ADHDADHDTreatmentTreatment

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ObjectivesObjectives

Be familiar with the evidence Be familiar with the evidence supporting particular forms of supporting particular forms of management for ADHD, including management for ADHD, including medicationmedication

Know the different classes of Know the different classes of stimulant medications and their stimulant medications and their potential side effectspotential side effects

Be familiar with Atomoxetine and its Be familiar with Atomoxetine and its potential side effectspotential side effects

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Recommendation 1:Recommendation 1:Management ProgramManagement Program

Primary care clinicians should Primary care clinicians should establish a management program establish a management program that recognizes ADHD as a that recognizes ADHD as a chronic conditionchronic condition

Strong evidenceStrong evidence Strong recommendationStrong recommendation

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Recommendation 1:Recommendation 1:Management ProgramManagement Program

Prevalence 4-12% of school-age Prevalence 4-12% of school-age childrenchildren

60-80% persist into adolescence60-80% persist into adolescence

Inform, educate, counsel, demystifyInform, educate, counsel, demystify family, childfamily, child

ResourcesResources local, national (CHADD, ADDA)local, national (CHADD, ADDA)

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Recommendation 1:Recommendation 1:Management ProgramManagement Program

What distinguishes this condition What distinguishes this condition from most other conditions from most other conditions managed by primary care managed by primary care clinicians is the important role clinicians is the important role that the that the educational systemeducational system plays plays in the treatment and monitoring of in the treatment and monitoring of children with ADHD.children with ADHD.

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Recommendation 2:Recommendation 2:Target Outcomes by TeamTarget Outcomes by Team The treating clinician, parents, The treating clinician, parents,

and the child, in collaboration with and the child, in collaboration with school personnel, should specify school personnel, should specify appropriate target outcomes to appropriate target outcomes to guide management.guide management.

Strong evidenceStrong evidence Strong recommendationStrong recommendation

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Recommendation 2:Recommendation 2:Outcomes- maximize Outcomes- maximize

functionfunction RelationshipsRelationships parents, siblings, peersparents, siblings, peers

Disruptive behaviorsDisruptive behaviors Academic performanceAcademic performance

work volume, efficiency, completion, work volume, efficiency, completion, accuracyaccuracy

IndividualIndividual self-care, self-esteemself-care, self-esteem

Safety in the community Safety in the community

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Objectives of the Literature Objectives of the Literature ReviewReview

EffectivenessEffectiveness (short and long-term) (short and long-term) and and safetysafety of therapies of therapies

Medication and non-medication Medication and non-medication therapiestherapies

Single therapy vs combinationSingle therapy vs combination 6-12 year olds6-12 year olds

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Sources for ReviewSources for Review

Agency for Healthcare Research & QualityAgency for Healthcare Research & Quality McMaster Univ. Evidence-based Practice CenterMcMaster Univ. Evidence-based Practice Center

Canadian Office for Health Technology Canadian Office for Health Technology Assessment Study (CCOHTA)Assessment Study (CCOHTA)

Multimodal Treatment Study (MTA Study)Multimodal Treatment Study (MTA Study) Pelham et al. review of psychosocial therapiesPelham et al. review of psychosocial therapies

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Recommendation 2:Recommendation 2:developing target outcomesdeveloping target outcomes

InputInput parents, children (patient), teachersparents, children (patient), teachers

3-6 key targets3-6 key targets realistic, attainable, measurablerealistic, attainable, measurable methods will change over time methods will change over time

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School InterventionsSchool InterventionsIndividual Education Plan Individual Education Plan

504 Plan504 Plan IDEA = Individuals IDEA = Individuals

with Disabilities with Disabilities Education ActEducation Act

ADHD under “Other ADHD under “Other Health Impaired”Health Impaired”

Educational DisabilityEducational Disability ServicesServices

Section 504 of the Section 504 of the Rehabilitation ActRehabilitation Act

ADHD medical ADHD medical diagnosisdiagnosis

Medical Disability Medical Disability with educational with educational impactimpact

