Transcript Medications and Alternative Therapies in the Treatment of Autism

MEDICATIONS AND ALTERNATIVE
THERAPIES IN THE TREATMENT
OF AUTISM
CT CHAPTER OF AAP: CRITICAL ISSUES IN SCHOOL HEALTH
MAY 20, 2010
Nili E. Major, M.D.
Instructor, Developmental-Behavioral Pediatrics
Yale University School of Medicine
Disclosure

Dr. Major has no conflicts of interest to disclose

The off label use of medication will be discussed
Outline of Presentation
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Introduction to Autism Spectrum Disorders
Clinical approach to behavioral symptoms
Overview of medications commonly used in ASD
 Clinical
use
 Evidence for efficacy
 Side effects and monitoring
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
Complementary and alternative therapies
Role of the school health professional
Autism Spectrum Disorders

Autism Spectrum Disorders (ASD) are a collection of
developmental disorders that are characterized by
impairments in social interaction and communication,
as well as the presence of restricted and repetitive
behaviors and interests
Autism Spectrum Disorders

DSM-IV-TR diagnostic categories under “Pervasive
Developmental Disorders”:
 Autistic
Disorder
 Asperger’s Disorder
 PDD-NOS
 Rett Syndrome
 Childhood Disintegrative Disorder
DSM Criteria: Social Impairment
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Impairment in use of non-verbal behaviors to
regulate social interaction
 Eye
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
contact, facial expressions, gestures
Failure to develop developmentally-appropriate
peer relationships
Lack of spontaneous seeking to share enjoyment
with others
 Lack
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of showing or pointing out objects of interest
Lack of social or emotional reciprocity
DSM Criteria: Communication Impairment
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Delay in, or total lack of development of spoken
language
 Failure
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to compensate with non-verbal gestures
In those with adequate speech, marked impairment
in ability to initiate or sustain conversation
Stereotyped, repetitive or idiosyncratic language
 Echolalia,
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scripting, unusual prosody
Lack of spontaneous, varied, make believe play
DSM Criteria: Repetitive and Stereotyped
Behaviors and Interests
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Stereotyped or restricted patterns of interest of
abnormal intensity or focus
Inflexible adherence to non-functional routines or
rituals
Stereotyped and repetitive motor mannerisms
 Spinning,
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hand flapping, rocking
Persistent preoccupation with parts of objects
Epidemiology of ASD

Most recent studies report best estimate of current
prevalence in US is ~ 1/110 (CDC, 12/2009)
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Ongoing debate regarding increasing numbers
Increased male to female ratio (~4.5:1)
Seen across all races, ethnic groups, socioeconomic
strata
Mean age of diagnosis ranged from 3 ½ - 5 yrs

More than 1/2 of children had developmental concerns
recorded in chart prior to age 3
Etiology of ASD

