postsynaptic receptors impacting the release and reuptake of brain neurotransmitters, including
norepinephrine, serotonin, and dopamine. Although antidepressants have variable effects on
various pre- and postsynaptic neurotransmitter systems, their effects and adverse-effect profiles
differ greatly according to drug class. Given that substantial interindividual variability in
metabolism and elimination has been demonstrated in children, dosages should always be
individualized.
The TCAs include the tertiary-amine (imipramine and amitriptyline) and the secondary-amine
(desipramine and nortriptyline) compounds. Treatment with a TCA should be initiated with a 10-mg
or 25-mg dose and increased slowly every 4–5 days by 20%–30%. When a daily dosage of 3 mg/kg
(or a lower effective dose), or of 1.5 mg/kg for nortriptyline, is reached, steady-state serum levels
and an electrocardiogram (ECG) should be obtained. The typical dosage range for the TCAs is
2.0–5.0 mg/kg (1.0–3.0 mg/kg for nortriptyline). Common short-term adverse effects of the TCAs
include anticholinergic effects, such as dry mouth, blurred vision, and constipation. However, there
are no known deleterious effects associated with chronic administration of these drugs.
Gastrointestinal symptoms and vomiting may occur when these drugs are discontinued abruptly;
thus, slow tapering is recommended. Because the anticholinergic effects of TCAs limit salivary flow,
these agents may promote tooth decay.
Evaluations of short- and long-term effects of therapeutic doses of TCAs on the cardiovascular
system in children have found TCAs to be generally well tolerated, with only minor ECG changes
associated with TCA treatment at daily oral doses up to 5 mg/kg. TCA-induced ECG abnormalities
(conduction defects) have been consistently reported in children at doses higher than 3.5 mg/kg
(1.0 mg/kg for nortriptyline) (Biederman et al. 1989). Although of unclear hemodynamic
significance, the development of conduction defects in children receiving TCA treatment merits
closer ECG and clinical monitoring, especially when relatively high doses of these agents are used.
In the context of cardiac disease, conduction defects may have potentially more serious clinical
implications. When in doubt about a particular patient’s cardiovascular status, a more
comprehensive cardiac evaluation is suggested, including 24-hour ECG and a cardiac consultation,
before initiating treatment with a TCA, to help determine the risk–benefit ratio of such an
intervention. Although changes in individual markers of heart rate variability were noted in ADHD
youth treated with desipramine, desipramine did not appear to adversely affect the overall balance
of sympathetic/parasympathetic input into the myocardium.
Several case reports in the 1980s of sudden death in children being treated with desipramine raised
concerns about the potential cardiotoxic risk associated with TCAs in the pediatric population
(Riddle et al. 1991). Despite uncertainty and imprecise data, an epidemiological evaluation of thisPrint: Chapter 4. Attention-Deficit/Hyperactivity Disorder http://www.psychiatryonline.com/popup.aspx?aID=250840&print=yes…
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issue (Biederman et al. 1995a) suggested that the risk of desipramine-associated sudden death
may be slightly elevated but not much greater than the baseline risk of sudden death in children not
on medication. Nevertheless, treatment with a TCA should be preceded by a baseline ECG, with
serial ECGs at regular intervals throughout treatment. Because of the potential lethality of TCAs in
overdose, parents should be advised to carefully store the medication in a place inaccessible to
children or their siblings.
Monoamine Oxidase Inhibitors
Although a small number of studies have suggested that MAOIs (see Table 4–2) may be effective in
juvenile and adult ADHD, the potential for hypertensive crisis associated with dietetic
transgressions and drug interactions seriously limits these agents’ use. The MAOIs include the
hydrazine (phenelzine) and nonhydrazine (tranylcypromine) compounds. In adults, MAOIs have
been found to be helpful in the treatment of atypical depressive disorders with reverse endogenous
features and depressive disorders with prominent anxiety features (Quitkin et al. 1991). Daily
dosages should be carefully titrated based on response and adverse effects; average doses range
from 0.5 to 1.0 mg/kg. Short-term adverse effects include orthostatic hypotension, weight gain,
drowsiness, and dizziness. However, major limitations associated with the use of MAOIs in children
and adolescents are the severe dietetic restrictions on foods containing tyramine (i.e., most
cheeses) or pressor amines (i.e., sympathomimetic substances), and the potential for severe drug
interactions (e.g., with amphetamines and most cold medicine), which can lead to hypertensive
crisis and serotonergic syndrome. Available in Europe and Canada but not yet in the United States,
a new family of reversible inhibitors of MAOI (RIMAs) has been developed that may be free of these
difficulties.
