Drug-Induced Movement Disorders - health.umt.eduhealth.umt.edu/pharmacypractice/CPE/images/RDD 2018 Presentations... · Masked facies, bradykinesia, reduced blink rate, reduced arm

Drug-InducedMovementDisordersIANMCGRANE,PHARMD,BCPP,BCPS

MARCH4TH,2018

Mardsen C.D. Journal of Neurology, Neurosurgery, and Psychiatry 1976;39:1205

DisclosuresDr.McGraneisamemberoftheDrugUtilizationReviewBoardforMountain-PacificQualityHealthandMontanaMedicaid.HeisaboardmemberfortheMontanaMentalHealthTrust.

HehasreceivedawardhonorariumfromtheCollegeofPsychiatricandNeurologicalPharmacistsin2015and2017.

HewillbereceivingroyaltiesfromHogrefe PublishingGroupasaneditoroftheClinicalHandbookofPsychotropicDrugsforChildrenandAdolescents:4th Edition(2018)

Hewillbediscussingoff-labelindicationsinthispresentation

RecommendedReferencesCollegeofPsychiatricandNeurologicPharmacists(CPNP)◦ Drug-InducedMovementDisorders:AClinicalGuidetoRatingScales(video,2012)◦ PsychiatricPharmacistReviewBook2017-2018

Pharmacogenetic TestingDosingRecommendations◦ www.pharmgkb.org

LearningObjectivesIdentifyfourdifferenttypesofdrug-inducedmovementdisorders

Describepharmacotherapyoptionsforfourdifferentdrug-inducedmovementdisorders

Compareandcontrastpharmacokineticpropertiesandclinicaloutcomesdatabetweenthreevesicularmonoaminetransporter2(VMAT2)inhibitorsusedfortardivedyskinesia

LectureOutlineDrug-InducedMovementDisorders◦ Akathisia◦ Dystonia◦ Drug-inducedparkinsonism◦ Dyskinesia

PharmacodynamicsofImplicatedNeuropsychiatricMedications

EvidenceBasedTreatments

Lohr et al. CNS Spectrums 2015;20:4-14.

Drug-InducedMovementDisorders•ExtrapyramidalSymptoms(EPS)isavagueterm

• TermcoinedbyPrus in1898

•EPScanbecausedbyantipsychoticsandotherneuropsychiatricmedications

•Treatmentemergentsideeffectsmayimpacttherapeuticrelationships

•Theclinicalchallenge:Managepsychiatricillnessgiventheknownrisksofdrug-inducedmovementdisorders,includingtardivedyskinesia

Akathisia“Akathisie”meaning“inabilitytosit” (Hascovec,1901)

SensorimotorDisorder

◦ MaynotberelatedtoExtrapyramidalsystem

◦ Movementsmayoccurasawaytorelievesensorycomponent

Verycommon,yetchallengingtoidentify,describe,andtreat

Subjectivecomplaints:

◦ “anxiety”,“itching”,“legsonfire”,“tinglinginbones”,“wanttojumpoutofskin”

Objectivesigns:

◦ Positionshifting,rocking,writhing,running,jumping,throwingbodyacrossroom


Akathisia- SubtypesAcute – withinweeks,progressive

Chronic – severalmonthsorlonger

Withdrawalakathisia – onsetwithin2weeksofreductionordiscontinuationofmedication,resolveswithtime

Tardiveakathisia – occurslateintreatmentcourse,mayoccuraftermedicationwithdrawal,severitymaybereducedwithrestartingmedication

Pseudoakathisia – objectivesignspresentbutnosubjectivesymptoms


BarnesAkathisiaRatingScale(BARS)Instructions:◦ Patientobservedseatedandstandingfor>2minuteswhileengagedinneutralconversation

ObjectiveAssessment:◦ Degreeofobservedrestlessnesssymptoms

SubjectiveAssessment:◦ Patientsawarenessofrestlessnessanddistressseverity

GlobalClinicalAssessment:◦ Absent,Questionable,MildAkathisia,Moderate,Marked,Severe

Barnes TR. British Journal of Psychiatry 1989; 154(5):672-676.

Whichofthefollowingcancauseakathisia?(selectallthatapply)a) Antipsychoticsb) Antidepressantsc) Lithiumd) Valproic Acide) Azithromycin

Whichpatientpopulationmayyouseeakathisia?(selectallthatapply)a) Psychiatricb) Oncologicc) MedicallyIllwithdelirium

Akathisia- ImplicatedMedicationsAntipsychotics◦ FirstGeneration:8-76%(mean25%)

◦ SecondGeneration:Similarvariability

◦ Lowerrisk:olanzapine,quetiapine,clozapine

◦ Higherrisk:aripiprazole,risperidone,lurasidone

Anti-emetics

Antidepressants

Dopaminedepleters (VMATinhibitors)

Others◦ Azithromycin,calciumchannelblockers,lithium,GHB,methamphetamine,MDMA,cocaine

RiskFactors◦ Higherdosages◦ Rapiddoseincreases◦ Psychoticormooddisorders◦ Traumaticbraininjury,cancer,irondeficiency◦ Chronicortardiveakathisia◦ Advancedage◦ Female

Lohr et al. CNS Spectrums 2015;20:4-14.Poyurovsky and Weizman. J Clin Psychopharmacol 2015;35:711-714.

