A novel evidence-based ranking scale for medications and...

Anovelevidence-basedrankingscaleformedicationsandsupplementsinautismspectrumdisorders

DanRossignolMDFAAFPRossignolMedicalCenter

FloridaOffice(Melbourne,FL):321.259.7111CaliforniaOffice(AlisoViejo,CA):321.259.7111

[email protected]:@danrossignol

NAAConferenceSeptember11,2016

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 that Dr. Rossignol is not giving 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.

Disclaimer

WhatisAutism?• DSM-5emphasizesthatautismisadisorder characterizedbydeficitsinsocialcommunicationandbyrestricted,repetitivepatternsofbehavior

• Autismisaspectrumdisorder(think“autisms”)– somechildrenaremildlyaffected,someareseverelyaffected;thereareprobablymanydifferentcauses

• Isdiagnosedsolely bybehavioralobservations:autismhaspositive andnegativesymptoms

• Therearenobloodorotherbiological testsforidentifyingautism• Therefore,adiagnosisofautismtellsusnothing about thepotentialcontributorsorcauses ofthedisorder

• Testingandtreatmentscanstartbeforeadiagnosisofautism ismade

“AutisticBehaviors”

•Autisticbehaviorsmayhaveamedicalcauseorcontributor(whichareobjective),e.g.:• Seizuresorseizure-like(epileptiform)activitymaycontributetohyperactivity,aggressive behaviors,irritability,speech delay,self-stimulatorybehaviorsandsleepproblems[Malow,2004;Mulligan,2014;Viscidi,2013]

• Gastrointestinalproblemsmayleadtoaggressive behaviorsorself-injurious behaviors[Buie,2005;Buie,2010]

• KeyConcept:Treatmentofthesemedicalproblemsmayleadtobehavioralimprovements

Aims:ToevaluateautisticchildrenwithGIcomplaintsandaggressionorself-injuriousbehaviorinordertodetermineifthesebehaviorsmaybesymptomsofGER(reflux).Methods:Sixconsecutiveautisticchildren(ages8–19years)undergoingendoscopyandscheduledforBRAVO(wireless)pHprobewereevaluatedforhistologyandpHmeterresults.Findings:GERwasidentifiedin5of5patientstestedbyBRAVOpHtesting.Esophagitis wasseenin3of6patientsbiopsied.Conclusions:Aggressiveorself-injuriousbehaviormaybeamanifestationofpainfromGERandshouldpromptconsiderationoffurtherinvestigation.

Buie, 2005 J Pediatr Gastroenterol Nutr 41(4):505

Krigsman, 2007 Medical Veritas 4:1528-36

ImportantConcept

• Severalmetabolicabnormalitieshavebeenreportedtocontributetoorcauseapotentiallyreversibleformofautism• e.g.,CerebralFolateDeficiency(CFD)

• Thegoal,fromdayoneofevaluation,istorapidlyscreenfortheseabnormalities,identifythem,andstarttreatingthem(Iwanttoknowaboutalltheproblemsupfront)

• Testingcanbedonebymeasuringcertainbiomarkers(laboratoryteststhatmayidentifyabnormalities)

Whenchoosingatherapy…

• Wetreatmetabolicorbiochemicalabnormalitiesthatmaybecontributingtobehavior;inthatsense,wearenottreating“autism”or“ADHD”

• e.g.,AutismistreatedwithABAtherapy• Useproventreatmentsbaseduponbiomarkers (laboratorytestsorothertestslikeEEGs)and/orevidence-basedmedicine(choosingthebesttreatmentsbasedonthepublishedmedicalliterature)

• Thetimetoaddmajortreatmentsarewhenthingsaregoingwell,notwhenthingsarebad(thisisoftentheoppositeofourinstinct)

Typesoftreatments

• A.Treatmentsbasedonlabresults(ideallythesearealsoproventreatments)

• e.g.,Irontreatmentforlowferritin• B. Proven treatmentsbasedonevidence-based,symptoms-basedranking

• e.g.,Double-blind, placebo-controlledstudies• Non-proven treatmentsthataremostlikelyharmlessorlowrisk:lesscautionneeded

• Non-proventreatmentsthathavehighriskorhighdegreeofsideeffects:becautious

Knowyourexpectationsabouttreatments

Doyouexpectrecoveryin6months?• Notgoingtohappen• Oftencantake1-2yearsormoreforsignificantimprovementstooccur

• MarathonnotasprintAreyouchasingthelatestandgreatesttreatment?

• Thereisnomagicpillorquickfixforautism• Bewareoftreatmentsthatpromisecure

• Whatworksforonechilddoesnotworkforall• Autismisveryheterogenousinitssymptomsandresponsetotreatments

2 yo 4 yo

Treatment Paradigm:Trajectory

TIME

TypicalDevelopment

Autism

Evidence Based Medicine (EBM)

• Using the best available evidence to aid clinical decision making

• Uses strength or level of evidence (LOE)ØBenefit(s) of treatment ØRisk(s) of treatment

• Basis is often randomized controlled trials (RCT), systematic reviews and meta-analysis

General lack of evidence in medicine

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

Over 50% of what is done in medicine is “Unknown Effectiveness”

Scoring

Rossignol,2009AnnClinPsychiatry21(4):213-236

Grade


Modified CGI – ParentalAutism Research Institute: adapted from www.autism.com

Rossignol, 2009 Annals Clin Psych 21(4):213-36

SearchparametersforsupplementsandmedicationsinASD• Dateofmostrecentsearch:8/21/16• Sources:PubMed,Scopus,GoogleScholar, referencesfromreviewandotherarticles,database

