10/3/2016. Disclaimer. What is Autism? Autistic Behaviors

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1 A novel evidence based ranking scale for medications and supplements in autism spectrum disorders Dan Rossignol MD FAAFP Rossignol Medical Center Florida Office (Melbourne, FL): California Office (Aliso Viejo, CA): Autism Society of Greater Phoenix October 8, 2016 Disclaimer While Dr. Rossignol has attempted to make the information in this presentation as accurate as possible, the information is provided without any expressed or implied warranty. The purpose of this lecture is to provide information about different conditions or treatments that may affect individuals with autism and other conditions. Please be advised d that t Dr. Rossignol is not giving i medical advice and that circumstances may dictate different treatments. All of the reviewed treatments in this lecture are considered off-label and not FDA-approved. Before beginning any treatment, please consult with your or your child s physician. The use of every treatment in autism is off-label except for Risperidone and Aripiprazole for the treatment of irritability. What is Autism? DSM 5 emphasizes that autism is a disorder characterized by deficits in social communication and by restricted, repetitive patterns of behavior Autism is a spectrum disorder (think autisms ) some children are mildly affected, some are severely affected; there are probably many different causes Is diagnosed solely by behavioral observations: autism has positive and negative symptoms There are no blood or other biological tests for identifying autism Therefore, a diagnosis of autism tells us nothing about the potential contributors or causes of the disorder Testing and treatments can start before a diagnosis of autism is made Autistic Behaviors Autistic behaviors may have a medical cause or contributor (which are objective), e.g.: Seizures or seizure like (epileptiform) activity may contribute to hyperactivity, y, aggressive behaviors, irritability, speech delay, self stimulatory behaviors and sleep problems [Malow, 2004; Mulligan, 2014; Viscidi, 2013] Gastrointestinal problems may lead to aggressive behaviors or self injurious behaviors [Buie, 2005; Buie, 2010] Key Concept: Treatment of these medical problems may lead to behavioral improvements Aims: To evaluate autistic children with GI complaints and aggression or self injurious behavior in order to determine if these behaviors may be symptoms of GER (reflux). Methods: Six consecutive autistic children (ages 8 19 years) undergoing endoscopy and scheduled for BRAVO (wireless) ph probe were evaluated for histology and ph meter results. Findings: GER was identified in 5 of 5 patients tested by BRAVO ph testing. Esophagitis was seen in 3 of 6 patients biopsied. Conclusions: Aggressive or self injurious behavior may be a manifestation of pain from GER and should prompt consideration of further investigation. Buie, 2005 J Pediatr Gastroenterol Nutr 41(4):505 Krigsman, 2007 Medical Veritas 4:

2 Important Concept Krigsman, 2007 Medical Veritas 4: Several metabolic abnormalities have been reported to contribute to or cause a potentially reversible form of autism e.g., Cerebral Folate Deficiency (CFD) The goal, from day one of evaluation, is to rapidly screen for these abnormalities, identify them, and start treating them (I want to know about all the problems up front) Testing can be done by measuring certain biomarkers (laboratory tests that may identify abnormalities) When choosing a therapy We treat metabolic or biochemical abnormalities that may be contributing to behavior; in that sense, we are not treating autism or ADHD e.g., g, Autism is treated with ABA therapy Use proven treatments based upon biomarkers (laboratory tests or other tests like EEGs) and/or evidence based medicine (choosing the best treatments based on the published medical literature) The time to add major treatments are when things are going well, not when things are bad (this is often the opposite of our instinct) Types of treatments A. Treatments based on lab results (ideally these are also proven treatments) e.g., Iron treatment for low ferritin B. Proven treatments based on evidence based, symptomsbased ranking e.g., Double blind, placebo controlled studies Non proven treatments that are most likely harmless or low risk: less caution needed Non proven treatments that have high risk or high degree of side effects: be cautious Know your expectations about treatments Do you expect recovery in 6 months? Not going to happen Often can take 1 2 years or more for significant improvements to occur Marathon not a sprint Are you chasing the latest and greatest treatment? There is no magic pill or quick fix for autism Beware of treatments that promise cure What works for one child does not work for all Autism is very heterogenous in its symptoms and response to treatments Treatment Paradigm: Trajectory Autism 2 yo 4 yo TIME Typical Development 2

3 Evidence Based Medicine (EBM) Using the best available evidence to aid clinical decision making Uses strength or level of evidence (LOE) Benefit(s) of treatment Risk(s) of treatment Basis is often randomized controlled trials (RCT), systematic reviews and meta-analysis General lack of evidence in medicine Over 50% of what is done in medicine is Unknown Effectiveness Scoring Rossignol, 2009 Ann Clin Psychiatry 21(4):

4 Grade Rossignol, 2009 Ann Clin Psychiatry 21(4): Rossignol, 2009 Ann Clin Psychiatry 21(4): Modified CGI Parental Autism Research Institute: adapted from Rossignol, 2009 Annals Clin Psych 21(4): Search parameters for supplements and medications in ASD Scoring Date of most recent search: 8/21/16 Sources: PubMed, Scopus, Google Scholar, references from review and other articles, database Excluded: review articles, letters to editor (unless new data presented) Number of studies identified and reviewed: 392 Number of studies on nutritional supplements: 119 (20 supplements) Number of studies on medications: 273 (45 medications) Did not look at Risperidone or Aripiprazole (both approved to treat irritability in autism) Rossignol, 2009 Ann Clin Psychiatry 21(4):