Akathisia– PathophysiologyMaybeduetomesocortical dopamineblockade(MarsdenandJenner,1980)

Generalizeddopaminereductiontriggerscompensatorynoradrenergicactivityinlocusceruleus (StahlandLoonen,2011)

◦ Supportsbeta-blockersinsymptomatictreatment

Maynot berelatedtoCNSdopamineactivity

◦ Peripherallyactingdopamineantagonist(domperidone)cancauseinParkinson'sdisease

Mayberelatedtodrugswithhigh5-HT2A/D2 receptoraffinityratios


Poyurovsky and Weizman. J Clin Psychopharmacol 2015;35:711-714.

Akathisia– TreatmentEvidencebaseissmallandlargelybasedonclinicalexperienceandcasereportsGeneralstrategies◦ Correctirondeficiencyifpresent

◦ Addressneedfordoseormedicationchanges◦ Considerwithdrawalsymptomsandpossibleworseningvs.tardivesyndrome

◦ Anticholinergics(benztropine,trihexyphenidyl)◦ Poorevidenceforakathisia

◦ Beta-blockers(propranolol)◦ Modestbenefits

◦ Benzodiazepines◦ Notfullyimplicatedtoameliorateakathisia

◦ Serotonin(5-HT)2Aantagonists(mirtazapine,cyproheptadine)


Akathisia– TreatmentAlgorithm

Poyurovsky and Weizman. J Clin Psychopharmacol 2015;35:711-714.

PatientCaseLBisa20-year-oldmale(180lb)withbipolar2disorder,currentlyinamixedepisode.Hispsychiatricproviderhasrecentlyaddedaripiprazole5mg/dtohiscurrenttreatmentoflithium450mgnightly.Uponfollowup,LBcomplainsofrestlessness,demonstratespsychomotoragitationinlowerextremities,andstatesthathefeelsworsewiththenewmedicationaddition.Whichwouldbeareasonablenextcourseofaction?

a) Increasearipiprazoleto10mg/d

b) Replacearipiprazolewithlurasidone 40mg/d

c) Discontinuearipiprazoleandstartsertraline50mg/d

d) Discontinuearipiprazole,increaselithium,obtainlithiumlevelandfurtheradjust

DystoniaFirstdescribedbyOppenheim (1911)

“Dystoniaisamovementdisordercharacterizedbysustainedor

intermittentmusclecontractionscausingabnormal,often

repetitive,movements,postures,orboth.Dystonicmovementsare

typicallypatterned,twisting,andmaybetremulous.Dystoniais

ofteninitiatedorworsenedbyvoluntaryactionandassociated

withoverflowmuscleactivation”(2013consensusdefinition)

Albanese et al. Movement Disorders 2013;28(7):863-73.Lohr et al. CNS Spectrums 2015;20:4-14.

Dystonia- CharacteristicsCanbeinheritedoracquired

Bodydistribution

◦ Focal- Oneareaaffected(ie.blepharospasm,oromandibular,laryngeal)

◦ Segmental- Twoormorecontiguousregionsaffected

◦ Multifocal- Twononcontiguousregionsaffected

◦ Generalized- Thetrunkandtwoothersitesinvolved

◦ Hemidystonia- Restrictedtoonesideofthebody

Temporalpattern

◦ Staticvs.progressive

◦ Persistent,actiondependent,diurnal,paroxysmal

Albanese et al. Movement Disorders 2013;28(7):863-73.Mardsen C.D. Journal of Neurology, Neurosurgery, and Psychiatry 1976;39:1206

Segmental Focal

AcuteDystonicReactionsPharmacologic Category Specific Drug(s)

Dopamineblocker FGAs, SGAs

Gastrointestinal promotility Metoclopramide, prochorpromazine

Antidepressants SSRIs,TCAs,MAO-Is

Others Stimulants, antihistamine,rivastigmine,opioids,propofol,gabapentin,quinine

Burkhard. Parkinsonism and Related Disorders 2014:S108-S112.Caroff and Campbell. Psychiatr Clin N Am 2016;391-411.

Dystonia – PathophysiologyUnknown

Hypodopaminergic stateresultsincholinergicoveractivity

Excessivedopaminergicactivityfromcompensatoryincreaseinturnoverafterdrugadministereddiminishes

RoleofGABAunclear

Geneticcontribution


Termsarasab et al. Journal of Clinical Movement Disorders 2016;3:19

Dystonia– RiskFactorsandClinicalCourseAcute/Subacute

◦ Occurwithinhourstodays

◦ 90-95%observedwithin5dayperiod

◦ FGA(2-60%)andSGA(2-3%)

◦ Selfresolvesin1-2daysafterdiscontinuationofdrug

TardiveDystonia

◦ Occursinsidiouslyafter>3monthsdopamineblocker

◦ Tickandeyeblinkingearlysymptoms


RiskFactors

◦ YoungerMales

◦ African-American

◦ Previousdystonicreaction

◦ Familyhistoryofdystonicreaction

◦ Cocaineuse

◦ Lowerriskinchronicschizophrenia(CATIEtrail)

Antipsychotics

◦ Highpotencydopamineblockade

◦ Highdosage

Dystonia– TreatmentandProphylaxisAcuteTreatmentwithAnticholinergicDrugs

◦ Biperiden (2.5-5mg)

◦ Benztropine (1-2mg)

◦ Diphenhydramine(25-50mg)

