ADHD: Identification and Treatment of Comorbid Disorders

1
ADHD Identification and Treatment of Comorbid
Disorders

• Steven R. Pliszka, MD

2
Topics To Be Covered

• ODD/CD
• Pharmacotherapy and Substance Abuse
• Aggression
• Tics
• Mood Disorders

CD conduct disorder
3
ADHDChildhood Common Comorbid Diagnoses
Approximate Prevalence Rate in Children With ADHD
()
Male Female
Biederman J et al. (1996), J Am Acad Child
Adolesc Psychiatry 35(3)343-351 Pliszka SR
(1998), J Clin Psychiatry 59(suppl 7)50-58
Biederman J et al. (1999), J Am Acad Child
Adolesc Psychiatry 38(8)966-975 Spencer T et
al. (1999), Pediatr Clin North Am 46(5)915-927
4
Nature of ODD and CD

• A descriptive diagnosis, does not imply etiology
• ODD may be secondary to ADHD
• ODD or CD may occur even without ADHD
• ODD/CD are sometimes due to environmental factors
  (late onset)
• Most likely has multiple causes

5
Meta-Analyses of the Effects of Stimulants on
Aggression

• Connor et al. (2002)
• 1970-2001, 28 studies
• Mean effect size of stimulants0.84 for overt and
  0.69 for covert aggression
• Pappadopulos et al. (2006)
• 1989-2004, 19 studies, gt1,000 participants
• Mean effect size of 0.78

Connor DF et al. (2002), J Am Acad Child Adolesc
Psychiatry 41(3)253-261 Pappadopulos E et al.
(2006), J Cdn Acad Child Adolesc Psychiatry
15(1)27-39
6
Psychopharmacology of ODD/CD

• ADHD children with ODD/CD respond to stimulants
  as well at those without ODD/CD
• No evidence that stimulants increase aggression
  at appropriate doses
• Relative to placebo, ADHD children on stimulants
  engage in less antisocial behavior

7
ADHD-ODD/CD Issues With Stimulants
Pharmacotherapy and Substance Abuse

• Fear stimulant therapy may lead to substance
  abuse
• Fact untreated ADHD is a significant risk factor
  for substance abuse in adolescence

8
Pharmacotherapy and Substance Abuse Adolescents
With ADHD
Unmedicated
Medicated
45
40
35
30
25
Rate of SA ()
20
15
10
5
0
EtOH Ab/Dep
Drug Ab/Dep
Ab alcohol or drug abuse Dep dependence
Wilens TE et al. (2002), Annu Rev Med 53113-131
9
Pharmacotherapy and Substance Abuse Adults With
ADHD

• Biederman et al.
• May 2008 Am J of Psychiatry
• Adult follow up, 110 patients with ADHD
• No difference between stimulant treated and
  untreated for any substance of abuse

10
Risperidone in Conduct DisorderStudy Design

• 6-week, double-blind, placebo-controlled study
• 110 children aged 5-12 with subaverage IQ (5-12
  years)
• 0.02-0.06 mg/kg/day (0.98 mg/kg/day) mean dose

Snyder R et al. (2002), J Am Acad Child Adolesc
Psychiatry 41(9)1026-1036
11
Efficacy of Risperidone in Conduct Disorder
Change in Aggression Score
Baseline
Wk. 1
Wk. 2
Wk. 3
Wk. 4
Wk. 5
Wk. 6
0
-2
Placebo (N57)
-4
Risperidone (N52)
-6
Mean Reduction in Conduct Scores
-8
-10
-12
-14
-16
-18
Snyder R et al. (2002), J Am Acad Child Adolesc
Psychiatry 41(9)1026-1036
12
Stimulants and antipsychotics
chg from bsl on Aberrant Beh Chk
Weight gain the same in stim vs. non stim
13
Is the combination better?

• On one hand, presence or absence of stimulant
  appears to make no difference, but
• Children on stimulant who entered the study were
  equally as symptomatic as those who were not on
  stimulant
• If stimulant had been stopped and all subjects
  randomized to four groups (Stimulant, placebo,
  SGA and Stimulant SGA), a different result might
  have emerged
• Study speaks mainly to safety issues

14
Combination of Stimulant and SGA

• Armenteros et al. (2007) JAACAP 46 558-565
• 25 children with ADHD and aggression
• Already on a stable dose of stimulant, but still
  had 3 aggressive acts in last week
• Randomzied to placebo or risperidone for 4 weeks

15
Combination of Stimulant and SGA
On Aggression scale, no difference between
placebo and risperidone placebo effect suggest
effect of psychosocial intervention
16
Divalproex Treatment for Youth With Explosive
Temper and Mood Lability A Double-Blind,
Placebo-Controlled Crossover Design

• 20 outpatients
• Mean age 13.8
• 80 male
• 90 special education
• Divalproex
• 6-week crossover trial
  