• Excluded:reviewarticles, letterstoeditor(unlessnewdatapresented)

• Numberofstudiesidentifiedandreviewed:392• Numberofstudiesonnutritional supplements:119(20supplements)• Numberofstudiesonmedications:273(45medications)

• DidnotlookatRisperidoneorAripiprazole(bothapprovedtotreatirritabilityinautism)

Scoring


Scoring• 1a:Meta-analysisorsystematicreviewofRCT• 1b:Prospective,highqualityRCT[10points]• 2a:Systematicreviewofprospective,non-randomizedstudy• 2b:Prospective,non-randomizedstudyorlowqualityRCT[5points]orprospective,uncontrolledstudy[3points]

• 3a:Systematicreviewofretrospectivestudies• 3b: Individualcase-control(retrospectivestudy)[3points]• 4: Caseseries(retrospective) [CS,2points]orcasereport[CR,1point]• 5:Expertopinion,benchresearch[0points]• Negativestudieswereassigneda0(zero)[0points]

RCT=randomizedcontroltrial

Scoring

Randomized,double-blind,placebo-controlledstudy=10pointsProspective,placebo-controlledstudy(butlowerquality)=5pointsOpen-label,prospective,non-controlledstudy=3pointsRetrospectivecase-controlstudy=3pointsCaseseries(retrospective,2ormorepatients)=2pointsCasereport(retrospective,1patient)=1pointNegativestudies=0points

NutritionalSupplements

Melatonin[Score:92;Grade:A]

• Thegood:Improvementsinsleeponsetlatency(timetofallasleep),nighttimeawakenings,lengthofsleep,socialinteraction,irritability,alertness

• Thebad:Morningdrowsiness(<3%),Enuresis(bedwetting,<3%)• Thedose/length:1-6mgatbedtime;upto4years• References [22studies]:(pointsperstudy=4.2)

• 1b:6studies;60points• 2b:3studies;9points• 3b:none• 4CS:10studies;20points• 4CR:3studies;3points

VitaminB6/Magnesium[Score:66;Grade:C]

• Thegood:Improvementsinspeech,socialinteraction,autismbehaviors,stereotypy,verbalIQ

• Thebad:Hyperactivity• Thedose/length:100mg/day;0.6/mg/kg/day;upto35weeks• References [19studies]:(pointsperstudy=3.5)

• 1b:3studies;10points (1x10points;2x0points)• 2b:14studies;54points(6x5points;8x3points)• 3b:none• 4CS:none• 4CR:2studies;2points

Carnitine[Score:44;Grade:A]

• Thegood:Improvementsinsleepefficiency,energylevel,apraxia,communicationskills,expressivespeech,autismbehaviors,musclestrength

• Thebad:Hyperactivity,loosestools• Thedose/length:50-100mg/kg/day;upto6months• References [12studies]:(pointsperstudy=3.7)

• 1b:3studies;30points• 2b:1study;3points• 3b:none• 4CS:3studies;6points• 4CR:5studies;5points

N-Acetylcysteine(NAC)[Score:33;Grade:A]

• Thegood:Improvementsinsocialinteraction,aggressiveness,irritability

• Thebad:Constipation(16%),increasedappetite(16%),fatigue(13%),nervousness (13%),daytimedrowsiness(13%)

• Thedose/length:600-2700mg/day;8-12weeks• References [8studies]:(pointsperstudy=4.1)

• 1b:5 studies;30points (3x10points;2x0points)• 2b:none• 3b:none• 4CS:none• 4CR:3 studies;3points

Folinicacid[Score:27;Grade:B]

• Thegood:Improvementsinexpressivespeech,playskills,socialskills,receptivelanguage,attention,stereotypy

• Thebad:Hyperactivity,self-stimulatorybehaviors,aggression• Thedose/length:400mcg/dayto2-3mg/kg/day;2-4months• References [11studies]:(pointsperstudy=2.5)

• 1b:none• 2b:9studies;24points (twostudieshadsamepopulation)• 3b:none• 4CS:1study;2points• 4CR:1study;1point

Omega3fattyacids[Score:26;Grade:D]

• Thegood:Improvementsinhyperactivity,self-stimulatorybehaviors,attention,socialinteraction,communication,eyecontact

• Thebad:None(bruising,loosestools)• Thedose/length:540mg- 1.5grams/day;6-12weeks• References [13studies]:(pointsperstudy=2.0)

• 1b:3studies;0points (0x3points)• 2b:7studies;22points (+22points;1x0points)• 3b:none• 4CS:1study;2points• 4CR:2studies;2points

Multivitamin[Score:21;Grade:A]

• Thegood:Improvementsinhyperactivity,tantrums,receptivelanguage,sleep,gastrointestinalproblems

• Thebad:None(nausea,loosestools)• Thedose/length:highpotencypreparation(seearticles);3months• References [3studies]:(pointsperstudy=7.0)

• 1b:2studies;20points• 2b:none• 3b:none• 4CS:none• 4CR:1study;1point

Methylcobalamin(MB12)[Score:20;Grade:B]

• Thegood:Improvementsinexpressivespeech,livingskills,playskills,socialskills,enuresis,autismbehaviors

• Thebad:Hyperactivity• Thedose/length:64.5-75mcg/kgevery3days;12weeks• References [7studies]:(pointsperstudy=2.9)

• 1b:2 studies;10points (1x10points;0x10points)• 2b:4studies;9 points (twostudieshadsamepopulation)• 3b:none• 4CS:none• 4CR:1study;1point

Probiotics[Score:20;Grade:B]

• Thegood:Improvementsinattention,compliance,autismbehaviors,stoolconsistency,lowerClostridiaspecies