◦ Trihexyphenidyl(2.5-5mg)*

Baclofen

◦ Second-linetherapy

Benzodiazepines

◦ Notaseffective

Generalapproach

◦ Useintramuscularformulationfirst

◦ Considerneedforrepeatdosing,shortt/12

◦ Oralanticholinergiccourseforafewdays

ProphylaxiswithAnticholinergics

◦ Generallynotrecommended(WHO1990)

◦ Considerinpatientwithreactionhistory

◦ Considerclozapineorquetiapine

Burkhard. Parkinsonism and Related Disorders 2014:S108-S112.Caroff and Campbell. Psychiatr Clin N Am 2016;391-411.; Jancovic. Movment Disorders 2013;28(7):1001-1012

Gourzis et al. Clin Neuropharmacol 2015;38:121-126. ; WHO Br J Psychiatry 1990; 156:412.

Whichpatientpopulationmayyouseedystonia?(selectallthatapply)a) Psychiatricb) Oncologyc) Combativenessinemergencyroomd) MedicallyIllwithdelirium

PatientCaseRJisan18-year-oldAfricanAmericanmalewithpsychosiswhopresentstotheEmergencyroomviapolice.HeishighlyagitatedandisadministeredIMhaloperidol5mgtwiceina10minuteperiod.Fiveminutesfollowingthis,heexperiencesapainfullockedjawandmusclespasmintheneckandback.Whichofthefollowingwouldbethenextcourseoftreatment?

a) Diphenhydramine50mgIVx1

b) Lorazepam2mgIMx1

c) Benztropine 1mgPOx1

d) Onabotulinum toxinA IMtoaffectedareas

Drug-InducedParkinsonism(DIP)Acuteorsubacutebilateralsymmetricsyndrome

Levodopaunresponsive

Prominentsymptoms

◦ Maskedfacies,bradykinesia,reducedblinkrate,reducedarmswing,rigidity,tremor,gaitdisturbance,freezing



Drug-InducedParkinsonismPotentialRiskforDIP Pharmacologic Category Specific Drug

High Dopamineantagonist FGAs andSGAs(higherdoses)

Dopamine depleters VMAT2inhibitors,reserpine

Calciumchannel blockers Flunarizine,cinnarizine

Intermediate Dopamine antagonists Ziprasidone(SGA)

Antiemetic Metoclopramide, prochlorperazine

Calciumchannel blockers Verapamil,diltiazem

Other Lithium,valproic acid,phenytoin

Low Antidepressants SSRI,TCA,MAO-I

Other Amiodarone, procaine,tacrolimus,cyclosporine,chemotherapy

Erro et al. Movement Disorders 2015;30(6):780-785.Burkhard. Parkinsonism and Related Disorders 2014:S108-S112.

Drug-InducedParkinsonismRiskFactors◦ Elderlyfemale◦ FGAuse(15-40%)andSGAuse(4-14%)◦ Familyhistory◦ Higherdosage◦ HIV,dementia,otherEPS◦ Genetics

ClinicalCourse◦ Onset:daystomonths◦ Akinetic-rigid◦ Asymetric distribution(possible)◦ Tremorandgaitdisturbancelessfrequent◦ Resolvesinmonthsafterdrugdiscontinuation

Parkinsonismfollowingneurolepticexposure◦ UnresolvedDIPfollowingdrugdiscontinuation◦ UnmaskedParkinson’sdisorder(theory)◦ Needfurtherautopsystudiestoconfirm

Erro et al. Movement Disorders 2015;30(6):780-785.Burkhard. Parkinsonism and Related Disorders 2014:S108-S112.

DIP – PathophysiologyHypodopaminergic statecausedbydrugs

Balancebetweendopaminereceptorbindingaffinityandmuscarinicbindingaffinity

NotallDIPcasesarethesame?◦ FGAs◦ “Pure”D2 blockade◦ Worsebradykinesia,rigidity,totalmotorimpairment

◦ SGAs◦ “Faster”D2 dissociation,5-HT1a antagonism◦ SimilartoFGAs,butlesssevere;lesstardivesyndromes

◦ Calciumchannelblockers◦ Inhibitdopaminereuptakeinstoragevesicles,inhibitpresynapticrelease,postsynapticD2 blockade◦ Worsetremorscores

Munhoz et al. Neurol Sci 2017;38:319-324.Caroff and Campbell. Psychiatr Clin N Am 2016;391-411.

Simpson-AngusScaleAssesses10itemson5-pointseverityscale◦ Gait◦ Armdropping◦ Shouldershaking◦ Elbowrigidity◦ Wristrigidityandflexation◦ Legpendulousness◦ Headdropping◦ Glabella(blink)test◦ Tremor◦ Salivation

TotalScoreSeverity◦ <3=normal

◦ 3-5=minimalmovementdisorder

◦ 6-11=clinicallysignificant

◦ 12-17=severemovementdisorder

Simpson and Angus. Acta Psychiatrica Scandinavica 1970;212:11-19.