Complex, biologically based neurodevelopmental
disorders
Great phenotypic variation
 Likely involve many genes
 Environmental factors may modulate expression
 Concordance rate of 60-90% in identical twins
 Recurrence risk of 2-8% in sibs of affected individuals
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~ 10% of cases associated with a known genetic
syndrome or medical condition (e.g., Fragile X
syndrome, tuberous sclerosis)
Screening and Diagnosis
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Current AAP recommendations (Myers and Johnson, 2007)
 ASD
surveillance at all well child visits
 ASD specific screening (e.g., M-CHAT) at 18 and 24
month visits or when surveillance raises concern
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Diagnosis is made clinically by a professional with
experience in evaluating children for ASD
Evaluation may include multi-disciplinary assessment
Diagnostic instruments commonly used: ADOS, ADIR,
CARS, GARS
Medical Evaluation
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Purpose
Rule-out other conditions (e.g., hearing impairment)
 Evaluate for co-morbid conditions (e.g., seizures)
 Search for underlying etiology (e.g., genetic syndrome)
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Components
Medical history (birth, current health, family history)
 Physical exam (growth, dysmorphic features, neuro, skin)
 Testing
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Audiologic evaluation
 Genetic testing (chromosomes, fragile x, microarray)
 Other: EEG, brain imaging, metabolic testing
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Approaches to Treatment
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Behavioral/Educational Interventions
 Early
Intervention programs
 Specialized school programs
 Applied Behavior Analysis
 Developmental models: DIR, Floortime, Denver
 Speech and language therapy
 Occupational therapy
 Social skills instruction
Approaches to Treatment
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Family support and training
Medical management
 Routine
well-child care
 Co-occurring conditions
 Seizure
disorders
 Sleep disturbances
 Gastrointestinal problems
 Challenging behaviors
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Complementary and alternative therapies
Challenging Behavioral Symptoms
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Hyperactivity
Impulsivity
Poor attention
Irritability:
 Temper
tantrums
 Mood lability
 Aggression
 Self-injurious behavior
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Anxiety
Depression
Sleep disturbances
Repetitive behaviors:
 Stereotypic
movements
 Repetitive play
 Inflexible routines
 Perseverative speech
Clinical Approach to Challenging Behaviors
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Careful assessment of target behaviors
 Timing,
intensity, triggers, response to interventions
 Use of behavioral scales
 Obtain input from multiple sources (home, school)
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Assess existing and available supports
 Behavioral
services
 Educational program
 Family supports
(Myers and Johnson, Pediatrics, 2007)
Clinical Approach to Challenging Behaviors
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Search for medical factors that may be causing or
exacerbating symptoms
Consider psychotropic medication use if
 Symptoms
are causing significant impairment
 Suboptimal response to behavioral modifications
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Choose medication based on
 Likely
efficacy for target symptoms
 Potential adverse effects
 Practical considerations (dosing, monitoring, cost)
Clinical Approach to Challenging Behaviors
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Establish plan for monitoring effects
 Identify
desired outcomes and assessment measures
 Discuss time course of expected effects
 Arrange follow-up: visits, telephone
 Outline plan for alternative options if medication is not
effective
 Obtain baseline lab data and plan follow-up
monitoring
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Consider withdrawal of medication after 6-12
months of therapy
Psychopharmacology in ASD
 Goal
is to reduce challenging behaviors and improve
response to behavioral and educational interventions
 Psychotropic medication use in ASD is common
 5,181
children < 18 yrs enrolled in web based registry
 35% used at least 1 psychotropic medication
 Increased use with older age, presence of ID or psychiatric
co-morbidity, residing in poorer county, South or Midwest US
 Stimulants, anti-psychotics, and SSRI’s most common
(Rosenberg et al, 2010)
Stimulants: Clinical Use
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Most commonly used in the treatment of ADHD
Two classes exist:
 Methylphenidate
 Ritalin,
Metadate, Concerta, Focalin, Daytrana patch
 Amphetamines
 Adderall,
 Work
Dexedrine, Vyvanse
by increasing concentrations of dopamine and
norepinephrine in the brain
Stimulants: Clinical Use
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Preparations: Pills, sprinkle capsules, liquid (short acting
only), transdermal patch
Varied durations of action:
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Short acting (3-6 hours)
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Intermediate acting (4-8 hours)
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Ritalin SR, Metadate ER, Dexedrine Spansule
Long acting (8-12 hours)
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Ritalin, Focalin, Adderall
Ritalin LA, Metadate CD, Adderall XR, Focalin XR, Concerta,
Vyvanse, Daytrana
All with short half-lives; rebound effect may be seen
Stimulants: Evidence of Effect
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Research Unit on Pediatric Psychopharmacology (RUPP)
Autism Network trial of Methylphenidate (2005)
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Design:
Double-blind, placebo-controlled crossover trial
 1 week each of placebo, low, medium, and high dose MPH in
random order
 Primary outcome of interest: Reduction of Hyperactivity subscale
score on ABC (Aberrant Behavior Checklist)
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Sample:
72 children with ASD ages 5 to 14 years
 Autistic Disorder (71%), PDD-NOS (21%), Asperger (7%)
 89% were male
 Mean IQ of 63 (range 16-135)
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Stimulants: Evidence of Effect
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RUPP trial of Methylphenidate (2005)
 Results
 ABC
Hyperactivity scores lower at all MPH dosage levels
compared to placebo
 49% were “responders” to MPH vs. 13% to placebo

Compared with 70-80% response rate in ADHD trials
 Adverse

effects led to discontinuation in 18% of subjects
1.4% discontinued due to adverse effects in ADHD MTA study
 Irritability,
decreased appetite, difficulty falling asleep,
emotional outbursts
Stimulants: Evidence of Effect
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Conclusions
 Methylphenidate
treatment may show benefit in some
patients with ASD and ADHD-like symptoms
 Rate and magnitude of response is lower than seen in
children with ADHD alone
 Rate of adverse effects is higher than in children with
ADHD alone
Stimulants: Side Effects & Monitoring
Potential Side Effects
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Headaches
Stomachaches
Decreased appetite
Slowed wt gain/growth
Sleep difficulty
Tics
Psychiatric symptoms
Cardiac effects
Recommended Monitoring
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Baseline medical Hx & PE
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Thorough cardiac history
EKG, cardiac evaluation if
indicated
Weight gain/growth
Heart rate, blood pressure
Other side effects
Anti-Psychotics: Clinical Use
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Primarily used in treatment of psychotic disorders
1st generation anti-psychotics
 Chlorpromazine,
thioridazine, haloperidol
 Work by blocking dopamine receptors
 Risk of extrapyramidal symptoms (EPS)

