MEDICATIONS AND ALTERNATIVE THERAPIES IN THE TREATMENT OF AUTISMCT CHAPTER OF AAP: CRITICAL ISSUES IN SCHOOL HEALTHMAY 20, 2010

Nili E. Major, M.D.Instructor, Developmental-Behavioral PediatricsYale 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 Asperger’s Disorder PDD-NOS Rett Syndrome Childhood Disintegrative Disorder

DSM Criteria: Social Impairment Impairment in use of non-verbal behaviors

to regulate social interaction Eye contact, facial expressions, gestures

Failure to develop developmentally-appropriate peer relationships

Lack of spontaneous seeking to share enjoyment with others 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 Failure 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, 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 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 ~ 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

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 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) Ritalin, Focalin, Adderall

Intermediate acting (4-8 hours) Ritalin SR, Metadate ER, Dexedrine Spansule

Long acting (8-12 hours) 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

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 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

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

Baseline medical Hx & PE Thorough cardiac history EKG, cardiac evaluation

if indicated Weight gain/growth Heart rate, blood

pressure Other side effects

Potential Side Effects Recommended Monitoring

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 long-term 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

Increased appetite and weight gain

Dyslipidemia Diabetes Increased liver enzymes Sedation Constipation Extrapyramidal

symptoms Prolactin elevation

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

Potential Side Effects Recommended Monitoring

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 Prevent reuptake of serotonin in the brain Fluoxetine, fluvoxamine, sertraline,

citalopram, escitalopram, paroxetine Liquid preparations available

SSRI’s: Evidence of Effect Fluvoxamine (Posey & McDougle, 2000)

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) 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 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?

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

Nausea and vomiting Sedation Weight gain Dry mouth Behavioral activation Induction of mania Insomnia Suicidal ideation (FDA

black box warning)

Baseline Hx & PE No routine baseline

labs/studies needed Careful monitoring,

especially for psychiatric side effects

Potential Side Effects Recommended Monitoring

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 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

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

Auditory integration therapy

Behavioral optometry Craniosacral

manipulation Music therapy Yoga

Biological Treatments Non-Biological Treatments

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 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 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) Hypothesis that children with ASD have mercury

toxicity No evidence to support link between thimerosal and

ASD No controlled studies examining chelation

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 Available as a nutritional supplement (not FDA regulated)

Sleep problems are highly prevalent in ASD (44-83%) 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. Also see companion report regarding identification of children with ASD

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. 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