Medications and Medications and Psychosocial Psychosocial

Treatments for ADHDTreatments for ADHDThomas E. Brown, PhD

Associate Director,Yale Clinic for Attention and Related Disorders

Department of PsychiatryYale Medical School

In the Human BrainIn the Human Brain

100 billion neurons each one linked to >1000 others in complex sub-systems that have to “talk to each other” using low voltage electrical impulses that have to jump across gaps so fast that 12 can cross in 1/1000 sec.

The Jungle

Neuron

SynapseIntertwined neurons

Chemicals Jump the GapsChemicals Jump the Gaps

Inside brain >50 different chemicals are continuously made

every neuron system uses 1 of them stored in little vesicles near tip of neuron when electrical impulse comes, mini-dots

of that chemical are released, cross the gap, fire next neuron, then

reload in fractions of a second

MessageZips in

Releasing transmitter

MessageZips on

Reloadingtransmitter

2 crucial chemicals: 2 crucial chemicals: (dopamine, noripinephrine)(dopamine, noripinephrine)

control most of functions impaired in ADHD Brain of person with ADHD makes these

chemicals, as does everyone else but does not release & reload effectively

control messages often not connecting For 80% of those with ADHD medications

improve this problem.

How do ADHD Impairments of EF How do ADHD Impairments of EF Usually Respond to Medication?Usually Respond to Medication?

This wide range of cognitive impairments responds to medication treatment in 70-90% of cases in children, adolescents and adults

Symptom improvement varies from modest to very dramatic

Adverse effects are usually transient, not significant

Safety of ADHD MedicationsSafety of ADHD MedicationsAmerican Medical Assn. ReportAmerican Medical Assn. Report

“More than 170 studies involving >6,000 children using stimulant medications for ADHD…up to 90% will respond to at least 1 stimulant without major adverse events if drug titration is done carefully “

Adverse effects from stimulants are generally mild, short-lived, & responsive to dosing or timing adjustments”

(Goldman, et. al., 1998, pp 1103-1104)

Substance Abuse Substance Abuse Associated With ADHDAssociated With ADHD

Risk of developing SUD over lifetime is 52% for adults with ADHD vs 27%

In ADHD, substance-use disorders onset earlier, last longer, & remit more slowly

If ADHD is appropriately treated with stimulant medications in childhood and adolescence, risk of SUD reduced 84%

Wilens, Farone, Biederman, et al, Pediatrics, 2003)

ADHD: Targets of PharmacotherapyADHD: Targets of Pharmacotherapy

Core symptoms:

• Inattentive ± hyperactive, impulsive

Associated impairment:

• occupational failure, social and academic deficits

Pattern of comorbid disorders:

• oppositional, antisocial, substance use, mood and anxiety disorders

MTA Study of ADHD TxMTA Study of ADHD Tx

579 children (7-9 years)

ADHD Combined Type

14 months duration (10 yr f/u)

Six sites

MTA GroupsMTA Groups

1. Med Mgmt: tailored dose design

TID dosing, monthly monitoring

2. Behav Tx: 8 wk summer prog, pt training child tx, schl aide, tchr consults, daily rpts.

3. Combined Med Mgmt + Behav Tx

4. Com Care: evals, 67% on meds, BID

MTA ResultsMTA Results

1. Med Mgmnt, Comb Tx >Beh Tx, ComCare

2. Combined Tx = Med Mgmt for ADHD Sx

3. Comb Tx slightly better for assoc probs

4. Med Mgmt better than ComCare meds

MTA StudyMTA Study“Excellent Response” to Tx“Excellent Response” to Tx

% of Ss scoring average of <1

(“just a little”) on SNAP-IV for

Inattn, Hyper/Impulsive, Opp/Defiant

25% Community Care

34% Behavioral Treatment only

56% Medication Mgmt only

68% Combination Tx(Swanson, et. al., 2001)

Rates of Sudden Death in Rates of Sudden Death in population vs. on stimulantspopulation vs. on stimulants

SD rates in General Population (Berger et al. Ped Clin N America, 2004)• 0.6-6 / 100,000 children/ year• 1 / 1000 adults/year

Estimated SD rate on stimulants (based on Rx data)• 0. 25/ 100,000 people/ year (calculated based on

data)• 0.50/ 100,000 people/ year (assuming 50%

underreporting)

(T.Wilens, 2006)

FDA Pediatric Advisory Committee 3/24/06FDA Pediatric Advisory Committee 3/24/06

Reassessment by larger FDA Pediatric Advisory 3/24/06

• No additional CV risk in medically healthy kids

• risk with structural heart defects approximates that in child athletes (T. Wilens, 2006)

FDA Advisory Committee 2/9/06FDA Advisory Committee 2/9/06RecommendationsRecommendations

