Evidence-BasedPharmacotherapy

EmilyHarris,MD,MPH,FAAPCincinnatiChildren’sHospitalMedicalCenter

CMEDisclosure

• IhavenopersonalfinancialrelationshipsinanycommercialinterestrelatedtothisCME.

• Idonotplantoreferenceofflabel/unapprovedusesofdrugsordevices.

Objectives

• ReviewbestpracticesinmedicationmanagementofADHD,depression,anxiety,anddisruptivebehavior

• Discusscommonadverseeffectsandcontraindications/precautions

• Discussapprovedindicationsforandmonitoringofatypicalantipsychotics

Ashleyisan8yearoldgirlreferredforanADHDevaluation.Hermotherdescribesproblemswithinattentionbothathomeandatschool.Sheisin2ndgradeandisstrugglinginschool.Herteachernotesthat“shejustdoesn’tpay

attention.”Shehastroublesittingstillandoftendisruptstheclassroom.Herfamilyisconcernedthattheseissuesareinterferingwithherschool

performance.

Ashleyhasalsomissedseveraldaysofschoolthisyearforstomachpainsandheadaches.

Hermotherhasrecentlytakenanewjob,andtheseabsenceshavebeendifficultforherfamilytomanage.Theywouldliketoget

AshleystartedonADHDmedicationtohelpherinschoolandreducefamilystress.

AssessmentProcess

AAP. Pediatrics. 2011.

PresenceofDSM-VCriteria

EvidenceofImpairment

Behavioralratingscales Clinician

judgment

AssessmentProcess

Importanceofaccuratediagnosis

1. Manyconditionscanmasqueradeas“attentionproblems”

2. ThereisahighdegreeofcomorbidityinchildrenwithADHD

Ashley’sVanderbiltRatingScalesParent Teacher

InattentionHyperactivity/Impulsivity

Totalsymptom score 46 36ODDScreenConductDisorderScreenAnxiety/Depression Screen# AreaswithImpairment 3 2Average PerformanceScore 3.5 3

Pliska etal.JAmAcad ChildAdolesc Psychiatr.2006;45:642-657.

ADHDFirstorDepressionFirst?

Interventions• DefineADHDasachroniccondition

• Identifytargetoutcomes• Usestimulantmedicationsandbehavioraltherapyasindicated

• Monitortreatmentresponsesystematically

AAP. Pediatrics. 2011;128:1007-1022.

AACAP. J Am Acad Child AdolescPsychiatr. 2007;46:894-921.

BehavioralTherapyas1st Choice

• IfADHDsymptomsaremild,minimalimpairment

• Uncertainofdiagnosis• Markeddisagreementaboutdiagnosisor

parentsrejectmedicine• Familypreference

*CombinedmedicationplusbehavioraltherapyleadstoLESSmedicationutilization

StimulantTitrationStrategies• Startlow,reassessandadjust

– Startat¼- ½childweightinkilograms– Youngerchild=smallerinitialdose– Increaseevery1-2weeks

• Goal- Fulltherapeuticeffectseenwithfewestsideeffects

• Finaltherapeuticdoseroughlyweight-based– Methylphenidate1-2mg/kg/day,SEover1mg/kg– Amphetaminesupto1mg/kg/day,SEover0.6mg/kg

• Followupmonthlyuntilstable,thenquarterly

MethylphenidateDosing• MaximumFDAdosingperday(off-label)

– Ritalin®,Methylin®,Methylin ER®,Metadate ER®,RitalinSR®,Metadate CD®,RitalinLA®60mg(100mgfor>50kg)

– Concerta®72mg(108mg)– Focalin®20mg(50mg);FocalinXR®30mg(50mg)– Daytrana®30mg(?)

