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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.