Psychopharmacology in autism: Fifteen Years of Progress, Long Way to Go
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Psychopharmacology in autism: Fifteen Years of Progress, Long Way to Go
Lawrence Scahill, MSN, PhDProfessor of Nursing & Child Psychiatry
Director of the Research Unit on Pediatric Psychopharmacology
Yale Child Study Center
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Disclosures• Consultant
- Biomarin- Roche - Bracket
• Research Funding- NIMH, NICHD- Shire Pharmaceuticals- Roche Pharmaceuticals- Pfizer- Tourette Syndrome Association
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NIH Multisite Trials in Children with ASDs past 14 yearsStudy N Target Ages Date Published
Risperidone vs placebo
101 Irritability 5-17 2002 NEJM
Methylphenidate vs placebo
66 Hyperactivity 5-14 2005 Arch Gen Psych
Citalopram vs placebo
149 Repetitive Behavior
5-17 2009 Arch Gen Psych
Risperidone vsRIS + Parent Training
124 Irritability & Adaptive Behavior
4.5-13
2009, 2012
J Am Acad Child Psych
Parent Training vs Parent Education
180 Irritability & Adaptive Behavior
3-7 In process
Guanfacine vs placebo
112 Hyperactivity 5-14 In process
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Psychopharmacology in ASDs
Outline• Goal of Clinical Research• Definition of ASD• Modern sociology of autism • Psychopharm Scorecards • Two Risperidone Trials • Future Directions
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Goal of Clinical Research
• Provide guidance to clinicians on the selection and staging of treatment interventions
• Identify the probability that a given treatment will benefit patients with specific characteristics
• Identify the magnitude of change, the time to effect and the risk/benefit ratio
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What Every Mother Wants to Know
If my child starts this medicine:• What are the chances that it will work?• If it works, how much will it help?• How long will it take to ‘kick in?’• How long will my child have to stay on the
medicine?• What are the short- and long-term side
effects?
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Autism Spectrum Disorders (ASDs)
• Autism• Asperger’s Disorder• Pervasive Developmental Disorder-Not
Otherwise Specified (PDD-NOS)
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Autism Spectrum Disorders (ASD)
• Early onset (before 30 months of age)• Delayed social interaction• Delayed & deviant communication
(not in Asperger’s)• Repetitive behaviors & restricted interests
(stereotypy, fans and air conditioners, British royalty)
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DSM-IV Differential diagnosis: Plain & Simple
ASD Social Language Repetitive Type Delay Delay Behavior* Autism Yes Yes Yes
Asperger’s Yes No Yes
PDD-NOS Yes Maybe Maybe
* or Restrictive Interests (preoccupied with train schedules, fans, air conditioners, horses)
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ASDs: Other Essential Features • 4:1 male to female• 30% to 70% Mentally Retarded • Impaired daily living skills (not explained by MR)• 25% have seizures • High rates of serious behavioral problems,
hyperactivity and anxiety
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Prevalence: How Common are ASDs?• Historically
- Autism 2 to 5 cases per 10,000 • Current
- Autism: 20 per 10,000 - ASDs: 110 per 10,000
• Is there a true rise in the frequency of ASDs?
Center for Disease Control, 2012*****
≈ 550,000 school-age
children
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Prevalence is all about counting cases
• Counting all cases (rarely achieved)• Clinically-referred cases
– subset of all cases (invariably underestimates prevalence)
• Community surveys– Necessary, but costly and not easy
prevalence is always an estimate!)
