ADHD: PHARMACOTHERAPY AND COMORBIDITIES
| MEDICATION AND ADHD: A STATE-OF-THE-ART UPDATE —Jefferson B. Prince, MD, Instructor in Psychiatry,
Harvard Medical School; Director, Child Psychiatry, North Shore Medical Center; Staff, Child Psychiatry, Massachusetts
General Hospital, Boston, MA
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| Response patterns in brain (overview): medications help to turn on network processes that occur in patients who do not
have attention-deficit/hyperactivity disorder (ADHD); patients with ADHD have trouble starting projects (getting engaged);
certain populations have difficulty with strength or vigor with which they encode and engage, or patients engage
well, but it declines too rapidly
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| Cognitive division of anterior cingulate cortex: site of decision making and sorting competing interests; patients with
ADHD who are not medicated do not use system as efficiently as those who do not have ADHD or patients with ADHD
on stimulant medication
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Stimulant Medications
 | Methylphenidate (MPH): without MPH, patient with ADHD using little dorsal anterior cingulate cortex (activity present,
but not as strong; using much insular cortex); after medication, processing in dorsal cingulate cortex more like that in
patients without ADHD
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| Mechanism of action: dopamine transporter protein reclaims dopamine from intrasynaptic cleft (can bind, be destroyed, or
be taken back into cell); amphetamine or MPH blocks dopamine transporter protein; prevents reuptake of dopamine (result
increased intrasynaptic concentration of dopamine)
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| Amphetamine: MPH stays outside cell (amphetamine penetrates cell); amphetamine causes vesicles to release dopamine
into cytoplasm (eventually causes reverse transport via dopamine transporter protein); pharmacodynamic properties
different (at different stages of life or in different patients, one better tolerated or more effective than another); method
of delivery of stimulant makes difference (different patients respond to different formulations of MPH or amphetamine)
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| Dosing: stimulants approved by Food and Drug Administration (FDA) up to specific dose; in general, weight used as guide;
target 1 mg/kg per day for MPH (≈0.5 mg/kg per day for amphetamine); start low and increase to target dose (speaker
uses weekly increments); speaker usually begins with extended-delivery preparations (some patients do not need them);
rating scales for 6 to 12 yr of age—Vanderbilt (American Academy of Pediatrics), Swanson, Nolan, and Pelham
(SNAP), and DePaul scale
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| Choice of stimulant: literature does not help clinician choose best stimulant for individual patient; group studies of psychostimulants
generally fail to show significant differences between MPH, dextroamphetamine, and mixed amphetamine
salts (MAS); conversely, large individual differences in response to different drugs and doses; therefore, best order of
presentation for particular patient unknown; any may be used first, on basis of inclination of physician, parent, or patient;
efficacy equal (tolerability varies)
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| Speaker’s approach: generally, extended-delivery formulations; latency age; informal rating scale—functioning in
school, with family, at job, and while driving
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| Side effects with MPH and amphetamine therapy (study by Efron): trouble sleeping and poor appetite; most patients
who continue taking stimulants able to eat; irritability and anxiety especially troublesome in patients who have comorbid
problems; comorbidity may affect ability to tolerate or respond to stimulants; treat anxiety and mood disorders first
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| Problem of tics: still listed as contraindication to use of MPH (not dextroamphetamine [Dexedrine]); off-label use (increased
dose of stimulant paradoxically may help tic); take-home message (make sure family aware that tics listed as
contraindication)
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| Cardiovascular side effects: Canada removed MAS from market; postmarketing surveillance noted 12 deaths or strokes
in pediatric and adult populations combined; of pediatric deaths, most had cardiovascular side effects (exposures 1
day-8 yr; doses 10-50 mg); in 2005, warning added that MAS should not be used in patients with cardiovascular illnesses;
FDA Advisory Committee (2006)—recommendations by Nissen (black box warning; development of guide
for patients)
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| Risk for sudden death (FDA study)
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| Amphetamine cases: 17 cases (of those, 12 in pediatric population [all boys]); case 1—boy died after taking 20 mg amphetamine
and dextroamphetamine (Adderall); on autopsy, diagnosis idiopathic hypertrophic subaortic stenosis
(IHSS); case 2—13-yr-old patient on 30 mg/day Adderall (one day, inadvertently given 50 mg); cause of death confounded
by heat exposure and dehydration at correctional camp; risk factors—identified in 8 of 12 patients (eg, aberrant
coronary arteries, IHSS)