Bupropion
The mixed dopaminergic–noradrenergic antidepressant bupropion (see Table 4–2) was shown to be
effective for ADHD in children in a controlled multisite study (n = 72) (Casat et al. 1987, 1989; K.
Conners et al. 1996) and in a comparison study with methylphenidate (n = 15) (Barrickman et al.
1995). In an open study in ADHD adults, sustained improvement was documented at 1 year at an
average bupropion dosage of 360 mg/day for 6–8 weeks (Wender and Reimherr 1990). A recent
double-blind controlled clinical trial of bupropion in adults with ADHD documented its superiority
over placebo (Wilens et al. 1999a), with an effect size highly consistent with that found in the
pediatric trials.
Bupropion hydrochloride is a novel structured antidepressant of the aminoketone class; although
related to the phenylisopropylamines, it is pharmacologically distinct from known antidepressants.
Bupropion’s specific site or mechanism of action remains unknown; however, the drug appears to
have an indirect mixed-agonist effect on dopamine and norepinephrine neurotransmission.
Bupropion is indicated for depression and smoking cessation in adults (Hurt et al. 1997). It is
rapidly absorbed, with peak plasma levels usually achieved after 2 hours and an average
elimination half-life of 14 hours (8–24 hours). The usual dosage range is 4.0–6.0 mg/kg/day in
divided doses. Side effects include irritability, anorexia, and insomnia and, rarely, edema, rashes,
and nocturia. Exacerbation of tic disorders has been also been reported with bupropion. While
bupropion has been found to carry a slightly increased risk (0.4%) of drug-induced seizures
relative to other antidepressants, this risk has been linked to high doses, a previous history of
seizures, and eating disorders. Bupropion formulations include long-acting (SR, XR) preparations
that can be administered twice daily.
Selective Serotonin Reuptake Inhibitors and Other Serotonergic Antidepressants
Although a single small open study (Barrickman et al. 1991) suggested that the SSRI fluoxetine
might be beneficial in the treatment of children with ADHD, the usefulness of SSRIs in the
treatment of core ADHD symptoms is not supported by clinical experience (National Institute of
Mental Health 1996). Similarly uncertain is the usefulness of the mixed serotonergic–noradrenergic
atypical antidepressant venlafaxine (see Table 4–2) in the treatment of ADHD. Whereas a 77%Print: Chapter 4. Attention-Deficit/Hyperactivity Disorder http://www.psychiatryonline.com/popup.aspx?aID=250840&print=yes…
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response rate in completers was reported in open studies of ADHD adults, 21% dropped out
because of side effects (n = 4 open studies; n = 61 adults) (Adler et al. 1995; Findling et al. 1996;
Hornig-Rohan and Amsterdam 1995; Reimherr et al. 1995). Additionally, a single open study of
venlafaxine in 16 ADHD children reported a 50% response rate in completers, with a 25% rate of
dropout due to side effects, most prominently increased hyperactivity (Olvera et al. 1996).
Currently available SSRIs include fluoxetine, paroxetine, sertraline, fluvoxamine, and citalopram
(see Table 4–2). At present, expert opinion does not support the usefulness of these serotonergic
compounds in the treatment of core ADHD symptoms (National Institute of Mental Health 1996).
Nevertheless, because of the high rates of comorbidity in ADHD, these compounds are frequently
combined with effective anti-ADHD agents.
Cautions Relating to Medication Coadministration
The antidepressants and many other psychotropics are metabolized in the liver by the cytochrome
P450 system (DeVane 1998; Greenblatt et al. 1998; Nemeroff et al. 1996). Because of genetic
polymorphism, there are slow and rapid metabolizers. In addition, exogenous compounds can
dramatically affect the efficacy of these enzymes and lead to drug–drug interactions. The
coadministration of TCAs with SSRIs (paroxetine, fluoxetine, sertraline, and fluvoxamine) may
result in increased levels of the TCAs. Citalopram, venlafaxine, and mirtazapine (see Table 4–2)
have minimal inhibition of P450 enzymes. Because levels of any drug metabolized by an isoenzyme
that is inhibited by another drug can rise to dangerous levels, caution should be exercised when
using combination treatments (DeVane 1998; Greenblatt et al. 1998; Nemeroff et al. 1996).
