How to Assess and Prioritize Treatments: Using Evidence-Based Medicine to Choose Effective Treatments for Autism and ADHD Dan Rossignol, MD FAAFP International Child Development Resource Center www.icdrc.org Autism One / Autism Canada 2009 Conference October 31, 2009

Disclosures: I have received funding for two studies on hyperbaric treatment in children with autism from the International Hyperbarics Association but I have no commercial or financial relationships with chamber manufacturers. With all treatments and recommendations, please consult with your child’s physician before implementation. The use of every treatment in individuals with autism is “off-label” except for risperidone for the treatment of irritability

ADHD Asperger Syndrome PDD-NOSAutism Autism Spectrum Underlying pathophysiology Psychologically / Behaviorally defined Communication Stereotypical behaviors Social interaction ???

Autism: Pathophysiology  Cerebral hypoperfusion  Inflammation –Cerebral –Gastrointestinal  Dysbiosis  Mitochondrial dysfunction  Oxidative stress  Impaired glutathione production  Environmental toxicant exposures

Study Descriptive Terms  Prospective: planned ahead of time  Randomized: participants assigned to a group by random allotment  Double-blind: Neither participants nor researchers know group assignment  Placebo-controlled: A placebo is given to one group of participants  Cross-over: placebo group crosses over and gets treatment

Placebo Effect  As high as 30-37% in several studies in children with autism  Points to need for double-blind, placebo-controlled studies  However, also need to treat children now, and cannot always wait for these types of study  Need to evaluate the risk/benefit ratio of each treatment

Evidence-based Medicine: Strength of Evidence (Efficacy)  A: Supported by at least 2 prospective randomized controlled trials (RCTs) or 1 systematic review  B: Supported by at least 1 prospective RCT or 2 nonrandomized controlled trials  C: Supported by at least 1 nonrandomized controlled trial or 2 case series  D: Troublingly inconsistent or inconclusive studies or studies reporting no improvements

Caveat  Double-blind, placebo-controlled studies can cause you to lose sight of the individual patient –e.g., DMG: 2 negative double-blind placebo- controlled studies in autism (however, dose in studies lower than we typically use). DMG is ranked #17 by parents on ARI list. Some children manifest good improvements with DMG, including speech. –e.g., Secretin

Caveat Over 50% of what is done in medicine is “off-label”

Example of Study: A in Autism  Melatonin: 2 randomized, double-blind, placebo-controlled studies demonstrating improvement in the amount of time to fall asleep, number of nighttime awakenings, and length of sleep compared to both baseline and to placebo. Garstang and Wallis, 2006 Child Care Health Dev 32(5):585-9 Goodlin-Jones et al., 2009 J Clin Sleep Med 5:

Garstang and Wallis, 2006 Child Care Health Dev 32(5):585-9

STEPS S afety: has it been studied in children? S afety: has it been studied in children? T olerability: what are the side effects? T olerability: what are the side effects? E fficacy: does it work? E fficacy: does it work? P rice: how much will it cost? P rice: how much will it cost? S implicity: how easy is it to do? S implicity: how easy is it to do?

STEPS: Melatonin  Safety: two double-blind studies showing safety in children with autism  Tolerability: very little side effects  Efficacy: Double-blind studies showing improvements compared to placebo  Price: less than $30 per month  Simplicity: pill taken at bedtime

DOEs versus POEMs  DOE: Disease Oriented Evidence –Example: Cholesterol pill lowers my cholesterol by 50 points –Example: Flecainide –Example: MB12 increases glutathione  POEM: Patient Oriented Evidence that Matters –Example: Cholesterol pill makes me live longer, or prevents a heart attack or stroke –Example: MB12 improves speech

Ideal Treatment  Backed by Strength of Evidence: A  Safe  Tolerable  Efficacious  Cheap  Simple, in-home treatment  POEM: Outcome matters to child/parent

Treatment Options: Know Your Reason for Treatment  Based upon symptoms –e.g., inattention: pycnogenol, zinc, carnitine, iron, omega-3 fatty acids  Based upon laboratory testing –e.g., oxidative stress: pycnogenol, carnitine, CoQ10  Based upon probabilities –e.g., most children with autism have low glutathione: MB12, folinic acid, pycnogenol

Modified CGI – Parental Autism Research Institute

Active Treatment Maintenance Chelation Anti-inflammatories Antioxidants HBOT Supplements Methyl B12 IVIG GFCF diet IV Chelation