AACAP. J Am Acad Child Adolesc Psychiatr. 2007;46;89-921

Methylphenidate• Otherconsiderations

– Manylongactingformscanbeopenedandsprinkledonapplesauceorpudding

• Metadate CD®,RitalinLA®,FocalinXR®

– Concerta®capsuleCANNOTbeopened(OROS)– Daytrana®

• Patchisappliedatthehip;maycauseskinirritation

– Quillivant®isanewXRliquidpreparation– Quillichew®

Amphetamine

• Startlow,reassess,andadjustifneeded– Startat5-10mg/day– Increase5-10mg/dayevery1-2weeksiflimitedbenefitsandadverseeffects

– Morepotentthanmethylphenidate,needLESS

Adapted from AACAP. J Am Acad Child Adolesc Psychiatr. 2007;46;89-921.

www.ohiomindsmatter.org

AmphetamineDosing• Therapeuticdosearound0.6mg/kg/day

– SEmorelikelytooccurathigherdoses• MaximumFDAdosingperday(off-label)

– Dexedrine,®Dextrostat,®Adderall,®andDexedrinespansule®40mg/day(60mgif>50kg)

– AdderallXR®30mg(60mgif>50kg)– Vyvanse®70mg(?)

Adapted from AACAP. J Am Acad Child Adolesc Psychiatr. 2007;46;89-921.

Amphetamine

• Otherconsiderations– AdderallXR®andDexedrinespansule®canbeopenedandsprinkled

– Vyvanse®capsulecanbeopenedandcontentsdissolvedinsmallamountofwater(1-2tsp)

– Vyvanse®mayhavedecreasedabusepotentialduetopro-drugdeliverysystem

NeurotransmittersofNon-stimulants

• Norepinephrinereuptakeinhibitor• Atomoxetine(Strattera)

• Alpha2(a) agonists(enhanceNEtransmission)

• Clonidine,Kapvay• Guanfacine (Tenex,Intuniv),moreselectivelybinds

• Dopaminereuptakeinhibitor• Bupropion(Wellbutrin),metaboliteweakNE

Atomoxetine

• Mechanismofaction– Selectivenorepinephrinereuptakeinhibitor

• NEincreasessignalstrengthinPFC• Antidepressantclass=BlackBoxwarning• Mildeffectonanxiety

– Maytakeupto8-12weeksforfulleffect– Pharmacogenomic testingmayassistwithdosing

Stahl SM. The Prescriber’s Guide. 3rd ed. New York, NY: Cambridge Press; 2009:329.

AtomoxetineDosing

• Dosingrecommendations– For<70kg:startwith0.5mg/kg/day,thenincreaseto1.2– 1.4mg/kg/dayafter4-7days

• Maxdose1.4mg/kg/dayor100mg(lesserof1.8mg/kd/dayor100mg)

– For>70kg:40mg/day,thenincreaseto80mg/dayafter7days

• Maxdose100mg(increaseafter2-4weeksifneeded)

AACAP. J Am Acad Child Adoles Psychiatr. 2007;46;89-921.

Stahl SM. The Prescriber’s Guide. 3rd ed. New York, NY: Cambridge Press; 2009:51-52.

Atomoxetine

• Otherconsiderations– CapsulesCANNOTbeopenedorsplit– CandividedoseBIDtominimizesideeffects– Mustgivedaily– Doseadjustmentinpatientswithimpairedliverfunction

AlphaAgonistsDosing• Guanfacine

– Longacting(Intuniv):startat1mgdaily;• Increase1mgweeklyto6mgmaximumdose[6mgor2mg/4mg]

– Shortacting(Tenex):startat1mgHSor0.5mgBID• Increase1mgweekly,max4mgdaily[1mg/1mg/2mg]

• Clonidine– Longacting(Kapvay®):startat0.1mgHS;0.4mg/daymax

• Increase0.1mgweeklydividedBID– Shortacting(Clonidine):startat0.05mgHS;0.2-4mg/daymax

• Maygive¼tab(0.025mg)AM

AlphaAgonistDosing

• Alpha agonists – blood pressure medication– Slow upward and downward titration– No more than 1 tablet per week– May start with ½ tablet in the evenings to watch for

sedation. If tolerates after 4-7 days, then add ½ morning dose.