• Thebad:Skinrash(3%),diarrhea(3%),weightloss(3%)• Thedose/length:varies/50billioncfu/day;4months• References [5studies]:(pointsperstudy=4.0)

• 1b:1study;10points• 2b:2studies;6 points• 3b:1study;3points• 4CS:none• 4CR:1study;1point

VitaminC[Score:14;Grade:B]

• Thegood:Improvementsinsensoryproblems,self-stimulatorybehaviors

• Thebad:None(loosestools)• Thedose/length:114mg/kg/day;30weeks• References [3studies]:(pointsperstudy=4.7)

• 1b:1study;10points• 2b:1study;3points• 3b:none• 4CS:none• 4CR:1study;1point

Digestiveenzymes[Score:13;Grade:B]

• Thegood:Improvementsinfoodvariety,socialinteraction,emotionalresponse,hyperactivity,autismbehaviors

• Thebad:skinrash,itching,abdominalpain• Thedose/length:varies;12weeks• References [3studies]:(pointsperstudy=4.3)

• 1b:2 studies;10points (1x10points;0x10points)• 2b:1study;3points• 3b:none• 4CS:none• 4CR:none

VitaminD[Score:11;Grade:B]

• Thegood:Improvementsinautismbehaviors• Thebad:None• Thedose/length:doseindividually,basedonlabs• References [5studies]:(pointsperstudy=2.2)

• 1b:none• 2b:3 studies;9 points• 3b:none• 4CS:none• 4CR:2studies;2points

Bvitamins[Score:10;Grade:C]

• Thegood:Improvementsinmetabolism• Thebad:Hyperactivity• Thedose/length:varies• References [6studies]:(pointsperstudy=1.7)

• 1b:none• 2b:none• 3b:none• 4CS:4studies;8points• 4CR:2studies;2points

Carnosine[Score:10;Grade:B]

• Thegood:Improvementsinsocialization,communication,autismbehaviors

• Thebad:Hyperactivity• Thedose/length:800mg/day;8weeks• References [1study]:(pointsperstudy=10.0)

• 1b:1study;10points• 2b:none• 3b:none• 4CS:none• 4CR:none

Piracetam[Score:10;Grade:B]

• Thegood:Improvementsinaberrantbehaviors• Thebad:Constipation(20%),daytimedrowsiness(35%),morningdrowsiness(55%),increasedappetite(35%)

• Thedose/length:upto800mg/day;10weeks• References [1study]:(pointsperstudy=10.0)


Sulforaphane[Score:10;Grade:B]

• Thegood:Improvementsinautismbehaviors,socialinteraction,speech

• Thebad:Weightgain,lowerpulse,vomiting(19%),aggression(15%),abdominalpain(15%),flatulence(15%)

• Thedose/length:50-150micromol/day;18weeks• References [1study]:(pointsperstudy=10.0)


CoenzymeQ10/Ubiquinol[Score:9;Grade:C]

• Thegood:Improvementsincommunication,playskills,sleep,appetite

• Thebad:Hyperactivity• Thedose/length:50mgtwiceaday;3months• References [5studies]:(pointsperstudy=1.8)

• 1b:none• 2b:1study;3 points• 3b:none• 4CS:2studies;4points• 4CR:2studies;2points

Supplementrankingsbytotalpoints

1.Melatonin…………...……….922.B6/Mag………………………..663.Carnitine…………………......444.NAC………….....................335.Folinicacid…...................276.Omega3……………………….267.Multivitamin…………………218.MB12…………………..……….208.Probiotics………….............2010.VitaminC……………………14

11.Digestiveenzymes…………………1312.VitaminD3…………………………….1113.Bvitamins……………………………..1013.Carnosine………………………………1013.Piracetam………………………………1013.Sulforaphane…………………………1017.CoenzymeQ10………………………918.Gingko…………………………………..318.Iron……………………………………….318.Pregnenolone……………………….3

Supplementrankingsbypointsperstudy

1.Sulforaphane(1study) 10.01.Piracetam(1study) 10.01.Carnosine(1study) 10.04.MVI(3studies) 7.05.VitaminC(3studies) 4.76.Digestenzymes(3studies) 4.37.Melatonin(22studies) 4.28.NAC(8studies) 4.19.Probiotics(5studies) 4.010.Carnitine(12studies) 3.7

11.B6/Mag(19studies) 3.512.Pregnenolone(1study) 3.012.Iron(1study) 3.014.MB12(7studies) 2.915.Folinicacid(11studies) 2.516.VitaminD(5studies) 2.217.Omega3’s(13studies) 2.018.CoQ10(5studies) 1.819.Bvitamins(6studies) 1.720.Gingko(2studies) 1.5

GradeARankings:Supplements

1. Melatonin(92points)2. Carnitine(44points)3. NAC(33points)4. Multivitamin(21points)

MeanScore=47.5

GradeBRankings:Supplements

1.Folinicacid(27points)2.Methylcobalamin(20points)2.Probiotics(20points)4.VitaminC(14points)5.Digestiveenzymes(13points)6.VitaminD3(11points)7.Carnosine(10points)7.Piracetam(10points)7.Sulforaphane(10points)

MeanScore=15.0

GradeCRankings:Supplements

1.B6/Mag(66points)2.Bvitamins(10points)3.CoenzymeQ10(9points)4.Iron(3points)4.Pregnenolone(3points)

MeanScore=18.2

Numberofdouble-blind,placebo-controlled,positivestudies:supplements1.Melatonin 62.Carnitine 32.NAC 34.Multivitamin 25.B6/Mag 15.Digestiveenzymes 1

