Role of ADHD medication in children with autism spectrum disorder Pieter Hoekstra

Role of ADHD medication in
children with autism
spectrum disorder
Pieter Hoekstra
University of Groningen,
Netherlands
Symptoms of ADHD are highly
prevalent in children with ASD
Two independent chart reviews reported that
59% (Goldstein & Schwebach, 2004) and
78% (Lee & Ousley, 2006), respectively, of
referred children with ASD fulfilled full DSM IV
criteria for an ADHD subtype.
Overlap between ADHD and
Autism
ADHD comorbidity in ASD
needs clinical attention
ASD+ADHD:
– more general psychopathology
(internalizing + externalizing symptoms)
– more impairments on the social
interaction scale of the ADI-R
Holtmann et al., 2005
ADHD comorbidity in ASD
needs clinical attention
ADHD symptoms in children with ASD
– associated with more severe oppositional,
aggressive, and ASD symptoms
– can interfere with ability to benefit from
psychosocial treatments
Gadow, DeVincent, & Pomeroy, 2006
Medication options
for ADHD in ASD
•
•
•
•
Alpha Agonists (clonidine)
Psychostimulants
Atomoxetine
Antipsychotics?
Clonidine
• Open label retrospective study (N=19)
• Improvement in reducing sleep initiation
latency and night awakening,
• To a less degree improvement in ADHD,
mood instability, and aggressiveness
Ming et al Brain & Development 30 (2008) 454–460
Clonidine cross-over with placebo
• N=8
• Improvement on
–
–
–
–
ABC irritability
Stereotypy,
Hyperactivity
Inappropriate speech
• Main side effects
– Drowsiness
– Decreased activity.
Jaselskis et al (1992) J Clin Psychopharmacol. 12(5):322-7
Transdermal clonidine
Plb cross-over trial
• N=9
• Improvement on three subscales of the
Ritvo-Freeman Real Life Rating Scale:
– social relationship to people
– affectual responses
– sensory responses
• Sedation and fatigue during the first 2
weeks of clonidine treatment
Fankhauser et al, (1992). J Clin Psychiatry; 53(3):77-82
Clonidine conclusions
• Very few controlled data!
• Positive effects on sleep latency and
hyperactivity?
• Is effect sedating or truly enhancing
inattention?
Methylphenidate
• Historical data and beliefs negative
• Small studies support use of MPH in
autism
• Anecdotal reports of a high frequency of
adverse drug reactions including
stereotypies and social withdrawal
Quintana et al (1995), J Autism dev Disorders
Handen et al (2000), J Autism Dev Disorders
RUPP Study of MPH in Children
with ASD + Hyperactivity
• 72 children with autism, Asperger’s, or
PDDNOS and significant ADHD symptoms
• Design
– 7-day test dose period
– 4-week double blind cross-over trial of 3 dose
levels (0.125, 0.25, 0.50 mg/kg/dose) of MPH
t.i.d. and placebo in random order
RUPP (2005) Arch Gen Psychiatry
Test-dose phase
• 6 out of 72 subjects were unable to
tolerate > 2 dose levels of MPH and were
dropped from the study
• 16 out of the remaining 66 subjects had
intolerable adverse effects at the highest
dose of MPH; entered modified crossover
phase
• Irritability was the most common reason
for intolerability
Cross-over phase
• 58/66 subjects completed the cross-over
phase
• 7 subjects dropped out due to intolerable
adverse effects
• Significant main effect of dose of MPH on
the ABC hyperactivity subscale as rated
by both teacher (p=0.009) and parent
(P<0.001)
Cross-over phase:
Other ABC Subscales
• Worsening of parent-rated social
withdrawal at high-dose MPH (P<0.001)
• No changes in other subscales (irritability,
stereotypy, inappropriate speech)
Categorical response
Asperger’s/
PDDNOS
(N=19)
Autism
(N=47)
Plb
Low
Medium High
6
(32%)
7
(37%)
7
(37%)
6
(32%)
6
(13%)
13
(28%)
15
(32%)
12
(26%)
Most common side effects of
MPH in ASD
•
•
•
•
•
Appetite decrease (24%)
Difficulty falling asleep (18%)
Emotional outburst (13%)
Irritability (12%)
Stomach discomfort (7%)
Rupp, 2005
MPH RUPP
summary
• Methylphenidate superior to placebo
(effect sizes 0.20 to 0.54) on hyperactivity
ABC (MTA: 0.35-.1.31)
• 35/72 (49%) responders.