DIP– TreatmentandProphylaxisResistanttomostanti-parkinsonismmedications

AnticholinergicDrugs

◦ Biperiden (2.5-5mg)

◦ Benztropine (1-2mg)

◦ Diphenhydramine(25-50mg)

◦ Trihexyphenidyl(2.5-5mg)

Prodopaminergics

◦ Amantadine

Generalapproach

◦ Dosereductionordrugdiscontinuation

◦ SwitchingfromFGAtoSGA

◦ Oralanticholinergics,considertapering

ProphylaxiswithAnticholinergics

◦ Datalesscompellingthanfordystonia

◦ Generallynotrecommended(WHO1990)

◦ Considerclozapineorquetiapine


Gourzis et al. Clin Neuropharmacol 2015;38:121-126. ; WHO Br J Psychiatry 1990; 156:412.

PatientCaseLMisa60-year-oldwomanwithschizophreniawhohasbeenstableonherregimenofrisperidone2mgnightlyandbenztropine 1mgtwicedaily,whichwerestartedatthesametimeseveralyearsago.Shehascognitivedeficits,mildconstipation,andnoevidenceoftremor,bradykinesiaorrigidity.HerSimpson-AngusScaletotalscoreis2.Whatwouldbethemostreasonableinterventionatthistime?

a) Continuecurrenttherapy

b) Reducerisperidoneto1mgnightlyduetoadverseeffects

c) Reducebenztropine by50%everyweekuntildiscontinued

d) Discontinuebenztropine withnotaper

DyskinesiaCommonclinicalpresentation◦ Oralandfacialabnormalities- chewing,blinking,grimace,lipsmacking(orofaciolingual)

◦ Writhingmovements- face,neck,back,trunk,andextremities(limb-truncal)

Subtypes◦ Acute(spontaneous)◦ Withdrawal-emergent◦ Tardive

Remissionvs.suppressionofsymptoms

Limitedtreatmentinterventions

Salem et al. Expert Rev Neurother 2017; 17(9):883-894.Lohr et al. CNS Spectrums 2015;20:4-14.

TardiveDyskinesiaChronicextrapyramidalsymptom

Potentiallyirreversible

Comparisonbetweentypicalandatypicalantipsychotics(n=11,493)◦ 41-studyrandomeffectmeta-analysis

◦ GlobalTDprevalence=25.3%

◦ Current:SGA(20.7%)vs.FGA(30.0%)(p=0.002)

◦ LowerTDprevalenceinFGA-naïvevs.SGAtreatedwithFGAhistory(p<0.001)

Carbon M et al. J Clin Psychiatry 2017; 78:3:e264-278.http://diseaseslab.com/wp-content/uploads/2014/12/Tardive-Dyskinesia.jpg

TardiveDyskinesiaRiskFactors◦ Increasedage

◦ Female

◦ Substanceabuse(smoking,alcoholabuse,others)

◦ MedicalIllness(diabetes,HIV,headinjury)

◦ EarlyonsetofcognitivedisordersandotherEPS

◦ Useoflithiumorantiparkinson drugs

◦ Concurrentmooddisorder

◦ PreviousECT

◦ HistoryofFGAuse

◦ Highdoseantipsychotic&longerexposure

PreventionStrategies◦ Followantipsychoticprescribinginformation

◦ Prescribelowesteffectivedose

◦ SGAshavelowerrisk

◦ AnticholinergicsmayworsenTD

◦ AdvisepatientofTDrisk

◦ Ongoingmonitoring

Salem et al. Expert Rev Neurother 2017; 17(9):883-894. Carbon M et al. J Clin Psychiatry 2017; 78:3:e264-278.;Correll et al. J Clin Psych 2017;78(8):1136-1147.

TardiveDyskinesia- TheoriesChronicantipsychoticuseleadstoD2 receptorhypersensitivity◦ Evidenceinmousemodels

◦ Notclearinhumanpostmortemstudies

StriatalNeurodegenerationfromOxidativeStressandExcitotoxicity◦ Possibleincreaseinfreeradicalssecondarytodopamineturnover

◦ MixedevidenceinMRIstudiesandneurotoxicity

DysfunctionofStriatalGABAergicNeurons◦ Selectivelesionscangeneratedyskinesia

GeneticContribution

SynapticPlasticity

Teo et al. Movement Disorders 2012;27(10):1205-1215.

AbnormalInvoluntaryMovementScale(AIMS)

Developedin1976byNIMHResearchers

Designedtoidentifydyskinesiainantipsychotictreatedpatients

MostcommonscaleforratingseverityofTD

TheExam

◦ Approx.10minutestoperform

◦ 12items

◦ Items1-10scoredon5-pointscale

◦ Items11&12addressproblemswithteethordentures

Scoringoftheexam

- Scorehighestamplitude,notanaverage

- Donotsumscores

- PositiveAIMSisscore◦ ≥2in≥2movementareas◦ ≥3inasinglemovement

Guy WG. EDCEU Assessment Manual for Psychopharmacology. 1976:534-7.

PatientCaseCCisa30-year-oldCaucasianmalewithbeginningantipsychotictreatmentforbipolardisorder.Heexperiencesparkinsoniansymptomsduringtheup-titrationofhisantipsychoticatanearmaximumdoseforacutemania.Whichofthefollowingisnot ariskfactorforTD?

a) PresenceofotheracuteEPS

b) Youngerage

c) Mooddisorder

d) Higherantipsychoticdose

AmericanAcademyofNeurology:ApproachtoTDManagementIswithdrawalofDopamineReceptorBlockereffectiveforTD?

