MedicationManagementinTicDisorders

EricaGreenberg,MDPediatricPsychiatryOCDandTicDisordersProgram

7/29/18

Norelevantdisclosures(ClinicalresearchstudyfundedinpartbytheAmericanAcademyofChildandAdolescent

Psychiatry(AACAP)’sPilotResearchAwardforAttentionDisorders,supportedbyAACAP’sElaineSchlosserLewisFund)

Discussionofoff-label&investigationaluse:Yes X No__

SpeakerDisclosures:

Outline

•BriefreviewofticsandTourettesyndrome(TS)•Pharmacologyfortics•PharmacologyforOCDandADHDwhenticsarealsopresent

Whataretics?

• Sudden,recurrent,non-rhythmic,movementsorsounds• Unvoluntary

•Waxandwaneovertime• Treatmentimplications

•Oftenprecededbyapremonitoryurge/itch/tension• Somatic,sensory,orideationalsymptomsthatprecedetics• Feelingof“notjustright”or“incompleteness”• Temporarilyrelievedbyperformingthetic

• They“jump”• Changelocation,number,frequency,type,complexityseverity

Millsetal.,2014Hallett 2015

WhatisTouretteSyndrome?

• Childhood-onsetneuropsychiatricdisordercharacterizedbytics• Estimatedtobebetween0.3%and0.9%(Scharfetal2015)

• Criteria:• AtleastTwomotorandOnevocalticoverthecourseoftheillness• Atleastoneyearduration,thoughtheticscanwaxandwaneinfrequency• Onsetbeforeage18• Notsecondarytoasubstanceoranothermedicalcondition

OtherTicDisorders

• Persistent(Chronic)MotororVocalTicDisorder:• SamecriteriaasTS,butonlymotorORvocaltics• Additional1-2%ofchildren

• ProvisionalTicDisorder• Partofnormaldevelopment?(~20-25%ofkids)

TSPathophysiology

• Dysfunctionoffronto-striatal-thalamo-corticalcircuits• Leadstodisinhibitionofthemotorandlimbicsystem

• Neurotransmittersinthiscircuit:• Glutamate• Serotonin• Dopamine• GABA

Beddows 2015 - http://scitechconnect.elsevier.com/neurobiology-basis-of-ocd/. Modified from original image, credits: Patrick J. Lynch and C. Carl Jaffe.

TreatmentconsiderationsinTourettesyndrome:• Improvement with age• Rule of Thirds: 1/3 resolve, 1/3 improve, 1/3 stay the same•~10% of patients have persistent, severe symptoms as adults

•Modifying factors (internal vs. external)

WhentoTreatTics?

• Whentics/urgesarecausingphysicalpain/impairment• Whenticsarecausingseveresocial/functionalproblems• Whenticsleadtopsychologicaldistress,suchasdepressiveandanxioussymptoms,lowself-esteemand/orsocialwithdrawal

ChildhoodPsychosocialMorbidity

•Over 2/3 children with TS reported impaired peer relations, difficulties with friendships• Rated as less popular/more withdrawn by peers and

teachers vs. healthy controls• Higher rates of peer victimization when compared to

children with a “medical” illness (Type I diabetes) and healthy controls

•Quality of life in children with TS significantly worse than normative sample

(Eapen,Cavanna,Robertson2016)

Treatments

•Behavioral•Pharmacologic

healthncare.info

OverallTreatmentGuidelines

• NostudiescomparingtheeffectivenessofbehavioralandpharmacologicaltreatmentsinpatientswithTS• Treatmentaimstoreduceticseverityandfrequency• Oftenmoreimportanttomanagethecomorbidconditionsinordertoimprovepsychosocialfunctioningand(child)development• Intensityofticsdoesnothavetoequatewithimpairment

EuropeanSocietyfortheStudyofTouretteSyndrome,2011

Pharmacotherapy

• Only FDA approved treatments: Pimozide, Haloperidol and Aripiprazole• Broadrangeofclinicalexperiences,butactualevidence(basedonRCTs)islimited

TSPharmacologyOverview

•Three“tiers”ofticmedications•Tier1:Alpha-2agonists:

• Clonidine,guanfacine, extended-releaseguanfacine

•Tier2:Atypicalneuroleptics(antipsychotics)• Risperidone, aripiprazole,etc.

•Tier3:Typicalneuroleptics(antipsychotics)• Haloperidol,pimozide,etc.

DosesofMedication

The image part with relationship ID rId3 was not found in the file.

