ADHD: DIAGNOSIS AND TREATMENT
| ATTENTION-DEFICIT/HYPERACTIVITY DISORDER IN ADULTS —Jefferson B. Prince, MD, Director, Child
Psychiatry, North Shore Medical Center, Salem, MA; Staff, Child Psychiatry, Massachusetts General Hospital, and
Instructor in Psychiatry, Harvard Medical School, Boston, MA
|
| Introduction: worldwide, 5% to 8% of school-age children meet criteria for attention-deficit/hyperactivity disorder
(ADHD); estimated that ADHD persists into adulthood in 30% to 60% of those children; ≈5% of adults thought to
meet criteria for ADHD, but do they need treatment? symptoms of impulsivity and hyperactivity seem to diminish
over time, leaving adults primarily with inattention; when adolescents with ADHD enter college, they often begin
using tobacco, alcohol, and marijuana, all of which interfere with learning
|
| Diagnosis of ADHD in adults: some symptoms present to some extent “in all of us,” but they must cause impairment
in ≥2 realms of life for diagnosis of ADHD to be made; impairment can be relative and difficult to determine,
especially in high-functioning patient; comorbidity common; childhood history essential to determine whether
symptoms due to comorbidity or to ADHD; memory of childhood symptoms may be limited and/or documentation
may be unavailable; family members or old report cards may help clarify history
|
| Migration of symptoms in adults: inattention may be manifested as—difficulty maintaining attention; not doing
paperwork; procrastination; forgetfulness; distraction; dramatically underestimating time it will take to get something
done; misplacing things; hyperactive and impulsive symptoms may be manifested as—inner restlessness; being
easily overwhelmed; self-selecting for active jobs; excessive talking; fidgeting when seated; impulsive job
changes; driving too fast or having traffic accidents; irritability or quickness in angering
|
| Diagnostic criteria from Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV): require
onset of some symptoms before 7 yr of age, chronicity (>6 mo of disturbance), and clear evidence of impairment
in ≥2 life domains
|
 | Subtypes of ADHD: predominantly inattentive type (20% to 25% of adults); predominantly impulsive/hyperactive
type (rare in adults); combined type (65% to 70% of adults)
|
| Comorbidity: most common conditions include major depressive disorder, bipolar disorder, anxiety disorders, agoraphobia,
social phobia, and obsessive-compulsive disorder; also common are behavior problems, oppositionality,
conduct disorder, tics, and high nicotine use; in adults with major depressive disorder, ≈16% have ADHD; in
those with bipolar disorder, ≈15%; with panic disorders, ≈24%; with substance abuse, ≈25%
|
| Diagnosing ADHD in adults: when symptoms start in childhood, at least some of them persist into adulthood, and
persistent symptoms cause impairment; use of rating scales and interviewing collaterals may help establish diagnosis;
several rating scales and other tools available at schoolpsychiatry.org
|
| Heritability: ≈75% of variance attributable to genetic factors, but no one gene that can be tested; no role for genetic
testing in evaluation
|
| Neuroimaging: no role for neuroimaging in assessment or diagnosis of ADHD, due to low sensitivity and specificity
of tests available; imaging studies from group data confirm abnormalities in frontal subcortical networks associated
with ADHD, but group data cannot be applied to individuals
|
| How treatments work: Food and Drug Administration (FDA) has approved amphetamine compounds, dexmethylphenidate,
and atomoxetine for use in adults
|
| Stimulants: methylphenidate blocks reuptake of dopamine; amphetamine causes release of more dopamine; methylphenidate
and amphetamine have equal efficacy, but differ widely in tolerability; in general, adults need lower
doses of stimulants than children; target doses are ≈1 mg/kg of methylphenidate and 0.5 mg/kg of amphetamine
(but start at lower doses and increase slowly, assessing tolerance and efficacy); in studies, patients who responded
to stimulants initially continue to get better over time; if patient’s response less than desired or if he or
she has tolerability problem, “just switch stimulants” (speaker suggests switching stimulants before switching to
atomoxetine); side effects include decrease in appetite and difficulty falling asleep; also, be wary of stimulant exacerbating
