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 socialinteraction 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

• Alpha Agonists (clonidine)

• Psychostimulants

• Atomoxetine

• Antipsychotics?

Medication options

for ADHD in ASD

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

• 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

RUPP Study of MPH in Children

with ASD + Hyperactivity

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

12

(26%)

15

(32%)

13

(28%)

6

(13%)

Autism

(N=47)

6

(32%)

7

(37%)

7

(37%)

6

(32%)

Asperger’s/

PDDNOS

(N=19)

HighMediumLowPlb

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

Direct on noradrenaline, indirect on dopamine

Time (hours)-1 0 1 2 3 4

% v

s.

ba

se

lin

e i

n p

refr

on

tale

co

rte

x

0

50

100

150

200

250

300

350

400

Serotonin

Dopamine

Noradrenaline

Atomoxetine1 mg/kg i.p.

* P < 0.05 vs. baseline

*

*

Bymaster et al.2002

Data from rat study

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 AtomoxetineHydrochloride and Placebo for Symptoms of Attention-

Deficit/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 II SP III

Visit 1

Screening /wash-out

Atomoxetine 1.2 mg/kg/day

Placebo

SP I

Visit 2 Visit 6 Visit 11

3-28 days

1 wk

1 1 13 3 123 3

Open-label atomoxetine*

* 1.2 mg/kg/day; the dose may be lowered to 0.8 mg/kg/day

Attachment 2

ADHD rating scale (p<.001)

MMRM LS-mean at endpoint (95% CI): Atomoxetine 31,6 (29,2-33,9); Placebo 38,3 (36,0 -40,6)

-1,2

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

0%0%Very much -

6.5%4.7%Much -

6.5%9.3%Minimally -

65.2%37.2%No change

13.0%27.9%Minimally +

6.5%20.9%Much +

2.2%0%Very much +

PLB ATX

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%)

• Appetite decrease (24.2%)

• Difficulty falling asleep (18.2%)

• Emotional outburst (13.6%)

• Irritability (12.1%)

• Stomach or abdominal discomfort (7.6%)

Rupp, 2005RADAR

Adverse eventsADHD+ASD versus ADHD only

• Nausea (29%)

• Decreased appetite

(27%)

• Headache (25%)

• Fatigue (23%)

• Abdominal pain upper

(19%)

• Vomiting (15%)

• Early morning awakening

(10%)

• 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 AtomoxetineRADAR, 2009

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 fortreatment in ASD

• Both MPH and ATX effective treatments, but not for every child!

• Children with ASD show less predictable, less robust response, and tend toexperience 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 self-injurious 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