Atomoxetine
Atomoxetine (Strattera) is one of a new class of compounds being developed, known as specific
norepinephrine reuptake inhibitors (see Table 4–2). An initial controlled clinical trial in adults
documented “proof of concept” for atomoxetine in the treatment of ADHD (Spencer et al. 1998b).
These initial encouraging results, coupled with extensive safety data in adults, fueled efforts to
further explore this agent’s potential in the treatment of pediatric ADHD. An open-label,
dose-ranging study of atomoxetine in pediatric ADHD documented strong clinical benefits with
excellent tolerability, including a safe cardiovascular profile, and provided dosing guidelines for
further controlled studies (Spencer et al. 2001).
The initial study (Spencer et al. 1998b) was a double-blind, placebo-controlled crossover trial of
atomoxetine in 22 well-characterized adults with ADHD that took into account issues of psychiatric
comorbidity. Treatment with atomoxetine at an average oral daily dose of 76 mg/day was well
tolerated. Drug-specific improvement in ADHD symptoms was highly significant overall and was
sufficiently robust to be detectable in a parallel-group comparison restricted to the first 3 weeks of
the protocol. The positive response rate for atomoxetine-treated subjects was greater than that for
placebo-treated subjects (52% vs. 10.5%). Significant atomoxetine-associated improvement was
noted on neuropsychological measures of inhibitory capacity from the Stroop Test. This preliminary
study showed that atomoxetine was effective in adult ADHD and was well tolerated. These
promising results provided support for further studies of atomoxetine.
Further controlled trials have led to FDA approval of atomoxetine for children and adults with
ADHD. In the first pediatric controlled studies, 291 children ages 7–13 years with ADHD were
randomized in two trials (combined: atomoxetine [n = 129], placebo [n = 124], and
methylphenidate [n = 38]) (Spencer et al. 2002b). The acute treatment period was 9 weeks.
Patients in the stimulant-naive stratum were randomized to double-blind treatment with
atomoxetine (n = 56), placebo (n = 53), or methylphenidate (n = 38). Patients in the
stimulant-prior-exposure stratum (prior exposure to any stimulant) were randomized to
double-blind treatment with atomoxetine (n = 73) or placebo (n = 71). Atomoxetine significantly
reduced total scores on an investigator-rated DSM-IV ADHD rating scale (ADHD Rating Scale IV;
Zhang et al. (2005). Under a response definition of 25% decrease in ADHD Rating Scale IV scores,
the response rates were greater with atomoxetine than with placebo (61.4% vs. 32.3%,Print: Chapter 4. Attention-Deficit/Hyperactivity Disorder http://www.psychiatryonline.com/popup.aspx?aID=250840&print=yes…
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respectively; P < 0.05). In the stimulant-naive stratum, 69.1% of atomoxetine-treated patients,
73% of methylphenidate-treated patients, and 31.4% of placebo patients were considered
responders. Atomoxetine was well tolerated. Mild appetite suppression was reported in 22%
of patients on atomoxetine versus 32% of those on methylphenidate and 7% of those on placebo.
Less insomnia was seen with atomoxetine than with methylphenidate (7.0% vs. 27.0%; P < 0.05).
Mild increases in diastolic blood pressure and heart rate were noted in the atomoxetine-treated
group, with no significant differences between atomoxetine and placebo in laboratory parameters
and ECG intervals.
In an additional controlled study, 297 children and adolescents were randomized to different doses
of atomoxetine or placebo for 8 weeks (Michelson et al. 2001). Atomoxetine showed a graded dose
response—1.2 or 1.8 mg/kg/day produced a better response than did 0.5 mg/kg/day, which in turn
was superior to placebo. In close parallel to the dose relationship to lowering ADHD symptoms, this
study documented a dose-dependent enhancement of social and family function. The Child Health
Questionnaire was used to assess the well-being of the child and family. Parents of children
receiving atomoxetine reported fewer emotional difficulties and behavioral problems as well as
greater self-esteem for their children and less emotional worry and fewer limitations in personal
time for themselves.
