1. 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 321-259-7111www.icdrc.org Autism One / Autism Canada 2009 Conference October 31, 2009

2. 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

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

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

5. 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

6. 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

7. 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

8. 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

9. http://clinicalevidence.bmj.com/ceweb/about/knowledge.jsp Caveat Over 50% of what is done in medicine is “off-label”

10. 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 5:145-150

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

12. 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?

13. 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

14. 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

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

16. 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

17. Modified CGI – Parental Autism Research Institute

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

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

20. Eikeseth et al., 2007 Behav Mod 31(3):265-78 25/720/6 ABA Therapy

21. Rossignol, 2009 Annals Clin Psych, in press

22. 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

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

24. 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

25. 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

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

27. 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

28. 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

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

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

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

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

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

34. Rossignol, 2009 Annals Clin Psych, in press

40. Typical Supplement Doses  Vitamin C: 100 mg/kg/day  CoEnzyme Q 10: 5-10 mg/kg/day  Acetyl-L-Carnitine: 50-100 mg/kg/day  L-Carnosine: 200-400 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 20-150 mg/day  Melatonin: 1-6 mg 30 mins before bedtime

41. Typical Med Doses: Use Only Under Physician Supervision  Clonidine 0.1-0.2 mg at bedtime  Guanfacine 0.25-1 mg 3 times a day  Donepezil 2.5-5 mg at bedtime  Galantamine 2-8 mg twice a day  Spironolactone 1-3 mg/kg/day  Pioglitazone 15-30 mg/day  Memantine 5-10 mg bid  Lamotrigine 3-5 mg/kg/day

42. 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