2nd generation anti-psychotics
 Gained
popularity due to decreased risk of EPS
 Clozapine, risperidone, quetiapine, aripiprazole
 Block dopamine and serotonin receptors
Anti-Psychotics: Clinical Use
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2006: Risperidone was first medication to be FDA
approved for treatment of irritability in children
aged 5-16 with ASD
2009: Aripiprazole approved for same indication in
children aged 6-17
Both available in liquid preparations
Anti-Psychotics: Evidence of Effect

RUPP trial of Risperidone (2002)
 Design:
 Phase
I: 8 week double-blind, placebo controlled study
 Phase II: 4 months of open label treatment
 Primary outcome of interest: Score at 8 weeks on ABC
Irritability subscale and CGI-I rating
 Sample:
 101

children with Autistic Disorder and significant irritability
ABC Irritability score >18, CGI-S >moderate
 5-17
years of age (mean age 8.8)
 ~75% with mental retardation
Anti-Psychotics: Evidence of Effect

RUPP trial of Risperidone (2002)
 Results
(at 8 weeks):
 Risperidone
group had 57% decrease in Irritability score vs.
14% decrease in placebo group
 69% of risperidone group were “responders” vs. 12% of
placebo group
 Improvements also seen on Hyperactivity and Stereotypy
subscales (no diff in Social Withdrawal and Inappropriate Speech scales)
Anti-Psychotics: Evidence of Effect
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Results (at 8 weeks)
 Adverse
Effects:
 Increased
weight gain (2.7 kg in risp vs. 0.8 kg in placebo)
 Drowsiness (49% in risp vs. 12% in placebo)

In most this was mild, and typically resolved by week 4
 Other
effects: Fatigue, drooling, constipation, dizziness,
tremor, tachycardia
 No serious adverse events in risperidone group or
withdrawal from study due to adverse effects
Anti-Psychotics: Evidence of Effect

Results (at 6 months):
 63
subjects entered the 4 month open label phase
 82.5%
of patients continued to be rated as “much
improved” or “very much improved” on CGI-I
 6 month weight gain of 5.1 kg (0.85 kg/month)
 One subject withdrew due to constipation
 6 subjects reported to have abnormal movements (none
confirmed on exam)
Anti-Psychotics: Evidence of Effect

Conclusions:
 Risperidone
was safe and effective for short-term
treatment of tantrums, aggression, and self-injurious
behavior in children with autistic disorder
 Improvements also seen in hyperactivity and stereotypic
behavior
 Short period limits inferences about long-term efficacy
and side effects
Anti-Psychotics: Evidence of Effect
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Additional risperidone studies:
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Shea et al, 2004:
79 children ages 5-12 with ASD, risp or placebo for 8 weeks
 64% reduction in ABC Irritability score in risp group vs. 18% in
placebo
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RUPP, 2009:
124 children ages 4-13 with PDD
 Risperidone + parent training superior to risperidone alone
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Aripiprazole
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Owen et al, 2009:
98 children ages 6-17 with Autistic Disorder, 8 weeks
 52% responders in aripiprazole group vs. 14% in placebo
 Adverse effects: Fatigue, somnolence, weight gain, tremor

Anti-Psychotics: Side Effects & Monitoring
Potential Side Effects
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Increased appetite and
weight gain
Dyslipidemia
Diabetes
Increased liver enzymes
Sedation
Constipation
Extrapyramidal symptoms
Prolactin elevation
Recommended Monitoring
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Baseline history, PE
Baseline labs
 Fasting glucose and lipids
 Liver function tests
 Prolactin?
Repeat labs at 12 weeks,
then every 3-6 months
Monitor weight/BMI
Monitor for side effects
SSRI’s: Clinical Use