comorbid disorder (especially depression)
|
| Atomoxetine: trials show initial response and long-term responsiveness, although initial response takes longer than
stimulants; patient who has “so-so” response may benefit from having stimulant added; studies show atomoxetine
works for hyperactivity and inattention; side effects include dry mouth, sleepiness, and nausea; sexual dysfunction
occurs in men, but apparently not in women; recent concerns about sudden death and cardiovascular
problems in adults not yet addressed by FDA, but, based on data in children and adolescents, no need for “black-
box” warning; speaker recommends monitoring blood pressure in adults, perhaps even having patient measure it
at home; if psychotic or aggressive event occurs, discontinue atomoxetine
|
| Other medications: good data for efficacy of tricyclic antidepressants and bupropion, although bupropion “doesn’t
seem as vigorous for the attention as compared to stimulants or atomoxetine”; speaker often uses bupropion in
combination with stimulants; clonidine and guanfacine seldom used in adults; adult trials underway with modafinil,
although FDA has not approved it for use in pediatric patients due to safety concerns; speaker has “a number of
adults” who take modafinil, some in combination with stimulant; Vyvanse (lisdexamfetamine dimesylate; formerly
NPR104) recently received approvable letter from FDA (consists of dextroamphetamine covalently linked to
lysine, minimizing potential for abuse)
|
| Conclusions: treat comorbidity, especially substance use disorders, as well as ADHD; stimulants and atomoxetine first-
line agents, antidepressants second-line; use combined pharmacotherapy for incomplete response or for comorbid
cases; give consideration to and prioritize comorbid conditions
|
| PSYCHOPHARMACOLOGY FOR ADHD—Stephen M. Stahl, MD, PhD, Adjunct Professor of Psychiatry, University
of California, San Diego, School of Medicine
|
| Learning objectives: identify children and adults with ADHD and prescribe strategies that target their key symptoms;
understand the neurobiology of ADHD in terms of rational treatment selection, sequence of treatments, and
combinations of treatments; integrate novel options into practice
|
| Dosing: children generally need higher doses of stimulants and modafinil than adults, because children metabolize
these drugs faster, but dose always can be lowered on individual basis
|
| ADHD in adulthood: impulsivity and hyperactivity tend to lessen in adulthood, but inattention tends to remain
stable; some children have only inattention and continue to have it throughout their lifetimes; others have
mixed symptoms and remain inattentive as adults; pediatricians tend to see no or little comorbidity in children
8 to 15 yr of age, whereas psychiatrists see much comorbidity; speaker suggests this phenomenon due to lack
of training in pediatricians
|
| Should treatment change as patients age? in general, doses must be lowered as adolescent reaches adulthood
and liver metabolism slows; assess dose at every visit and adjust as necessary
|
| Neurotransmitters: low norepinephrine and low dopamine because activity associated with ADHD symptoms, but
improving symptoms more complicated than just increasing norepinephrine and dopamine because raising either
neurotransmitter too much can cause decompensation
|
| Stimulants: generally do not act as reuptake blockers in cortex, but as monoamine releasers; when individual interested
in whatever is going on around him or her, and it is relevant to him or her, dopamine released; when
not interested or when bored, no dopamine released; methylphenidate increases dopamine in prefrontal cortex,
striatum, and nucleus accumbens, increases norepinephrine by releasing it out of vesicles, and increases
histamine (although histamine release not primary effect, secondary release good for cognition); new formulation
of amphetamine binds amphetamine with lysine, minimizing potential for abuse; advantages—
immediate onset and offset of action; many formulations available, including immediate release, extended release,
and sustained release; disadvantages—patients may develop tolerance or psychological dependence;
may worsen motor and phonic tics, impulsivity, and bipolarity; controversial whether it affects growth (no
black-box warning from FDA, but they advise not using stimulants in people with structural defects); tips and