5 Scoring 1a: Meta analysis or systematic review of RCT RCT = randomized control trial 1b: Prospective, high quality RCT [10 points] 2a: Systematic review of prospective, non randomized study 2b: Prospective, non randomized study or low quality RCT [5 points] or prospective, uncontrolled study [3 points] 3a: Systematic review of retrospective studies 3b: Individual case control (retrospective study) [3 points] 4: Case series (retrospective) [CS, 2 points] or case report [CR, 1 point] 5: Expert opinion, bench research [0 points] Negative studies were assigned a 0 (zero) [0 points] Scoring Randomized, double blind, placebo controlled study = 10 points Prospective, placebo controlled study (but lower quality) = 5 points Open label, prospective, non controlled study = 3 points Retrospective case control study = 3 points Case series (retrospective, 2 or more patients) = 2 points Case report (retrospective, 1 patient) = 1 point Negative studies = 0 points Nutritional Supplements Melatonin [Score: 92; Grade: A] The good: Improvements in sleep onset latency (time to fall asleep), nighttime awakenings, length of sleep, social interaction, irritability, alertness The bad: Morning drowsiness (<3%), Enuresis (bed wetting, <3%) The dose / length: 1 6 mg at bedtime; up to 4 years References [22 studies]: (points per study = 4.2) 1b: 6 studies; 60 points 2b: 3 studies; 9 points 4 CS: 10 studies; 20 points 4 CR: 3 studies; 3 points Vitamin B6 / Magnesium [Score: 66; Grade: C] The good: Improvements in speech, social interaction, autism behaviors, stereotypy, verbal IQ The bad: Hyperactivity The dose / length: 100 mg/day; 0.6/mg/kg/day; up to 35 weeks References [19 studies]: (points per study = 3.5) 1b: 3 studies; 10 points (1 x 10 points; 2 x 0 points) 2b: 14 studies; 54 points (6 x 5 points; 8 x 3 points) 4 CR: 2 studies; 2 points Carnitine [Score: 44; Grade: A] The good: Improvements in sleep efficiency, energy level, apraxia, communication skills, expressive speech, autism behaviors, muscle strength The bad: Hyperactivity, loose stools The bad: Hyperactivity, loose stools The dose / length: mg/kg/day; up to 6 months References [12 studies]: (points per study = 3.7) 1b: 3 studies; 30 points 4 CS: 3 studies; 6 points 4 CR: 5 studies; 5 points 5

6 N Acetylcysteine (NAC) [Score: 33; Grade: A] The good: Improvements in social interaction, aggressiveness, irritability The bad: Constipation (16%), increased appetite (16%), fatigue (13%), nervousness (13%), daytime drowsiness (13%) The dose / length: mg/day; 8 12 weeks References [8 studies]: (points per study = 4.1) 1b: 5 studies; 30 points (3 x 10 points; 2 x 0 points) 4 CR: 3 studies; 3 points Folinic acid [Score: 27; Grade: B] The good: Improvements in expressive speech, play skills, social skills, receptive language, attention, stereotypy The bad: Hyperactivity, self stimulatory behaviors, aggression The dose / length: 400 mcg/day to 2 3 3mg/kg/day;24months 2 4 months References [11 studies]: (points per study = 2.5) 2b: 9 studies; 24 points (two studies had same population) Omega 3 fatty acids [Score: 26; Grade: D] The good: Improvements in hyperactivity, self stimulatory behaviors, attention, social interaction, communication, eye contact The bad: None (bruising, loose stools) The dose / length: 540 mg 15grams/day; weeks References [13 studies]: (points per study = 2.0) 1b: 3 studies; 0 points (0 x 3 points) 2b: 7 studies; 22 points (+22 points; 1 x 0 points) 4 CR: 2 studies; 2 points Multivitamin [Score: 21; Grade: A] The good: Improvements in hyperactivity, tantrums, receptive language, sleep, gastrointestinal problems The bad: None (nausea, loose stools) The dose / length: high potency preparation (see articles); 3 months References [3 studies]: (points per study = 7.0) 1b: 2 studies; 20 points Methylcobalamin (MB12) [Score: 20; Grade: B] The good: Improvements in expressive speech, living skills, play skills, social skills, enuresis, autism behaviors The bad: Hyperactivity The dose / length: mcg/kg every 3 days; 12 weeks References [7 studies]: (points per study = 2.9) 1b: 2 studies; 10 points (1 x 10 points; 0 x 10 points) 2b: 4 studies; 9 points (two studies had same population) Probiotics [Score: 20; Grade: B] The good: Improvements in attention, compliance, autism behaviors, stool consistency, lower Clostridia species The bad: Skin rash (3%), diarrhea (3%), weight loss (3%) The dose / length: varies / 50 billion cfu/day; 4 months The dose / length: varies / 50 billion cfu/day; 4 months References [5 studies]: (points per study = 4.0) 2b: 2 studies; 6 points 3b: 1 study; 3 points 6