Safety and efficacy data were evaluated in a year-long open follow-up of atomoxetine-treated
children and adolescents (n = 325). Atomoxetine treatment continued to be effective and well
tolerated. The acute mild increases in diastolic blood pressure and heart rate persisted without
worsening. Growth in height and weight was normal, and there were no significant differences
between atomoxetine and placebo in laboratory parameters and ECG intervals (Kratochvil et al.
2001; Spencer et al. 2005).
Two large controlled studies were performed (Michelson et al. 2003) to follow up the initial study
by Spencer et al. 1998b). These two identical studies used randomized, double-blind,
placebo-controlled designs and a 10-week treatment period in adults with DSM-IV (American
Psychiatric Association 1994)–defined ADHD as assessed by clinical history and confirmed by a
structured interview (study I, n = 280; study II, n = 256). The primary outcome measure was a
comparison of atomoxetine and placebo using repeated-measures mixed-model analysis of
postbaseline values of the Conners Adult ADHD Rating Scale. In each study, atomoxetine was
statistically superior to placebo in reducing both inattention and hyperactive/impulsive symptoms
as assessed by primary and secondary measures. Discontinuations secondary to adverse events
among atomoxetine patients were below 10% in both studies. This series of studies was the basis
for the FDA approval of atomoxetine for adult ADHD.
Adults with ADHD who were previously enrolled in the acute study of atomoxetine were enrolled in
a 3 year open-label follow-up study (Adler et al. 2005). Recently, results were reported of a
preliminary study of 384 patients at 31 sites who had been studied for a period of up to 97 weeks
thus far. The primary efficacy measure was the Conners Adult ADHD Rating Scale—Investigator
Rated: Screening Version (CAARS-Inv:SV) Total ADHD Symptom score. In addition, safety, adverse
events, and vital-sign measurements were assessed. Significant improvement was noted with
atomoxetine therapy, with mean CAARS-Inv:SV Total ADHD Symptom scores decreasing 33.2%,
from 29.2 (baseline of open-label therapy) to 19.5 (end of open-label therapy). Similar and
significant decreases were noted for the secondary efficacy measures. The relatively small
increases in heart rate and blood pressure observed in the acute study were persistent but did not
worsen during the 3 years. These are pharmacologically (noradrenergic) expected effects. These
results support the long-term efficacy, safety, and tolerability of atomoxetine for the treatment of
adult ADHD.
Current dosing guidelines recommend that atomoxetine be initiated at 0.5 mg/kg/day for 2 weeks
and increased to a target dose of 1.2 mg/kg/day, with a recommended maximum dosage of 1.4
mg/kg/day or 100 mg/day. While higher dosages are not FDA approved, clinicians familiar with the
medication have reported further improvement at dosages up to 1.8 mg/kg/day, the maximumPrint: Chapter 4. Attention-Deficit/Hyperactivity Disorder http://www.psychiatryonline.com/popup.aspx?aID=250840&print=yes…
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dosage reported in both the juvenile and the adolescent studies. Although atomoxetine is effective
in once-a-day dosing, twice-a-day dosing can provide a better tolerability profile and potentially a
more robust effect later in the day. Because atomoxetine is metabolized by the hepatic 2D6
enzymatic system, care should be taken when coadministering the drug with medications that
inhibit 2D6 (e.g., fluoxetine, paroxetine). In addition, atomoxetine has been shown to have low
abuse potential (Heil et al. 2002).
Two cases of severe liver injury were reported in a denominator of greater than 2 million patients
who have taken atomoxetine since approval. Both patients recovered, achieving normal liver
function after discontinuing the medication. Although rare, severe drug-related liver injury may
progress to acute liver failure, resulting in death or the need for a liver transplant. Eli Lilly
announced that it has added a bolded warning to the product label for atomoxetine (www.lilly.com)
as of December 2004. The bolded warning indicates that the medication should be discontinued in
patients with jaundice (yellowing of the skin or whites of the eyes) or laboratory evidence of liver
injury. Patients taking atomoxetine are cautioned to contact their physician immediately if they
develop pruritus, jaundice, dark urine, upper right-sided abdominal tenderness, or unexplained
“flu-like” symptoms. As this is very recent information, it will be important to remain current on
any new information on this risk.
