Transcript Pharmacotherapy of Autism Spectrum Disorders: A Small Piece of

PHARMACOTHERAPY OF
AUTISM SPECTRUM
DISORDERS:
A SMALL PIECE OF THE
PUZZLE
Heather Damhoff,
PharmD
C l i n i c al S p e c i al i s t
– Pe d i a t r i c
I n te n s i v e C a r e
Ko s a i r C h i l d r e n ’ s
H o s p i t al
WHAT IS AUTISM SPECTRUM DISORDER
(ASD)?
 Continuum of neurodevelopmental disorders characterized by
deficits in:
 Social communication and interactions
 Restrictive, repetitive patterns of behaviors, interests, activities
 Prevalence
 Parent reported – 2%
 CDC – 1 in every 88 children
 1 in 54 males
 1 in 252 females
 Increase of 23% compared to 2006
Harv Rev Psych 2014; 22(2):76-92.
Autism Spectrum Disorder
Asperger disorder
PDD
Autistic disorder
INDICATIONS FOR MEDICATION THERAPY
 In addition to the core symptoms may patients with ASD
experience co-occurring psychiatric and behavioral problems
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Aggression
Self – injury
Impulsivity
Hyperactivity
Anxiety
Mood symptoms
Curr Opin Psychiatry 2015; 28:91-101.
REVIEW OF
ANTIPSYCHOTIC USE
ANTIPSYCHOTIC USE IN ASD
 FDA approved medications for irritability (aggression, self
injury, severe tantrums)
 Risperidone (Risperdal ® )
 Aripiprazole (Abilify ® )
RISPERIDONE
 Mechanism of Action
RISPERIDONE – SHORT TERM
Risperidone in Children with Autism and Serious Behavioral Problems
Design
•
Randomized, double-blind, placebo-controlled
Population
•
•
Children 5 – 17 years with ASD
Risperidone (49), Placebo (52)
Primary
Outcome
•
•
Score on the Irritability subscale of the Aberrant Behavior Checklist
Rating on the Clinical Global Impressions (CGI-I) scale
Intervention
•
•
•
< 20 kg: 0.25 mg at bedtime
20 – 45 kg: 0.5 mg at bedtime, ↑ 0.5 mg BID on Day 4 (max: 2.5 mg/day by Day 29)
> 45 kg: Accelerated dose schedule (max 2.5 mg/day)
N Engl J Med 2002; 347:314-231
RISPERIDONE – SHORT TERM
RISPERIDONE – SHORT TERM
RISPERIDONE – SHORT TERM
Risperidone in Children with Autism and Serious Behavioral Problems
Medication
Dose
•
Mean daily dose during final week: 1.8 mg (range, 0.5 – 3.5 mg)
Adverse
Events
•
•
•
Increased weight
Fatigue
Drowsiness
Conclusion
•
Risperidone safe and effective for the short-term treatment of tantrums, aggression
and self-injurious behavior in ASD
Reserve for treatment of moderate-to-severe behavioral problems
•
Am J Psychiatry 2005;162:1361-1369
RISPERIDONE – LONG TERM
Aripiprazole in Children with Autism: Long Term Benefits
Design
•
Extension trial
Population
•
•
Children 5 – 17 years with ASD
63 patients from Phase 1
Primary
Outcome
•
•
Aberrant Behavior Checklist – Irritability
Clinical Global Impression – Improvement
Intervention
•
Clinicians allowed to adjust dose for response/adverse effects
• 15 – 45 kg: up to 3.5 mg
• > 45 kg: up to 4.5 mg
Am J Psychiatry 2005;162:1361-1369
RISPERIDONE – LONG TERM
Risperidone in Children with Autism: Long Term Benefits
Outcomes
•
•
Irritability score: 59% reduction from mean rating at initiation of treatment
CGI-I: 82.5% improved or very much improved
Medication
dosage
•
Only 6% increase in mean dose over 4 month period
Adverse Effects
•
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Increased appetite
Tiredness
Drowsiness
Discontinuation
•
Relapse rate: 62.5% in placebo-treated group, 12.5% in continued risperidone
group
Immediately stopped
•
Conclusion
•
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Risperidone safe and effective up to 6 months for treatment of tantrums,
aggression and self-injurious behavior in ASD
Little evidence of accommodation effects
Am J Psychiatry 2005;162:1361-1369
RISPERIDONE – CORE SYMPTOMS
Risperidone for the Core Symptoms of Autism