7 Vitamin C [Score: 14; Grade: B] Digestive enzymes [Score: 13; Grade: B] The good: Improvements in sensory problems, self stimulatory behaviors The bad: None (loose stools) The dose / length: 114 mg/kg/day; 30 weeks References [3 studies]: (points per study = 4.7) The good: Improvements in food variety, social interaction, emotional response, hyperactivity, autism behaviors The bad: skin rash, itching, abdominal pain The dose / length: varies; 12 weeks References [3 studies]: (points per study = 4.3) 1b: 2 studies; 10 points (1 x 10 points; 0 x 10 points) Vitamin D [Score: 11; Grade: B] The good: Improvements in autism behaviors The bad: None The dose / length: dose individually, based on labs References [5 studies]: (points per study = 2.2) 2b: 3 studies; 9 points 4 CR: 2 studies; 2 points B vitamins [Score: 10; Grade: C] The good: Improvements in metabolism The bad: Hyperactivity The dose / length: varies References [6 studies]: (points per study = 1.7) 4 CS: 4 studies; 8 points 4 CR: 2 studies; 2 points Carnosine [Score: 10; Grade: B] The good: Improvements in socialization, communication, autism behaviors The bad: Hyperactivity The dose / length: 800 mg/day; 8 weeks References [1 study]: (points per study = 10.0) Piracetam [Score: 10; Grade: B] The good: Improvements in aberrant behaviors The bad: Constipation (20%), daytime drowsiness (35%), morning drowsiness (55%), increased appetite (35%) The dose / length: up to 800 mg/day; 10 weeks The dose / length: up to 800 mg/day; 10 weeks References [1 study]: (points per study = 10.0) 7

8 Sulforaphane [Score: 10; Grade: B] The good: Improvements in autism behaviors, social interaction, speech The bad: Weight gain, lower pulse, vomiting (19%), aggression (15%), abdominal pain (15%), flatulence (15%) The dose / length: micromol/day; 18 weeks References [1 study]: (points per study = 10.0) Coenzyme Q10 / Ubiquinol [Score: 9; Grade: C] The good: Improvements in communication, play skills, sleep, appetite The bad: Hyperactivity The dose / length: 50 mg twice a day; 3 months References [5 studies]: (points per study = 1.8) 4 CS: 2 studies; 4 points 4 CR: 2 studies; 2 points Supplement rankings by total points Supplement rankings by points per study 1. Melatonin B6/Mag Carnitine NAC Folinic acid Omega Multivitamin MB Probiotics Vitamin C Digestive enzymes Vitamin D B vitamins Carnosine Piracetam Sulforaphane Coenzyme Q Gingko Iron Pregnenolone Sulforaphane (1 study) Piracetam (1 study) Carnosine (1 study) MVI (3 studies) Vitamin C (3 studies) Digest enzymes (3 studies) Melatonin (22 studies) NAC (8 studies) Probiotics (5 studies) Carnitine (12 studies) B6 / Mag (19 studies) Pregnenolone (1 study) Iron (1 study) MB12 (7 studies) Folinic acid (11 studies) Vitamin D (5 studies) Omega 3 s (13 studies) CoQ10 (5 studies) B vitamins (6 studies) Gingko (2 studies) 1.5 Grade A Rankings: Supplements Mean Score = 47.5 Grade B Rankings: Supplements Mean Score = Melatonin (92 points) 2. Carnitine (44 points) 3. NAC (33 points) 4. Multivitamin (21 points) 1. Folinic acid (27 points) 2. Methylcobalamin (20 points) 2. Probiotics (20 points) 4. Vitamin C (14 points) 5. Digestive enzymes (13 points) 6. Vitamin D3 (11 points) 7. Carnosine (10 points) 7. Piracetam (10 points) 7. Sulforaphane (10 points) 8

9 Grade C Rankings: Supplements Mean Score = 18.2 Number of double blind, placebo controlled, positive studies: supplements 1. B6/Mag (66 points) 2. B vitamins (10 points) 3. Coenzyme Q10 (9 points) 4. Iron (3 points) 4. Pregnenolone (3 points) 1. Melatonin 6 2. Carnitine 3 2. NAC 3 4. Multivitamin 2 5. B6/Mag 1 5. Digestive enzymes 1 5. M Probiotics 1 5. Vitamin C 1 5. Carnosine 1 5. Piracetam 1 5. Sulforaphane 1 Oxytocin [Score: 177; Grade: A] Medications The good: Improvements in eye contact, social interaction, emotional behavior, quality of life The bad: Emotional problems, irritability, headache, migraine The dose / length: 8 24 IU; 8 16 weeks References [23 studies]: (points per study = 7.7) 1b: 20 studies; 170 points (17 x 10 points; 3 x 0 points) 2b: 2 studies; 6 points Naltrexone [Score: 120; Grade: A] The good: Improvements in self injurious behaviors, hyperactivity, agitation, irritability, temper tantrums, social interaction, stereotypy, attention, eye contact The bad: Transient sedation, nausea The dose / length: mg/kg/day; 7 days to 6 months References [24 studies]: (points per study = 5.0) 1b: 10 studies; 90 points (+90 points; 1 x 0 points) 2b: 6 studies; 18 points 4 CS: 4 studies; 8 points 4 CR: 4 studies; 4 points Propranolol [Score: 66; Grade: A] The good: Improvements in speech, conversations, cognition, memory, hypersexual behaviors, aggression, social interaction, eye contact The bad: Decreased heart rate and blood pressure, fatigue The dose / length: mg/day; up to 1 year The dose / length: mg/day; up to 1 year References [10 studies]: (points per study = 6.6) 1b: 6 studies; 60 points 4 CR: 3 studies; 3 points 9