5.M12 15.Probiotics 15.VitaminC 15.Carnosine 15.Piracetam 15.Sulforaphane 1

Medications

Oxytocin[Score:177;Grade:A]

• Thegood:Improvementsineyecontact,socialinteraction,emotionalbehavior,qualityoflife

• Thebad:Emotionalproblems,irritability,headache,migraine• Thedose/length:8-24IU;8-16weeks• References [23studies]:(pointsperstudy=7.7)

• 1b:20studies;170points(17x10points;3x0points)• 2b:2studies;6points• 3b:none• 4CS:none• 4CR:1study;1point

Naltrexone[Score:120;Grade:A]

• Thegood:Improvementsinself-injuriousbehaviors,hyperactivity,agitation,irritability,tempertantrums,socialinteraction,stereotypy,attention,eyecontact

• Thebad:Transientsedation,nausea• Thedose/length:0.5-2mg/kg/day;7daysto6months• References [24studies]:(pointsperstudy=5.0)

• 1b:10studies;90points(+90points;1x0points)• 2b:6studies;18points• 3b:none• 4CS:4studies;8points• 4CR:4 studies;4points

Propranolol[Score:66;Grade:A]

• Thegood:Improvementsinspeech,conversations,cognition,memory,hypersexualbehaviors,aggression,socialinteraction,eyecontact

• Thebad:Decreasedheartrateandbloodpressure, fatigue• Thedose/length:10-40mg/day;upto1year• References [10studies]:(pointsperstudy=6.6)

• 1b:6 studies;60points• 2b:1study;3 points• 3b:none• 4CS:none• 4CR:3studies;3points

Fluoxetine[Score:50;Grade:A]

• Thegood:Improvementsinobsessiveness, compulsiveness,speech,stereotypy,socialinteraction,repetitivebehaviors

• Thebad:Baddreams(14%),depressedmood(9%),drymouth(14%),headache(14%),insomnia(14%),nausea(9%)

• Thedose/length:20-80mg/day;16weeksto76months• References [11studies]:(pointsperstudy=4.5)

• 1b:2studies;20points• 2b:8studies;28points (2x5points;6x3points)• 3b:none• 4CS:1study;2points• 4CR:none

Atomoxetine[Score:49;Grade:A]

• Thegood:Improvementsinhyperactivity,impulsivity,speech,stereotypy,fearofchange,attention

• Thebad:Aggression,abdominalpain(2-7%),decreasedappetite(9-18%),fatigue(7-18%),headache(15-20%),nausea(13%)

• Thedose/length:0.5-1.4mg/kg/day;10-20weeks• References [11studies]:(pointsperstudy=4.5)

• 1b:3studies;30points• 2b:6studies;15points (+15points,1x0points)• 3b:none• 4CS:2studies;4points• 4CR:none

Memantine[Score:42;Grade:A]

• Thegood:Improvementsinspeech,socialinteraction,attention,self-stimulatorybehaviors,irritability,hyperactivity

• Thebad:Stuttering,irritability,dizziness(15%),nausea(10%),rash(10%),sedation(15%)

• Thedose/length:upto20mg/day;upto21months• References [13studies]:(pointsperstudy=3.2)

• 1b:3 studies;20points (2x10points;1x0points)• 2b:6 studies;18points (5x5points;1x3points)• 3b:none• 4CS:2studies;2points(+2points;1x0points)• 4CR:2studies;2points

Buspirone[Score:30;Grade:A]

• Thegood:Improvementsinaggression,irritability,hyperactivity,compliance,andrestrictive/repetitivebehaviors

• Thebad:Involuntarymovements(4%),increasedappetite(61%),fatigue(11%),drowsiness(11%)


• 1b:2 studies;20points• 2b:3studies;9points• 3b:none• 4CS:none• 4CR:1study;1point

Galantamine[Score:26;Grade:A]

• Thegood:Improvementsinirritability,socialinteraction,expressivespeech,hyperactivity,eyecontact,attention

• Thebad:Rash,headache,nervousness, increasedappetite,weightgain• Thedose/length:8-24mg/day,10-12weeks• References [4studies]:(pointsperstudy=6.5)

• 1b:2studies;20points• 2b:2studies;6points• 3b:none• 4CS:none• 4CR:none

Guanfacine[Score:25;Grade:A]

• Thegood:Improvementsinhyperactivity,attention,insomnia,tics• Thebad:Drowsiness,irritability,rash,sleepdisturbance,constipation,decreaseappetite

• Thedose/length:1-3mg/day;upto6weeks• References [5studies]:(pointsperstudy=5.0)

• 1b:2 studies;20points• 2b:1study;3points• 3b:none• 4CS:1study;2points• 4CR:1study;0points

Pentoxifylline[Score:25;Grade:B]

• Thegood:Improvementsinreceptiveunderstanding,hyperactivity,socialinteraction,seizures(EEG),autismbehaviors,attention,speech

• Thebad:Nausea,vomiting,lowbloodpressure,headache,sleepproblems,hyperactivity

• Thedose/length:200-600mg/day;3months• References [6studies]:(pointsperstudy=4.2)

• 1b:1study;10points• 2b:5studies;15points• 3b:none• 4CS:none• 4CR:none

Amantadine[Score:21;Grade:A]

• Thegood:Improvementsinhyperactivity,speech,irritability• Thebad:Increasedappetite(30%),insomnia(5%),tremor(5%),morningdrowsiness(5%)

• Thedose/length:2.5-5mg/kg/day;4-10weeks• References [3studies]:(pointsperstudy=7.0)