pearls—effective for motor and attention symptoms (but higher dose may be needed for inattention than for
motor symptoms); may cause insomnia, so do not administer too close to bedtime; monitor growth and blood
pressure of children; half-life and duration of action may be shorter in younger children; methylphenidate
transdermal patch (Daytrana) has onset within 2 hr (same as oral formulation), peaks at 7 to 9 hr; action can
be stopped by removing patch; disadvantages include its being large, which may cause child to feel stigmatized
|
| Atomoxetine: increases dopamine and norepinephrine in cortex but no dopamine in striatum or nucleus accumbens;
in studies, more effective for inattention symptoms than for hyperactivity and impulsivity; in studies, first dose
did not work as well as stimulants, but over 8 wk, “comes a lot closer to matching a stimulant”; if dosed too high,
does not work; in trials, shown to work, but “clinical wisdom is that it doesn’t quite have the punch” of stimulants;
tips and pearls—tricky to dose; ≈7% of white population does not have cytochrome P450 (CYP2D6) in
liver, meaning dose of atomoxetine should be reduced by half; if dose too high, blood pressure may go up, and
there are rare reports of severe liver damage; dosed once daily; no known abuse; does not affect growth, exacerbate
tics, or have cardiovascular effects
|
| Bupropion: speaker uses “a lot” in adults because of uncertainty whether symptoms due to incomplete recovery
from depression or to residual ADHD; little known about its use in children; greatest disadvantage is risk for seizures
in adults and children; other antidepressants that might work include venlafaxine (Effexor), duloxetine
(Cymbalta), and tricyclic antidepressants
|
| Modafinil: releases histamine and increases monoamines cortically; mechanism of action not clearly understood;
needs α1 receptor and dopamine transporter to work, “but it actually doesn’t stick to those things; so there’s some
sort of a wiring diagram that’s going on that we don’t quite understand, but it’s got a very unique action”; in 3
studies of modafinil in children with ADHD, teachers and parents rated all symptoms as getting better; primary
effect on inattention, but by end of study, impulsivity and hyperactivity also had improved; onset of action slow,
with most robust effect occurring in seventh to ninth week; side effects—adults report headache at doses of 200
mg once or twice daily; children report no headaches, but insomnia and decreased appetite reported at doses of
300 to 500 mg daily; however, side effects tend to wear off over time; efficacy maintained for 52 wk of trial; no
problems with tolerance, growth, or blood pressure; tips and pearls—when given in 200-mg dose for narcolepsy,
trade name Provigil, but 85-mg dose for ADHD will be called Sparlon; children require higher doses than adults;
in women, can decrease effectiveness of contraceptives; little abuse potential
|
| Clonidine and guanfacine: guanfacine soon available as transdermal patch; both drugs may be useful for tics as
well as for impulsiveness and aggression; some reports of sudden death or high blood pressure; causes sedation,
so may be helpful in patient with insomnia; studies of guanfacine in primates indicate it may help with inattention;
in patients with ADHD and tics, combination of methylphenidate and clonidine may help both
|
| Conclusions: ADHD persists into adulthood, but symptom profile changes; adults generally more inattentive but
have less impulsivity and hyperactivity; adults may have more comorbidity; individuals with symptoms only of inattention
may be overlooked; ADHD symptoms related to levels of dopamine, norepinephrine, and histamine;
treatment must be individualized to each patient
|
Educational Objectives
| The goal of this program is to educate the listener about attention-deficit/hyperactivity disorder (ADHD) in adults and
children. After hearing and assimilating this program, the clinician will be better able to:
|
| 1. Differentiate symptoms of ADHD in children from symptoms in adults.
|
| 2. Adapt diagnostic criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-
IV) to adults.
|
| 3. Discuss the neurobiology of ADHD.
|
| 4. Explain the mechanisms of action of several drug classes used to treat ADHD.
|
| 5. Describe new treatments for ADHD that are on the horizon.