AccommodationsAccommodations

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Recommendation 3:Recommendation 3:make some make some

recommendationsrecommendations The clinician should recommend The clinician should recommend

stimulant medication and/or behavior stimulant medication and/or behavior therapy as appropriate, to improve therapy as appropriate, to improve target outcomes in children with target outcomes in children with ADHDADHD

StrongStrong evidence (medication), evidence (medication), FairFair evidence (behavior evidence (behavior therapy) therapy)

Strong recommendationStrong recommendation

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Recommendation 3:Recommendation 3:Efficacy of StimulantsEfficacy of Stimulants

Short-term benefits well establishedShort-term benefits well established

Core symptoms: attention, Core symptoms: attention, hyperactivity, and impulsivityhyperactivity, and impulsivity

observable social and classroom observable social and classroom behaviorsbehaviors

IQ and achievement testing- less IQ and achievement testing- less effect effect

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Recommendation 3:Recommendation 3:MTA StudyMTA Study

Effects over 14 monthsEffects over 14 months 579 children 7-9.9 years old579 children 7-9.9 years old 4 randomized groups4 randomized groups

medication alonemedication alone medication and behavior medication and behavior

managementmanagement behavior managementbehavior management standard community care standard community care

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Recommendation 3:Recommendation 3:MTA StudyMTA Study

Medication management alone Medication management alone Medication + behavior therapy Medication + behavior therapy

> Community management> Community management > Behavior management alone> Behavior management alone

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The StimulantsThe StimulantsNobody does it betterNobody does it better

Short, intermediate (the “old” long-Short, intermediate (the “old” long-lasting), truly long actinglasting), truly long acting

22 studies show 22 studies show NONO difference between difference between methylphenidate, dextroamphetamine, methylphenidate, dextroamphetamine, or mixed amphetamine salts (Adderall)or mixed amphetamine salts (Adderall)

Individual’s response may varyIndividual’s response may vary NONO serologic, hematologic tests needed serologic, hematologic tests needed**EKG – based on history and risk**EKG – based on history and risk

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Non-stimulantsNon-stimulantsSecond rate-only 2Second rate-only 2

Tricyclic antidepressantsTricyclic antidepressants 9 studies alone9 studies alone 4 studies =/< methylphenidate4 studies =/< methylphenidate

Bupropion (Wellbutrin, Zyban)Bupropion (Wellbutrin, Zyban) Clonidine Clonidine

limited studieslimited studies > placebo> placebo

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StimulantsStimulantsDose determinationDose determination

NOTNOT weight dependent weight dependent Optimal effects with minimal side Optimal effects with minimal side

effectseffects nothing ventured, nothing gainednothing ventured, nothing gained

Match target outcomes and timingMatch target outcomes and timing crucial step prior to startingcrucial step prior to starting

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StimulantsStimulantsSide effectsSide effects

appetite suppressionappetite suppression stomachache, headachestomachache, headache delayed sleep onsetdelayed sleep onset jitterinessjitteriness overfocused, dull demeanoroverfocused, dull demeanor mood disturbancesmood disturbances

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StimulantsStimulantsSide effects- NOTSide effects- NOT

seizures- seizures- NONO increased frequency with increased frequency with mphmph

growth delay- at least one negative studygrowth delay- at least one negative study Tourette syndromeTourette syndrome

15-20% of patients have motor tics15-20% of patients have motor tics 50% of TS have ADHD50% of TS have ADHD 7 studies comparing stimulants vs 7 studies comparing stimulants vs

placebo/other show placebo/other show NONO increase in tics with increase in tics with stimulantsstimulants

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Short Intermediate Short Intermediate ExtendedExtended

Methylphenidate Ritalin Focalin

Ritalin 20 SR Metadate ER

Concerta Metadate CD Ritalin LA

Dextroamphetamine Dexedrine Dextrostat

Dexedrine spansule

Adderall

Adderall XR

3-4 hours 5-6 hours 8-10 (12)hours

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AtomoxetineAtomoxetineStratteraStrattera