• 1b:2studies;20points• 2b:none• 3b:none• 4CS:none• 4CR:1study,1point

Medicationrankingsbytotalpoints

1.Oxytocin 1772.Naltrexone 1203.Haloperidol 774.Fenfluramine 695.Propranolol 666.BH4 517.Fluoxetine 508.Atomoxetine 499.Memantine 4210.Valproate 37

11.Methylphenidate 3312.Buspirone 3013.Clomipramine 2814.Galantamine 2615.Clonidine 2515.Guanfacine 2515.Pentoxifylline 2518.Fluvoxamine 2319.Olanzapine 2220.Amantadine 21

Medicationrankingsbytotalpoints

21.Donepezil 1822.Bumetanide 1723.D-cycloserine 1524.Pioglitazone 1325.Cyproheptadine 1225.Topiramate 1227.Celecoxib 1027.Minocycline 1027.Riluzole 1030.Sertraline 931.Acamprosate 8

31.Mirtazapine 831.Ramelteon 831.Steroids 835.Dextromethorphan 736.Levetiracetam 637.Citalopram 537.Famotidine 539.Arbaclofen 339.Escitalopram 339.Vancomycin 342.Amitriptyline 2

Medicationrankingsbypointsperstudy

1.Celecoxib(1study) 10.01.Riluzole(1study) 10.03.Methylphenidate(4studies) 8.34.Oxytocin(23studies) 7.75.Amantadine(3studies) 7.06.Propranolol(10studies) 6.67.Galantamine(4studies) 6.57.Pioglitazone(2studies) 6.59.Cyproheptadine(2studies) 6.09.Topiramate(2studies) 6.0

11.Haloperidol(14studies) 5.512.BH4(10studies) 5.113.Naltrexone(24studies) 5.013.Clonidine(5studies) 5.013.Famotidine(1study) 5.013.Guanfacine(5studies) 5.013.Minocycline(2studies) 5.018.Valproate(8studies) 4.619.Atomoxetine(11studies) 4.519.Fluoxetine(11studies) 4.5

Medicationrankingsbypointsperstudy

21.Bumetanide(4studies) 4.322.Pentoxifylline(6studies) 4.223.Clomipramine(7studies) 4.023.Buspirone(5studies) 4.023.Acamprosate(2studies) 4.026.D-Cycloserine(4studies) 3.827.Donepezil (5studies) 3.628.Fluvoxamine(7studies) 3.329.Memantine(13studies) 3.230.Sertraline(3studies) 3.0

30.Arbaclofen(1study) 3.030.Escitalopram(1study) 3.030.Vancomycin(1study) 3.034.Ramelteon(3studies) 2.735.Fenfluramine(29studies) 2.436.Dextromethorphan(3studies)2.337.Olanzapine(11studies) 2.037.Steroids(4studies) 2.037.Amitriptyline(1study) 2.040.Citalopram(3studies) 1.7

GradeARankings:Medications

1.Oxytocin(177points)2.Naltrexone(120points)3.Haloperidol(77points)4.Propranolol(66points)5.BH4(51points)6.Fluoxetine(50points)7.Atomoxetine(49points)8.Memantine(42points)9.Methylphenidate(33points)10.Buspirone(30points)

11.Galantamine(26points)12.Clonidine(25points)12.Guanfacine(25points)14.Amantadine(21points)

MeanScore=56.6

GradeBRankings:Medications

1.Valproate(37points)2.Pentoxifylline(25points)3.Fluvoxamine(23points)4.Bumetanide(17points)5.D-Cycloserine(15points)6.Pioglitazone(13points)7.Cyproheptadine(12points)7.Topiramate(12points)

9.Celecoxib(10points)9.Minocycline(10points)9.Riluzole(10points)12.Sertraline(9points)13.Acamprosate(8points)13.Ramelteon(8points)

MeanScore=14.9

GradeCRankings:Medications

1.Clomipramine(28points)2.Olanzapine(22points)3.Donepezil(18points)4.Mirtazapine(8points)4.Steroids(8points)6.Dextromethorphan(7points)7.Famotidine(5points)8.Arbaclofen(3points)8.Escitalopram(3points)8.Vancomycin(3points)

MeanScore=10.5

Numberofdouble-blind,placebo-controlled,positivestudies:medications1.Oxytoxin…………………… 172.Naltrexone……………….. 93.Haloperidol………………. 74.Propranolol………………. 65.BH4………………………….. 35.Atomoxetine…………….. 35.Methylphenidate……… 35.Valproate………………….. 3

Twostudies:Amantadine,Buspirone,Clomipramine,Clonidine,Fenfluramine,Fluoxetine,Galantamine,Guanfacine,MemantineOnestudy:Bumetanide,Celecoxib,Cyproheptadine,Dextromethorphan,Donepezil,Fluvoxamine,Minocycline,Olanzapine,Pentoxifylline,Pioglitazone,Riluzole,Topiramate

Symptombasedlistings

Speech/VerbalCommunication

• Carnitine[A,44]• Folinicacid[B,27]• Carnosine[B,10]• Sulforaphane [B,10]• B6/Mag[C,66]• MB12[C,10]• CoenzymeQ10[C,9]• Omega3fattyacids[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]

ReceptiveLanguage/Understanding

• Multivitamin [A,21]• Folinicacid[B,27]

• Propranolol [A,66]• Pentoxifylline [B,25]• Donepezil [C,18]• Steroids[C,8]• Spironolactone [D,1]

SocialInteraction• Melatonin[A,92]• NAC[A,32]• Folinicacid[B,27]• Carnosine[B,10]• Sulforaphane [B,10]• B6/Mag[C,66]• MB12[C,10]• Omega3fishoil[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/RepetitiveBehaviors