10 Fluoxetine [Score: 50; Grade: A] The good: Improvements in obsessiveness, compulsiveness, speech, stereotypy, social interaction, repetitive behaviors The bad: Bad dreams (14%), depressed mood (9%), dry mouth (14%), headache (14%), insomnia (14%), nausea (9%) The dose / length: mg/day; 16 weeks to 76 months References [11 studies]: (points per study = 4.5) 1b: 2 studies; 20 points 2b: 8 studies; 28 points (2 x 5 points; 6 x 3 points) Atomoxetine [Score: 49; Grade: A] The good: Improvements in hyperactivity, impulsivity, speech, stereotypy, fear of change, attention The bad: Aggression, abdominal pain (2 7%), decreased appetite (9 18%), fatigue (7 18%), headache (15 20%), nausea (13%) The dose / length: mg/kg/day; weeks References [11 studies]: (points per study = 4.5) 1b: 3 studies; 30 points 2b: 6 studies; 15 points (+15 points, 1 x 0 points) 4 CS: 2 studies; 4 points Memantine [Score: 42; Grade: A] The good: Improvements in speech, social interaction, attention, selfstimulatory behaviors, irritability, hyperactivity The bad: Stuttering, irritability, dizziness (15%), nausea (10%), rash (10%), sedation (15%) The dose / length: up to 20 mg/day; up to 21 months References [13 studies]: (points per study = 3.2) 1b: 3 studies; 20 points (2 x 10 points; 1 x 0 points) 2b: 6 studies; 18 points (5 x 5 points; 1 x 3 points) 4 CS: 2 studies; 2 points (+2 points; 1 x 0 points) 4 CR: 2 studies; 2 points Buspirone [Score: 30; Grade: A] The good: Improvements in aggression, irritability, hyperactivity, compliance, and restrictive/repetitive behaviors The bad: Involuntary movements (4%), increased appetite (61%), fatigue (11%), drowsiness (11%) The dose / length: 5 20 mg/day; 4 8 weeks References [6 studies]: (points per study = 5.0) 1b: 2 studies; 20 points 2b: 3 studies; 9 points Galantamine [Score: 26; Grade: A] Guanfacine [Score: 25; Grade: A] The good: Improvements in irritability, social interaction, expressive speech, hyperactivity, eye contact, attention The bad: Rash, headache, nervousness, increased appetite, weight gain The dose / length: 8 24 mg/day, weeks References [4 studies]: (points per study = 6.5) 1b: 2 studies; 20 points 2b: 2 studies; 6 points The good: Improvements in hyperactivity, attention, insomnia, tics The bad: Drowsiness, irritability, rash, sleep disturbance, constipation, decrease appetite The dose / length: 1 3 mg/day; up to 6 weeks References [5 studies]: (points per study = 5.0) 1b: 2 studies; 20 points 4 CR: 1 study; 0 points 10

11 Pentoxifylline [Score: 25; Grade: B] The good: Improvements in receptive understanding, hyperactivity, social interaction, seizures (EEG), autism behaviors, attention, speech The bad: Nausea, vomiting, low blood pressure, headache, sleep problems, hyperactivity The dose / length: mg/day; 3 months References [6 studies]: (points per study = 4.2) 2b: 5 studies; 15 points Amantadine [Score: 21; Grade: A] The good: Improvements in hyperactivity, speech, irritability The bad: Increased appetite (30%), insomnia (5%), tremor (5%), morning drowsiness (5%) The dose / length: 255mg/kg/day; weeks References [3 studies]: (points per study = 7.0) 1b: 2 studies; 20 points 4 CR: 1 study, 1 point Medication rankings by total points Medication rankings by total points 1. Oxytocin Naltrexone Haloperidol Fenfluramine Propranolol BH Fluoxetine Atomoxetine Memantine Valproate Methylphenidate Buspirone Clomipramine Galantamine Clonidine Guanfacine Pentoxifylline Fluvoxamine Olanzapine Amantadine Donepezil Bumetanide D cycloserine Pioglitazone Cyproheptadine Topiramate Celecoxib Minocycline Riluzole Sertraline Acamprosate Mirtazapine Ramelteon Steroids Dextromethorphan Levetiracetam t Citalopram Famotidine Arbaclofen Escitalopram Vancomycin Amitriptyline 2 Medication rankings by points per study Medication rankings by points per study 1. Celecoxib (1 study) Riluzole (1 study) Methylphenidate (4 studies) Oxytocin (23 studies) Amantadine (3 studies) Propranolol (10 studies) Galantamine (4 studies) Pioglitazone (2 studies) Cyproheptadine (2 studies) Topiramate (2 studies) Haloperidol (14 studies) BH4 (10 studies) Naltrexone (24 studies) Clonidine (5 studies) Famotidine (1 study) Guanfacine (5 studies) Minocycline (2 studies) Valproate (8 studies) Atomoxetine (11 studies) Fluoxetine (11 studies) Bumetanide (4 studies) Pentoxifylline (6 studies) Clomipramine (7 studies) Buspirone (5 studies) Acamprosate (2 studies) D Cycloserine (4 studies) Donepezil (5 studies) Fluvoxamine (7 studies) Memantine (13 studies) Sertraline (3 studies) Arbaclofen (1 study) Escitalopram (1 study) Vancomycin (1 study) Ramelteon (3 studies) Fenfluramine (29 studies) Dextromethorphan (3 studies) Olanzapine (11 studies) Steroids (4 studies) Amitriptyline (1 study) Citalopram (3 studies)