Selective norepinephrine uptake Selective norepinephrine uptake inhibitorinhibitor

Little effect on dopamine or Little effect on dopamine or serotonin uptakeserotonin uptake

Little effect on Ach, H1, alpha-2, DA Little effect on Ach, H1, alpha-2, DA receptorsreceptors

Well-tolerated in adult and pediatric Well-tolerated in adult and pediatric studiesstudies

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Atomoxetine...Atomoxetine...Randomized, Randomized, Placebo-Controlled, Dose-Placebo-Controlled, Dose-

Response...Response... 297 children and adolescents297 children and adolescents 8-18 years old; 71 % male8-18 years old; 71 % male 70% had prior stimulant therapy70% had prior stimulant therapy Combined/Inattentive/Hyper-impulsiveCombined/Inattentive/Hyper-impulsive 63/33/2 %63/33/2 % 37 % Oppositional-defiant disorder37 % Oppositional-defiant disorder 1 depression, 1 anxiety disorder1 depression, 1 anxiety disorder

Atomoxetine…AD/HD…Study. Pediatrics 108:e83, 2001

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Side EffectsSide Effects Small samples:Small samples:

dizziness 9% vs 1% placebodizziness 9% vs 1% placebo vomiting 6% vs 7% vomiting 6% vs 7%

Weight loss dose dependentWeight loss dose dependent mean 0.4kg at 1.2 mg/kg/dmean 0.4kg at 1.2 mg/kg/d

small pulse, BP changessmall pulse, BP changes no EKG changesno EKG changes <5% dropout rate atmx and placebo<5% dropout rate atmx and placebo

Atomoxetine…AD/HD…Study. Pediatrics 108:e83, 2001

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Efficacy of Atomoxetine vs Efficacy of Atomoxetine vs Placebo in School-Age Girls Placebo in School-Age Girls

with AD/HDwith AD/HD 52 children and adolescents52 children and adolescents 7-13 years old7-13 years old Combined/Inattentive/Hyper-Combined/Inattentive/Hyper-

impulsiveimpulsive 79/21/0 %79/21/0 % 38.5 % Oppositional-defiant disorder38.5 % Oppositional-defiant disorder 13.5% phobias13.5% phobias

Efficacy…Girls...AD/HD. Pediatrics 110:e75, 2002

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MeasuresMeasures

ADHD Rating Scale- ParentADHD Rating Scale- Parent Conners’ Parent RS-RevisedConners’ Parent RS-Revised

No Teacher ratingsNo Teacher ratings

Clinical Global Impressions of ADHD Clinical Global Impressions of ADHD Severity- ClinicianSeverity- Clinician

Efficacy…Girls...AD/HD. Pediatrics 110:e75, 2002

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Side EffectsSide Effects Small sample size subset here Small sample size subset here

(279 total); so no significant (279 total); so no significant differencesdifferences

Vomiting 19% vs 0%Vomiting 19% vs 0% Abdominal pain 29% vs 14%Abdominal pain 29% vs 14% Nausea 6.5% vs 14%Nausea 6.5% vs 14% ?Weight, cardiac...?Weight, cardiac... Increased cough 16% vs 4.8%Increased cough 16% vs 4.8%Efficacy…Girls...AD/HD. Pediatrics 110:e75, 2002

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Atomoxetine and Atomoxetine and Methylphenidate... Methylphenidate... Prospective Prospective

Randomized, Open-Label TrialRandomized, Open-Label Trial 228 children and adolescents228 children and adolescents 184 atomoxetine, 44 mph; 10 weeks184 atomoxetine, 44 mph; 10 weeks 7-15 year old boys; 7-9 year old girls7-15 year old boys; 7-9 year old girls Most/all had prior stimulant therapyMost/all had prior stimulant therapy Combined/Inattentive/Hyper-Combined/Inattentive/Hyper-

impulsiveimpulsive 76/23/1 %76/23/1 % 53% ODD, 7% major depression 53% ODD, 7% major depression

Atomoxetine and Methylphenidate... Prospective Randomized, Open-Label Trial JAACAP 41:7, 2002