Noradrenergic Modulators
Alpha-Adrenergic Agents: Clonidine and Guanfacine
Clonidine (see Table 4–2) is an imidazoline derivative with alpha-adrenergic agonist properties that
has primarily been used in the treatment of hypertension. At low doses, it appears to stimulate
inhibitory presynaptic autoreceptors in the CNS. The most common use of clonidine in pediatric
psychiatry is the treatment of Tourette’s and other tic disorders (Leckman et al. 1991), ADHD, and
ADHD-associated sleep disturbances (Hunt et al. 1990; Prince et al. 1996). In addition, clonidine
has been reported to be useful in developmentally disordered patients to control aggression toward
self and others. Clonidine is a relatively short-acting compound, with a plasma half-life ranging
from approximately 5.5 hours (in children) to 8.5 hours (in adults). Daily dosages should be titrated
and individualized. Usual daily dosages range from 3 to 10 micrograms per kilogram, generally
given in divided doses, bid, tid, and sometimes qid. Therapy is usually initiated at the lowest
manufactured dose of a full or half tablet of 0.1 mg, depending on the size of the child
(approximately 1–2 microgram/kilogram) and increased depending on clinical response and
adverse effects. Initial dosage can more easily be given in the evening hours or before bedtime due
to sedation. The most common short-term adverse effect of clonidine is sedation. It can also, in
some cases, cause hypotension, dry mouth, depression, and confusion. Clonidine is not known to be
associated with long-term adverse effects. In hypertensive adults, abrupt withdrawal of clonidine
has been associated with rebound hypertension. Thus, the drug requires slow tapering when
discontinued. Clonidine should not be administered concomitantly with beta-blockers, because
adverse interactions have been reported with this combination. Reports of death in several children
on the combination of methylphenidate and clonidine generated concerns about its safety. Although
more work is needed to evaluate whether an increased risk exists with this combination, a cautious
approach is advised, including increased surveillance and cardiovascular monitoring.
Recently, there has been anecdotal evidence that the more selective alpha (2a) agonist guanfacine
(see Table 4–2) may have a spectrum of benefits similar to those of clonidine but with less sedation
and a longer duration of action (Chappell et al. 1995; Horrigan and Barnhill 1995; Hunt et al. 1995).
Usual daily dosages of guanfacine range from 42 to 86 micrograms per kilogram, generally given in
divided doses, bid or tid.
Despite clonidine’s wide use in children with ADHD, there have been relatively few (n = 6 studies [4
controlled], n = 292 children) (Gunning 1992; Hunt 1987; Hunt et al. 1985; Singer et al. 1995;
Steingard et al. 1993; Tourette’s Syndrome Study Group 2002) studies supporting the efficacy of
clonidine. A recent study compared clonidine with methylphenidate in a sample of children withPrint: Chapter 4. Attention-Deficit/Hyperactivity Disorder http://www.psychiatryonline.com/popup.aspx?aID=250840&print=yes…
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ADHD and Tourette’s disorder (Tourette’s Syndrome Study Group 2002). The investigators reported
that clonidine worked as well as methylphenidate as assessed by teacher ratings of ADHD but that
clonidine was most helpful for impulsivity and hyperactivity and not as helpful for inattention.
Moreover, sedation was a common side effect, occurring in 28% of subjects.
Equally limited is the literature on guanfacine. There are three open studies (n = 36) and one
controlled study (n = 34) of guanfacine in children and adolescents with ADHD (Chappell et al.
1995; Horrigan and Barnhill 1995; Hunt et al. 1995; Scahill et al. 2001). In these studies, beneficial
effects on hyperactive behaviors and attentional abilities were reported. In the controlled study of
children with tic disorders and ADHD, guanfacine improved attention on teacher ratings and
performance on a continuous performance test (Scahill et al. 2001). In a study in adults with ADHD
(n = 17), guanfacine was shown to improve both ADHD symptoms and performance on a cognitive
test of response inhibition as measured by the Stroop Test (Taylor 2000). Several cases of sudden
death have been reported in children treated with clonidine plus methylphenidate, raising concerns
about the safety of this combination (Wilens and Spencer 1999). A recent study examined the
combination in 33 children and found no evidence of cardiac toxicity (Tourette’s Syndrome Study
Group 2002).