12 Grade A Rankings: Medications Mean Score = 56.6 Grade B Rankings: Medications Mean Score = Oxytocin (177 points) 2. Naltrexone (120 points) 3. Haloperidol (77 points) 4. Propranolol (66 points) 5. BH4 (51 points) 6. Fluoxetine (50 points) 7. Atomoxetine (49 points) 8. Memantine (42 points) 9. Methylphenidate (33 points) 10. Buspirone (30 points) 11. Galantamine (26 points) 12. Clonidine (25 points) 12. Guanfacine (25 points) 14. Amantadine (21 points) 1. Valproate (37 points) 2. Pentoxifylline (25 points) 3. Fluvoxamine (23 points) 4. Bumetanide (17 points) 5. D Cycloserine (15 points) 6. Pioglitazone (13 points) 7. Cyproheptadine (12 points) 7. Topiramate (12 points) 9. Celecoxib (10 points) 9. Minocycline (10 points) 9. Riluzole (10 points) 12. Sertraline (9 points) 13. Acamprosate (8 points) 13. Ramelteon (8 points) Grade C Rankings: Medications 1. Clomipramine (28 points) 2. Olanzapine (22 points) 3. Donepezil (18 points) 4. Mirtazapine (8 points) 4. Steroids (8 points) 6. Dextromethorphan (7 points) 7. Famotidine (5 points) 8. Arbaclofen (3 points) 8. Escitalopram (3 points) 8. Vancomycin (3 points) Mean Score = 10.5 Number of double blind, placebo controlled, positive studies: medications 1. Oxytoxin Naltrexone Haloperidol Propranolol BH Atomoxetine Methylphenidate 3 5. Valproate..3 Two studies: Amantadine, Buspirone, Clomipramine, Clonidine, Fenfluramine, Fluoxetine, Galantamine, Guanfacine, Memantine One study: Bumetanide, Celecoxib, Cyproheptadine, Dextromethorphan, Donepezil, Fluvoxamine, Minocycline, Olanzapine, Pentoxifylline, Pioglitazone, Riluzole, Topiramate Speech / Verbal Communication Symptom based listings Carnitine [A, 44] Folinic acid [B, 27] Carnosine [B, 10] Sulforaphane [B, 10] B6/Mag [C, 66] MB12 [C, 10] Coenzyme Q10 [C, 9] Omega 3 fatty acids [D, 26] Propranolol [A, 66] BH4 [A, 51] Fluoxetine [A, 50] Atomoxetine [A, 49] Memantine [A, 42] Galantamine [A, 26] Clonidine [A, 25] Amantadine [A, 21] Valproate [B, 37] Pentoxifylline [B, 25] Cyproheptadine [B, 12] Olanzapine [C, 22] Donepezil [C, 18] Steroids [C, 8] 12

13 Receptive Language / Understanding Multivitamin [A, 21] Folinic acid [B, 27] Propranolol [A, 66] Pentoxifylline [B, 25] Donepezil [C, 18] Steroids [C, 8] Spironolactone [D, 1] Social Interaction Melatonin [A, 92] NAC [A, 32] Folinic acid [B, 27] Carnosine [B, 10] Sulforaphane [B, 10] B6/Mag [C, 66] MB12 [C, 10] Omega 3 fish oil [D, 26] Oxytocin [A, 177] Naltrexone [A, 120] Propranolol [A, 66] BH4 [A, 51] Fluoxetine [A, 50] Memantine [A, 42] Galantamine [A, 26] Clonidine [A, 25] Valproate [B, 37] Pentoxifylline [B, 25] Fluvoxamine [B, 23] Bumetanide [B, 17] D Cycloserine [B, 15] Celecoxib [B, 10] Riluzole [B, 10] Acamprosate [B, 8] Olanzapine [C, 22] Stereotypy / Repetitive Behaviors Attention Folinic acid [B, 27] Vitamin C [B, 14] B6 / Mag [C, 66] Omega 3 fatty acids [D, 26] Naltrexone [A, 120] Fluoxetine [A, 50] Atomoxetine [A, 49] Memantine [A, 42] Clonidine [A, 25] Fluvoxamine [B, 23] Pioglitazone [B, 13] Cyproheptadine [B, 12] Topiramate [B, 12] Celecoxib [B, 10] Riluzole [B, 10] Sertraline [B, 9] Olanzapine [C, 22] Escitalopram [C, 3] Spironolactone [D, 1] Folinic acid [B, 27] Probiotics [B, 20] Iron [C, 3] Omega 3 fish oil [D, 26] Naltrexone [A, 120] Atomoxetine [A, 49] Memantine [A, 42] Galantamine [A, 26] Clonidine [A, 25] Guanfacine [A, 25] Pentoxifylline [B, 25] Acamprosate [B, 8] Donepezil [C, 18] Fenfluramine [D, 60] Levetiracetam [D, 6] Hyperactivity Irritability Multivitamin [A, 21] Omega 3 fish oil [D, 26] Naltrexone [A, 120] Haloperidol [A, 77] BH4 [A, 51] Atomoxetine [A, 49] Memantine [A, 42] Methylphenidate [A, 33] Buspirone [A, 30] Galantamine [A, 26] Clonidine [A, 25] Guanfacine [A, 25] Amantadine [A, 21] Pentoxifylline [B, 25] Topiramate [B, 12] Riluzole [B, 10] Acamprosate [B, 8] Clomipramine [C, 28] Olanzapine [C, 22] Mirtazapine [C, 8] Dextromethorphan [C, 7] Famotidine [C, 5] Escitalopram [C, 3] Melatonin [A, 92] NAC [A, 32] Pregnenolone [C, 3] Naltrexone [A, 120] Haloperidol [A, 77] Memantine [A, 42] Buspirone [A, 30] Galantamine [A, 26] Clonidine [A, 25] Amantadine [A, 21] Valproate [B, 37] Pioglitazone [B, 13] Topiramate [B, 12] Celecoxib [B, 10] Riluzole [B, 10] Olanzapine [C, 22] Mirtazapine [C, 8] Famotidine [C, 5] Escitalopram [C, 3] Spironolactone [D, 1] Mecamylamine [D, 0] 13

