How to Assess and Prioritize Treatments: Using Evidence-Based

Medicine to Choose Effective Treatments for Autism and ADHD

Dan Rossignol, MD FAAFPInternational Child Development Resource Center

321-259-7111 www.icdrc.orgAutism One / Autism Canada 2009 Conference

October 31, 2009

Disclosures:Disclosures:I have received funding for two studies on I have received funding for two studies on hyperbaric treatment in children with autism hyperbaric treatment in children with autism from the International Hyperbarics Association from the International Hyperbarics Association but I have no commercial or financial but I have no commercial or financial relationships with chamber manufacturers. relationships with chamber manufacturers.

With all treatments and recommendations, With all treatments and recommendations, please consult with your child’s physician please consult with your child’s physician before implementation. before implementation.

The use of every treatment in individuals with autism is “off-label” except for

risperidone for the treatment of irritability

ADHD AspergerSyndrome

PDD-NOS Autism

Autism Spectrum

Underlying pathophysiology

Psychologically / Behaviorally defined

Communication Stereotypicalbehaviors

Socialinteraction

???

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

http://clinicalevidence.bmj.com/ceweb/about/knowledge.jsp

CaveatCaveatOver 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 5:145-150

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

STEPSSTEPS

SSafety: has it been studied in children?afety: has it been studied in children?

TTolerability: what are the side effects?olerability: what are the side effects?

EEfficacy: does it work?fficacy: does it work?

PPrice: how much will it cost?rice: how much will it cost?

SSimplicity: how easy is it to do?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 – ParentalModified CGI – ParentalAutism Research InstituteAutism Research Institute

ActiveTreatment 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):265-78

25/7 20/6

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

Rossignol, 2009 Annals Clin Psych, in press

Rossignol, 2009 Annals Clin Psych, in press

Rossignol, 2009 Annals Clin Psych, in press

Rossignol, 2009 Annals Clin Psych, in press

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: 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

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

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