Secondary
Outcomes
•
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•
Ritvo-Freeman Real Life Rating Scale
Compulsion scale – Children’s Yale-Brown Obsessive Compulsive Scale
Maladaptive behavior domain of Vineland Adaptive Behavior Scale
Hypothesis
•
Risperidone is superior to placebo for reducing repetitive behavior and improves
measures of social relatedness and impaired communication
Am J Psychiatry 2005; 162:1142–1148
RITVO-FREEMAN REAL LIFE
Am J Psychiatry 2005; 162:1142–1148
YALE-BROWN OBSESSIVE COMPULSIVE
SCALE
Am J Psychiatry 2005; 162:1142–1148
VINELAND ADAPTIVE BEHAVIOR
Am J Psychiatry 2005; 162:1142–1148
RISPERIDONE - SUMMARY
 Indication:
 FDA approved for treatment of irritability associated with ASD in
children and adolescents
 Dosing:
 Dosing:
Weight
Initial Dose
Titration
15 – 20 kg
0.25 mg/day
•
•
After ≥ 4 days increase to 0.5 mg/day
After ≥ 14 days increase by 0.25 mg/day at 2 week
intervals
≥ 20 kg
0.5 mg /day
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After ≥ 4 days increase to 1 mg/day
After ≥ 14 days increase by 0.5 mg/day at 2 week
intervals
 Higher doses 1.25 – 1.75 mg/day have been shown to be more
effective; however, lowest effective dose should be use
RISPERIDONE - SUMMARY
 Adverse Ef fects:
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Weight gain
Increased appetite
Fatigue
Drowsiness
Dizziness
Drooling
 Dosage Forms:
 Oral solution: 1 mg/mL
 Tablets: 0.25, 0.5, 1, 2, 3, 4 mg
 Dispersible tablet: 0.25, 0.5, 1, 2, 3, 4 mg
ARIPIPRAZOLE – SHORT TERM
Aripiprazole in the Treatment of Irritability in Children with ASD
Design
•
Randomized, double-blind, placebo-controlled
Population
•
•
Children 6 – 17 years with ASD
Aripiprazole (47), Placebo (51)
Primary
Outcome
•
Mean change from baseline in the Aberrant Behavior Checklist
Secondary
Outcome
•
Rating on the Clinical Global Impressions (CGI-I) scale
Intervention
•
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Initial dose: 2 mg
Target dose: 5, 10, or 15 mg/day
N Engl J Med 2002; 347:314-231
ARIPIPRAZOLE – SHORT TERM
Pediatrics 2009;124:1533-1540.
ARIPIPRAZOLE – SHORT TERM
Pediatrics 2009;124:1533-1540.
ARIPIPRAZOLE – SHORT TERM
Aripiprazole in the Treatment of Irritability in Children with ASD
Medication
Dose
•
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•
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2 mg/day (5%)
5 mg/day (33%)
10 mg/day (41%)
15 mg/day (21%)
Adverse
Events
•
•
•
•
Increased appetite
Fatigue
Somnolence/sedation
Vomiting
Conclusion
•
Aripiprazole was efficacious and generally well tolerated in the treatment of
irritability associated with ASD
Long-term controlled trials are warranted
•
Pediatrics 2009;124:1533-1540.
ARIPIPRAZOLE– LONG TERM
Aripiprazole in Children with Autism: Long Term Benefits
Design
•
Double-blind, randomized, placebo-controlled, relapse-prevention trial
Population
•
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Children 6 – 17 years with ASD
Phase 1: 157 patients
Phase 2: 85 patients
• Aripiprazole (41), Placebo (44)
Primary
Outcome
•
Time from randomization to relapse
• Determined using ABC-I and CGI-I
Intervention
•
2 – 15 mg/day
J Clin Psychiatry 2014;75(1):22-30.
ARIPIPRAZOLE – LONG TERM
Aripiprazole in the Treatment of Irritability in Children with ASD
•
Relapse Rates at week 16
• 35% for aripiprazole
• 52% for placebo
Post-hoc NNT = 6 to prevent 1 additional relapse
Adverse
Events
•
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•
•
•
Weight gain
Increased appetite
Somnolence
Vomiting
Upper respiratory tract infection
Conclusion
•
Some patients will benefit from maintenance aripiprazole therapy
Primary
Outcome
•
J Clin Psychiatry 2014;75(1):22-30.