|
Suggested Reading
Adler LA et al: Quality of life assessment in adult patients with attention-deficit/hyperactivity disorder treated with
atomoxetine. J Clin Psychopharmacol 26:648, 2006; Aldenkamp et al: Optimizing therapy of seizures in children
and adolescents with ADHD. Neurology 67(Suppl 4):S49, 2006; Bostic JQ, Prince JB et al: Pemoline treatment of
adolescents with attention-deficit/hyperactivity disorder: a short-term controlled trial. J Child Adolesc Psychopharmacol
10:205, 2000; Davis WB et al: Steady-state clinical pharmacokinetics of bupropion extended-release in youths. J
Am Acad Child Adolesc Psychiatry 45:1503, 2006; Dowson JH et al: Questionnaire ratings of attention-deficit/hyperactivity
disorder (ADHD) in adults are associated with spatial working memory. Eur Psychiatry Nov 30, 2006
[Epub ahead of print]; Gunter TD et al: Adult outcomes of attention-deficit/hyperactivity disorder and conduct disorder:
are the risks independent or additive? Ann Clin Psychiatry 18:233, 2006; Lee SS et al: Association of dopamine
transporter genotype with disruptive behavior disorders in an eight-year longitudinal study of children and
adolescents. Am J Med Genet B Neuropsychiatr Genet Dec 27, 2006 [Epub ahead of print]; Newcorn JH et al: Atomoxetine
Low-dose Study Group. Low-dose atomoxetine for maintenance treatment of attention-deficit/hyperactivity
disorder. Pediatrics 118:e1701, 2006; Prince JB et al: A controlled study of nortriptyline in children and adolescents
with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 10:193, 2000; 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; Rybak YE et al: An open trial
of light therapy in adult attention-deficit/hyperactivity disorder. J Clin Psychiatry 67:1527, 2006; Schredl M, Alm
B, Sobanski E: Sleep quality in adult patients with attention-deficit/hyperactivity disorder (ADHD). Eur Arch Psychiatry
Clin Neurosci Nov 25, 2006 [Epub ahead of print]; Singh MK et al: Co-occurrence of bipolar and attention-
deficit/hyperactivity disorders in children. Bipolar Disord 8:710, 2006; Solhkhah R, Prince JB 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; Spencer TJ et al: Adult ADHD Research Group.
Efficacy and safety of dexmethylphenidate extended-release capsules in adults with attention-deficit/hyperactivity disorder.
Biol Psychiatry Nov 28, 2006 [Epub ahead of print]; Stahl SM: Neurotransmission of cognition, part 1:
Dopamine is a hitchhiker in frontal cortex; norepinephrine transporters regulate dopamine. J Clin Psychiatry 64:4,
2003; Stahl SM: Neurotransmission of cognition, part 2. Selective NRIs are smart drugs: exploiting regionally selective
actions on both dopamine and norepinephrine to enhance cognition. J Clin Psychiatry 64:110, 2003; Stahl SM:
Neurotransmission of cognition, part 3. Mechanism of action of selective NRIs: both dopamine and norepinephrine increase
in prefrontal cortex. J Clin Psychiatry 64:230, 2003; Volkow ND et al: Brain dopamine transporter levels in
treatment and drug naive adults with ADHD. Neuroimage Nov 22, 2006 [Epub ahead of print]; Wilens TE, Prince
JB et al: Adjunctive donepezil in attention-deficit/hyperactivity disorder youth: case series. J Child Adolesc Psychopharmacol
10:217, 2000; Wilens TE, Prince JB et al: An open trial of bupropion for the treatment of adults with attention-deficit/hyperactivity
disorder and bipolar disorder. Biol Psychiatry 54:9, 2003.
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. For this issue,
Dr. Prince disclosed that he is on the Speakers’ Bureaus of McNeil and Shire, and is a consultant to Cephalon, McNeil,
and Novartis. Dr. Stahl disclosed that he has received honoraria and/or has been a consultant for Cephalon,
Pfizer, Bristol-Myers Squibb, and Eli Lilly. Both physicians discussed the off-label use of certain drugs.
Dr. Prince was recorded at Transcendent Tangible Truths from Talented Translucent Teachers, held October 13-14,
2006, in Madison, WI, and sponsored by the University of Wisconsin School of Medicine and Public Health and the
Madison Institute of Medicine, Inc. Dr. Stahl was recorded at the 2006 Psychopharmacology Academy, held June 10-
11, 2006, in San Diego, CA, and sponsored by the Neuroscience Education Institute and the University of California,
San Diego, School of Medicine. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation
in the production of this program.
|