Beta-Blockers
Beta-adrenergic blockers also have been studied for use in ADHD (see Table 4–2). An open study of
propranolol in ADHD adults with temper outbursts reported improvement at dosages of up to 640
mg/day (Mattes 1986). Another report indicated that beta-blockers may be helpful in combination
with stimulants (Ratey et al. 1991). In a controlled study of pindolol in 52 ADHD children,
symptoms of behavioral dyscontrol and hyperactivity were improved, with less apparent cognitive
benefit (Buitelaar et al. 1996). However, prominent adverse effects such as nightmares and
paresthesias led to discontinuation of the drug in all test subjects. An open study of nadolol in
aggressive developmentally delayed children with ADHD symptoms reported effective diminution of
aggression, with little apparent effect on ADHD symptoms (Connor et al. 1997).
Other Compounds
Modafinil
Modafinil (see Table 4–2) is an antinarcoleptic agent that is structurally and pharmacologically
different from other agents approved to treat ADHD. Although its mechanism of action is unknown,
modafinil may improve symptoms of ADHD via the same mechanism by which it improves
wakefulness. Preclinically, modafinil selectively activates the cortex without causing widespread
CNS stimulation (Engber et al. 1998). Modafinil does not appear to activate areas of the brain that
mediate reward and abuse and thus has a low potential for abuse (Myrick et al. 2004).
Although initial studies of modafinil demonstrated significant improvement in ADHD symptoms,
more recent studies reported increased efficacy with higher doses (340–425 mg/day) in children
and adolescents (Swanson et al. 2004). A concentrated form of modafinil (a small tablet) was
developed to ease administration of medication doses in the pediatric population. A 9-week
randomized, double-blind, placebo-controlled, flexible-dosage trial evaluated the efficacy and
tolerability of this new formulation of modafinil in once-daily dosing (Biederman et al. 2005b).
Medication was titrated to an optimal dose based on efficacy and tolerability (range: 170–425 mg
once daily). Two hundred forty-six patients were treated with modafinil (n = 164) or placebo
(n = 82). Significant improvements were observed with modafinil treatment on the ADHD Rating
Scale, 4th Edition (ADHD-RS-IV, School Version) at week 1, with an effect size of 0.69 by final visit.
At the final visit, 48% of modafinil-treated patients were rated as “much” or “very much” improved
in overall clinical condition (on the CGI-I), compared with 17% of placebo-treated patients. The
most commonly reported adverse events in the modafinil group were insomnia (29%), headache
(20%), and decreased appetite (16%). On the basis of these positive findings, Cephalon filed for
FDA approval of modafinil for the indication of ADHD.Print: Chapter 4. Attention-Deficit/Hyperactivity Disorder http://www.psychiatryonline.com/popup.aspx?aID=250840&print=yes…
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Anxiolytics, Antipsychotics, and Anticonvulsants
An open study of 12 ADHD children reported that the nonbenzodiazepine anxiolytic buspirone at 0.5
mg/kg/day improved both ADHD symptoms and psychosocial function (Malhotra and Santosh
1998). Buspirone has a high affinity for 5-HT1A receptors, both pre- and postsynaptic, as well as a
modest effect on the dopaminergic system and alpha-adrenergic activity.
Whereas the older literature suggested that typical antipsychotics might have efficacy in the
treatment of children with ADHD, the spectrum of both short-term (extrapyramidal reactions) and
long-term (tardive dyskinesia) adverse effects of these agents greatly limits their usefulness.
Finally, a meta-analysis pooling data from 10 studies provided preliminary evidence that
carbamazepine may have activity in ADHD (Silva et al. 1996).
Nicotinic Drugs
In recent years, evidence has emerged that nicotinic dysregulation may contribute to the
pathophysiology of ADHD. This is not surprising, considering that nicotinic activation enhances
dopaminergic neurotransmission (Mereu et al. 1987; Westfall et al. 1983). Independent lines of
investigation have documented that ADHD is associated with an increased risk and earlier age at
onset of cigarette smoking (Milberger et al. 1997b; Pomerleau et al. 1996), that maternal smoking
during pregnancy increases the risk for ADHD in the offspring, and that in utero exposure to
nicotine in animals confers a heightened risk for an ADHD-like syndrome in the newborn (Fung
1988; Fung and Lau 1989; Johns et al. 1982; Milberger et al. (1996). In non-ADHD subjects, central
nicotinic activation has been shown to improve temporal memory (Meck and Church 1987),
attention (Jones et al. 1992; Peeke and Peeke 1984; Wesnes and Warburton 1984), cognitive
vigilance (Jones et al. 1992; Parrott and Winder 1989; Wesnes and Warburton 1984), and executive
function (Wesnes and Warburton 1984).