Selective Serotonin Reuptake Inhibitor’s (SSRI’s)
primarily used in the treatment of depression and
anxiety
 Similarity
between repetitive behaviors of ASD and
symptoms of OCD
 Evidence of serotonin system abnormalities in ASD
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Prevent reuptake of serotonin in the brain
Fluoxetine, fluvoxamine, sertraline, citalopram,
escitalopram, paroxetine
Liquid preparations available
SSRI’s: Evidence of Effect
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Fluvoxamine (Posey & McDougle, 2000)
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Double-blind, placebo controlled study
34 children with ASD ages 5-18, 12 weeks
Only 1 of 18 patients responded to treatment
14 of 18 patients experienced adverse effects (hyperactivity,
insomnia, agitation, and aggression)
Fluoxetine (Hollander, 2005)
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Double-blind, placebo controlled crossover study
44 children with ASD ages 5-17, 16 weeks
Fluoxetine superior to placebo in reducing repetitive behaviors
No difference in adverse effects between fluoxetine and placebo
SSRI’s: Evidence of Effect
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Citalopram (STAART Network, 2009)
149 children with ASD ages 5-17
 Randomized to citalopram or placebo for 12 weeks
 No difference between groups on CGI-I (33% tx vs. 34%
pbo), CYBOCS-PDD, or repetitive behavior scale
 Adverse effects: Increased energy level, impulsiveness,
decreased concentration, stereotypy, diarrhea, insomnia,
dry skin, and nightmares
 Are repetitive behaviors in ASD fundamentally different from
behaviors in OCD?
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SSRI’s: Evidence of Effect

Conclusions:
 Small,
open-label studies with various SSRI’s have
shown some benefits
 Placebo controlled studies to date show mixed results
 Largest study performed failed to show improvement of
repetitive behaviors with citalopram
 Side effects are common
SSRI’s: Side Effects & Monitoring
Potential Side Effects
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Nausea and vomiting
Sedation
Weight gain
Dry mouth
Behavioral activation
Induction of mania
Insomnia
Suicidal ideation (FDA
black box warning)
Recommended Monitoring
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Baseline Hx & PE
No routine baseline
labs/studies needed
Careful monitoring,
especially for psychiatric
side effects
Other Medications used in ASD
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Alpha-2 adrenergic agonists (clonidine, guanfacine)
 Hyperactivity,
inattention
 Sedation, dry mouth, decreased BP, dizziness,
constipation, irritability
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Atomoxetine
Anti-epileptics (topiramate, valproate)
Donepezil
Memantine
Complementary & Alternative Therapies

CAM is defined by the National Center for
Complementary and Alternative Medicine as “a
group of diverse medical and health care systems,
practices, and products that are not presently
considered to be part of conventional medicine.”
Complementary & Alternative Therapies

CAM use is common in children with ASD
In recent studies, 50-75% of children with ASD were being
treated with CAM (Wong et al, 2006, Hanson et al, 2007)
 Almost 1/3 of children referred for ASD evaluation were
being treated with dietary therapies (Levy et al, 2003)
 Parents may be reluctant to share information regarding
CAM use with their child’s doctor (Wong et al, 2006)

Concern about physician disapproval
 No need for disclosure
 Physician did not ask
 Physician not knowledgeable about CAM

Complementary & Alternative Therapies
Biological Treatments
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Non-Biological Treatments
Dietary modifications
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Vitamins/supplements
Chelation therapy
Melatonin
Antibiotics/Antifungals
Immunoglobulins
Hyperbaric oxygen
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Auditory integration therapy
Behavioral optometry
Craniosacral manipulation
Music therapy
Yoga
Gluten/Casein Free Diet

Background
 Gluten
- protein found in wheat, rye, barley
 Casein - protein found in dairy products
 Based on hypothesis that:
 Gluten
and casein break down into opioid-like peptides
 Diffuse across an abnormally permeable GI lining (“leaky
gut theory”)
 Excess opiate activity in CNS results in symptoms of autism
Gluten/Casein Free Diet

Evidence of effect

Knivsberg et al, 2002
20 children, assigned to GFCF or typical diet for 1 year
 GFCF group showed improvements in attention, social/emotional
factors, cognition, motor skills
 Limitations: Small sample, lack of strict dietary control, single
blinded

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Elder et al, 2006
Double-blind, placebo controlled study of 13 children
 12 week duration, crossover design
 No differences between groups on outcome measures
 Limitations: Small sample, no wash-out period

Gluten/Casein Free Diet

Conclusions:
 Cochrane
review, 2009: Insufficient evidence at this
time to support the use of gluten/casein free diets
 Further study needed with well-designed trials
 Further information needed regarding potential risks