14 Sleep Eye contact Melatonin [A, 92] Carnitine [A, 44] Multivitamin [A, 21] Coenzyme Q10 [C, 9] Iron [C, 3] Clonidine [A, 25] Guanfacine [A, 25] Ramelteon [B, 8] Donepezil [C, 18] Mirtazapine [C, 8] Omega 3 fatty acids [D, 26] Oxytocin [A, 177] Naltrexone [A, 120] Propranolol [A, 66] BH4 [A, 51] Galantamine [A, 26] Famotidine [C, 5] Overall Autism Behaviors Training Physicians Carnitine [A, 44] Probiotics [B, 20] Carnosine [B, 10] Sulforaphane [B, 10] B6 / Mag [C, 66] MB12 [C, 10] Vitamin D [C, 5] Digestive enzymes [D, 3] Gingko biloba [D, 3] Naltrexone [A, 120] Haloperidol [A, 77] BH4 [A, 51] Pentoxifylline [B, 25] Bumetanide [B, 17] D Cycloserine [B, 15] Cyproheptadine [B, 12] Ramelteon [B, 8] Donepezil [C, 18] Vancomycin [C, 3] Citalopram [D, 5] MAPS Curriculum Focused on 6 major areas: 1. Neurology 2. Metabolic 3. Immunology 4. GI / nutrition 5. Toxicology 6. Integration into clinical care / cases Partnering with Parent Groups A novel evidence based ranking scale for medications and supplements in autism spectrum disorders Dan Rossignol MD FAAFP Rossignol Medical Center Florida Office (Melbourne, FL): Florida Office (Melbourne, F ): California Office (Aliso Viejo, CA): rossignolmd@gmail.com NAA Conference September 11,

15 Supplemental material: nutritional supplements Ginkgo biloba [Score: 3; Grade: D] The good: Improvements in aberrant behaviors The bad: None The dose / length: mg/day; 4 10 weeks References [2 studies]: (points per study = 1.5) 1b: 1 study; 0 points Iron [Score: 3; Grade: C] The good: Improvements in sleep and attention The bad: Constipation The dose / length: 6 mg elemental iron/day; 8 weeks References [1 study]: (points per study = 3.0) Pregnenolone [Score: 3; Grade: C] The good: Improvements in irritability, sensory abnormalities, lethargy The bad: Diarrhea (8%), tiredness (8%), depressive episode (8%) The dose / length: up to 500 mg/day; 12 weeks References [1 study]: (points per study = 3.0) Supplemental material: medications Haloperidol [Score: 77; Grade: A] The good: Improvements in irritability, hyperactivity, autism behaviors The bad: Drowsiness, weight gain, increased liver tests The dose / length: mg/day; 4 12 weeks References [14 studies]: , 2008; (points per study = 5.5) 1b: 7 studies; 70 points 2b: 5 studies; 6 points (+3 points x 2; 0 x 3 points) 4 CR: 2 studies; 1 point (+1 point; 1 x 0 points) 15

