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Maximizing Treatment Success
New Strategies for Treating ADHD
and Associated Comorbidities
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Network for Continuing Medical Education
This CME activity is supported by an educational grant
from Shire US Inc.
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Treatment of ADHD in Children
Learning Objectives

Characterize the comorbid disorders commonly associated with
attention-deficit/hyperactivity disorder (ADHD) in children,
adolescents, and adults

Apply effective approaches to screening for associated
comorbidities, such as mood disorders, substance use disorder,
and disruptive behavior disorders, in patients with ADHD

Discuss how to differentiate between ADHD and a disorder with
similar features, and ADHD comorbid with that disorder

Assess current pharmacologic and behavioral treatment
strategies for patients with ADHD and various comorbid
disorders

Outline a comprehensive treatment plan that includes other
healthcare professionals in the management of patients with
ADHD and associated comorbidities
Contributing Faculty
Steven R. Pliszka, MD, Chair
Professor and Chief
Division of Child and Adolescent
Psychiatry
University of Texas Health Science
Center at San Antonio
San Antonio, Texas
Russell A. Barkley, PhD
Research Professor
Department of Psychiatry
SUNY Upstate Medical University
Syracuse, New York
Adjunct Professor of Psychiatry
Medical University of South Carolina
Charleston, South Carolina
James Robert Batterson, MD
Child Psychiatrist
Children’s Mercy Hospitals
and Clinics
Kansas City, Missouri
William W. Dodson, MD
Private Practice
Specializing in Adult ADHD
Denver, Colorado
Robert D. Hunt, MD
CEO and Medical Director
Center for Attention and
Hyperactivity Disorders
Nashville, Tennessee
ADHD in Children: Objective

Present strategies for diagnosis and
treatment of disorders commonly comorbid
with ADHD in children and adolescents
– Disruptive behavior disorders
– Anxiety
– Depression
– Bipolar disorder
Empirically Proven Treatments for ADHD
in Children: Psychopharmacology

Stimulants
– Methylphenidate (Ritalin®, Concerta®)
– Mixed amphetamine salts (Adderall®/Adderall XR®)

Nonstimulant
– Atomoxetine (Strattera®)

Other noradrenergic medications
– Bupropion (Wellbutrin®)

Tricyclic antidepressants
– Desipramine (Norpramin®)

Antihypertensives
– Clonidine (Catapres®)
– Guanfacine (Tenex®)
Physicians’ Desk Reference. 59th ed. Montvale, NJ: Thomson PDR; 2005.
Empirically Proven Treatments for ADHD
in Children: Psychosocial Interventions
Parent education about ADHD1,2
 Parent training in child management3
– Children (<11 yrs, 65%-75% respond)
– Adolescents (25%-30% show reliable change)
 Family therapy for teens: problem-solving,
communication training4
– 30% show change
– Best to combine with BMT to reduce dropouts

1. Weiss M. Child Adolesc Psychiatr Clin North Am. 1992;1:467-479.
2. Dulcan M. J Am Acad Child Adolesc Psychiatry. 1997;36:85S-121S.
3. Barkley RA. Defiant Children: A Clinician’s Manual for Assessment and Parent Training.
2nd ed. New York: Guilford Press; 1997.
4. Murphy K. J Clin Psychol. 2005;61:607-619.
Empirically Proven Treatments for ADHD in
Children: Psychosocial Interventions (cont.)

Teacher education about ADHD

Teacher training in classroom behavior
management

Special education services (IDEA, section 504)

Regular physical exercise

Residential treatment (5%-8%)

Parent/family services (25+)