American Heart Association Guidelines (Gutgesell et al., Circulation; 1999; J Am Acad Child Adoles Psych; 1999)

No need for ECG, Echo, Cardiac biopsy in routine cases

But if:

-- Family history of SD (<30 yrs of age)• Hx of structural / congenital cardiac structural defects• Syncope• Chest pain• Palpitations• Hypertension

Monitor during treatment(T. Wilens, 2006)

Patients’ Fears of Medications Patients’ Fears of Medications for ADHDfor ADHD

Change personality “zombie”? Slow growth? Start tics? Lose appetite? Sleep? Later drug or alcohol problems? Dependence on meds for lifetime? Being labeled, attribution problems? Reactions of family, teachers, peers?

Controversial Treatments for ADHDControversial Treatments for ADHD

Dietary restrictions (food dyes, sugar) Diet supplements: anti-oxidants, algae optometric vision training EEG neuro-feedback

No scientific evidence for the safety or effectiveness of these treatments for ADHD, but NIMH is doing study on neurofeedback

ADHD “miracle” duped thousandsADHD “miracle” duped thousands

Dore treatment claimed to help ppl with dyslexia and ADHD by stimulating cerebellum with exercises

40K ppl completed 12 mo program at cost of $4970.

Journal article in Dyslexia praised Dore (biased & flawed)

Clinics closed, company bankrupt, many clients got no refund

A Chemical ProblemA Chemical Problem

ADHD is fundamentally a chemical problem

Most effective treatment is to change the chemistry with medication

Unless the problematic chemistry is changed, other interventions are not likely to be very effective

Adapted from Wilens TE, et al. Annu Rev Med. 2002;53:113-131. Greenhill LL. Childhood attention deficit hyperactivity disorder: pharmacological treatments. In: Nathan PE, Gorman J, eds. Treatments That Work. Philadelphia, Pa: Saunders; 1998:42-64.

Attention Deficit Attention Deficit Hyperactivity DisorderHyperactivity Disorder

Pharmacologic Treatments

Not Approved by FDA for ADHD

AntidepressantsTricyclicsBupropionAntihypertensives

Clonidine Guanfacine

Miscellaneous

Combined pharmacotherapyModafinilVenlafaxineNeuroleptics (only in severe cases with monitoring)

Approved by FDA for ADHD

Stimulants

MethylphenidateAmphetamine compounds Dextroamphetamine Lisdexamfetamine

Nonstimulant

Atomoxetine

Stimulant MedicationsStimulant Medications Amphetamine

- dextroamphetamine (Dexedrine): 4-6 hours

• d, l amphetamine (Adderall): 4-6 hours

• Extended release (Adderall-XR) 8-10 hours

• Lisdexamfetamine (Vyvance) 10-12 hours

Methylphenidate• Ritalin: 4 hours

• Concerta: triphasic, 10-12 hours

• Metadate CD: biphasic, 8 hrs

• Focalin (d -isomer) 4 hours

• Focalin-XR 8 hours

• Ritalin-LA (biphasic) 6-8 hours

Medications for ADHD SyndromeMedications for ADHD Syndrome

Demonstrated safe and effective

Often do not follow mg/kg

Effective dose not based on age, wt or severity of sx

Require titration and monitoring to “fine tune” to:

- individual sensitivity

- time frames for schedule and tasks

Time Frames and ReboundTime Frames and ReboundIf sustained feeling/acting

excessively:

• “wired” or racy

• irritable

• serious, loss of “sparkle”

during the time dose is active, dose is probably too high

ActiveDrop-off

If these effects occur as med is wearing off, problem is more likely to be “rebound”, ie dropping too fast.

IngestionTime

Lev

el o

f m

ed i

n t

he

blo

od

stre

am

TE Brown, 2002

ADHDADHDResponse to StimulantsResponse to Stimulants

0

10

20

30

40

Best Response(Percent)

Dextroamphetamine Methylphenidate Equal response to either stimulant

Meta-analysis of within-subject comparative trials evaluating response to stimulant medications

36%

26%

38%

OROS (methylphenidate HCI)-

Concerta Capsule-Shaped Tablet

Orifice/Exit Port

Drug Compartment #1

DrugCompartment #2

PushCompartment

Before Operation During Operation

Water

Water

R

Drug Overcoat

Rate Controlled Membrane

MetadateMetadate™™ CD CD (methylphenidate) (methylphenidate)

Extended-Release Capsules for ADHD Extended-Release Capsules for ADHD

Biphasic Release: Bead-Delivery SystemBiphasic Release: Bead-Delivery System

dd-MPH-XR -MPH-XR (Focalin XR(Focalin XR™™))