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Reasons for Increasing Prevalence
• Broadening of diagnostic rules• Better population sampling • Better diagnostic methods (especially
among lower IQ and higher IQ children)
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Sociology of Autism
• Refrigerator mothers• Rising Prevalence• Secretin• Vaccines• Andrew Wakefield• Doug Flutie
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Lancet retracts ‘utterly false’ MMR paper guardian.co.uk 2/2/2010
Andrew Wakefield, 1998 paper in Lancet – retracted
due to misconduct
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www.dougflutiejrfoundation.com
Reduced stigma (Doug Flutie factor)
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The ABCDs of DSM-V
• A: Deficits in social communication and social interaction (blends social with communication)
• B: Restricted, repetitive patterns of behavior (includes insistence on sameness)
• C: Symptoms are present in early childhood• D: Symptoms impair everyday functioning
www.dsm5.org/ProposedRevisions
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Target of Medication
• Core Features of Autism– Social Interaction– Repetitive Behavior/Restricted Interests – Impaired Communication
• Specific Behavioral Problems– Hyperactivity– Tantrums, Aggression, Self-injury– Anxiety
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Drugs Used in ASD
• Haloperidol• Fenfluramine • Clonidine • Guanfacine
• Naltrexone • Propranolol • Stimulants
• Clomipramine, SSRIs • Atomoxetine • Secretin• Amantadine, memantine • Oxytocin• Anticonvulsants• Atypical antipsychotics
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Drug trials in ASD with sample size > 60 subjects Drug target Resultsfenfluramine Social interaction Act=Plasecretin Social Interaction A=Prisperidone Tantrums/aggression A > P +++aripiprazole Tantrums/aggression A > P ++methylphenidate Hyperactivity A > P +citalopram Repetitive behavior A=Pfluoxetine Repetitive behavior A=P+ = small effect; ++ = medium; +++ = large
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Most Common Drug Classes in ASD
• SSRIs• Atypical Antipsychotics*• Stimulants
* risperidone & aripiprazole are FDA-approved for children with autism and irritability
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SSRIs in Children with ASDsTarget Repetitive
BehaviorRigidity (Trouble with Transitions)
Anxiety Irritability
Rationale Effective for OCD (repetitive behavior)
Need for sameness (? obsessional or anxiety)
Effective in anxiety disorders
? Mood/ Anxiety over-reaction in everyday living situations
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Treatment of Repetitive Behavior in ASDs
PlaceboDrug open controlled N > 60Fluoxetine X X XFluvoxamineX XCitalopram X X XSertraline XEscitalopramXClomipramine* X X Not commonly used in ASDs
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Serotonin System
Nolte & Angevine, 1995
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Neuropharm “a specialty pharmaceutical group focused on the development of drugs for the treatment and management of selected developmental and degenerative disorders.”
www.stockopedia.co.uk/share-prices/neuropharm-LON:NPH/
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www.fiercebiotech.com/story/neuropharm-shares-tank-phase
-iii-failure/2009-02-18“NPL-2008 failed to demonstrate a significant reduction in repetitive behavior in autistic pateints when compared to placebo. A totral of 158 pateits, aged between 5 and 17, were enrolled into the SOFIA study in which patient received either NPL-2008 or placebo during a 14-week treatment period.”
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STAART Consortium: Citalopram in PDD
• RCT in 149 subjects with PDD (Age 5 to 17)• Citalopram (n=73) or placebo (n=76) 12 Weeks• Primary outcomes Clinical Global Impression -
Improvement and a clinician measure of repetitive behavior (CYBOCS-PDD).
King et al., STAART Group (2009) Arch Gen Psych
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Citalopram vs Placebo (N=149)
1 = Very Much Improved2 = Much Improved3 = Minimally Improved4 = No Change5 = Minimally Worse6 = Much Worse7 = Very Much Worse
Clinical Global Impression-Improvement
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0 %
1 0 %
2 0 %
30%
4 0 %
5 0 %
6 0 %
7 0 %
8 0 %
9 0 %
0 2 4 6 8 1 0 1 2
Muc
h Im
prov
ed o
r Ver
y M
uch
Impr
oved
P l a c e b o
C it a l o p r a m
Week
p = 0·94
Much Improved or Very Much Improved on (CGI-I) over 12-Week
N=149
p=0.94
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Citalopram vs Placebo: Adverse Events*
Adverse Event CITAL PLAN (%) N (%)
energy 28 (38.4%) 15 (19.7%)- initial insomnia 17 (23.3%) 7 (9.2%)impulsiveness14 (19.2%) 5 (6.6%)↓ concentration 9 (12.3%) 2 (2.6%) Hyperactivity 9 (12.3%) 2 (2.6%) Stereotypy 8 (11.0%) 1 (1.3%) Diarrhea 19 (26.0%) 9 (11.8%) initial insomnia 17 (23.3%) 7 (9.2%)
* < .05; King et al., STAART Group (2009) Arch Gen Psych
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Conclusions: SSRIs in Children with ASDs
Evidence Repetitive Behavior
Anxiety Rigidity (trouble with Transitions)
Irritability
Placebo-controlled
yes no nono?