Parent/client support groups (CHADD, ADDA,
independents)
Barkley RA. Attention-Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment.
2nd ed. New York: Guilford Press; 1998.
Major Behavioral Tactics for ADHD
Balance the following two strategies:
 Altering antecedents – getting proactive:
– Giving effective instructions
– Altering performance settings
– Point-of-performance prompts and cues
 Altering consequences – being reactive:
– Positive reinforcement (tokens, rewards, etc.)
– Punishment (time outs, grounding, fines, etc.)
– Changing schedules (increasing frequency and
immediacy of consequences)
DuPaul GJ, Stoner G. ADHD in the Schools. 2nd ed. New York: Guilford Press; 2003.
ADHD in Childhood:
Common Comorbid Diagnoses
Approximate Prevalence Rate
in Children With ADHD (%)
0
10
20
30
40
50
60
Oppositional defiant disorder
Conduct disorder
Mood disorders
Anxiety disorders
Learning disorders
Pliszka SR. J Clin Psychiatry. 1998;59(suppl 7):50-58.
Biederman et al. J Am Acad Child Adolesc Psychiatry. 1999;38:966-975.
Biederman et al. J Am Acad Child Adolesc Psychiatry. 1996;35:343-351.
Spencer et al. Pediatr Clin North Am. 1999;46:915-927.
Male
Female
Disruptive Behavior Disorders
Conduct Disorder (CD)


A repetitive and persistent pattern of behavior in
which the basic rights or well-being of others is
disregarded1
Common symptoms1:
–
–
–
–

Aggression to people or animals
Destruction of property
Deceitfulness or theft
Serious violation of rules
CD may be more severe and persistent when
comorbid with ADHD2
1. American Psychiatric Association. DSM-IV; 1994:85-91.
2. Kuhne et al. J Am Acad Child Adolesc Psychiatry. 1997;36:1715-1725.
Oppositional Defiant Disorder (ODD)

A negativistic, hostile, and defiant pattern of
behavior that varies greatly in severity
 Common symptoms
– Often loses temper
– Often actively defies adults
– Often deliberately annoys people
American Psychiatric Association. DSM-IV; 1994:91-94.
Nature of CD and ODD

A descriptive diagnosis; does not imply etiology

ODD may be secondary to ADHD

CD/ODD may occur even without ADHD

CD/ODD are sometimes due to environmental
factors (late onset)

CD with ADHD may represent a distinct familial
subtype and genetic variant of ADHD

CD with ADHD is a worse condition than either alone
or than their combination would suggest

Most likely has multiple causes
ADHD Without and With CD/ODD
Without
CD/ODD
With
CD/ODD
Prevalence of learning
disorder
↑
↑↑
Risk for delinquent behavior
=
↑↑
Risk for substance abuse
↑ (adult)
↑↑ (adol & adult)
Family history of behavior
problems
=
↑↑
Note: Symbol shows rate relative to controls.
Psychopharmacology of CD/ODD




ADHD children with (and without) CD/ODD respond
to stimulants1
Indeed, effect-size changes in ODD symptoms may
be as large as those in ADHD symptoms in comorbid
cases
No evidence that stimulants increase aggression at
appropriate doses; evidence shows decreased
aggression2
Relative to placebo, ADHD children on stimulants
engage in less antisocial behavior
1. MTA Cooperative Group. Arch Gen Psychiatry. 1999;56:1073-1086.
2. Spencer et al. J Am Acad Child Adolesc Psychiatry. 1996;35:409-432.
ADHD and CD/ODD:
Psychopharmacologic Recommendations

Divalproex: may be effective for explosive
temper and mood lability1
 Risperidone: has reduced disruptive behavior
and hyperactivity2
 Atomoxetine: has produced meaningful
improvement in ADHD and ODD symptoms3
1. Donovan et al. Am J Psychiatry. 2000;157:818-820.
2. Aman et al. J Child Adolesc Psychopharmacol. 2004;14:243-254.
3. Newcorn et al. J Am Acad Child Adolesc Psychiatry. 2005;44:240-248.
Psychosocial Treatment of ADHD
and CD/ODD in Children

When CD/ODD is present, interventions focused on
parenting are essential given the recognized contribution of
parenting to both disorders
 Parent training (PT) in behavior management methods has
strong empirical support, particularly for addressing the
ODD problems in ADHD children
 PT is most effective (65%-75%) with elementary school-age
children but declines markedly by adolescence (30%)
 Problem-solving communication training combined with
behavior management training has the greatest evidence
for effectiveness (30%) for those 14 and older
–
Traditional family therapies are less helpful (10% response rate)
Barkley RA. Attention-Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment.
2nd ed. New York: Guilford Press; 1998.
Psychosocial Treatment of ADHD
and CD/ODD in Children (cont.)