16 Fenfluramine [Score: 69; Grade: D] The good: Improvements in distractibility, better mood, attention The bad: Decrease in discrimination learning, lethargy, weight loss, agitation, insomnia, anorexia The dose / length: 1.5 mg/kg/day; up to 27 months References [29 studies]: (points per study = 2.4) 1b: 11 studies; 20 points (+20 points; 9 x 0 points) 2b: 16 studies; 48 points (5 points x 6; 3 points x 6; 4 x 0 points) 4 CS: 1 study; 0 points Tetrahydrobiopterin (BH4) [Score: 51; Grade: A] The good: Improvements in social interaction, eye contact, autism behaviors, hyperactivity, speech The bad: Irritability (22%), sleep problems (9%), hyperactivity (9%), rash (9%), repetitive behaviors (4%) The dose / length: 3 20 mg/kg/day; 16 weeks References [10 studies]: (points per study = 5.1) 1b: 3 studies; 30 points 2b: 7 studies; 21 points Valproate [Score: 37; Grade: B] The good: Improvements in irritability, language, social skills, reduction in seizures, impulsivity, aggression, obsessiveness The bad: Irritability, increased appetite, skin rash, slurred speech, cognitive slowing, increased serum ammonia The dose / length: mg/day; 8 12 weeks References [8 studies]: (points per study = 4.6) 1b: 4 studies; 30 points (+30 points; 0 x 1 points) 4 CS: 2 studies; 4 points 4 CR: 1 study; 0 points Methylphenidate [Score: 33; Grade: A] The good: Improvements in hyperactivity, impulsivity The bad: Irritability, decreased appetite, trouble falling asleep, headache The dose / length: mg/day / mg/kg/day; 8 weeks References [4 studies]: (points per study = 8.3) 1b: 3 studies; 30 points Clomipramine [Score: 28; Grade: C] The good: Improvements in repetitive thoughts, repetitive behaviors, hyperactivity, compulsive behaviors The bad: Urinary retention, worsened behaviors The dose / length: mg/day; 5 12 weeks References [7 studies]: (points per study = 4.0) 1b: 3 studies; 20 points (+20 points; 1 x 0 points) 2b: 3 studies; 6 points (+6 points; 1 x 0 points) Clonidine [Score: 25; Grade: A] The good: Improvements in social interaction, sensory problems, irritability, stereotypy, hyperactivity, speech, attention, mood problems, sleep The bad: Drowsiness, decreased activity The bad: Drowsiness, decreased activity The dose / length: mg/kg/day; 4 weeks References [5 studies]: (points per study = 5.0) 1b: 2 studies; 20 points 4 CS: 2 studies; 4 points 16

17 Fluvoxamine [Score: 23; Grade: B] The good: Improvements in stereotypy, repetitive behaviors, anxiety, aggression, social behaviors, self injurious behaviors The bad: Mild sedation, nausea, hyperactivity The dose / length: 1.5 mg/kg/day; 12 weeks References [7 studies]: (points per study = 3.3) 2b: 2 studies; 8 points 4 CR: 3 studies; 3 points Olanzapine [Score: 22; Grade: C] The good: Improvements in irritability, stereotypy, hyperactivity, speech, social interaction, self injurious behaviors The bad: Weight gain, rhabdomyolysis, increased appetite, loss of strength, drowsiness The dose / length: 5 10 mg/day; 8 13 weeks References [11 studies]: (points per study = 2.0) 2b: 4 studies; 9 points (+9 points; 1 x 0 points) 4 CR: 5 studies; 1 point (+1 point; 4 x 0 points) Donepezil [Score: 18; Grade: C] The good: Improvements in REM sleep, expressive speech, receptive speech, autism behaviors, ADHD symptoms The bad: Irritability, gastrointestinal problems The dose / length: 5 10 mg/day; 6 12 weeks References [5 studies]: (points per study = 3.6) 1b: 2 studies; 10 points (+10 points, 1 x 0 points) 2b: 2 studies; 6 points Bumetanide [Score: 17; Grade: B] The good: Improvements in emotion recognition, sensory behaviors, sensory processing, autism behaviors, social interaction The bad: Mild hypokalemia (low potassium, 22%), hyperactivity The dose / length: 1mg/day; months References [4 studies]: (points per study = 4.3) 2b: 2 studies; 6 points D Cycloserine [Score: 15; Grade: B] The good: Improvements in social withdrawal, overall autism severity The bad: Motor tics, echolalia The dose / length: mg/kg/day; 8 weeks References [4 studies]: (points per study = 3.8) 1b: 1 study, 0 points 2b: 3 studies; 15 points Pioglitazone [Score: 13; Grade: B] The good: Improvements in irritability, lethargy, stereotypy, and hyperactivity The bad: Slightly elevated liver function tests The dose / length: mg per day; 3 4months The dose / length: mg per day; 3 4 months References [2 studies]: (points per study = 6.5) 1b: 1 study, 10 points 17

18 Cyproheptadine [Score: 12; Grade: B] The good: Improvements in autism behaviors, speech, stereotypy The bad: Constipation (20%), morning drowsiness (15%), increased appetite (45%), fatigue (15%) The dose / length: up to 0.2 mg/kg/day; 8 weeks References [2 studies]: (points per study = 6.0) Topiramate [Score: 12; Grade: B] The good: Improvements in irritability, hyperactivity, stereotypy The bad: Skin rash, decreased cognition, drowsiness The dose / length: mg/day; 8 weeks References [2 studies]: (points per study = 6.0) 2b: Celecoxib [Score: 10; Grade: B] The good: Improvements in irritability, social interaction, stereotypy The bad: Abdominal pain (15%), increased appetite (15%), nausea (10%), insomnia (10%), sedation (15%) The dose / length: up to 300 mg/day; 10 weeks References [1 study]: (points per study = 10.0) Minocycline [Score: 10; Grade: B] The good: Slight improvements in some cytokines The bad: Gastrointestinal problems, upper respiratory symptoms, headache, hematuria The dose / length: 1.4 mg/kg/day to 50 mg twice a day; 6 months References [2 studies]: (points per study = 5.0) 1b: 1 study, 10 points 2b: 1 study; 0 points Riluzole [Score: 10; Grade: B] The good: Improvements in irritability, social interaction, stereotypy, hyperactivity The bad: Increased appetite (60%), abdominal pain (25%), morning drowsiness (35%), constipation (10%) The dose / length: mg/day; 10 weeks References [1 study]: (points per study = 10.0) Sertraline [Score: 9; Grade: B] The good: Improvements in repetitive behaviors, aggression The bad: Worsened behaviors, agitation, self picking The dose / length: mg/day; 12 weeks References [3 studies]: ; (points per study = 3.0) 2b: 3 studies; 9 points 18