◦ Insufficientdatatosupportorrefute

◦ Recommendedinpatientswhocantolerate,consideringsymptomrelapserisks

◦ ShorttermwithdrawalworsensTD,andaddingstrongeragentreducesTD

DoesswitchingfromFGAtoSGAreduceTD?

◦ Insufficientdatatosupportorrefute

◦ Mixeddatawithusingclozapine

Datainsufficientforbotulinumtoxinanddeepbrainstimulationtherapies

Bhidayasiri et al. Neurology 2013; 81:463-469.

AmericanAcademyofNeurology:ApproachtoTDManagement


Agent Data Reviewed Recommendation Level

Acetazolamide (1)ClassIII studyreducedAIMsscore~45%vs.placebo Insufficientdata LevelU

Amantadine (1) ClassIIstudyand(2)classIIIstudies;ReducedAIMsby15%whencombined withFGA

Maybeconsideredforshort-term use

LevelC

ECT Casereports Insufficient data LevelU

Dopamine-depleters

(2) ConsistentclassIIIstudies Tetrabenazine maybeconsidered

LevelC

Cholinergicdrugs

(1) ClassIIstudyfoundnobenefitwithgalantamine Do notrecommendgalantamine;insufficientevidenceforothers

Level(CandU)

Anticholinergics Nocontrolledtrialsforbenztropine,biperiden,ortrihexyphenidyl

Insufficient data LevelU

AmericanAcademyofNeurology:ApproachtoTDManagement


Agent Data Reviewed Recommendation Level

Clonazepam (1)classI, 12-weektrialdemonstratedreducedsymptomsfor3months;continuedtreatmentshowednobenefit

Probablyeffectiveshort-term

LevelB

Ginko biloba (1)classI,12-weektrialdemonstratedAIMSreductionsof2.13vs.-0.1withplacebo(p<0.0001)

Probably effective,butdatalimitedtoinpatients

LevelB

Levetiracetam (1)class trialIIItrialreportedbenefitafter12-weeks,buthighdropoutrate

Insufficientdata LevelU

Melatonin (2)classII trialsdemonstratednobenefitwith2mg/dbutsomewith10mg/d

Possiblyeffectiveat10mg/d

LevelU

VitaminE (1)classIItrial demonstratednobenefit,(2)classIIandIIIstudiesshowednobenefit;(2)classIIandIIIstudiesshowedAIMsreductionof19-43%

Insufficient data LevelU

VesicularMonoamineTransporter2(VMAT2)InhibitorsTetrabenazine (Xenazine™)

Deutetrabenazine (Austedo™)

Valbenazine (Ingrezza™)

Meyer J. CNS Spectrums 2016;21:16-23.

VMAT2:ProposedRoleinTD

VMAT2– Monoaminetransportfromcellularcytosolintosynapticvesicles

VMAT2Inhibitors – Bindtositesontheproteinandreducemonoamineconcentrationsinsynapticcleft

Tetrabenazine(Xenazine™)

Valeant Pharmaceuticals International Inc. Xenazine (Tetrabenazine) package insert. Deerfield, IL; 2017

Indication:◦ ChoreawithHuntington’sDisease(2008)

DosageandAdministration(TD):◦ 12.5mgdailyx1weekthen12.5mgBID◦ Dosesof≥37.5mg/d,useTIDdosing◦ Increaseby12.5mgatweeklyintervals(Max37.5mgpersingledoseand100mgtotaldailydose)

DoseAdjustments:◦ CYP2D6InhibitorUseorPoorMetabolizers:

◦ Max25mgpersingledoseand50mgtotaldailydose◦ Genetictestingrecommendedpriortodoses>50mg/d

◦ Mild-ModerateRenalImpairment:None

Contraindications:◦ Suicidalityoruntreateddepression[boxedwarning]◦ HepaticImpairment◦ Takingreserpine,MAOIs,orVMAT2inhibitor

Warnings:Moodworsening,cognition,rigidity,somnolence,QTprolongation(8msec),NMS,akathisia,agitation,restlessness,parkinsonism,orthostatichypotension,hyperprolactinemia,bindingtomelanin-containingtissues

Adversereactions:Somnolence,fatigue,insomnia,depression,akathisia,anxiety,nausea,balancedifficulty,dysuria,shortnessofbreath

Pregnancy:MayCauseFetalHarm

BreastFeeding:NotAdvised/unknown

Tetrabenazine(Xenazine™)Absorption:◦ 75%(oral)withpeakconcentrations1-1.5hoursafterdosing◦ FoodhasnoeffectonAUCorCmax

Distribution:◦ 82-85%proteinbound(parent),59-68%(metabolites)◦ Highbindinginstriatumandlowincortex

Metabolism:◦ 19metabolitesidentified;α-HTBZ,β-HTBZ,9-desmethyl-β-DHTBXaremajor◦ Half-life:5-12hours◦ CYP2D6(major),CYP1A2(minor)

◦ Poormetabolizer/CYP2D6Inhibitor:3and9foldhighermetabolites◦ Mild-moderateHepaticimpairment:7-190-foldhigherpeakconcentrations(parent),30-39%highermetabolites

Excretion:◦ Urine(75%)◦ Fecal(16%)

Valeant Pharmaceuticals International Inc. Xenazine (Tetrabenazine) package insert. Deerfield, IL; 2017

Tetrabenazine forAntipsychotic-InducedTDAuthor Design Intervention Outcomes Safety