Where CD is present, parental psychological disorders are
highly likely and may require additional intervention beyond
those for the ADHD child1
Family relocation to better neighborhoods and schools may also
be important and assist with disrupting deviant peer groups,
criminogenic neighborhood environments, and ineffective
schools2
Avoid group treatment programs that bring antisocial youth
together, as they have been shown to increase antisocial
behavior outside the group (deviancy training)2
Multisystemic therapy that involves therapists in the home
setting daily is an empirically supported alternative to traditional
clinic-based therapies or incarceration for juveniles3
1. Biederman et al. J Am Acad Child Adolesc Psychiatry. 1996;35:343-351.
2. Dishion et al. Am Psychol. 1999;54(9):755-764.
3. Henggelar et al. J Am Acad Child Adolesc Psychiatry. 2003;42:543-551.
Anxiety and Depressive
Disorders
ADHD and Anxiety Disorders
 Children with ADHD and comorbid anxiety disorders tend
to display:
– High levels of arousal
– Fearfulness, separation anxiety
– Phobias, fear of sleeping alone
– Fear of social situations
– Anxiety beyond that associated with consequences
of misbehavior
 Anxiety symptoms must be overt; should not be assumed
to be present based on ADHD symptoms alone
ONLY SIGNIFICANT, IMPAIRING ANXIETY SHOULD BE
A FOCUS OF PHARMACOLOGIC TREATMENT
Spencer et al. Pediatr Clin North Am. 1999;46:915-927.
ADHD and Comorbid Depression

Major depressive disorder
– Pervasive sadness or
irritability nearly every
day
– Loss of energy
– Guilt
– Serious suicidal
ideation
– Suicidal gestures
– Cannot be reassured
– Chronic low self-esteem

Dysphoria or “demoralization”
– Brief periods of sadness
when frustrated
– Energy normal
– Lack of guilt except when
in trouble
– Brief threats of self-harm
when frustrated
– Responds to redirection
– Positive attitude about
good areas of function
ONLY MAJOR DEPRESSIVE DISORDER SHOULD BE
A FOCUS OF ANTIDEPRESSANT TREATMENT
American Psychiatric Association. DSM-IV; 1994:317-327, 339-350.
Pharmacologic Treatment
of Depression in Children
FDA Meta-analysis

Pooled all studies, published and unpublished

Blinded reviewers at Columbia assessed each
adverse event as to its self-harm potential

N >4,000

No completed suicides

4% suicidal ideation on drug vs 2% on placebo,
statistically significant difference
FDA Public Health Advisory. October 15, 2004. Available at: http://www.fda.gov/cder/drug/
antidepressants/SSRIPHA200410.htm. Accessed June 6, 2005.
Treatment for Adolescents
With Depression Study (TADS)


Response rates
– Fluoxetine + CBT: 71%
– Fluoxetine alone: 61%
– CBT alone: 43%
– Placebo: 35%
Presence of SI
– 29% at baseline
– All 4 groups improved significantly,
but SI still higher in SSRI group
CBT = cognitive-behavioral therapy; SI = suicidal ideation;
SSRI = selective serotonin reuptake inhibitor.
March et al. JAMA. 2004;292:807-820.
Treatment of ADHD With MDD:
Stimulant First vs Antidepressant First

Stimulant first1,2
– ADHD chief complaint
– ADHD symptoms more disabling
– MDD found on interview, no current
functional impairment from depression
– Mild neurovegetative signs
– ADHD symptoms clearly preceded MDD
symptoms
1. Pliszka et al. ADHD with Comorbid Disorders: Clinical Assessment and Management.
New York: Guilford Press; 1999.
2. Pliszka et al. J Am Acad Child Adolesc Psychiatry. 2000;39:908-919.
Treatment of ADHD With MDD:
Stimulant First vs Antidepressant First
(cont.)