ARIPIPRAZOLE- SUMMARY
 Indication:
 FDA approved for treatment of irritability associated with ASD in children and
adolescents
 Dosing:
 Dosing:
Initial Dose
2 mg/day
Titration
•
•
After 7 days may increase to 5 mg/day
Increase by 5 mg/day every ≥ 7 days to maximum of 15 mg/day
 Adverse Ef fects:
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Weight gain
Vomiting
Increased appetite
Nasopharyngitis
 Dosage Forms:
 Oral solution: 1 mg/mL
 Tablet: 2, 5, 10, 15, 20, 30 mg
 Dispersible tablet: 10, 15 mg
RISPERIDONE VS. ARIPIPRAZOLE
Head to Head Comparison for Risperidone and Aripiprazole in ASD
Design
•
Prospective, randomized clinical trial
Population
•
59 children and adolescents with ASD
• Aripiprazole (29), Risperidone (30)
Primary
Outcome
•
•
Aberrant Behavior Checklist – Irritability subscale
Clinical Global Impression – Improvement
Intervention
•
Risperidone
• 10 – 40 kg: 0.25 mg/day titrated to max 2 mg/day
• > 40 kg: 0.25 mg/day titrated to max 3 mg/day
Aripiprazole
• < 40 kg: 1.25 mg/day titrated to max 10 mg/day
• > 40 kg: 1.25 mg/day titrated to max 15 mg/day
•
Child Psychiatry Hum Dev 2014;45:185-192.
RISPERIDONE VS. ARIPIPRAZOLE
p = 0.5
Child Psychiatry Hum Dev 2014;45:185-192.
RISPERIDONE VS. ARIPIPRAZOLE
Head to Head Comparison for Risperidone and Aripiprazole in ASD
Adverse
Effects
(Aripiprazole
vs
Risperidone)
•
•
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Increased appetite (34.5% vs 40%)
Increased drooling (31% vs 40%
Drowsiness (20.7% vs 16.7%)
Conclusion
•
Safety and efficacy of aripiprazole (mean dose 5.5 mg/day) and risperidone (1.12
mg/day) were comparable
Child Psychiatry Hum Dev 2014;45:185-192.
OTHER ANTIPSYCHOTICS
 Olanzapine (Zyprexa ® )
 Effective in improving behavioral measures in a RDBPC study
 Significantly more weight gain than placebo
 Haloperidol
 Improved behavioral symptoms
 Use is limited due to risk of extrapyramidal symptoms
COMPLEMENTARY AND
ALTERNATIVE MEDICINE
(CAM) TREATMENTS
USE OF CAM IN ASD
 Higher rates of usage in families of children with ASD
 28 – 95%
 Commonly used CAM treatments for ASD
 Natural products: 13 – 54%
 Special diet: 17 – 33%
 Mind and body practices: 25 – 30%
 Goals of treatment:
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Relief of specific symptoms
Alleviation of side effects of conventional treatments
Philosophic reasons
Wanting greater control over health management
Child Adolesc Psychiatric Clin N Am 2015;24:117-143.
DIETARY INTERVENTION
 Gluten and/or caesin-free diets
 2002 – RCT, single blind
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10 pairs of autistic children
GFCF diet or normal diet
Follow up – 1 year
Observed modification of attention,
social and emotional factor, cognitive
level, language and motor skills
 2011 – Prospective, randomized,
parallel group
 22 children with ASD
 GFCF diet or healthy, low -sugar diet
 No difference in core symptoms
Nutritional Neuroscience 2002;5(4):251-261
Journal of Developmental and Physical Disabilities 2011;23(3):213-225.
OMEGA – 3 FATT Y ACIDS
 Reason for use:
 Essential for brain development and function
 Hypothesis behind use in ASD not fully formulated
 Cochrane review of 2 randomized trials:
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Total n = 37
Dose 1.3 – 1.5 g/day
Duration 6 – 12 weeks
No significant effect on ABC
Cochrane Database of Systematic Reviews, vol. 11, Article ID CD007992, 2011
VITAMIN SUPPLEMENTATION
 Reason for use:
 Frequently observed dietary deficiency of vitamins/micronutrients in
children with ASD
 Combined Vitamin B6-Magnesium
 Cochrane review of 3 randomized trials:
 Data could not be meta-analyzed due to significant heterogeneity
 All 3 trials reported no significant difference compared to placebo
 Vitamin B12
 Double-blind, placebo-controlled, randomized, crossover trial
 No difference from placebo
 Open label trial
 Significant improvement in Vineland total and subscales score
Cochrane Database of Systematic Reviews, no. 4, Article ID CD003497, 2005..