Godwin-Austin,1971

Double-blinded,placebo-controlled;1weekdurationN=6

TBZ25mgBID titratedto100mg/dPlaceboDiazepam4mgdaily

MeanChangeBaselinePlacebo:-0.5Diazepam: -2.2TBZ:-3.6Nostatsperformed

DyskinesiareturnedinallpatientsatendoftrialADRsnotquantifiedSedationcommon

Asher, 1981 Single-blinded,crossover3weeksatfulldoseN=12

TBZ25mgBIDtitratedtomaxof200mg/d

Marked response(40%)Moderateresponse(20%)Noresponse(40%)

Welltolerated, nobehavioralchange

Jankovic, 1982 Double-blind,crossoverN=20, 4withTD

TBZ25mg/d titratedtomaxof200mg/d

AllTD patientsmarkedas“improved”

ADRsin75% ofTDpatients-restless,drooling,gaitchange,parkinsonism,anxiety

Leung and Breden. Annals of Pharmacotherapy 2011; 45:525-31.

Tetrabenazine forAntipsychotic-InducedTDAuthor Design Intervention Outcomes Safety andComment

Fahn,1983

Open-label,prospective;N=14

TBZ 25mg/dincreasedtomaximumof300mg/d

79%consideredtreatmentresponders7%symptoms resolved

Poordesign,unclear method,difficulttoascertaintreatmentgroups;ADRs:- Parkinsonism(93%)

Jankovic,1988

Open-label,prospective;N= 217;44withTD

TBZ 25mg/dtitratedto100mg/d

Markedreduction:14%Moderatereduction:57%Fairreduction:25%Noresponse:2%Worsening:2%

ADRs:- Parkinsonism(24%)- Drowsiness (13%)- Depression(13%)

Watson,1988

Case-seriesN=23

TBZ12.5mgTIDtitratedtomeanof91mg/d

78%patientshadseverityscoreof3 or4atbaseline87%achievedscoreof0or1atendpoint

ADRs:-Drooling (8.5%)-Parkinsonism(4%)


Tetrabenazine forAntipsychotic-InducedTDAuthor Design Intervention Outcomes Safety

Jankovic,1997

Open-labelN=400;93withTD

TBZmeandose96.9mg/d(range25-400mg)

89.3% ofTDhadmarkedresponseatfirstfollow-up23%discontinuedtherapyduetoADR

ADRs:-Fatigue(36%)-Parkinsonism (28.5%)-Depression(15%)-Akathisia(9.5%)

Paleacu,2004

RetrospectiveReviewN=118;17withTD

TBZ12.5mgBIDtitrated to150mg/d

Mildworsening:(6%)Nochange(24%)MildImproved:(18%)ModerateImproved:(35%)Markedimproved:(6%)Nodata(12%)

ADRs:-Weakness (6%)- Parkinsonism(2.5%)

Kenney,2007

RetrospectiveReviewN=448; 149withTD

TBZ meandose60mg/d

Markedtomoderateresponsefromfirst(83%)tolast(86%)followup

ADRs:-Drowsiness(25%)-Parkinsonism (15%)-Akathisia(8%)-Depression(8%)


Deutetrabenazine(Austedo™)“Deuterated”tetrabenazine◦ Deuteriumsubstitutionforstrongerbonding(8-fold)

◦ Stable,nonradioactive,non-toxic,naturalhydrogenisotope

◦ Sloweddrugmetabolismwithallegedly reducedsideeffectprofile

Meyer J. CNS Spectrums 2016;21:16-23.Correll et al. J Clin Psych 2017;78(8):1136-1147.

Deutetrabenazine

Tetrabenazine

Deutetrabenazine(Austedo™)Indication:◦ ChoreawithHuntington’sDisease◦ AdultswithTD

DosageandAdministration(TD):◦ 6mgtwicedaily,thenincreaseby6mgweeklyastolerated/needed(MAXof48mg/day)

◦ Dosesof≥12mg/dshouldbedivided◦ AdministerwithFood◦ ObtainEKGindoses>24mg/dayandthoseatriskofQTprolongation(4.5msec inc.)

DoseAdjustments:◦ StrongCYP2D6Inhibitors/CYP2D6PoorMetabolizers:~3-foldincrease;Maximumdoseof36mg/day

◦ RenalImpairment:Notstudied

Contraindications:◦ Suicidalityoruntreateddepression[boxedwarning]◦ HepaticImpairment◦ Takingreserpine,MAOIs,orVMAT2inhibitor

Warnings:Somnolence,QTprolongation,NMS,akathisia,agitation,restlessness,parkinsonism,hyperprolactinemia,accumulationinmelanin-containingtissue

Adversereactions:Somnolence,diarrhea,drymouth,fatigue,nasopharyngitis,insomnia


BreastFeeding:NotAdvised/unknown

Teva Pharmaceuticals Inc. Austedo (Deutetrabenazine) package insert. North Wales, PA; 2017

Deutetrabenazine(Austedo™)Absorption:◦ 80%(oral)withpeakconcentrations3-4hoursafterdosing◦ FoodhasnoeffectonAUC,butincreasesCmax ~50%

Distribution:◦ 82-85%proteinbound;500-730Ldistributionrespectivelyformetabolites◦ Highbindinginstriatumandlowincortex

Metabolism:◦ Half-life:9-10hours◦ CYP2D6(major),CYP1A2(minor),andCYP3A4/5(minor)