Antidepressant first1,2
– Clear history of stimulant nonresponse
– Prominent neurovegetative signs/
health compromised
– MDD present complaint
– ADHD symptoms late onset or coincident
with MDD symptoms
– Suicidal/psychotic
1. Pliszka et al. ADHD with Comorbid Disorders: Clinical Assessment and Management.
New York: Guilford Press; 1999.
2. Pliszka et al. J Am Acad Child Adolesc Psychiatry. 2000;39:908-919.
Treatment of ADHD With Anxiety

Start with stimulant first unless1,2:
– Full-blown panic symptoms
– Full-blown separation anxiety with complete
refusal to separate, but:
 Studies conflict on whether children with
anxiety have poorer response to stimulants
– Consider using atomoxetine for both ADHD and
anxiety or as a supplement to stimulant treatment
– May add SSRI to stimulant to treat anxiety1,2
1. Pliszka et al. ADHD with Comorbid Disorders: Clinical Assessment and Management.
New York: Guilford Press; 1999.
2. Pliszka et al. J Am Acad Child Adolesc Psychiatry. 2000;39:908-919.
Psychosocial Treatment of ADHD
With Anxiety/Depression

Comorbid ADHD/anxiety shows best response to
behavioral and social skills intervention1
 Cognitive therapy relative to ADHD alone or with other
disruptive disorders may be helpful2
–
In behavioral token systems, keep thresholds for success
low initially; high likelihood of success eliminates worry
about earning quotas for privileges

Low self-esteem is specifically associated with comorbid
depression, not due to ADHD
 Use “go slow” approach to punishment contingencies
(eg, time outs) in comorbid ADHD/depression so as not
to contribute to depressive cognitive schemas
–
Start with all-reward programs until depression symptoms
lift, then introduce selective mild punishments
1. MTA Cooperative Group. Arch Gen Psychiatry. 1999;56:1088-1096.
2. Brent et al. Arch Gen Psychiatry. 1997;54:877-885.
Bipolar Disorder
DSM-IV Bipolar Disorders




Bipolar I disorder (manic-depressive illness)
– Manic
– Depressed
– Mixed
Bipolar II disorder
– Hypomania + depression
Cyclothymia
– Hypomania
– Depression
Bipolar disorder NOS
American Psychiatric Association. DSM-IV; 1994:350-366.
Bipolar Disorders in a Community
Sample of Older Adolescents

1,709 high school students
 Mean age, 16.6 ± 1.2 yr
 Randomly selected from 9 senior high
schools
 Time 1 assessment (1987-1989)
– Adolescent Interview
– K-SADS/E/P

Time 2 assessment (14 mos later)
– K-Life
Lewinsohn et al. J Am Acad Child Adolesc Psychiatry. 1995;34:454-463.
Bipolar Disorders in a Community
Sample of Older Adolescents:
Summary

18 Cases – prevalence of ~1%
– 2 Bipolar I disorder
– 11 Bipolar II disorder
– 5 Cyclothymia

97 Bipolar disorder NOS
 Significant functional impairments
 High rates of:
– Psychiatric comorbidity
– Mental health service utilization
Lewinsohn et al. J Am Acad Child Adolesc Psychiatry. 1995;34:454-463.
Bipolar Disorder:
Adult vs Child Criteria
Elation vs irritability1
 Definition of an “episode”2

– “Distinct period”
– Simple cycling
– Complex cycling

Strict adult criteria vs developmentally
appropriate criteria
1. Geller et al. J Affect Disord. 1998;51:81-91.
2. Wozniak et al. J Clin Psychiatry. 2001;62:10-15.
Bipolar Disorder in Children and Adults:
Different Developmental Trajectories?
Pediatric Euphoric BPs
Mood State
Manic
?
Adult Subtype
BP NOS?
Euthymic
ADHD Rx
Adolescent Subtype
BP II or I
Depressed
0
2
4
6
8
10
12
14
Age/Years
16
18
20
22
Treatment of Pediatric Bipolar Disorder:
Mood Stabilizers