• Folinicacid[B,27]• VitaminC[B,14]• B6/Mag[C,66]• Omega3fattyacids[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]

Attention

• Folinicacid[B,27]• Probiotics[B,20]• Iron[C,3]• Omega3fishoil[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• Multivitamin [A,21]• Omega3fishoil[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]

Irritability

• 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]

Sleep

• Melatonin[A,92]• Carnitine[A,44]• Multivitamin[A,21]• CoenzymeQ10[C,9]• Iron[C,3]

• Clonidine[A,25]• Guanfacine[A,25]• Ramelteon[B,8]• Donepezil[C,18]• Mirtazapine[C,8]

Eyecontact

• Omega3fattyacids[D,26] • Oxytocin[A,177]• Naltrexone[A,120]• Propranolol[A,66]• BH4[A,51]• Galantamine[A,26]• Famotidine[C,5]

OverallAutismBehaviors

• Carnitine[A,44]• Probiotics [B,20]• Carnosine[B,10]• Sulforaphane [B,10]• B6/Mag[C,66]• MB12[C,10]• VitaminD[C,5]• Digestiveenzymes[D,3]• Gingkobiloba [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]

Training Physicians

MAPS Curriculum

Focused on 6 major areas:1. Neurology2. Metabolic3. Immunology4. GI / nutrition5. Toxicology6. Integration into clinical care / cases

Partnering with Parent Groups

Anovelevidence-basedrankingscaleformedicationsandsupplementsinautismspectrumdisorders

DanRossignolMDFAAFPRossignolMedicalCenter

FloridaOffice(Melbourne,FL):321.259.7111CaliforniaOffice(AlisoViejo,CA):321.259.7111

[email protected]:@danrossignol

NAAConferenceSeptember11,2016

Supplementalmaterial:nutritionalsupplements

Ginkgobiloba[Score:3;Grade:D]

• Thegood:Improvementsinaberrantbehaviors• Thebad:None• Thedose/length:80-200mg/day;4-10weeks• References [2studies]:(pointsperstudy=1.5)

• 1b:1study;0points• 2b:1study;3 points• 3b:none• 4CS:none• 4CR:none

Iron [Score:3;Grade:C]

• Thegood:Improvementsinsleepandattention• Thebad:Constipation• Thedose/length:6mgelementaliron/day;8weeks• References [1study]:(pointsperstudy=3.0)

• 1b:none• 2b:1study;3 points• 3b:none• 4CS:none• 4CR:none

Pregnenolone[Score:3;Grade:C]

• Thegood:Improvementsinirritability,sensoryabnormalities,lethargy

• Thebad:Diarrhea(8%),tiredness(8%),depressiveepisode(8%)• Thedose/length:upto500mg/day;12weeks• References [1study]:(pointsperstudy=3.0)

• 1b:none• 2b:1study;3points• 3b:none• 4CS:none• 4CR:none

Supplementalmaterial:medications

Haloperidol[Score:77;Grade:A]

• Thegood:Improvementsinirritability,hyperactivity,autismbehaviors• Thebad:Drowsiness,weightgain,increasedlivertests• Thedose/length:0.25-4mg/day;4-12weeks• References [14studies]:1978-2002,2008;(pointsperstudy=5.5)

• 1b:7studies;70points• 2b:5studies;6points (+3pointsx2;0x3points)• 3b:none• 4CS:none• 4CR:2studies;1 point (+1point;1x0points)

Fenfluramine[Score:69;Grade:D]

• Thegood:Improvementsindistractibility,bettermood,attention• Thebad:Decreaseindiscriminationlearning,lethargy,weightloss,agitation,insomnia,anorexia

• Thedose/length:1.5mg/kg/day;upto27months• References [29studies]:(pointsperstudy=2.4)

• 1b:11studies;20points(+20points;9x0points)• 2b:16studies;48points(5pointsx6;3pointsx6;4x0points)• 3b:none• 4CS:1study;0points• 4CR:1study;1point

Tetrahydrobiopterin(BH4)[Score:51;Grade:A]

• Thegood:Improvementsinsocialinteraction,eyecontact,autismbehaviors,hyperactivity,speech

• Thebad:Irritability(22%),sleepproblems(9%),hyperactivity(9%),rash(9%),repetitivebehaviors(4%)

• Thedose/length:3-20mg/kg/day;16weeks• References [10studies]:(pointsperstudy=5.1)

• 1b:3studies;30points• 2b:7studies;21points• 3b:none• 4CS:none• 4CR:none

Valproate[Score:37;Grade:B]

• Thegood:Improvementsinirritability,language,socialskills,reductioninseizures,impulsivity,aggression,obsessiveness

• Thebad:Irritability,increasedappetite,skinrash,slurredspeech,cognitiveslowing,increasedserumammonia


• 1b:4studies;30points (+30points;0x1points)• 2b:1study;3points• 3b:none• 4CS:2studies;4points• 4CR:1study;0points

Methylphenidate[Score:33;Grade:A]

• Thegood:Improvementsinhyperactivity,impulsivity• Thebad:Irritability,decreasedappetite,troublefallingasleep,headache

• Thedose/length:7.5-50mg/day/0.125-0.5mg/kg/day;8weeks• References [4studies]:(pointsperstudy=8.3)

• 1b:3studies;30points• 2b:1study;3points• 3b:none• 4CS:none• 4CR:none

Clomipramine[Score:28;Grade:C]

• Thegood:Improvementsinrepetitivethoughts,repetitivebehaviors,hyperactivity,compulsivebehaviors

• Thebad:Urinaryretention,worsenedbehaviors• Thedose/length:25-250mg/day;5-12weeks• References [7studies]:(pointsperstudy=4.0)