• Discontinuation 18% (MTA: 1.4%)
• No effect on irritability, lethargy/social
withdrawal, stereotypy, or inappropriate
speech
Methylphenidate-secondary
effects
• Hyperactivity and impulsivity improved more
than inattention.
• No effects on ODD or stereotyped and repetitive
behavior
• Effects on joint attention initiations, response to
bids for joint attention, self-regulation, and
regulated affective state (examined through
direct observation)
Jahromi et al, 2008; Posey et al, 2007
Atomoxetine
% vs. baseline in prefrontale cortex
Direct on noradrenaline,
indirect on dopamine
Serotonin
Dopamine
Noradrenaline
400
350
* P < 0.05 vs. baseline
300
250
*
200
*
150
100
50
Atomoxetine
1 mg/kg i.p.
0
-1
0
1
2
3
4
Time (hours)
Data from rat study
Bymaster et al.2002
Three open label studies;
atomoxetine in ASD
• Posey, et al; Journal of Child & Adolescent
Psychopharmacology, 16, 5, 2006; 599-610
n=16, 75% improved on the CGI-I
• Troost, et al; Journal of Child & Adolescent
Psychopharmacology, 16, 5, 2006; 611-619
n=12 , decreased with 44% measured by the
ADHDRS
• Jou, et al; Journal of Child & Adolescent
Psychopharmacology, 15, 2, 2005; 325-330
n=20, 60% response
Placebo controlled
cross-over study
• 6 weeks atx vs placebo (n=16)
• ATX superior to placebo (p=.043, effect
size d=0.90).
Arnold et al, 2006
A Randomized, Double-blind Comparison of Atomoxetine
Hydrochloride and Placebo for Symptoms of AttentionDeficit/Hyperactivity Disorder in Children and Adolescents with
Autism Spectrum Disorder
Sponsored by Eli Lilly and company
RADAR study
•
•
•
•
Dutch multi-center study (n=97)
Children with ASD plus ADHD
Atomoxetine versus placebo (8 weeks)
Open label extension (16 weeks)
Study design
SP I
SP II
SP III
Atomoxetine 1.2
mg/kg/day
Open-label
atomoxetine*
Screening /
wash-out
Placebo
Attachment 2
3-28
days
Visit 1
1
wk
Visit 2
1
3
3
11
3
Visit 6
* 1.2 mg/kg/day; the dose may be lowered to 0.8
mg/kg/day
3
12
Visit 11
ADHD rating scale (p<.001)
-1,2
MMRM LS-mean at endpoint (95% CI): Atomoxetine 31,6 (29,2-33,9); Placebo 38,3 (36,0 -40,6)
Inattentive symptoms (p=.003)
MMRM LS-mean at endpoint (95% CI): Atomoxetine 17,2 (15,9-18,4); Placebo 19,9 (18,7 -21,1)
Hyperactive/impulsive symptoms
(p<.001)
MMRM LS-mean at endpoint (95% CI): Atomoxetine 14,5 (13,0-15,9); Placebo 18,4 (17.0 -19,7)
Teacher ADHD ratings (p=.077)
LOCF LS-mean at endpoint (95% CI): Atomoxetine 15,1 (13,0-17,2); Placebo 17,8 (15,7 -19,8)
Teacher hyperactivity ratings
(p=.024)
*
LOCF LS-mean at endpoint (95% CI): Atomoxetine 6,8 (5,5 - 8,0); Placebo 8,8 (7,6 -10,0)
Atomoxetine
categorical response
ATX
PLB
0%
2.2%
Much +
20.9%
6.5%
Minimally +
27.9%
13.0%
No change
37.2%
65.2%
Minimally -
9.3%
6.5%
Much -
4.7%
6.5%
0%
0%
Very much +
Very much -
Adverse events;
ATX-Radar vs MPH-RUPP
• Appetite decrease
(27.1%)
• Initial insomnia (6.3%)
• Feeling abnormal
(4.2%)
• Agitation (2.1%)
• Abdominal pain
(18.8%)
RADAR
• Appetite decrease
(24.2%)
• Difficulty falling
asleep (18.2%)
• Emotional outburst
(13.6%)
• Irritability (12.1%)
• Stomach or
abdominal discomfort
