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
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
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”
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• 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
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)
• 1b:1study;10points• 2b:none• 3b:none• 4CS:none• 4CR:none
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)
• 1b:1study;10points• 2b:none• 3b:none• 4CS:none• 4CR:none
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
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%)
• Thedose/length:5-20mg/day;4-8weeks• References [6studies]:(pointsperstudy=5.0)
• 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
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]
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
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
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
• Thedose/length:125-2500mg/day;8-12weeks• References [8studies]:(pointsperstudy=4.6)
• 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
• Thedose/length:5-10mg/day;8-13weeks• References [11studies]:(pointsperstudy=2.0)
• 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)
• 1b:1study;10points• 2b:none• 3b:none• 4CS:none• 4CR:none
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)
• 1b:1study;10points• 2b:none• 3b:none• 4CS:none• 4CR:none
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)
• 1b:none• 2b:1study;5points• 3b:none• 4CS:none• 4CR:none
Arbaclofen[Score:3;Grade:C]
• Thegood:Improvementsinirritability,socialinteraction• Thebad:Agitation,irritability• Thedose/length:8weeks• References [1study]:(pointsperstudy=3.0)
• 1b:none• 2b:1study;3points• 3b:none• 4CS:none• 4CR:none
Escitalopram[Score:3;Grade:C]
• Thegood:Improvementsinirritability,stereotypy,hyperactivity• Thebad:Aggression• Thedose/length:upto20mg/day;10weeks• References [1study]:(pointsperstudy=3.0)
• 1b:none• 2b:1study;3points• 3b:none• 4CS:none• 4CR:none
Vancomycin[Score:3;Grade:C]
• Thegood:Improvementsinautismbehaviors• Thebad:Hyperactivity,lethargy• Thedose/length:500mgperday;8weeks• References [1study]:(pointsperstudy=3.0)
• 1b:none• 2b:1study;3points• 3b:none• 4CS:none• 4CR:none
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