open yes yes yes yes
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Treatment of Hyperactivity in Children with ASDs
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Hyperactivity in ASD: Brief Background
• DSM-IV - don’t diagnose ADHD in children with ASD
• Hyperactivity, disruptive behavior, and impulsiveness are common in children with ASD
• Community surveys show that stimulants are commonly used in children with ASD
• Evidence was limited
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Treatment of Hyperactivity in PDD
Drug open controlled N > 60Methylphenidate X XAtomoxetineX XClonidine X XGuanfacine X XAmantadine X XNaltrexone X X
RUPP TrialMPH > PLA
Effect size: small to medium
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RUPP Autism Network: Methylphenidate in Children
With PDD + Hyperactivity
RUPP = Research Unit on Pediatric Psychopharmacology
RUPP Autism Network. Arch Gen Psych 2005;62(11):1266-74
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Dopamine System
Nolte & Angevine, 1995
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MPH in Children With PDD + Hyperactivity: Subject Characteristics in Crossover
• Sample N=66 (59 boys, 7 girls) • Mean age = 7.5 2.2 years (range 5.0-13.7)• Mean IQ = 63 33• Autism = 56• Three doses of MPH and placebo in random order
RUPP Autism Network. Arch Gen Psych. 2005;62(11):1266-74
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MPH Improvement on Teacher Rating of ADHD symptoms
Dose Level % Change*
RUPP Low 12%RUPP Medium 13%RUPP High 17%
* Corrected for Placebo
In ADHD ≈ 40% over placebo
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MPH in PDD: Conclusions1) At low doses (12.5-25 mg/day), the
medicine helps about 50-60% of children.2) At low doses, it will produce about 20%
improvement3) At low doses, it will be well-tolerated4) Higher doses are unlikely to bring about
additional benefit and may risk of adverse effects
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Treatment of Serious Behavioral Problems in Children with ASDs
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Atypical Antipsychotics in ASDPlacebo
Drug open controlled N > 60
Risperidone* X X XOlanzapine XZiprasidone X Quetiapine XAripiprazole* X X X
* FDA Approved for Rx of ‘irritability’ in autism
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DA Synapse
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Research Units on Pediatric Psychopharmacology Autism
NetworkRisperidone Trials
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RUPP Risperidone: Sample
• N=101 (82 males, 19 females)– Risperidone: N=49– Placebo: N=52
• 8-week, randomized, double-blind, placebo-controlled, parallel groups
• Mean age = 8.8 years (range 5-17)
RUPP Autism Network. NEJM, 347(5): 314-321.
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ABC Irritability Scores at Baseline and End Point by Treatment Group
Risperidone Placebo
ABC Baseline End Point Baseline End PointScale Mean (SD) Mean (SD) Mean (SD) Mean (SD) Irritability 26.2 (7.9) 11.3 (7.4) 25.5 (6.6) 21.9 (9.5)
p<0.0001; Effect Size = 1.3; RUPP Autism Network. NEJM, 347(5): 314-321.
Mean Dose=1.8 mg/day
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RUPP Autism Network: Irritability Scale
RUPP Autism Network. NEJM, 347(5): 314-321.
0
5
10
15
20
25
30
0 2 4 6 8
Week
AB
C Ir
ritab
ility
Tot
al
Risperidone mean
Placebo mean
Mean =1.8 mg/day; ES=1.3
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Clinical Global Impression-Improvement
1 = Very Much Improved2 = Much Improved3 = Minimally Improved4 = No Change5 = Minimally Worse6 = Much Worse7 = Very Much Worse
RUPP Autism Network. NEJM, 347(5): 314-321.