Donovan SJ et al. (2000), Am J Psychiatry
157(5)818-820
17
Divalproex Treatment for Youth With Explosive
Temper and Mood Lability Response to Treatment
Phase 2Completed Treatment (N15)
Phase 1Initial Treatment (N20)
Improvement
Improvement

N
N

N
N
Treatment
86
6
7
80
8
10
Divalproex
25
2
8
0
0
10
Placebo
Donovan SJ et al. (2000), Am J Psychiatry
157(5)818-820
18
Treatment Plan for ADHD/ODD

• Serotonin reuptake inhibitors (e.g., fluoxetine
  Prozac, paroxetine Paxil) not helpful for
  ADHD per se, rarely help ODD in absence of
  depression
• Rational and irrational polypharmacy

19
CMAP Algorithm for Pharmacologic Management of
ADHD and Aggression
Pliszka SR et al. (2006), J Am Acad Child Adolesc
Psychiatry 45(6)642-657
20
Tics and ADHD

• Many children with tics and ADHD can tolerate
  stimulants without an increase in tics
• Law and Schachar (1999) 12-month study, 91
  children
• MPH treatment did not produce significantly more
  tics than placebo in children with or without
  mild-to-moderate pre-existing tic disorder
• Gadow et al. (1999) 24-month study, 34 children
  with ADHD and tic disorder or Tourettes syndrome
  
• Stimulant treatment was effective in controlling
  ADHD symptoms without adversely affecting tics
• Lipkin et al. (1994), in a review of 122 children
  treated with stimulant medication found 9
  developed transient tics and lt1 developed
  chronic tics

Law SF, Schachar RJ (1999), J Am Acad Child
Adolesc Psychiatry 38(8)944-951 Gadow KD et al.
(1999), Arch Gen Psychiatry 56(4)330-336 Lipkin
PH et al. (1994), Arch Pediatr Adolesc Med
148(8)859-861
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Induction or Exacerbation of Tics

• Tics are usually transient only very rarely do
  patients develop a chronic tic disorder
• When tics occur or increase
• Decrease dose
• Switch to another stimulant
• Adjunct agent to treat tics
• Try nonstimulant medication

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Controlled Trial of MPH and Clonidine
Week 0
Week 4
Week 8
Week 12
Week 16
0
-2
-4
PLA
Change in Y-GTSSTotal Score
-6
MPH
CLON
-8
MPH CLON
-10
-12
-14
Y-GTSS Yale Global Tic Severity Scale Tourette
Syndromes Study Group (2002), Neurology
58(4)527-536
23
CMAP Algorithm for Pharmacologic Management of
ADHD With Comorbid Tic Disorder
Pliszka SR et al. (2006), J Am Acad Child Adolesc
Psychiatry 45(6)642-657
24
Depressive Disorders

• Major depressive disorder
• Dysthymia
• Adjustment disorder with depressed mood
• Chronic dysphoria of adolescence (Non-DSM)
• Ethical aspects of diagnosisdo really help
  people by broadening or ignoring our diagnostic
  criteria?

25
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 suicides
• 4 SI on drug, 2 on placebo, statistically
  significant

Hammad TA et al. (2006), Arch Gen Psychiatry
63(3)332-339
26
Relationship of Suicide and SSRI Prescription Rate
1.8
1.6
1.4
1.2
Number of Suicides per 100,000
1.0
0.8
0.6
0.4
0.2
0
1
2
3
4
5
6
7
8
9
10
Higher SSRI Prescription Rate
Gibbons RD et al. (2006), Am J Psychiatry
163(11)1898-1904
27
Recent Meta Analysis

• Reviewed 27 studies of MDD, OCD and anxiety
  disorders in children and adolescents
• 15 MDD studies
• 6 OCD studies
• 6 anxiety studies
• Included studies not in FDA review
• Number of participants
• MDD 3,430
• OCD 718
• Anxiety 1,162

Bridge JA et al. (2007), JAMA 297(15)1683-1696
28
Recent Meta Analysis (Cont.)
Bridge JA et al. (2007), JAMA 297(15)1683-1696
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Clinical Guidelines

• Based on FDA meta-analysis, we tell families
  there is a 2-4 of SI vs. 1-2 on placebo TADS
  study shows 60-70 chance of improvement of MDD
• Tell families to watch for and report increase in
  agitation or SI
• Use alternative SSRI (sertraline, citalopram) if
  fluoxetine fails, NRI after that1

1CMAP Hughes et al. (in press), J Am Acad Child
Adolesc Psychiatry
30
Algorithm for ADHD and depression
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Issues in Pediatric Bipolar Disorder

• What is the prevalence of BD in childhood and
  adolescence?
• How should diagnostic criteria differ from
  adults, if at all?
• What is the role of the comorbidity of ADHD with
  pediatric BD?
• Aggression and BD
• Controversies in treatment

32
Different Developmental Trajectories?
Pediatric Euphoric BPs
Mood State
?
Adult Subtype
Manic
BP NOS?
Euthymic
ADHD Rx
Adolescent Subtype BP II or I
Depressed
0 2 4 6 8 10 12 14 16 18
20 22
Age/Years
33
What is Bipolar NOS?