– Taper off short acting before trial of long acting

AdverseEffects

• Stimulants– Aggression– Irritability– Socialwithdrawal– Hypertension,tachycardia– Appetitesuppression– Sleepdisturbance

SeriousAdverseEffects

• Contraindication– Mania– Psychosis– Withdrawaldyskinesia

• Precautions– Anxiety– Parentalsubstanceabuse

• Considerations– Tics

AdverseEffects

• Atomoxetine– Suicidalideation– Hypertension,tachycardia– GIupset,appetitesuppression– Behavioralactivation

• Alphaagonists– Hypotension,bradycardia– Sedation,dizziness

Perrin et al. Pediatrics. 2008;122:451-453.

Update on Ashley• AshleyisprescribedConcerta®18mgeachmorning.Atoneweek,nosideeffectsarenoted,butnobenefitsareseen.Concerta®isincreasedto27mg.

• Atonemonth,Ashleyisseenforafollowupvisit.Sheisnowtaking36mgeachmorningafteranotherdoseincrease.

• Vanderbiltquestionnairesareavailableforyourreview.

Vanderbilt Rating ScalesParent Teacher

InattentionHyperactivity/Impulsivity

Totalsymptom score 46→38 36→20ODDScreenConductDisorderScreenAnxiety/Depression Screen# AreaswithImpairment

Average PerformanceScore Considerafternoonshortactingdose

Whatif…• Shedoesn’ttolerateConcerta?

– Considerswitchtoamphetamineproduct

• Symptomsimprovebutpersistatthetopofthedosinginterval?– Considerswitchtoamphetamineproduct

– Ifpreviousmedicationsunsuccessful,consideradjunctivetherapywithnon-stimulant

http://ppn.mh.ohio.gov

Whatif…• Sheisdoingwell,butgettingheadaches?– Selfcare– hydration,rest– Lowerdose,considerdifferentstimulant

• Sheisdoingwell,butlosingweight?– Addcalories,changetimeofpill– ConsiderCyproheptadine/appetiteinducer

– Decreasedose,changestimulant http://ppn.mh.ohio.gov

Pliska etal.JAmAcad ChildAdolescPsychiatr.2006;45:642-657.

ADHDFirstorDepressionFirst?

Cheungetal.Pediatrics.2007;120(5):1313-1326.

SSRI Indications• AnxietyDisorders

– Sertraline(Zoloft®):FDAindicatedage6andupforOCD– Fluoxetine(Prozac®):FDAindicatedOCDage7andup

• Depression– Fluoxetine(Prozac®): FDAindicatedage8andup– Escitalopram(Lexapro®):FDAindicatedage12andup

Whenmoderatetosevereimpairmentispresent

SelectiveSerotoninReuptakeInhibitors(SSRI’s)

SSRI Starting Dose, mg

Increments, mg

Effective Dose, mg

Maximum Dose, mg

Fluoxetine (Prozac®)

2.5, 5 10-20 20-40 60

Sertraline(Zoloft®)

12.5, 25 25 50 200

Escitalopram(Lexapro®)

2.5, 5 5 10 20

Adapted from Cheung et al. Pediatrics. 2007;120(5):e1313-1326.