J Alt Com Med 2010;16(5):555-560.
Autism Research and Treatment 2013; Article ID 609705.
CHELATION
 What is it?
 Administration of chemical substances for the purpose of binding and then
withdrawing specific metals from a person’s body
 Why in ASD?
 Theoretical basis for mercury or other heavy metals as cause of ASD
 Interfere with developmental processes implicated in ASD
 Examples of Chelating A gents
Name
Heavy metal target
Route
Common
adverse effects
DMSA
Lead, arsenic, mercury
poisoning
Oral
Rash, GI upset
EDTA
Calcium
IV
Fatigue, thrombophlebitis,
hypocalciemia
DMPS
Arsenic, bismuth
subcitrate, mercury,
Wilson’s disease (copper)
IV and Oral
Rash, nausea, dysgeusia
Edetate calcium
disodium
Lead
IV and IM
Fatigue, nephrotoxicity
Cochrane Database Syst Rev. 2015 May 11;5:CD010766
CHELATION
 Cochrane Review
 To assess evidence for the effects of pharmaceutical chelating
agents for symptoms of ASD
 Only 1 randomized trial included
 Phase 1: 7 days glutathione lotion or placebo lotion followed by 3 days of
of oral DMSA
 Phase 2: 3 days of oral DMSA or placebo followed by 11 days off, cycle
repeated up to 6 times
 NO effect on ASD symtpoms
 Review conclusion:
 No clinical trial evidence that suggests chelation is an effective strategy
for ASD
 Risks outweigh benefits (Reported renal impairment, hypocalcemia,
death)
Cochrane Database Syst Rev. 2015 May 11;5:CD010766
NOVEL THERAPIES FOR
ASD
TARGETED THERAPY
Exp Neurobiol 2015;24(4):301-311.
GLUTAMATE/GABA AGENTS
GABA (inhibitory)
Glutamate (excitatory)
Agent
Study Outcome
NAC (NMDA modulator)
Improved irritability
Amantadine, Memantine(NMDA antagonist)
•
•
Curr Opin Psychiatry 2015;28:91-101.
No efficacy shown alone
Improvement in behavior in combination
with risperidone
OXY TOCIN
Oxytocin
Social behaviors
OXY TOCIN
Study
Results
Watanabe et al •
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•
6 week IN oxytocin
Significantly improved social reciprocity
Oxytocin-induced enhancement of resting-state connectivity between
anterior cingulate cortex and dorso-medial prefrontal cortex
Gordon et al
Functional MRI study with IN oxytocin
Enhanced activity for social stimuli
Attenuated response to non-social stimuli
Most therapeutic when used before evidence-based behavioral
treatments
Enhances social learning
•
•
•
•
•
• Over a dozen clinical trials are currently recruiting!
JAMA Psychiatry 2014;71:166-175.
Proc Natl Acad Sci 2013;110:20953-20958.
NALTREXONE
 Disturbance in opiate
system  Chronic
elevation of
endogenous opiates 
self-injurious behavior
and hypoalgesia
J Intellect Disabil Res 2014;E pub ahead of print
 Naltrexone
 Competitive
antagonist at opioid
receptor
 Outcomes
 Review of 10 RDBPC trials
 May improve hyperactivity
and restlessness
 No evidence of impact on
core symptoms
CONCLUSIONS
 Despite high rates of medication usage in ASD, current
evidence-based pharmacotherapy options are extremely
limited
 Risperidone and aripiprazole are ef fective in reducing
irritability, stereotypy and hyperactivity
 Data regarding ef ficacy of CAM in ASD is limited
 New pharmacotherapy options for severely impairing co existing and core symptoms are in urgent need
PHARMACOTHERAPY OF
AUTISM SPECTRUM
DISORDERS:
A SMALL PIECE OF THE
PUZZLE
Heather Damhoff,
PharmD
C l i n i c al S p e c i al i s t
– Pe d i a t r i c
I n te n s i v e C a r e
Ko s a i r C h i l d r e n ’ s
H o s p i t al