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Clinical Global Impressions-Improvement
RUPP Autism Network. NEJM, 347(5): 314-321.
0102030405060708090
0 1 2 3 4 5 6 7 8
Week
Perc
enta
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f Par
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ants
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I-I <
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Risperidone
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RUPP Risperidone Study: Adverse Effects
Appetite (Mild) 24 (49.0) 15 (28.8) 0.05
Appetite (Mod) 12 (24.5) 2 (3.8) 0.01
Tiredness 29 (59.2) 14 (26.9) 0.002
Drowsiness 24 (49.0) 6 (11.8) <0.001
Drooling 13 (26.5) 3 (5.8) 0.01
Tremor 7 (14.3) 1 (1.9) 0.05
Mean Weight Gain (kg) 2.7 2.9 0.8 2.2 <0.01
RUPP Autism Network. NEJM, 347(5): 314-321.
RISP (N=49) PLA (N=52)Adverse Effect N (%) N (%) p-Value
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Four Month Open label
RUPP Autism Network. Am J Psychiatry. 2005;162(7):1361-9
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ABC Irritability Scores by Week in Open-Label (N=63)
RUPP Autism Network. Am J Psychiatry. 2005;162(7):1361-9
05
10152025303540
Week 0 Week 4 Week 8 Week 12 Week 16
Mean Irritability score
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Mean Dose in Open-Label Risperidone A
vera
ge m
g/da
y
RUPPP Autism Network. Am J Psychiatry. 2005;162(7):1361-9
00.5
11.5
22.5
33.5
44.5
55.5
6
Week 4 Week 8 Week 12 Week 16
Risperidone dose
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Risperidone Extension: Weight Gain
• N=63 followed for 6 months of treatment
• Mean weight gain = 5.6 3.9 kg– No clear predictors of weight gain
• Weight gain greatest in first 2 months– 1.4 kg/month vs. average of 0.88 kg/month
• Monitoring and counseling about diet and weight at the start of treatment
Martin A et al. Am J Psychiatry. 2004;161(6):1125-7
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Risperidone in Autism: Conclusions 1) At low to medium doses (1.25 to 1.75 mg/day),
70% of children with autism + tantrums, aggression, self-injury will show positive response.
2) Magnitude of improvement > 50% 3) At low to medium doses, drug is well-tolerated and
benefits endure over time4) Discontinuation at 6 months relapse 5) Weight gain requires monitoring throughout
treatment
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RUPP Autism Network:Risperidone only vs.
Risperidone + Parent Training
RUPP Autism Network, JAm Acad Child Adoles Psychiatry, 11/09
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Risperidone only vs Risperidone + Parent Training
Design• 6-month study• 124 subjects (age 4 to 13 years) • Random assignment
– risperidone only (N=49) or – risperidone + Parent training (N=75)
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Risperidone only vs Risperidone + PT
Study Model: The medication tantrums, aggression and self-injury, setting the stage for PT improve adaptive skills.