SSRI’s• Startlow,reassess,andadjustasneeded

– Increasedoseafter1-2weeks,thenmonitor– Maximaleffectivenessafter4-6weeks– Continuefor9-12monthsaftersymptomsresolve– Taperwhendiscontinuingtoavoidwithdrawaleffects

Medicationfordepressionandanxietydisorderscanbeapproachedsimilarly

BLACKBOXWARNING• Issuedin2004afterconcernsaboutanincreaseinsuicidalthinkinginchildrenprescribedSSRI’s

• 24clinicaltrialsreviewed;over4000children• Nocompletedsuicides• Prevalenceofsuicidalthoughts/actions2XhigherinthosetakingSSRIs(2%vs.4%,notsignificantonlytrend)

• Highestriskwasseenin1st 4weeks,thenprotectionbenefitsseen

• Closemonitoringforsuicidalthinkingisrecommended• Phonecontact1-2weeks(nurse,therapist)• Facetofacewithphysician4-6weeksafterinitiation

http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-10-TAB08-Hammads-

Review.pdf

SSRIAdverseEffects– Nausea,GIdiscomfort– Appetitechanges– Headaches– Dizziness– Insomnia– Activation– Bipolarswitching– Sexualdysfunction– Suicidalthinking– Vividdreams(teens)

http://www.glad-pc.org/

SSRI’s• Contraindications

– Bipolardisorder– Psychosis

• Interactions/precautions– Cautionwithserotonergics

• TCAs,Lithium,Cocaine– Serotoninsyndrome

• Mentalstatuschanges• Autonomicinstability• Tremor,myoclonus

Summary

• Considertherisksandbenefitsofmedication• Discussopenlywithpatientsandfamilies• Developaprocessforcontinuedmonitoring• Respondpromptlytoconcerns

Ashley’s6yearoldbrother,Antwon,hasalsobeendiagnosedwithADHD.Heistaking

AdderallXR®,andsymptomshaveimproved.Hecontinuestohaveproblemswithrefusingtofollowdirections.Hetendstogetangryeasily.Heoftentriestogetbackatpeopleandcanbespiteful.Whenhismothertriestosetlimits,hehastantrumsthatlastforseveralminutes.Hismothernotesthatthingsathomehavebeen

verystressfulbecauseofhisbehavior.

Antwon hasalsobeendiagnosedwithOppositionalDefiantDisorder.Hismotherdoesn’tknowifmoremedicationistherightchoice,butshedoesn’tknowwhatelsetodo.

Shefeelsthattheyare“attheendoftheirrope.”

IsmedicationappropriateforthetreatmentofOppositionalDefiantDisorder?

OppositionalDefiantDisorder

• Behavioralinterventionsarefirstlinetreatment– Officebasedinterventions– Parenttrainingprograms

• IncredibleYears• ParentChildInteractionTraining• TriplePPositiveParentingProgram

AACAP. J Am Acad Child AdolescPsychiatr. 2007;46:126-141.

OppositionalDefiantDisorder

• MedicationscanbeconsideredasadjunctivetreatmentbutareNOTcurative– MaximallytreatunderlyingADHDsymptomsfirst,ifpresent

– Useisoff-labelandnotwellstudied• Alpha-agonists• Atypicalantipsychoticmedications

– Impulsiveaggressionwithautism,mentalretardation

– ConsiderconsultationwithPPN

AntipsychoticsOverview

• Antipsychoticmedicationsareusedtostabilizepatientsincrisis

• Symptomstargetedtypicallyinvolveaggressionand/ormania,possiblepsychosis

• Mostcommonfirstlinemedicationisrisperidoneoraripiprazole

• Secondlinemedicationmaybequetiapine

AntipsychoticsandPrimaryCare

• StewardsofmedicalhealththatmaybeaffectedbyAntipsychoticmedications– MetabolicSyndrome:whentoconsiderMetformin

– Orthostaticeffects– Antihistaminergic effects– drymouth,constipation

• Needtounderstandthemedicalmonitoring• Actasabridge

AntipsychoticSideEffects• Sedation• WEIGHTGAIN(evenaripiprazole)• Metaboliceffects

– Increasedglucose,insulinresistance,dyslipidemia(especiallyTG)

– Baseline:CBC,BMP,LFTs,FastingLipidsandGlucose– Every6months:Fastingglucoseandlipids,Hgb A1c