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| MPH cases: 8 cases of sudden death (7 pediatric patients [3 boys, 4 girls]); 3 on MPH (Ritalin); none on dimethylphenidate
(Focalin); 4 on MPH (Concerta); exposure 2 mo to 10 yr; risk factors—identified in 4 of 7 (3 of 7 on other medications)
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| Nonfatal serious cardiovascular events: eg, fainting, tachycardia; patients <19 yr of age; estimated that each patient with
ADHD fills mean of 4.5 prescriptions/yr; 0.18 occurrences per million prescriptions; 0.18 occurrences/million prescriptions
with MPH; 0.53 occurrences/million prescriptions with amphetamine; rate of sudden death—even assuming
50% rate of underreporting, rate 1 to 2/million per year (base rate 0.6-6.0/million per year); bottom line—no
increase in rate of sudden unexplained death in patients exposed to stimulant; for comparison—rate of fatal rhabdomyolysis
from high-dose statins 1 to 2 million/year
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| Cardiovascular monitoring of psychotropics (Gutgesell; American Heart Association): no cardiovascular evaluation indicated
before use of stimulants, unless symptoms referable to cardiovascular problems (eg, syncope, tachycardia, dizziness)
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Other Medications
| Atomoxetine (Strattera): tricyclic antidepressant (TCA); affects noradrenergic system; alternative for patients who do
not respond to stimulants; reuptake inhibitor for norepinephrine; no addictive liability; good studies show efficacy; risk
for hepatitis—1 in 3.4 million exposures (case resolved with discontinuation); in general, speaker does not measure
liver function, unless family needs reassurance; risk for suicidal ideation—in randomized studies, 5 of 1357 patients
reported thoughts about suicide (1 patient made minor attempt); black box warning added to labeling; atomoxetine helpful
for children with attentional problems and anxiety (drug does not help depression or bipolar disorder ([some patients
get worse; drug can cause dysphoria]); other side effects—appetite suppression; dizziness; stomach upset; fatigue and
nausea; give first dose after breakfast (if patient tired, consider administration at night)
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| Strategies: evaluate for comorbidities; consider combined pharmacotherapy or higher doses of medication
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| Increased dose: in speaker’s experience, maximum dose of Ritalin 240 mg/day (as long as child doing well, has good vital
signs, and eats and sleeps normally; rare); many patients do well on low doses; do not move to high doses quickly; monitor
for tolerability and do not worry alone (consider consultation)
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| Combined pharmacotherapy: stimulants plus atomoxetine—not formally studied or approved; stimulants plus TCA—
study by Wharton (combination can lead to increased TCA levels); case series (MPH or amphetamine with desipramine
did not affect desipramine clearance)
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| Bupropion: not approved for managing ADHD, but can be helpful; good for moodiness; can exacerbate tics; not used in
patients with seizures or eating disorders; if patient develops depression on stimulant, consider switch to bupropion (then
add low-dose stimulant)
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| More about TCAs: can be helpful but not used often; imipramine used in patients with insomnia and enuresis (consider
20-50 mg)
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| Clonidine: α-agonist centrally; helpful in tablet form for tics and ADHD; consider patch; helpful in patients who have suffered
family trauma; not approved for use in ADHD; overtreatment (case)—problem corrected by switching to 0.2-mg
patch every 2 days; later, aripiprazole (Abilify; half of 5-mg tablet)
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| Guanfacine (Tenex): similar to clonidine, but not as sedating; seems to last longer
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| COMORBID CONDITIONS IN ADHD—Eugene R. Hershorin, MD, Associate Professor of Clinical Pediatrics, and Medical
Director, Behavioral Pediatrics Clinic, University of Miami Miller School of Medicine, Miami, FL
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| Diagnosis (American Academy of Pediatrics): Recommendation #5—evaluation of ADHD should include assessment
for coexisting conditions; up to 60% to 80% of children have oppositional defiant disorder (ODD); 10% to 35% of children
with ADHD have specific learning disability
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| Incidence of comorbidity: ODD common comorbid condition; rate of language disorders 30% to 35%; substance use disorder;
anxiety disorders; mood disorders
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| Diagnosis of ODD: presence of 4 of 8 criteria; most children with ADHD easily meet criteria for ODD
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| Conduct disorder: must meet criteria in 4 categories; aggression; destruction of property; deceitfulness or theft; severe violation
of rules; torturing animals; child <10 yr of age only needs to meet 1 criteria
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| Treatment of ODD: involves colleagues in psychology and psychiatry; stimulants alone can influence ODD and conduct
disorder (based on standardized rating of behaviors, significant improvement)