19 Acamprosate [Score: 8; Grade: B] The good: Improvements in social interaction, attention, hyperactivity The bad: Gastrointestinal problems, irritability, emesis The dose / length: Mean dose 1,110 mg/day; up to 30 weeks References [2 studies]: (points per study = 4.0) 2b: 2 studies; 8 points Mirtazapine [Score: 8; Grade: C] The good: Improvements in aggression, self injury, irritability, hyperactivity, anxiety, depression, insomnia The bad: Increased appetite, weight gain, sedation, irritability The dose / length: mg/day; 4 8 weeks References [5 studies]: (points per study = 1.6) 4 CR: 3 studies; 3 points Ramelteon [Score: 8; Grade: B] The good: Improvements in sleep, autistic behaviors The bad: None reported The dose / length: 4 8 mg/day; weeks References [3 studies]: (points per study = 2.7) 2b: 2 studies; 6 points 4 CR: Steroids [Score: 8; Grade: C] The good: Improvements in receptive language, expressive speech, improvement in EEG The bad: Weight gain (95%), Cushingoid appearance (90%), sleep disturbance (10%), infection (5%) The dose / length: up to 2 mg/kg/day; up to 14 months References [4 studies]: (points per study = 2.0) 2b: 2 studies; 6 points 4 CR: 2 studies; 2 points Dextromethorphan [Score: 7; Grade: C] The good: Improvements in hyperactivity, aggression The bad: Nasal congestion, nausea, decreased appetite The dose / length: mg twice a day; 10 weeks References [3 studies]: (points per study = 2.3) 2b: 1 study; 5 points 4 CR: 2 studies; 2 points Levetiracetam [Score: 6; Grade: D] The good: Improvements in attention, hyperactivity, impulsivity, aggression, panic The bad: Stereotypy, decrease in communication and social interaction The dose / length: mg/kg/day; 4 10 weeks The dose / length: mg/kg/day; 4 10 weeks References [5 studies]: (points per study = 1.2) 1b: 1 study; 0 points 2b: 2 studies; 6 points 4 CR: 2 studies; 0 points (2 x 0 points) 19

20 Citalopram [Score: 5; Grade: D] The good: Improvements in anxiety, mood, autism behaviors The bad: Agitation, insomnia, tics, impulsiveness, decreased concentration, hyperactivity, stereotypy, diarrhea, insomnia, pruritus The dose / length: 5 40 mg/day; months References [3 studies]: (points per study = 1.7) 1b: 1 study; 0 points Famotidine [Score: 5; Grade: C] The good: Improvements in eye contact, hyperactivity, irritability The bad: Weight gain, head tapping The dose / length: 2 mg/kg/day; 10 weeks References [1 study]: (points per study = 5.0) 2b: 1 study; 5 points Arbaclofen [Score: 3; Grade: C] The good: Improvements in irritability, social interaction The bad: Agitation, irritability The dose / length: 8 weeks References [1 study]: (points per study = 3.0) Escitalopram [Score: 3; Grade: C] The good: Improvements in irritability, stereotypy, hyperactivity The bad: Aggression The dose / length: up to 20 mg/day; 10 weeks References [1 study]: (points per study = 3.0) Vancomycin [Score: 3; Grade: C] Amitriptyline [Score: 2; Grade: D] The good: Improvements in autism behaviors The bad: Hyperactivity, lethargy The dose / length: 500 mg per day; 8 weeks References [1 study]: (points per study = 3.0) The good: Improvements in hyperactivity, impulsivity, aggressiveness, and self injury The bad: Drowsiness, disturbed sleep The dose / length: mean dose 1 3 mg/kg/day; mean 3 4 years The dose / length: mean dose 1.3 mg/kg/day; mean 3.4 years References [1 study]: (points per study = 2.0) 20

21 Spironolactone [Score: 1; Grade: D] The good: Improvements in irritability, stereotypy, hyperactivity, speech, receptive language The bad: Electrolyte abnormalities The dose / length: 2 mg/kg/day; 4 weeks References [1 study]: (points per study = 1.0) Lamotrigine [Score: 0; Grade: D] The good: No improvements noted The bad: Insomnia, hyperactivity The dose / length: 5 mg/kg/day; 18 weeks References [2 studies]: (points per study = 0) 1b: 1 study; 0 points 4 CR: 1 study; 0 points Mecamylamine [Score: 0; Grade: D] The good: Improvements in hyperactivity, speech, irritability The bad: Constipation (50%), EKG QT prolongation The dose / length: mg/day; 14 weeks References [1 study]: (points per study = 0) 1b: 1 study; 0 points 21