• 1b:3studies;20points (+20points;1x0points)• 2b:3studies;6 points (+6points;1x0points)• 3b:none• 4CS:1study;2points• 4CR:none

Clonidine[Score:25;Grade:A]

• Thegood:Improvementsinsocialinteraction,sensoryproblems,irritability,stereotypy,hyperactivity,speech,attention,moodproblems,sleep

• Thebad:Drowsiness,decreasedactivity• Thedose/length:0.005mg/kg/day;4weeks• References [5studies]:(pointsperstudy=5.0)

• 1b:2studies;20points• 2b:none• 3b:none• 4CS:2studies;4points• 4CR:1study;1point

Fluvoxamine[Score:23;Grade:B]

• Thegood:Improvementsinstereotypy,repetitivebehaviors,anxiety,aggression,socialbehaviors,self-injuriousbehaviors

• Thebad:Mildsedation,nausea,hyperactivity• Thedose/length:1.5mg/kg/day;12weeks• References [7studies]:(pointsperstudy=3.3)

• 1b:1study;10points• 2b:2 studies;8points• 3b:none• 4CS:1study;2points• 4CR:3studies;3points

Olanzapine[Score:22;Grade:C]

• Thegood:Improvementsinirritability,stereotypy,hyperactivity,speech,socialinteraction,self-injuriousbehaviors

• Thebad:Weightgain,rhabdomyolysis,increasedappetite,lossofstrength,drowsiness


• 1b:1study;10points• 2b:4studies;9 points (+9points;1x0points)• 3b:none• 4CS:1study;2points• 4CR:5studies;1 point (+1point;4x0points)

Donepezil[Score:18;Grade:C]

• Thegood:ImprovementsinREMsleep,expressivespeech,receptivespeech,autismbehaviors,ADHDsymptoms

• Thebad:Irritability,gastrointestinalproblems• Thedose/length:5-10mg/day;6-12weeks• References [5studies]:(pointsperstudy=3.6)

• 1b:2studies;10points (+10points,1x0points)• 2b:2studies;6 points• 3b:none• 4CS:1study;2 points• 4CR:none

Bumetanide[Score:17;Grade:B]

• Thegood:Improvementsinemotionrecognition,sensorybehaviors,sensoryprocessing,autismbehaviors,socialinteraction

• Thebad:Mildhypokalemia(lowpotassium,22%),hyperactivity• Thedose/length:1mg/day;3-10months• References [4studies]:(pointsperstudy=4.3)

• 1b:1study;10points• 2b:2studies;6points• 3b:none• 4CS:none• 4CR:1study;1point

D-Cycloserine[Score:15;Grade:B]

• Thegood:Improvementsinsocialwithdrawal,overallautismseverity• Thebad:Motortics,echolalia• Thedose/length:0.7-2.8mg/kg/day;8weeks• References [4studies]:(pointsperstudy=3.8)

• 1b:1study,0points• 2b:3 studies;15points• 3b:none• 4CS:none• 4CR:none

Pioglitazone[Score:13;Grade:B]

• Thegood:Improvementsinirritability,lethargy,stereotypy,andhyperactivity

• Thebad:Slightlyelevatedliverfunctiontests• Thedose/length:30-60mgperday;3-4months• References [2studies]:(pointsperstudy=6.5)

• 1b:1study,10points• 2b:1study;3points• 3b:none• 4CS:none• 4CR:none

Cyproheptadine[Score:12;Grade:B]

• Thegood:Improvementsinautismbehaviors,speech,stereotypy• Thebad:Constipation(20%),morningdrowsiness(15%),increasedappetite(45%),fatigue(15%)

• Thedose/length:upto0.2mg/kg/day;8weeks• References [2studies]:(pointsperstudy=6.0)

• 1b:1study;10points• 2b:none• 3b:none• 4CS:1study;2 points• 4CR:none

Topiramate[Score:12;Grade:B]

• Thegood:Improvementsinirritability,hyperactivity,stereotypy• Thebad:Skinrash,decreasedcognition,drowsiness• Thedose/length:100-200mg/day;8weeks• References [2studies]:(pointsperstudy=6.0)

• 1b:1study;10points• 2b:• 3b:none• 4CS:1study;2points• 4CR:none

Celecoxib[Score:10;Grade:B]

• Thegood:Improvementsinirritability,socialinteraction,stereotypy• Thebad:Abdominalpain(15%),increasedappetite(15%),nausea(10%),insomnia(10%),sedation(15%)

• Thedose/length:upto300mg/day;10weeks• References [1study]:(pointsperstudy=10.0)


Minocycline[Score:10;Grade:B]

• Thegood:Slightimprovementsinsomecytokines• Thebad:Gastrointestinalproblems,upperrespiratorysymptoms,headache,hematuria

• Thedose/length:1.4mg/kg/dayto50mgtwiceaday;6months• References [2studies]:(pointsperstudy=5.0)

• 1b:1study,10points• 2b:1study;0points• 3b:none• 4CS:none• 4CR:none

Riluzole[Score:10;Grade:B]

• Thegood:Improvementsinirritability,socialinteraction,stereotypy,hyperactivity

• Thebad:Increasedappetite(60%),abdominalpain(25%),morningdrowsiness(35%),constipation(10%)

• Thedose/length:50-100mg/day;10weeks• References [1study]:(pointsperstudy=10.0)


Sertraline[Score:9;Grade:B]

• Thegood:Improvementsinrepetitivebehaviors,aggression• Thebad:Worsenedbehaviors,agitation,self-picking• Thedose/length:25-150mg/day;12weeks• References [3studies]:1996-1998;(pointsperstudy=3.0)