↓ noncompliance adaptive skills (can’t do vs won’t do)
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Behavior Therapy: Basics• Antecedents & consequences (function of the behavior)• Environmental manipulation (↓ triggering situation) functional communication (teach child to request a break vs acting out to escape demands)
• Extinction (selective ignoring) • Positive reinforcement (go for incremental success)
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Sample Characteristics
Variable MED COMB Age 7.5 7.4 Irritability 29.7 (6.10) 29.3 (6.97)Autism 32 (65.3) 49 (65.3) PDD-NOS 13 (26.5) 22 (29.3)Asperger’s 4 (8.2) 4 (5.3)Average IQ 11 (22.5) 28 (38.4)*
*P < .05
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Maladaptive Behavior Outcomes
Measure COMB (75)|-- BL--||-- EP--|
MED (N=49)|-- BL-- ||--EP--|
ES
HSQ 4.3(1.67)
1.23(1.36)
4.16 (1.47)
1.68 (1.36)
0.34*
ABC-Irritability
29.3 (6.97)
11.0(6.64)
29.7 (6.10)
14.5 (9.90)
0.48*
* p < .05
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Maladaptive Behavior Outcomes
Measure COMB (75)|-- BL--||-- EP--|
MED (N=49)|-- BL--||-- EP--|
ES
ABC-Irritability
29.3 (6.97)
11.0(6.64)
29.7 (6.10)
14.5 (9.90)
0.48*
* p < .05
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ABC Irritability
1012141618202224262830
BL Week 8 Week 16 Week 24
HSQ
Sco
re
MEDCOMB
ES = .48
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Parent-rated Home Situations Questionnaire Scores
at Baseline Through Week 24 with LSMeans
0
1
2
3
4
5
0 5 10 15 20 25
WEEK
MED
COMB
Mea
n Se
verit
y Sc
ore
E.S. = .34
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Adaptive Behavior Outcomes
Vineland Domain
COMB (65)| -- BL--| |-- EP--|
MED (N=42)|-- BL--| |-- EP--|
ES
Daily Living 50.8 (18.49)
55.6 (21.86)
41.1 (19.81)
45.3(20.48)
.13
Socialization 59.5 (15.01)
67.4 (18.48)
53.5 (14.41)
56.6 (17.38)
.35*
Communication 61.2 (20.95)
63.9 (22.65)
53.2 (19.94)
53.6 (20.23)
.15
Adaptive Composite
53.1 (15.66)
57.9(19.03)
45.8 (15.50)
47.8 (15.81)
.22*
* p < .05
RUPP Autism Network, JAm Acad Child Adoles Psychiatry, 02/12
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Adaptive Behavior Outcomes
Vineland Domain
COMB (65)| -- BL--| |-- EP--|
MED (N=42)|-- BL--| |-- EP--|
ES
Daily Living 50.8 55.6 41.1 45.3 .13
Socialization 59.5 67.4 53.5 56.6 .35*
Communication 61.2 63.9 53.2 53.6 .15
Adaptive Composite 53.1 57.9 45.8 47.8 .22*
* p < .05
RUPP Autism Network, JAm Acad Child Adoles Psychiatry, 02/12
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RIS + PT vs RIS only on Vineland Adaptive Behavior scales
Daily Living Socialization Communication
COMB > MEDNo yes No
Scahill et al., JAm Acad Child Adoles Psychiatry, 02/12
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Adaptive Behavior Outcomes
Vineland Domain
COMB (65)| -- BL--| |-- EP--|
MED (N=42)|-- BL--| |-- EP--|
ES
Daily Living 50.8 55.6 41.1 45.3 .13
Socialization 59.5 67.4 53.5 56.6 .35*
Communication 61.2 63.9 53.2 53.6 .15
Adaptive Composite
53.1 57.9 45.8 47.8 .22*
* p < .05
RUPP Autism Network, JAm Acad Child Adoles Psychiatry, 02/12
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Vineland (Scahill et al., 2012; JAACAP)
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NIH Multisite Trials in Children with ASDs past 15 years
Study N Target Ages ResultsRisperidone vs placebo (2002)
101 Irritability 5-17 RIS > PLA (large effect)
Methylphenidate vs placebo (2005)
66 Hyperactivity
5-14 MPH > PLA (small to medium effect)
Citalopram vs placebo (2009)
149 Repetitive Behavior
5-17 CITALO = PLA
RIS vs RIS + Parent Training (2009, 2012)
124 Irritability & Adaptive Behavior
4.5-13
RIS + PT > RIS alone (small to medium effect)*
* Small to medium effect over large effect of drug alone
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Future Directions
• Parent Training as a ‘stand alone’ treatment• Drug selection
- Based on ↑ understanding of neurobiology- Drugs not on the market (industry partnership) - Begin with adults (establish safety) • Needed- Better outcome measures (e.g., social disability, anxiety)
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Compounds worthy of study in ASDCompound On
marketTarget Available
measureSSRI Yes Anxiety Not Quite
PregabalinD1 Antagonist No SIB OK
Oxytocin Yes
Social interaction
Yes, but
mGluR antagonist No
mGluR agonist No
Vasopressin R antagonist No
Ready?
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Thank you