THOMSONREUTERS– DrugsofToday2014,50(2)

Alpha-agonists

•Clonidine,guanfacine• “Bloodpressure”medications

• IndicationintreatingADHD• Off-label,usedforsleep,impulsivity,?anxiety• Short-acting,extended-release,transdermal

• Leastsideeffects• Sedation,dizziness,headache,lowbloodpressure

•Goodforticsoflimitedseverity**• Improvementabout30%

•**Caveat:Mayonlybehelpfulifco-occurringADHD• Recentnegativestudyusingextended-releaseguanfacineinchildrenwithchronictics (Murphyetal.,2017)

AtypicalAntipsychotics

• Risperidone,Aripiprazole(Dopaminergic/serotonergic)• (ClassB:Ziprasidone,Olanzapine,Quetiapine)

• Otherindications:Mooddisorders(bipolardisorder,severeaggressivebehavior/mooddysregulationinASD,psychosis)

•Moderatesideeffects:•Metabolicsymptoms(cholesterol,weightgain,glucose)• Akathisia,lowbloodpressure,GI,sedation• Lowriskoftardivedyskinesia• Requiresmonitoring(blood)

•Moderatebenefit:• 35-60%ticreduction

TypicalAntipsychotics

•Haloperidol,Pimozide(Dopaminergic)• (ClassB:Fluphenazine)

•Otherindications:Psychoticdisorders,severebipolardisorder/mooddysregulation

•Potentialforseveresideeffects:•Tardivedyskinesia,dystonia,•Sedation,weightgain,fogginess•Requiresmonitoring(EKG)

•Oftennottolerated2otosideeffects

•Largestbenefit:•Haloperidol upto80%;fluphenazine/pimozideupto60%

OtherMedications

• Benzodiazepines (clonazepam)

• Topiramate (anticonvulsant): Meta-analysis negative, but positive RCT in kids

• Baclofen (GABA modulator): Some positive effect

• Atomoxetine: Some benefit, at times exacerbates tics

• Nicotine: Some benefit• Tetrabenazine: some positive effect, increased risk of

depression• Trialing new VMAT-2 inhibitors

• Metoclopramide(mixeddopamine/serotoninantagonist)• Botox:Onlyforsimplemotortic• Cannabinoids**

Thomasetal2013EgolfandCoffey2014

Cannabanoids(Delta-9-THC)

• Anecdotalreportsthatmarijuana maybehelpfulwithticsand behavioralproblems• WhitingetalinJAMA(2015)suggestedthat“suggestedthatTHCcapsulesmaybeassociatedwithasignificantimprovementinticseverityinpatientswithTourettesyndrome”• Tworecentcontrolledtrialswithselfandexaminerscales

• Statisticallysignificantticreductionwithoutsignificantadverseeffects(someshort-termmemoryloss,reboundanxiety)

• RecentCochranestudy,however,statesinabilitytodrawdefinitiveconclusionsatthistime• NOTforchildren<21

• Concernforassociationwithpsychosis

Curtisetal2009Mueller-Vahl2012

OCDinTS

• 30-60% of TS pts meet DSM-IV criteria for OCD• Compared to 0.5-3.6% in general population

• Distinct symptoms:• Obsessions: symmetry, aggression, sexuality, religiosity• Compulsions: checking, touching, re-writing, evening

• Anxietyanddepressionmorelikely• PatientswithOCD+ticsshowlessrobustresponsetoSSRIscomparedtothosewithouttics• Augmentation:

• Haloperidol,risperidone,aripiprazole– positivetrials

GomesdeAlvarenga etal2012Høolgaard Detal.2012Mansueto andKeuler 2005

ADHDinTouretteSyndrome

• 60-90%ofTSpatientshaveADHD• Vs.5.8-13.6%inmales;1.9-4.5%infemales

• TicdisordersaremorefrequentinchildrenwithADHD

• TSandADHDisassociatedwith:• Decreasedqualityoflife(secondarytoADHDandOCD)• Worsesocialdifficulties

• Additionalco-occurringdisorders:• Oppositionaldefiantdisorder,Intermittentexplosivedisorder

TheTSStudyGroup(2002).NeurologyPeasgood etal(2016).Eur ChildAdol PsychEddyetal(2012).MovementDis.Pringsheim etal(2017).ChildPsychandHumanDev.

TreatmentofADHDandTics(TACT):TargetedCombinedPharmacotherapyStudy

•Multi-centertreatmentstudyinchildrenwithADHDandTourette/chronicticdisorder• Clonidine(alpha-agonist)•Methylphenidate(stimulant)• Combined(clonidineandmethylphenidate)• Placebo

•Design:136children(ages7-14);16weeks•Summarizedresults:• TicsandADHDsymptomsbothdidbestwithCombinedalpha-agonist/stimulant

TouretteSyndromeStudyGroup(2002).Neurology.

TSandADHDPharmacotherapy

• IfADHDismildandticsareproblematic,cantryalpha-agonist• Goodforhyperactivity/impulsivity

•Solostimulantuseinpatientswithticshastraditionallybeenavoided,but•Meta-analysisbyCohenetal(2015)• Nodifferenceinticworseninginstimulantvs.placebogroup• Noassociationbetweennewonsetorworseningofticsandstimulantuse

Cohenetal.(2015)JAACAP

Summary

• Formildticsthatneedpharmacologictreatment,firsttryclonidineorguanfacine,especiallyifADHD• Atypicalortypicalneurolepticsshouldbereservedforseverecases,usedcautiously&monitoredclosely.

• New medications using different proposed mechanisms in the pipeline• It is okay to use stimulants (case by case)• SSRIs do not worsen tics• Ultimate goal is to help patient develop and maintain

appropriate self-esteem and coping skills

Questions?

SpecialthankstoDrs.JeremiahScharf,SabineWilhelm,CathyBudman