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 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, Work Dexedrine, Vyvanse 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 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 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 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 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 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 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 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 Non-Biological Treatments Dietary modifications Vitamins/supplements Chelation therapy Melatonin Antibiotics/Antifungals Immunoglobulins Hyperbaric oxygen 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 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 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 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