(7.6%)
Rupp, 2005
Adverse events
ADHD+ASD versus ADHD only
• Nausea (29%)
• Decreased appetite
(27%)
• Headache (25%)
• Fatigue (23%)
• Abdominal pain upper
(19%)
• Vomiting (15%)
• Early morning awakening
(10%)
RADAR, 2009
• Nausea (10-11%)
• Decreased appetite
(16%)
• Headache (19%)
• Fatigue (1-10%)
• Abdominal pain upper
(18%)
• Vomiting (10-11%)
• Early morning awakening
(0.1-1%)
SPC Atomoxetine
Main conclusions of
atomoxetine trial
•
•
•
•
•
Atmoxetine is better than placebo
Most effects in hyperactivity domain
Not many true responders
Less robust effects than ADHD as such
Relatively well tolerated but more adverse
events than in ADHD as such
Conclusions
• ADHD symptoms frequent in ASD
• ADHD symptoms important focus for
treatment in ASD
• Both MPH and ATX effective treatments,
but not for every child!
• Children with ASD show less predictable,
less robust response, and tend to
experience more side effects
Future focus
• Effective treatments for non-responders
• Identification of treatment moderators
• Effectiveness of combined treatments
• Better treatments!!
What about antipsychotics?
• Risperidone
• Aripiprazole
Risperidon for irritability (Rupp,
2002)
• Multisite, randomized, double-blind trial
of risperidone versus placebo
• Autistic disorder accompanied by
severe tantrums, aggression, or selfinjurious behavior
• N=101 (5 to 17 years old)
• Mean daily dose 1.8±0.7 mg (range,
0.5-3.5)
Decrease in irritability
CGI Improvement status
Risperidone for core symptoms of
autism?
• Improvements in restricted, repetitive, and
stereotyped patterns of behavior, interests,
and activities
• No change in social interaction and
communication.
McDougle et al, 2005
Risperidone effective on longer
term
• Double-blind discontinuation after 24 weeks of
treatment; placebo switch versus continuing use
of risperidone
• Risperidone superior in preventing relapse: in 3
of 12 patients (25%) continuing on risperidone
versus 8 of 12 (67%) switched to placebo
(Troost et al, 2005)
• Rupp (2005): 12.5% (risperidone) versus 62.5%
(placebo)
Cognitive effects of risperidone:
sedation or enhancement
• No deterioriation of focused attention
• Improvement of divided attention
Troost et al., 2006
• Better on a verbal learning task (word
recognition and spatial memory task). No
deterioration.
Amman et al., 2008
Side effects of risperidone may be
genetically based
• Weight gain:
– 5HT2C promoter T allele carriers (22%):
0.017 BMI z scores (1.84 + 1.51 kg)
– Non-T carriers 0.64 + 0.35 z (3.23 + 1.47 kg)
Hoekstra et al (under review)
• Prolactin elevation:
– Positively associated with number of functional
CYP2D6 genes
Troost et al, 2007
Aripiprazole for irritability
• N=218
• 8 weeks: placebo/5/10/15 mg (fixed dose)
• Decrease in ABC-I: 12.4-14.4 (5-15 mg
ari) vs 8.4 (plb)
• Weight gain 1.3 kg vs placebo 0.3 kg
(risperidone RUPP 2.7 vs 0.8 kg)
Marcus et al, 2009
Aripiprazole-flexible dose
• N=98; 8 weeks
• Placebo or aripirazole (5-15 mg)
• 12.9 vs 5.0 decrease ABC-I
(Rupp risperidone 14.9 vs 3.6)
• Weight gain 2.0 vs 0.8 kg
Owen et al., 2009