Support for a “nicotinic hypothesis” of ADHD can be derived from a study that evaluated the
therapeutic effects of nicotine in the treatment of adults with ADHD (Levin et al. 1996). Although
this controlled clinical trial documented that commercially available transdermal nicotine patch
resulted in significant improvement of ADHD symptoms, working memory, and neuropsychological
functioning (Levin et al. 1996), the trial was very short (2 days) and included only a handful of
patients. More promising results supporting the usefulness of nicotinic drugs in ADHD derive from a
controlled clinical trial of ABT-418 in adults with ADHD (Wilens et al. 1999b). ABT-418 is a CNS
cholinergic nicotinic-activating agent with structural similarities to nicotine. Phase 1 studies of this
compound in humans indicated its low abuse liability, as well as adequate safety and tolerability in
elderly adults (Potter et al. 1999). A double-blind, placebo-controlled, randomized crossover trial
comparing a transdermal patch of ABT-418 (75 mg daily) with placebo in adults with DSM-IV ADHD
showed a significantly higher proportion of ADHD adults to be very much improved when receiving
ABT-418 than when receiving placebo (40% vs. 13%; 2 = 5.3, P = 0.021). Although preliminary,
these results suggest that nicotinic analogues may have activity in ADHD.
Additional Agents
Several other compounds have been evaluated and found to be ineffective in the treatment of
ADHD; these include dopamine agonists (amantadine and L-dopa) (Gittelman-Klein 1987) and
amino acid precursors (DL-phenylalanine and L-tyrosine) (Reimherr et al. 1987). Finally, a
controlled study failed to find therapeutic benefits in ADHD for the antiserotonergic anorexogenic
drug fenfluramine (Donnelly et al. 1989).
NONPHARMACOLOGICAL INTERVENTIONS
The largest-scale study examining the relative and combined effectiveness of medical and
nonmedical interventions for ADHD is the National Institute of Mental Health Multimodal Treatment
Study for ADHD Study (MTA). In this 5-year, six-site project, 579 elementary-age children with
ADHD were randomly assigned to one of four 14-month treatment conditions: behavioral treatment,
medication management (mostly methylphenidate), combined behavioral treatment and medicationPrint: Chapter 4. Attention-Deficit/Hyperactivity Disorder http://www.psychiatryonline.com/popup.aspx?aID=250840&print=yes…
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management, and a community comparison group. Children in the behavioral treatment arm
received a very intensive combination of treatments, including school consultation, a classroom
aide, an 8 week summer treatment program, and 35 sessions of parent management training.
Findings from the MTA study at 14 months indicate that medical intervention was significantly more
effective than behavioral and community treatments, that behavioral treatment only modestly
enhanced the effect of medication alone, and that behavioral treatment alone was no more effective
than the treatment received by children in the community comparison group (Jensen 1998).
CONCLUSION
ADHD is a heterogeneous disorder with a strong neurobiological basis that afflicts millions of
individuals of all ages worldwide. Although the stimulants remain the mainstay of treatment for this
disorder, a new generation of nonstimulant drugs is emerging that provides a viable alternative for
patients and families. It is essential to apply a careful differential diagnosis in the assessment of
the ADHD patient that considers psychiatric, social, cognitive, educational, and
medical/neurological factors that may contribute to the individual’s clinical presentation. Realistic
expectations of interventions, precise definition of target symptoms, and careful assessment of the
potential risks and benefits of each type of intervention for such patients are the major ingredients
of successful treatment.
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Copyright © 2009 American Psychiatric Publishing, Inc. All Rights Reserved.
Course Content
Introduction to ADHD: History, Prevalence, and Myths
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The Historical Perspective of ADHD
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Prevalence of ADHD Across Different Populations
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Common Myths and Misconceptions About ADHD
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Quiz on the History and Prevalence of ADHD
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Myths and Facts About ADHD
ADHD Diagnosis: Criteria, Assessment Tools, and Challenges
Core Symptoms and Comorbidities of ADHD
Management Strategies: Behavioral, Pharmaceutical, and Lifestyle Interventions
Advanced Considerations: Long-term Management and Support Systems
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