Excretion:◦ Urine(75-86%)◦ Fecal(8-11%)

Teva Pharmaceuticals Inc. Austedo (Deutetrabenazine) package insert. North Wales, PA; 2017

ARM-TD:Deutetrabenazine forTDPurpose:Determinesafetyandefficacyofdeutetrabenazine (DTZ)formoderate-severeTD

Methods:

◦ Sites:46inEuropeandUSA

◦ Subjects(n=117):≥3monthTDdiagnosis;≥3monthantipsychoticuse;AIMSscore≥6

◦ Duration:12weeks

◦ Outcomes:AIMSscore(primary),ClinicalGlobalImpressionofChange(CGIC)

◦ Randomization:1:1withDTZ(n=58)andplacebo(n=59)

◦ Dosing:DTZ6mgtwicedaily,titratedweeklyby6mgincrements

◦ Maximumdose48mg/dor36mg/dinthoseonstrongCYP2D6inhibitor

Fernandez et al. Neurology 2017;88:2003-2010

ARM-TD:Deutetrabenazine forTDExclusionCriteria:

◦ Useofthefollowinginpast30-days:tetrabenazine,reserpine,alpha-methyl-p-tyrosine,stronganticholinergics,metoclopramide,dopamineagonists,levodopa,and/orpsychostimulants

◦ Neurologicconditions,untreatedpsychiatricormedicalconditions

◦ Activesuicidality

◦ QTc prolongation:>450msec (male)or>460msec (female)

Dropouts:

◦ DTZ(n=6):withdrewconsent(3),ADE(1),losttofollow-up(1),noncompliance(1)

◦ Placebo(n=7):withdrewconsent(2),ADE(2),losttofollow-up(1),protocolviolation(2)


ARM-TD:Deutetrabenazine forTD


ARM-TD:Deutetrabenazine forTD


AdverseEvent DTZ(n=58) Placebo(n=59)

AnyADE 70.7% 61%

AErelatedtodosereduction 10.3% 5.1%

AEleadingtodiscontinuation 1.7% 3.4%

Depressed mood 1.7% 0%

Suicidalideation 0% 1.7%

Somnolence 13.8% 10.2%

Fatigue 6.9% 8.5%

Headache 5.2% 10.2%

Akathisia 5.2% 0%

Anxiety 3.4% 6.8%

Drymouth 3.4% 10.2%

AIM-TD:Deutetrabenazine forTDPurpose:Assessefficacy,safety,andtolerabilityoffixeddoseDTZforTD

Methods:

◦ Sites:75inEuropeandUSA

◦ Subjects(n=298):≥3monthTDdiagnosis;≥3monthantipsychoticuse;AIMSscore≥6

◦ Randomization:1:1:1:1toplaceboandDTZ12mg/d,24mg/d,and36mg/d

◦ Duration:12weeks

◦ Outcomes:AIMsscore(primary),ClinicalGlobalImpressionofChange(CGIC)

Anderson et al. Lancet Psychiatry. 2017;4:595-604.

AIM-TD:Deutetrabenazine forTDExclusionCriteria:

◦ Useofthefollowinginpast30-days:tetrabenazine,reserpine,metirosine,stronganticholinergics,metoclopramideandrelatedanti-emetics,dopamineagonists,levodopa,botulinumtoxin,MAO-I’sand/orpsychostimulants

◦ Recentpsychiatricmedicationchange:<30days(antipsychotics,moodstabilizers,sedatives)and<45days(antidepressants)

◦ Neurologicconditions,untreatedpsychiatricormedicalconditions

◦ Suicidalityinpast6months

◦ QTc prolongation:>450msec (male)or>460msec (female)

Dropouts:

◦ Placebo(n=7):withdrawalconsent(1),ADE(2),protocolviolation(1),lostfollow-up(2),noncompliant(1)

◦ DTZ12mg/d(n=8):withdrawalconsent(2),ADE(4),lostfollow-up(1),noncompliant(1)

◦ DTZ24mg/d(n=9):withdrawalconsent(1),ADE(1),lostfollow-up(4),noncompliant(2),death(1)

◦ DTZ36mg/d(n=10):withdrawalconsent(4),ADE(2),protocolviolation(1),noncompliant(1),death(1),other(1)


AIM-TD:Deutetrabenazine forTD






AdverseEvent DTZ12mg(n=74)

DTZ24mg(n=73)

DTZ36mg(n=74)

Placebo(n=72)

AnyADE 49% 44% 51% 47%

AErelatedtodosereduction 0% 1% 4% 0%

AEleadingtodiscontinuation 5% 3% 4% 3%

Deaths 0% 1% 1% 0%

Suicidalideation 0% 3% 1% 0%

Depressed mood 1% 4% 1% 0%

Somnolence 0% 1% 4% 4%

Nausea 10% 1% 1% 1%

Headache 7% 3% 7% 5%

Akathisia 0% 1% 0% 0%

Anxiety 4% 3% 4% 3%

Valbenazine(Ingrezza™)Indication:AdultswithTD

DosageandAdministration:40mgoncedailyforoneweek,then80oncedaily

DoseAdjustments:

◦ StrongCYP3A4Inducers:Avoid

◦ StrongCYP3A4Inhibitors:40mgoncedaily

◦ StrongCYP2D6Inhibitors:Considerdosereduce

◦ Mild-ModerateRenalImpairment:None

Contraindications:None

Warnings:Somnolence,QTprolongation

Adversereactions:Somnolence


BreastFeeding:NotAdvised

Neurocrine Biosciences Inc. Ingrezza (Valbenazine) package insert. San Diego, CA; 2017

Valbenazine(Ingrezza™)Absorption:◦ 49%(oral)withpeakconcentrationsat0.5-1hour(parent)and4-8hours(metabolite)◦ High-fatmealincreasesCmax (49%)andAUC(13%)

Distribution:◦ 99%proteinbound(parent),64%(metabolite)

Metabolism:◦ Half-life:15-22hours◦ Valbenazine metabolizedtoactivemetaboliteviahydrolysisandCYP3A4/5◦ MetabolitefurthermetabolizedbyCYP2D6

◦ Poormetabolizer/CYP2D6Inhibitor:3and9foldhighermetabolites

◦ Moderate-severeHepaticimpairment:~2-3foldincreaseinvalbenazine andmetabolite

Excretion:◦ Urine(60%)◦ Fecal(30%)

Neurocrine Biosciences Inc. Ingrezza (Valbenazine) package insert. San Diego, CA; 2017

KINECT3:Valbenazine forTDPurpose:Determinesafety,efficacy,andtolerabilityofvalbenazine (VBZ)formoderate-severeTD

Methods:

◦ Sites:63inCanada,PuertoRico,andUSA

◦ Subjects(n=234):≥3monthTDdiagnosis;moderate-severeTD

◦ Randomization:1:1:1withPlacebo,VBZ40mg/d,andVBZ80mg/d

◦ Duration:6weeks

◦ Outcomes:AIMSscore(primary),ClinicalGlobalImpressionofChange-TD(CGI-TD)

Hauser et al. Am J Psychiatry 2017;174(5):476-484.


KINECT3:Valbenazine forTDExclusionCriteria:

◦ Useofthefollowinginpast30-days:strongCYP3A4inducers,dopamineagonists,MAO-Is,VMAT2inhibitors,psychostimulants

◦ Neurologicconditions,unstablepsychiatricormedicalconditions,othercomorbidmovementdisorder

◦ Suicidalityorviolencerisk

◦ Historyofneurolepticmalignantsyndrome

Dropouts:

◦ Placebo(n=7):withdrawalconsent(1),ADE(2),lostfollow-up(2),noncompliant(2)

◦ VBZ40mg/d(n=13):withdrawalconsent(5),ADE(4),lostfollow-up(1),noncompliant(1),investigatordecision(2)

◦ VBZ80mg/d(n=9):withdrawalconsent(4),ADE(2),lostfollow-up(1),death(1),investigatordecision(1)


KINECT3:Valbenazine forTD


KINECT3:Valbenazine forTD


KINECT3:Valbenazine forTDAdverseEvent VBZ40mg(n=72) VBZ80mg(n=79) Placebo(n=76)

AnyADE 43% 50% 43%

AEleadingtodiscontinuation 5% 6% 5%

Deaths 0% 0% 1%

Suicidalideation 5% 4% 1%

Somnolence 6% 5% 4%

Akathisia 4% 3% 1%

Drymouth 7% 0% 1%

Dyskinesia 0% 4% 0%

Anxiety 1% 3% 0%

Weightgain 1% 3% 0%

ComparisonofVMAT-2InhibitorsTetrabenazine(Xenazine™)

Deutetrabenazine(Austedo™)

Valbenazine(Ingrezza™)

FDA approval(s) Huntington’sChorea Huntington’sChoreaTardiveDyskinesia

Tardive Dyskinesia

DosingFrequency Thrice Daily TwiceDaily Daily

Concentrationhalf-life 5-12(h) 9-10(h) 15-22(h)

TimetoPeak N/A(parent) and1-2h(metabs)

N/A(parent)and3-4h(metabs) 1h(parent)and4-8h (metab)

Metabolism Conjugation; CYP2D6and1A2

CYP2D6(primary), 1A2,3A4/5 HydrolysisandCYP3A4/5(primary),CYP2D6

Metabolites Alpha-HTBZ,beta-HTBZ,9-desmethyl-beta-DHTBZ

Alpha-HTBZ,beta-HTBZ [+]-alpha-HTBZ

MonthlyCost(dollars) ~4300 ~3300 ~5200

MontanaMedicaidPriorAuthorizationCriteriaPrescribedbyorinconsultwithpsychiatristorneurologist

≥18yearsofage

Diagnosisofmoderate-severeantipsychoticinducedTDfor≥2months

Nosuicideorviolencerisk

NocongenitallongQTsyndromeorarrhythmiasassociated

NoconcomitantMAOI,reserpine,VMAT-2inhibitors,strongCYP2D6inhibitors(valbenazine only)

AnnualrenewalbasedondocumentedimprovedTD

ConclusionsEPSisavagueterm

Treatmentoptionsarenotthesame

◦ Akathisia

◦ Dystonicreactions

◦ Drug-inducedparkinsonism

◦ Dyskinesia

Pharmacotherapy

◦ Medicationsensitivityandinsufficientevidence

Drug-InducedMovementDisordersIANMCGRANE,PHARMD,BCPP,BCPS

MARCH4TH,2018

Mardsen C.D. Journal of Neurology, Neurosurgery, and Psychiatry 1976;39:1205

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