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MeasuresMeasures

ADHD Rating Scale- Parent ADHD Rating Scale- Parent CompletedCompleted

ADHD Rating Scale- Parent InterviewADHD Rating Scale- Parent Interview Conners’ Parent RS-RevisedConners’ Parent RS-Revised

No Teacher ratingsNo Teacher ratings Clinical Global Impressions of ADHD Clinical Global Impressions of ADHD

Severity- ClinicianSeverity- Clinician Atomoxetine and Methylphenidate... Prospective Randomized, Open-Label Trial JAACAP 41:7, 2002

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FindingsFindings

Comparable improvement between the Comparable improvement between the twotwo

mean dose 1.4 mg/kg/d extensive mtb, mean dose 1.4 mg/kg/d extensive mtb, 0.5mg/kg/d slow mtb 0.5mg/kg/d slow mtb

mph mph 0.85 mg/kg/d, (31mg/d) 0.85 mg/kg/d, (31mg/d)

High rate of dropoutsHigh rate of dropouts

Atomoxetine and Methylphenidate... Prospective Randomized, Open-Label Trial JAACAP 41:7, 2002

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FindingsFindings 43% of mph, 36 % atmx dropped out!43% of mph, 36 % atmx dropped out! 11%; 5 % because of adverse effects 11%; 5 % because of adverse effects

comparablecomparable

atomoxetine wt loss avg 0.6 kg; (mph 0.1)atomoxetine wt loss avg 0.6 kg; (mph 0.1) small changes both in pulse, BPsmall changes both in pulse, BP EKG, labs no problems, no differencesEKG, labs no problems, no differences

Atomoxetine and Methylphenidate... Prospective Randomized, Open-Label Trial JAACAP 41:7, 2002

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Side EffectsSide Effects Generally comparableGenerally comparable Vomiting 12% vs 0%Vomiting 12% vs 0% Abdominal pain 23% vs 17.5% (NS)Abdominal pain 23% vs 17.5% (NS) Nausea 10% vs 5% (NS)Nausea 10% vs 5% (NS) ?Weight, cardiac...?Weight, cardiac... Cough 5% sameCough 5% same ““Thinking abnormal” 0% vs 5% (N=2)Thinking abnormal” 0% vs 5% (N=2)

Atomoxetine and Methylphenidate... Prospective Randomized, Open-Label Trial JAACAP 41:7, 2002

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Pros and Pros and Cons Cons

No abuse potentialNo abuse potential adolescent usageadolescent usage adult usageadult usage

24/7 coverage24/7 coverage No tic relationshipNo tic relationship Novel class of medNovel class of med

use use withwith stimulants, toostimulants, too

Little data head to Little data head to head vs stimulantshead vs stimulants

Weight loss/vomitingWeight loss/vomiting Takes week(s) to Takes week(s) to

effectseffects Tolerance Tolerance

““starter kit” issuestarter kit” issue adjust if SSRI added adjust if SSRI added

CostCost

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Behavior TherapyBehavior Therapyaccept no substitutesaccept no substitutes

Behavior therapyBehavior therapy Emotions-based therapy Emotions-based therapy

e.g. play therapy-e.g. play therapy-NOTNOT efficacious in efficacious in ADHDADHD

Thought patterns directedThought patterns directed cognitive, cognitive-behavioral therapycognitive, cognitive-behavioral therapy NOTNOT efficacious in ADHD efficacious in ADHD

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Behavior TherapyBehavior TherapyParent TrainingParent Training

8-12 weeks with trained therapist8-12 weeks with trained therapist teaches parent teaches parent skillsskills incorporates maintenance and incorporates maintenance and

relapsesrelapses improves child’s functioning and improves child’s functioning and

behaviorbehavior not necessarily achieves normal not necessarily achieves normal

behaviorbehavior

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Behavior TherapyBehavior Therapy Examples of Techniques Examples of Techniques

Positive reinforcementPositive reinforcement reward for performancereward for performance