• 1b:none• 2b:3studies;9points• 3b:none• 4CS:none• 4CR:none

Acamprosate[Score:8;Grade:B]

• Thegood:Improvementsinsocialinteraction,attention,hyperactivity• Thebad:Gastrointestinalproblems,irritability,emesis• Thedose/length:Meandose1,110mg/day;upto30weeks• References [2studies]:(pointsperstudy=4.0)

• 1b:none• 2b:2studies;8points• 3b:none• 4CS:none• 4CR:none

Mirtazapine[Score:8;Grade:C]

• Thegood:Improvementsinaggression,self-injury,irritability,hyperactivity,anxiety,depression,insomnia

• Thebad:Increasedappetite,weightgain,sedation,irritability• Thedose/length:7.5-45mg/day;4-8weeks• References [5studies]:(pointsperstudy=1.6)

• 1b:none• 2b:1study;3points• 3b:none• 4CS:1study;2points• 4CR:3studies;3points

Ramelteon[Score:8;Grade:B]

• Thegood:Improvementsinsleep,autisticbehaviors• Thebad:Nonereported• Thedose/length:4-8mg/day;16-18weeks• References [3studies]:(pointsperstudy=2.7)

• 1b:none• 2b:2studies;6points• 3b:none• 4CS:1study;2points• 4CR:

Steroids[Score:8;Grade:C]

• Thegood:Improvementsinreceptivelanguage,expressivespeech,improvementinEEG

• Thebad:Weightgain(95%),Cushingoidappearance(90%),sleepdisturbance(10%),infection(5%)

• Thedose/length:upto2mg/kg/day;upto14months• References [4studies]:(pointsperstudy=2.0)

• 1b:none• 2b:2studies;6points• 3b:none• 4CS:none• 4CR:2studies;2points

Dextromethorphan[Score:7;Grade:C]

• Thegood:Improvementsinhyperactivity,aggression• Thebad:Nasalcongestion,nausea,decreasedappetite• Thedose/length:30-60mgtwiceaday;10weeks• References [3studies]:(pointsperstudy=2.3)

• 1b:none• 2b:1study;5points• 3b:none• 4CS:none• 4CR:2studies;2points

Levetiracetam[Score:6;Grade:D]

• Thegood:Improvementsinattention,hyperactivity,impulsivity,aggression,panic

• Thebad:Stereotypy,decreaseincommunicationandsocialinteraction• Thedose/length:10-60mg/kg/day;4-10weeks• References [5studies]:(pointsperstudy=1.2)

• 1b:1study;0points• 2b:2studies;6points• 3b:none• 4CS:none• 4CR:2studies;0points (2x0points)

Citalopram[Score:5;Grade:D]

• Thegood:Improvementsinanxiety,mood,autismbehaviors• Thebad:Agitation,insomnia,tics,impulsiveness,decreasedconcentration,hyperactivity,stereotypy,diarrhea,insomnia,pruritus

• Thedose/length:5-40mg/day;1-15months• References [3studies]:(pointsperstudy=1.7)

• 1b:1study;0points• 2b:1study;3points• 3b:none• 4CS:1study;2points• 4CR:none

Famotidine[Score:5;Grade:C]

• Thegood:Improvementsineyecontact,hyperactivity,irritability• Thebad:Weightgain,headtapping• Thedose/length:2mg/kg/day;10weeks• References [1study]:(pointsperstudy=5.0)


Arbaclofen[Score:3;Grade:C]

• Thegood:Improvementsinirritability,socialinteraction• Thebad:Agitation,irritability• Thedose/length:8weeks• References [1study]:(pointsperstudy=3.0)


Escitalopram[Score:3;Grade:C]

• Thegood:Improvementsinirritability,stereotypy,hyperactivity• Thebad:Aggression• Thedose/length:upto20mg/day;10weeks• References [1study]:(pointsperstudy=3.0)


Vancomycin[Score:3;Grade:C]

• Thegood:Improvementsinautismbehaviors• Thebad:Hyperactivity,lethargy• Thedose/length:500mgperday;8weeks• References [1study]:(pointsperstudy=3.0)


Amitriptyline[Score:2;Grade:D]

• Thegood:Improvementsinhyperactivity,impulsivity,aggressiveness,andself-injury

• Thebad:Drowsiness,disturbedsleep• Thedose/length:meandose1.3mg/kg/day;mean3.4years• References [1study]:(pointsperstudy=2.0)

• 1b:none• 2b:none• 3b:none• 4CS:1study;2points• 4CR:none

Spironolactone[Score:1;Grade:D]

• Thegood:Improvementsinirritability,stereotypy,hyperactivity,speech,receptivelanguage

• Thebad:Electrolyteabnormalities• Thedose/length:2mg/kg/day;4weeks• References [1study]:(pointsperstudy=1.0)

• 1b:none• 2b:none• 3b:none• 4CS:none• 4CR:1study;1point

Lamotrigine[Score:0;Grade:D]

• Thegood:Noimprovementsnoted• Thebad:Insomnia,hyperactivity• Thedose/length:5mg/kg/day;18weeks• References [2studies]:(pointsperstudy=0)

• 1b:1study;0points• 2b:none• 3b:none• 4CS:none• 4CR:1study;0 points

Mecamylamine[Score:0;Grade:D]

• Thegood:Improvementsinhyperactivity,speech,irritability• Thebad:Constipation(50%),EKGQTprolongation• Thedose/length:0.5-5mg/day;14weeks• References [1study]:(pointsperstudy=0)


A novel evidence-based ranking scale for medications and...

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