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| Substance abuse (study in young adults): 55% of ADHD group had substance misuse (in non-ADHD group, rate lower
by half); with 1-yr treatment, numbers improved; untreated, unmedicated ADHD group remained at highest risk; treatment
can decrease risk for substance use during adolescence
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| Academic impairment: well documented; patients with ADHD perform more poorly in school and on standardized tests
(eg, SAT); condition significant inhibitor of performance
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| Learning difficulties: 25% to 35% of children with ADHD have specific learning disability (eg, communication, reading,
math, processing, perceptual, and visual motor disorder); children with comorbid learning disabilities respond to ADHD
treatment (academically, they improve; however, treatment for ADHD does not improve learning disabilities); ability to
sit still and pay attention improves performance, but still need to address learning disabilities; diagnosis—
psychoeducational assessment; early diagnosis and aggressive intervention can make big difference; if reading disorder
diagnosed by first grade and aggressively treated, ≈90% curable; if diagnosed in third grade, up to 70% have learning disabilities
in tenth grade
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| Increased risk for injury: problem of impulsivity; more trips to emergency room; more head injuries; more significant and severe
injuries than other children; intervention can prevent injuries
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| Motor vehicle issues: increased traffic violations, deaths, driver-caused accidents, license suspensions, and traffic citations;
eg, MPH can normalize driving behaviors
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| Sexual behavior: children with ADHD start having sex at earlier age; more partners, pregnancies, and sexually transmitted
diseases; problem of teen pregnancy due to impulsivity; educate patients and parents
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| Criminality: high comorbidity with ODD and conduct disorder; high incidence of substance abuse (eg, alcohol abuse);
higher risk for arrest, jailing, and conviction
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| Social functioning: more difficult for patients to make and maintain friendships; problem of alienation from peers; older
patients face increasing difficulty academically and socially; divorce rate higher; they change jobs more frequently and
fired more frequently; lower incomes
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| Mood disorders: in 15% to 25% of ADHD patients, depression first episode of bipolar disorder; 20% to 25% have mood
disturbance during course of ADHD
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| Bipolar I disorder: characterized by ≥1 recent manic episodes; look for depressive episode in past; bipolar II disorder—
≥1 major depressive episodes with ≥1 hypomanic episodes; irritability important clue
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| Mania: eg, elevated mood; hypomania—shorter period of same symptoms (4 days instead of 1 wk)
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| Major depressive disorder: children with depression present differently than adults; irritability; anger and temper tantrums;
not necessarily increase in or lack of sleep, or other signs associated with adult depression
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| Treatment of childhood affective disorders: for mood disorders, refer to experienced therapist; medications helpful; prioritizing
treatment—determine which disorder causing most dysfunction; if ADHD significant and mood issues present,
consider treating ADHD first (may see elevation of mood as academic and social functioning improves); if depression major
feature, treat first; antidepressants—mainstay therapy; selective serotonin reuptake inhibitors (SSRIs) work well for depression;
bupropion and atypical antipsychotics for bipolar disorder; some mood stabilizers, lithium, and combinations helpful;
consider referral to psychiatric colleague
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| ADHD and bipolar disorders: common comorbidities; bipolar disorder occurs in ≈5% of patients with ADHD; address
symptoms of bipolarity first; treatment for ADHD alone may worsen manic or depressive symptoms of bipolarity
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| Anxiety disorders: occurs in 15% to 20% of children with ADHD; presentation may differ from that in adults; look for irritability,
temper tantrums, and oppositional behavior; treatment—cognitive behavioral therapy mainstay; medications
may be necessary (eg, antidepressants, SSRIs, atypical antipsychotics)
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Educational Objectives
| The goal of this program is to educate the listener about attention-deficit/hyperactivity disorder (ADHD) in children. After
hearing and assimilating this program, the clinician will be better able to:
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| 1. Describe the neurobiology of ADHD.
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| 2. Describe indications for stimulant medications in patients with ADHD.
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| 3. Recognize indications for nonstimulant medications for managing ADHD.