Time-outTime-out removing positive reinforcementremoving positive reinforcement

Response costResponse cost losing advance rewards losing advance rewards

Token economyToken economy combinationcombination

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Behavior TherapyBehavior Therapy Meta-analyses difficult and Meta-analyses difficult and

fewfew Must be maintained to be effectiveMust be maintained to be effective Stimulant effects much > behavioral Stimulant effects much > behavioral

therapytherapy MTA study: combination > med alone, but MTA study: combination > med alone, but notnot

a statistically significant differencea statistically significant difference However, parents and teachers However, parents and teachers more satisfiedmore satisfied

Schools can implementSchools can implement 504 Plan504 Plan IEPIEP

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Recommendation 4:Recommendation 4:When to re-evaluateWhen to re-evaluate

When the selected management for a When the selected management for a child with ADHD has child with ADHD has not met target not met target outcomesoutcomes, clinicians should evaluate , clinicians should evaluate the the original diagnosisoriginal diagnosis, , use use of all of all appropriate treatments, adherence to appropriate treatments, adherence to the treatment plan, and presence of the treatment plan, and presence of coexistingcoexisting conditions conditions

Weak evidenceWeak evidence Strong recommendation Strong recommendation

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Recommendation 4:Recommendation 4:Ddx in re-evaluationDdx in re-evaluation

unrealistic target symptomsunrealistic target symptoms poor information regarding child’s poor information regarding child’s

behaviorbehavior incorrect diagnosis and/orincorrect diagnosis and/or coexisting condition interferingcoexisting condition interfering

ODD, conduct disorder, mood, anxiety, LDODD, conduct disorder, mood, anxiety, LD poor adherence/compliancepoor adherence/compliance treatment failure treatment failure

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Recommendation 4:Recommendation 4:Steps in re-evaluationSteps in re-evaluation

Re-establish target symptomsRe-establish target symptoms ““team” communicationteam” communication

Gather further information, other Gather further information, other sourcessources

Consider consultationConsider consultation Consider psycho-educational testingConsider psycho-educational testing

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Recommendation 4:Recommendation 4:True treatment failureTrue treatment failure

Lack of response to 2-3 stimulantsLack of response to 2-3 stimulants maximum dosemaximum dose without side effects without side effects any dose with intolerable side effectsany dose with intolerable side effects

Inability to control child’s behaviorInability to control child’s behavior Interference of coexisting conditionInterference of coexisting condition

Refer to mental healthRefer to mental health

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Recommendation 5:Recommendation 5:follow-up guidelinesfollow-up guidelines

The clinician should periodically The clinician should periodically provide a systematic follow-up for provide a systematic follow-up for the child with ADHD. Monitoring the child with ADHD. Monitoring should be directed to should be directed to target target outcomesoutcomes and and adverse effectsadverse effects by by obtaining specific information from obtaining specific information from parents, teachers, and the child.parents, teachers, and the child.

Fair evidenceFair evidence Strong recommendationStrong recommendation

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Recommendation 5:Recommendation 5:follow-up guidelinesfollow-up guidelines

TeamTeam management plan management plan not just : “What does the doctor not just : “What does the doctor

recommend?”recommend?” Recording clinical dataRecording clinical data

flow sheet, progress noteflow sheet, progress note Interview, T-Con, teacher reports, Interview, T-Con, teacher reports,

report cards, checklistsreport cards, checklists

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Recommendation 5:Recommendation 5:frequency of follow-upfrequency of follow-up

NONO controlled trials document the controlled trials document the appropriate frequencyappropriate frequency

MTA study: more frequent did MTA study: more frequent did better, BUTbetter, BUT

Once stable, visit every 3-6 monthsOnce stable, visit every 3-6 months

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Conclusion nuggetsConclusion nuggets ADHD is a ADHD is a chronicchronic condition condition

Explicit negotiations regarding Explicit negotiations regarding targettarget outcomes are key outcomes are key

Stimulant and behavior therapy Stimulant and behavior therapy use are the mainstay of therapyuse are the mainstay of therapy