McCracken et al., 2002 N Engl J Med 347(5):314-21

Eikeseth et al., 2007 Behav Mod 31(3): /720/6 ABA Therapy

Rossignol, 2009 Annals Clin Psych, in press

Medications  A: Acetylcholinesterase inhibitors –rivastigmine, donepezil, galantamine  B: Alpha-2 adrenergic agonists –Clonidine, guanfacine  B: Anti-inflammatory medications –Spironolactone, pioglitazone, minocycline, IVIG, ACTH, prednisone, pentoxifylline  C: Glutamate antagonists –Amantadine, memantine, lamotrigine

Overall Autistic Behavior  A: Acetylcholinesterase inhibitors, music therapy  B: Alpha-2 adrenergic agonists, HBOT, vision therapy  C: Carnosine, piracetam, B6/Mg, GFCF diet, cyproheptadine

Speech/Communication  A: Acetylcholinesterase inhibitors, music therapy  B: Carnitine, Tetrahydrobiopterin (BH4), Alpha-2 adrenergic agonists, HBOT  C: Carnosine, B6/Mg, Omega-3 fatty acids, piracetam, GFCF diet, Cyproheptadine, Famotidine, Glutamate antagonists, Auditory Integration Therapy, Neurofeedback

Stereotypy  A: Naltrexone  B: Vitamin C, alpha-2 adrenergic agonists  C: Omega-3 fatty acids, B6/Mg, cyproheptadine, famotidine, glutamate antagonist, auditory integration training, massage

Social Interaction  A: Acetylcholinesterase inhibitors, naltrexone  B: Carnitine, tetrahydrobiopterin, HBOT, oxytocin  C: Carnosine, B6/Mg, GFCF diet, Famotidine, Glutamate antagonists, massage, neurofeedback

Attention/Concentration  A: Omega-3 fatty acids (ADHD), Pycnogenol (ADHD), zinc (ADHD), acetylcholinesterase inhibitors, nicotine, music therapy  B: Carnitine, zinc, alpha-2 adrenergic agonists  C: Omega-3 fatty acids, glutamate antagonists, Iron (if deficient, ferritin < 30), phosphytidylserine

Hyperactivity  A: Eliminate food coloring, additives and dyes; acetylcholinesterase inhibitors, naltrexone  B: Carnitine, alpha-2 adrenergic agonists  C: Omega-3 fatty acids, magnesium, chelation, glutamate antagonists, AIT, massage

Sleep  A: Melatonin  B: Carnitine, alpha-2 adrenergic agonists  C: Multivitamin, Omega-3 fatty acids  D: Iron, 5-HTP

Irritability/Aggression  A: Risperidone, Acetylcholinesterase inhibitors, naltrexone (esp. self-injury)  B: Alpha-2 adrenergic agonists, anti- inflammatory medications  C: Glutamate antagonists, auditory integration therapy

Eye contact  A: Acetylcholinesterase inhibitors, music therapy  B: Tetrahydrobiopterin, HBOT  C: Omega-3 fatty acids, famotidine

Coordination  A: Pycnogenol  B: Carnitine, Vision therapy  C: Omega-3 fatty acids  Tryptophan deficiency (5-HTP or TP)  GI-related Toe-walking

Supplements with Antiseizure Activity  Taurine  Vitamin B6 / P5P  Magnesium  Omega-3 fatty acids  GABA  DMG  L-Carnosine

Rossignol, 2009 Annals Clin Psych, in press

Typical Supplement Doses  Vitamin C: 100 mg/kg/day  CoEnzyme Q 10: 5-10 mg/kg/day  Acetyl-L-Carnitine: mg/kg/day  L-Carnosine: mg twice a day  Pycnogenol: 1 mg/kg/day (often higher)  MB12 injections: 75 mcg/kg every 1-3 days  Folinic acid 400 mcg twice a day  Omega-3’s: DHA and EPA ~800 mg/day each  Zinc mg/day  Melatonin: 1-6 mg 30 mins before bedtime

Typical Med Doses: Use Only Under Physician Supervision  Clonidine mg at bedtime  Guanfacine mg 3 times a day  Donepezil mg at bedtime  Galantamine 2-8 mg twice a day  Spironolactone 1-3 mg/kg/day  Pioglitazone mg/day  Memantine 5-10 mg bid  Lamotrigine 3-5 mg/kg/day

Summary: Where to start?  Sleep / Melatonin / 5-HTP  Multivitamin  Omega-3 fatty acids  Anti-oxidants  Methyl B12 (SC injections)  Diet, at least organic and eliminate food colorings and preservatives, GFCF  Digestive enzymes / probiotics