nili e. major, m.d. instructor, developmental-behavioral pediatrics
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
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