Recent data:
 Whiteley
 72
et al, 2010, Nutritional Neuroscience
children, diet vs. no diet, improvements in tx group
 Awaiting
results of NIMH trial
Gluten/Casein Free Diet

Clinical Considerations
 Feasibility
of implementing diet
 Child’s
current eating habits
 Added time, effort and expense
 Plans to ensure compliance in and out of home
 Nutritional
considerations
 Monitor
weight gain
 Maintaining adequate intake of protein, calcium, vitamin D
 Consultation with nutritionist
 Plan
for evaluating response to intervention
Vitamins and Supplements

Vitamin B6 and Magnesium
 Cochrane
review of 3 small controlled studies,
insufficient evidence to support use
 Generally safe, but toxicity may occur at elevated
doses
 Tolerable


 NIH
upper limits in children:
Vitamin B6 (30-80 mg/day)
Magnesium (65-350 mg/day)
Office of Dietary Supplements: http://ods.od.nih.gov
Vitamins and Supplements

Omega 3 Fatty Acids

Polyunsaturated fatty acids
ALA from nuts, seeds; EPA and DHA from fatty fish
 High concentrations of DHA in neural tissues
 Some studies show decreased levels of omega 3 in ASD children


1 placebo controlled trial in 13 children (Amminger et al, 2007)
Hyperactivity and stereotypy scales on ABC trended towards
significance
 1 child withdrew due to GI complaints & lack of benefit

Remaining studies uncontrolled, some showing benefit
 Main side effects related to GI upset

Chelation Therapy

Agents used to bind and remove heavy metals from
body (e.g., lead poisoning)
Hypothesis that children with ASD have mercury toxicity
 No evidence to support link between thimerosal and ASD


No controlled studies examining chelation

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Trial initiated by NIMH in 2006 but halted due to concern
over risk-benefit ratio
Can be associated with severe side effects
Arrhythmia, kidney failure, bone marrow suppression
 2005: 5 yo boy with ASD died from hypocalcemia related
to EDTA use
 Oral preparations available without prescription
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Melatonin
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Hormone produced by pineal gland that regulates sleep

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Sleep problems are highly prevalent in ASD (44-83%)

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Available as a nutritional supplement (not FDA regulated)
Evidence of abnormal melatonin regulation in ASD
Clinical studies have shown some benefit

Small randomized, placebo-controlled trials showed increased
sleep duration and reduced sleep latency (Wirojanan, 2009, Garstang,
2006)


Retrospective study of 107 children showed only 3 with side
effects of daytime sleepiness and enuresis (Andersen, 2008)
Recommendations of 1-3 mg 30 minutes prior to bedtime
Complementary & Alternative Therapies

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
Ask families about use of CAM therapies
Encourage families to educate themselves about
evidence
Advise parents to be wary of treatments that:
 Are
based on overly simplified scientific theories
 Promise dramatic improvements or cure
 Have shown efficacy only in case reports/anecdotal
data
 Are said to have no adverse side effects

Develop plan to evaluate efficacy, side effects
Role of School Health Professionals

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Provide important information regarding functioning
and behavior in school to guide treatment decisions
Assist with implementation of treatments (e.g.,
medication administration, special diets)
Participate in ongoing monitoring of response to
treatments
 Behavioral
changes: Activity level, aggression, mood,
repetitive behaviors
 Side effects: Appetite changes, sedation, GI complaints
Selected Resources

Johnson CP, Myers SM; American Academy of Pediatrics, Council on
Children with Disabilities. Management of Children with Autism Spectrum
Disorders. Pediatrics. 2007;120:1162-1182.


Bellando J, Lopez M. The School Nurse’s Role in Treatment of the Student
with Autism Spectrum Disorders. Journal for Specialists in Pediatric
Nursing. 2009;14 (3):173-182.


Issue devoted to ASD (including article on helping families evaluate CAM)
Leskovec et al. Pharmacological Treatment Options for Autism Spectrum
Disorders in Children and Adolescents. Harvard Review of Psychiatry.
2008; 16:97-112.


Also see companion report regarding identification of children with ASD
Good review of current use of psychopharmacology
Levy SE, Hyman SL. Complementary and Alternative Treatments for
Children with Autism Spectrum Disorders. Child and Adolescent
Psychiatric Clinics of North America. 2008; Oct 17(4):803-820

Entire issue devoted to treatment of ASD