• Age 7-17 yrs
• Abnormal mood (anger or sadness) present half the
  day
• Hyperarousal
• Increased reactivity to negative stimuli
• Symptoms present at 1 year, not symptom free for
  longer than 2 months
• Severe in at least one setting (i.e., violence)
  with mild symptoms in at least two settings

Leibenluft, et al. Am J Psychiatry
2003160(3)430-7.
34
Mood Stabilizers

• Classic mood stabilizers
• Lithium, divalproex, carbamazepinedespite use in
  adults, limited studies in children
• Negative studies
• Gabapentin (Neurontin)
• Tiagabine (Gabitril)
• Oxcarbazepine (Trileptal)
• Topiramate (Topamax)
• Lamotrigine (Lamictal)an emerging treatment

35
Lithium, Divalproex Sodium and Carbamazepine in
the Treatment of Bipolar Disorder Study Design

• 42 outpatient participants
• Mean age 11.4 3.0 years
• 6-8 week monotherapy period
• Randomized to lithium, divalproex or
  carbamazepine
• Assessed weekly for 6-8 weeks
• Low dose chlorpromazine allowed as rescue
  medication

Kowatch RA et al. (2000), J Am Acad Child Adolesc
Psychiatry 39(6)713-720
36
Lithium, Divalproex Sodium and Carbamazepine in
the Treatment of BD Response Rates and Effect
Size
Effect Size
ITT Response Rate ()
Medication
1.63
46
Valproate
1.06
42
Lithium
1.00
34
Carbamazepine
p0.66 Kowatch RA et al. (2000), J Am Acad Child
Adolesc Psychiatry 39(6)713-720
37
Lithium, Divalproex Sodium and Carbamazepine in
the Treatment of BD Responders Pattern of
Response
35
Carbamazepine
Valproate
30
Lithium
25
20
Mean Y-MRS Score
15
10
5
0
1
2
3
4
5
6
7
8
Randomized
Week
Kowatch RA et al. (2000), J Am Acad Child Adolesc
Psychiatry 39(6)713-720
38
Divalproex and Lithium for Pediatric Mania

• Kowatch et al. (2006), presented at AACAP meeting
  in Boston
• 150 patients aged 7-17 years randomized to
  divalproex, lithium or placebo for 8 weeks
• Divalproex superior to placebo, trend for lithium
  to be superior to placebo

39
Depakote ER in pediatric mania

• Wagner et al. (2006), presented at AACAP meeting,
  Boston
• 150 adolescents (10-17 years) with mania
  randomzied to placebo or Depakote ER for 4 weeks,
  then enrolled in 6 month open label study
• Titrated to serum level of 80-125 µg/mL
• No difference between Depakote ER and placebo in
  reducing symptoms of mania

40
Valproate and PCOS (Cont.)
12
10
8
Valproate
6
Rate of PCOS ()
Non-Valproate
4
2
0
Type of Mood Stabilizer
p0.002 Joffe H et al. (2006), Biol Psychiatry
59(11)1078-1086
41
SGA Antipsychotics

• Current agents
• Risperidone
• Olanzapine (Zyprexa)
• Quetiapine (Seroquel)
• Ziprasidone (Geodon)
• Aripiprazole (Abilify)

• Powerful
• Sometimes necessary
• Limit use because of ...
• Sedation
• Weight gain

42
Olanzapine in pediatric mania

• Tohen et al. Am J Psychiatry 164 1547
• 161 adolescents randomized to placebo or
  olanzapine
• Difference from placebo noted in week 1, very
  significant difference by week 3
• Very serious weight gain and increase in serum
  lipids, glucose

43
Quetiapine in pediatric mania

• Delbello et al. (AACAP, 2006)
• 277 randomized to quetiapine (400/600) or placebo
  for 3 weeks
• Difference from placebo at days 4 and 7
• Sedation common (28-30)
• 1.7 kg (3.7 lbs) weight gain

44
Aripiprazole in pediatric mania
N 296 4 week study Remission rates Low
EPS Little wt gain
Chang et al, (2006) presented at AACAP
45
Antipsychotic Weight Gain Meta-Analysis

• 95 CI for weight change after 10 weeks on
  standard drug doses, estimated from a random
  effects model

6 5 4 3 2 1 0 -1 -2 -3
Placebo Conventional antipsychotics Novel
antipsychotics
95 CI for Weight Change (kg)
Placebo
Clozapine
Haloperidol
Olanzapine
Risperidone
Ziprasidone
Chlorpromazine
Allison DB et al. (1999), Am J Psychiatry 156(11)
1686-1696
46
Thank you