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| 4. Diagnose common comorbid conditions in patients with ADHD.
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| 5. Manage comorbid conditions in patients with ADHD.
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Discussed on This Program
Amphetamine and dextroamphetamine [Adderall, Adderall XR]
Amphetamine sulfate (racemic amphetamine sulfate)
Aripiprazole [Abilify]
Atomoxetine HCl [Strattera]
Bupropion HCl [Wellbutrin, Wellbutrin SR, Wellbutrin XL, Zyban]
Clonidine HCl [Catapres, Duraclon]
Desipramine HCl [Norpramin]
Dimethylphenidate HCl [Focalin, Focalin XR]
Dextroamphetamine sulfate [Dexedrine, Dexedrine Spansules, DextroStat]
Guanfacine HCl [Tenex]
Imipramine HCl [Tofranil]
Lithium [Eskalith, Eskalith CR, Lithobid, Lithonate, Lithotabs]
Methylphenidate HCl [Concerta, Metadate CD, Metadate ER, Methylin, Methylin ER, Ritalin, Ritalin LA, Ritalin–SR]
Suggested Reading
Abikoff H et al: Sequential pharmacotherapy for children wit.comorbid attention deficit hyperactivity disorder. J Am Acad
Child Adolesc Psychiatry 44:418, 2005; Erenberg G: The relationship between Tourette syndrome, attention deficit hyperactivity
disorder, and stimulant medication: a critical review. Semin Pediatr Neurol 12:217, 2005; Halperin JM,
Schulz KP: Revisiting the role of the prefrontal cortex in the pathophysiology of attention-deficit/hyperactivity disorder.
Psychol Bull 132:560, 2006; Kaplan S: et al: Efficacy and safety of atomoxetine in childhood attention-deficit/hyperactivity
disorder with comorbid oppositional defiant disorder. J Atten Disord 8:45, 2005; Kratochvil CJ et al: Effects of long-
term atomoxetine treatment for young children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc
Psychiatry 45:919, 2006; Newcom JH et al: Atomoxetine treatment in children and adolescents with attention-deficit/hyperactivity
disorder and comorbid oppositional defiant disorder. J Atten Disord 8:45, 2004; Prince JB: Pharmacotherapy
of attention-deficit hyperactivity disorder in children and adolescents: update on new stimulant preparations, atomoxetine,
and novel treatments. Child Adolesc Psychiatr Clin N Am 15:13, 2006; Rappaport N et al: Lost in the black box: juvenile
depression, suicide, and the FDA’s black box. J Pediatr 147:719, 2005; Roessner V et al: First-onset tics in patients
with attention-deficit-hyperactivity disorder: impact of stimulants. Dev Med Child Neurol 48:616; Solhkhah R et al: Bupropion
SR for the treatment of substance-abusing outpatient adolescents with attention-deficit/hyperactivity disorder and
mood disorders. J Child Adolesc Psychopharmacol 15:777, 2005; Sukhodolsky DG et al: Adaptive, emotional, and family
functioning of children with obsessive-compulsive disorder and comorbid attention deficit hyperactivity disorder. Am J
Psychiatry 162:1125, 2005; Waxmonsky J: Assessment and treatment of attention deficit hyperactivity disorder in children
with comorbid psychiatric illness. Curr Opin Pediatr 15:476, 2003; Wilens TE et al: Long-term atomoxetine treatment
in adolescents with attention-deficit/hyperactivity disorder. J Pediatr 149:112, 2006; Wooltoron E: Medications for
attention deficit hyperactivity disorder: cardiovascular concerns. CMAJ 175:29, 2006;
Resources
fdaadvisorycommittee.com
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. Dr. Prince has participated
in the Speakers’ Bureau for McNeil, Lilly, and Forest, and has been a consultant to, or received honoraria from McNeil,
Shire, Cephalon, and Novartis.
Dr. Prince was recorded at Developmental-Behavioral Pediatrics, presented March 24-25, 2006, in Cambridge, MA, by
Boston University School of Medicine; Dr. Hershorin was recorded at Masters of Pediatrics—Contemporary and Future
Pediatrics, presented January 25-30, 2006, in Bal Harbour, FL, by the University of Miami Miller School of Medicine, Department
of Pediatrics and Department of Dermatology and Cutaneous Surgery. The Audio-Digest Foundation thanks the
speakers and the sponsors for their cooperation in the production of this program.
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