MEDICATIONS AND

ALTERNATIVE THERAPIES
IN THE TREATMENT OF
AUTISM
CT CHAPTER OF AAP: CRITICAL ISSUES IN
SCHOOL HEALTH
MAY
2010
Nili
E. 20,
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

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

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
Aspergers Disorder
PDD-NOS
Rett Syndrome
Childhood Disintegrative Disorder

DSM Criteria: Social

Impairment

Impairment in use of non-verbal behaviors

to regulate social interaction

Failure to develop developmentallyappropriate peer relationships

Lack of spontaneous seeking to share
enjoyment with others

Eye contact, facial expressions, gestures

Lack of showing or pointing out objects of

interest

Lack of social or emotional reciprocity

DSM Criteria: Communication

Impairment

Delay in, or total lack of development of

spoken language

In those with adequate speech, marked

impairment in ability to initiate or sustain
conversation
Stereotyped, repetitive or idiosyncratic
language

Failure to compensate with non-verbal gestures

Echolalia, scripting, unusual prosody

Lack of spontaneous, varied, make believe

play

DSM Criteria: Repetitive and

Stereotyped Behaviors and
Interests
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, 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)

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 - 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

~ 10% of cases associated with a known

genetic syndrome or medical condition (e.g.,
Fragile X syndrome, tuberous sclerosis)

Screening and Diagnosis

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

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

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)

Components

Medical history (birth, current health, family history)

Physical exam (growth, dysmorphic features, neuro,
skin)
Testing
Audiologic evaluation
Genetic testing (chromosomes, fragile x, microarray)
Other: EEG, brain imaging, metabolic testing

Approaches to Treatment

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

Family support and training

Medical management

Routine well-child care

Co-occurring conditions
Seizure

disorders
Sleep disturbances
Gastrointestinal problems
Challenging behaviors

Complementary and alternative therapies

Challenging Behavioral
Symptoms

Hyperactivity
Impulsivity
Poor attention
Irritability:

Temper tantrums
Mood lability
Aggression
Self-injurious
behavior

Anxiety
Depression
Sleep disturbances
Repetitive
behaviors:

Stereotypic
movements
Repetitive play
Inflexible routines
Perseverative speech

Clinical Approach to Challenging

Behaviors

Careful assessment of target behaviors

Timing, intensity, triggers, response to

interventions
Use of behavioral scales
Obtain input from multiple sources (home,
school)

Assess existing and available supports

Behavioral services
Educational program
Family supports
(Myers and Johnson, Pediatrics, 2007)

Clinical Approach to Challenging

Behaviors

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

Choose medication based on

Likely efficacy for target symptoms

Potential adverse effects
Practical considerations (dosing, monitoring,
cost)

Clinical Approach to Challenging

Behaviors

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

Consider withdrawal of medication after 612 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 SSRIs most common
(Rosenberg et al, 2010)

Stimulants: Clinical Use

Most commonly used in the treatment of

ADHD
Two classes exist:

Methylphenidate
Ritalin,

Metadate, Concerta, Focalin, Daytrana

patch

Amphetamines
Adderall,

Dexedrine, Vyvanse

Work by increasing concentrations of

dopamine and norepinephrine in the brain

Stimulants: Clinical Use

Preparations: Pills, sprinkle capsules, liquid

(short acting only), transdermal patch
Varied durations of action:

Short acting (3-6 hours)

Intermediate acting (4-8 hours)

Ritalin SR, Metadate ER, Dexedrine Spansule

Long acting (8-12 hours)

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

Research Unit on Pediatric

Psychopharmacology (RUPP) Autism Network
trial of Methylphenidate (2005)

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)

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)

Stimulants: Evidence of
Effect

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

Adverse effects led to discontinuation in 18% of

subjects

Compared with 70-80% response rate in ADHD trials

1.4% discontinued due to adverse effects in ADHD MTA

study

Irritability, decreased appetite, difficulty falling

asleep, emotional outbursts

Stimulants: Evidence of
Effect

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

Headaches
Stomachaches
Decreased appetite
Slowed wt gain/growth
Sleep difficulty
Tics
Psychiatric symptoms
Cardiac effects

Recommended Monitoring

Baseline medical Hx &

PE

Thorough cardiac history

EKG, cardiac evaluation
if indicated

Weight gain/growth
Heart rate, blood
pressure
Other side effects

Anti-Psychotics: Clinical Use

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

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

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 longterm efficacy and side effects

Anti-Psychotics: Evidence of
Effect

Additional risperidone studies:

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

RUPP, 2009:
124 children ages 4-13 with PDD
Risperidone + parent training superior to risperidone alone

Aripiprazole

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

Increased appetite and

weight gain
Dyslipidemia
Diabetes
Increased liver enzymes
Sedation
Constipation
Extrapyramidal
symptoms
Prolactin elevation

Recommended Monitoring

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

SSRIs: Clinical Use

Selective Serotonin Reuptake Inhibitors

(SSRIs) 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

Prevent reuptake of serotonin in the brain

Fluoxetine, fluvoxamine, sertraline,
citalopram, escitalopram, paroxetine
Liquid preparations available

SSRIs: Evidence of Effect

Fluvoxamine

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

(Posey & McDougle, 2000)

(Hollander, 2005)

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

SSRIs: Evidence of Effect

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?

SSRIs: Evidence of Effect

Conclusions:

Small, open-label studies with various

SSRIs 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

SSRIs: Side Effects &

Monitoring
Potential Side Effects

Nausea and vomiting

Sedation
Weight gain
Dry mouth
Behavioral activation
Induction of mania
Insomnia
Suicidal ideation (FDA
black box warning)

Recommended Monitoring

Baseline Hx & PE
No routine baseline
labs/studies needed
Careful monitoring,
especially for
psychiatric side
effects

Other Medications used in

ASD

Alpha-2 adrenergic agonists (clonidine,

guanfacine)

Hyperactivity, inattention
Sedation, dry mouth, decreased BP,
dizziness, constipation, irritability

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 childs 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

Dietary modifications

Vitamins/supplements
Chelation therapy
Melatonin
Antibiotics/Antifungals
Immunoglobulins
Hyperbaric oxygen

Non-Biological Treatments

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

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 et al, 2010, Nutritional Neuroscience

72

children, diet vs. no diet, improvements in tx group

Awaiting results of NIMH trial

Gluten/Casein Free Diet

Clinical Considerations

Feasibility of implementing diet

Childs 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

upper limits in children:

Vitamin B6 (30-80 mg/day)

Magnesium (65-350 mg/day)

NIH

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)

No controlled studies examining chelation

Hypothesis that children with ASD have mercury

toxicity
No evidence to support link between thimerosal and
ASD
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

Melatonin

Hormone produced by pineal gland that regulates

sleep

Sleep problems are highly prevalent in ASD (44-83%)

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

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

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 Nurses 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