Study of 42 outpatients (mean age, 11.4 yr)
with bipolar I or II disorder randomized to
open treatment with lithium, divalproex, or
carbamazepine over a 6- to 8-week period
– Low-dose chlorpromazine allowed as
“rescue medication”
 All 3 mood stabilizers showed a large effect
size, as measured by a ≥50% change from
baseline to exit in the Y-MRS scores
Y-MRS = Young Mania Rating Scale.
Kowatch et al. J Am Acad Child Adolesc Psychiatry. 2000;39:713-720.
Mood Stabilizer Treatment of Pediatric Bipolar
Disorder: Responders’ Pattern of Response
Mean Young MRS Score
35
Carbamazepine
30
Valproate
Lithium
25
20
15
10
5
0
Random.
1
2
3
4
5
6
7
Week
Reproduced with permission from Kowatch et al. J Am Acad Child Adolesc Psychiatry.
2000;39:713-720.
8
Potential Mood Stabilizers






Gabapentin (Neurontin®): negative
Lamotrigine (Lamictil®): BP depressed, maintenance
of BP, risk of rash/Stevens-Johnson syndrome
Tiagabine (Gabitril®): negative
Topiramate (Topamax®): trials in adults negative;
trials in children discontinued
Oxcarbazepine (Trileptal®): new risk of rash/StevensJohnson syndrome
FDA performing review of anticonvulsants and the
risk of suicide
Atypical Antipsychotics

Current agents
– Risperidone
– Olanzapine
– Quetiapine
– Ziprasidone
– Aripiprazole
 Powerful
 Sometimes necessary
 Limit use because of
– Sedation
– Weight gain
Kowatch et al. J Am Acad Child Adolesc Psychiatry. 2005;44:213-235.
Antipsychotic Weight Gain: Meta-analysis
5
4
Placebo
Ziprasidone
Haloperidol
Risperidone
Chlorpromazine
Olanzapine
Clozapine
Kg
3
2
1
0
-1
Weight gain
Allison et al. Am J Psychiatry. 1999;156:1686-1696.
ADHD and Mania: Treatment

If floridly manic, stabilize mood before treating ADHD
(or discontinue ADHD treatment until mood stabilized)
– Stimulant may be added to mood stabilizer
or atypical antipsychotic later
 If mania/BP diagnosis is equivocal, treat ADHD first
– If all symptoms resolve, mania unlikely
 If stimulant or ADHD medication induces partial remission
of ADHD and manic symptoms without worsening of
manic symptoms, may add atypical antipsychotic or
classic mood stabilizer (lithium or valproate)
Spencer et al. Attention-deficit/hyperactivity disorder with mood disorders. In: Brown TE, ed.
Attention-Deficit Disorders and Comorbidities in Children, Adolescents, and Adults.
Washington, DC: American Psychiatric Press; 2000:79-124.
ADHD and Mania: Treatment
(cont.)

Use diagnosis of intermittent explosive
disorder for children with severe aggression
but no other symptoms of mania
– Atypical antipsychotic, lithium, or
valproate may be added to stimulant for
treatment of aggression
 Do not use atypical antipsychotic for ODD
symptoms alone
Spencer et al. Attention-deficit/hyperactivity disorder with mood disorders. In: Brown TE, ed.
Attention-Deficit Disorders and Comorbidities in Children, Adolescents, and Adults.
Washington, DC: American Psychiatric Press; 2000:79-124.
Psychosocial Treatment
of ADHD and Bipolar Disorder





Limit behavioral contingencies to all positive approaches
to reduce explosive outbursts in response to parental
limit-setting
Consider Ross Greene’s program for the explosive child
Interventions are more likely to be focused on parental
coping with explosive episodes rather than remediation
of disruptive behavior
Counsel parents on stress management
– ADHD/BPD cases have the highest rates of physical
abuse and PTSD of all ADHD cases
Special educational services in BPD/ED classes under
IDEA are likely given severely disruptive behavior
ADHD in Children: Summary

Strategies for managing ADHD in children comprise a
combination of pharmacologic and psychosocial
interventions, including parent training in behavior
management
 These strategies can also be effective in managing
disorders commonly comorbid with ADHD
– Disruptive behavior disorders
– Depression and anxiety disorders
– Bipolar disorder
 Developing a treatment plan for children with ADHD and
comorbid disorders requires careful evaluation of the
symptoms and severity of each disorder
 Guidelines for effective management of pediatric ADHD
and associated comorbidities are evolving, based on
research findings and clinical experience