AntipsychoticAdverseEffects

• Dystonia,Oculogyriccrisis,parkinsonism• Akathisia• WithdrawalDyskinesia• TardiveDyskinesia• Prolactinelevation

– Highestinrisperidone– Aripiprazolemaylowerit

• QTCprolongation(ziprasidone)

AtypicalAntipsychoticMedications• Dramaticincreaseinprescribing

– Childreninfostercare– ChildrenwithSevereEmotionalDisturbance(SED)– ChildrenwithADHD

• Concerns– Safety– Questionableefficacy– Cost

www.ohiomindsmatter.org

UpdateonAntwon

• Antwon’smotherparticipatedinaparenttrainingprogramforchildrenwithdisruptivebehavior

• Antwon receivesadditionalschoolsupportsdesignedtoincreasedesirablebehavior

• YouworkwithAnton’sfamilytomaximizetreatmentofADHDsymptoms

Summary

• Medicationscanbeaneffectivecomponentofacomprehensivetreatmentplan

• Evidence-informedresourcesareavailabletoguidecare– PediatricPsychiatryNetwork– OhioMindsMatter– E-LearningmodulesfromBuildingMentalWellness(BMW)

References• AmericanAcademyofChildandAdolescentPsychiatry.Practiceparameterfortheassessmentand

treatmentofchildrenandadolescentswithAttention-DeficitHyperactivityDisorder.JAmAcad ChildAdolesc Psychiatr.2007;46:894-921.

• AmericanAcademyofChildandAdolescentPsychiatry.Practiceparameterfortheassessmentandtreatmentofchildrenandadolescentswithoppositionaldefiantdisorder.JAmAcad ChildAdolescPsychiatr.2007;46:126-141.

• CheungAH,Zuckerbrot RA,JensenPSetal.GuidelinesfortheAdolescentDepressioninPrimaryCare(GLAD-PC):II.TreatmentandOngoingManagement.Pediatrics.2007;120:e1313-e326.

• GibbonsRD,BrownCH,Hur K,etal.EarlyEvidenceontheEffectsofRegulators’Suicidality WarningsonSSRIPrescriptionsandSuicideinChildrenandAdolescents.AmJPsychiatry2007;164:1356–1363.

• Hammad TA.Reviewandevaluationofclinicaldata.Washington,DC,FoodandDrugAdministration,Aug16,2004(http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-10-TAB08-Hammads-Review.pdf).AccessedOctober22,2012.

• Pappadopulos E,MacIntyre JC,Crismon MLetal.Treatmentrecommendationsfortheuseofantipsychoticsforaggressiveyouth(TRAAY).PartII.JAmAcad ChildAdolesc Psychiatr.2003;42:145-161.

• Pliszka SR,Crismon ML,HughesCW,etal.TheTexasChildren’sMedicationAlgorithmProject:RevisionofthealgorithmforpharmacotherapyofAttention-Deficit-HyperactivityDisorder.JAmAcad ChildAdolescPsychiatr.2006;46:642-657.

• SubcommitteeonAttention-Deficit/HyperactivityDisorderandtheCommitteeonQualityImprovement.Clinicalpracticeguideline:treatmentoftheschool-agedchildwithAttention-Deficit/HyperactivityDisorder.Pediatrics.2001;108(4):1033-1044.

• SubcommitteeonAttention-Deficit/HyperactivityDisorder,SteeringCommitteeonQualityImprovementandManagement.ADHD:Clinicalpracticeguidelineforthediagnosis,evaluation,andtreatmentofAttention-Deficit/HyperactivityDisorderinchildrenandadolescents.Pediatrics.2011;128:1007-1022.

ADHDMedications

• Mostrecentguidancebasedonstrengthofevidence:

Methylphenidate~Amphetamine>>Atomoxetine

>LongactingGuanfacine>LongactingClonidine

AAP. Pediatrics. 2011;128:1007-22.