SODASTM release system

• 50% IR d-MPH beads and 50% ER d-MPH beads covered by polymer overcoat

• Can be sprinkled on food

Single isomer technology

• Composed of only the d-MPH stereoisomer (dexmethylphenidate)

0 4 8 12 16 20 24 28 320

5

10

15

20

Time (h)

d-MPH-XR 20 mg qd

SODASTM MPH 40 mg qd

MPH MR 20 mg qd

OROS® MPH 18 mg qd

Mea

n P

lasm

a M

eth

ylp

hen

idat

eC

on

cen

trat

ion

(n

g/m

L)

Mean plasma concentrations over time

• Two peaks

Source: Focalin XRTM [package insert], Novartis Pharmaceuticals Corporation.

Stimulant DosingStimulant Dosing Medication Starting Dose Maximum Dose* Usual Dosing

Ritalin® 5 mg QD/BID 2 mg/kg/day TID (4 h) Focalin® 2.5 mg 1 mg/kg/day BID (5-6h?)

Dexedrine® 2.5 to 5 mg QD 1.0 mg/kg/d BID/TID (4 h)Dex Spansule 5 mg 1.0 mg/kg/d BID (6 h)

Adderall® 2.5 to 5 mg QD 1.0 mg/kg/d BID (6 h)AdderallXR® 5-10 mg 1.0 mg/kg/d QD (12 h)Vyvanse 30 mg 30 to 70 qd QD (13 hr)

Wilens, et al. Annu Rev Med. 2002;53:113-131; updated 2005.

Concerta® 18 mg QD 2 mg/kg/day QD (12 h)MetadateCD® 20 mg QD 2 mg/kg/day QD (6-8 h)Ritalin LA 10 mg QD 2 mg/kg/day QD (6-8 h)Focalin XR 5 mg QD 2 mg/kg/day QD (8-10h?12)

*Maximum dosing may exceed FDA approved dose limits.

Advantages of Extended-Release Advantages of Extended-Release Formulations of StimulantsFormulations of Stimulants

Provides sustained medication levels Provides sustained medication levels throughout the daythroughout the day

Smoother: minimizes ups and downs during Smoother: minimizes ups and downs during dayday

No midday dose required, eliminating trips to No midday dose required, eliminating trips to the school nurse, doses during workdaythe school nurse, doses during workday

Reduces stigmaReduces stigma

Enhances patient complianceEnhances patient compliance

May reduce illicit diversion and abuseMay reduce illicit diversion and abuse

Management Strategies for:Management Strategies for:

Severe Decrease

In appetite

• Monitor weight

• Administer with or after meals

• Give high-calorie snacks

• Consider medication holidays

• Eat in reverse

Headache/Stomachache,

Irritability/Moodiness, or OCD Symptoms

• Decrease dose

• Switch to another stimulant

• Switch to 2nd line agent

Wilens & Spencer, 2000

Management Strategies for:Management Strategies for:

Delayed Sleep Latency

Sleep Hygiene/Bedtime rituals

Change to shorter acting stimulant

Consider adjunctive treatment (e.g., clonidine)

Relaxation training

Irritability Evaluate when it

occurs• Peak (too high dose)

• Wear off (? rebound)

Change dose Assess for comorbidity Consider adjunctive

therapy

Wilens & Spencer, 2000

Non-StimulantNon-Stimulant options for ADHD options for ADHD

Specific noradrenergic agent approved for ADHD -Strattera (atomoxetine)

Antidepressants (not approved for ADHD)-Wellbutrin (buproprion)-Pamelor (nortriptyline)-Norpramin (desipramine)

Alpha-2 Agonists (not for cognition) (Not Approved for ADHD)-Catapres (clonidine)-Tenex (guanfacine)

PDR Recommendations (Not a controlled substance)

• Start ≈ 0.5 mg/kg/d

• Target 1.2 mg/kg/d

• Max of 1.4 mg/kg/d or 100 mg/d

Example: 8 year old

• Start 18 mg for 4-7 days in AM after food

• 25 mg for 4-7 days then increase to 40 mg

If already on stimulant, cross-taper, introduce ATMX then reevaluate need for stimulant

Available in 10mg, 18mg, 25mg, 40mg, 60mg

Sprinkling not formally tested and may irritate GI tract

Full benefits often not seen until 4 to 6 weeks of treatment!

Dosing of Atomoxetine in ADHDDosing of Atomoxetine in ADHD

Physician Desk ReferencePhysician Desk Reference®®.. MMonvale, NJ:Thompson PDR;2005.onvale, NJ:Thompson PDR;2005.

Dosing of Atomoxetine in AdultsDosing of Atomoxetine in Adults

Initial: total daily dose of 40 mg increased after ≥ 1 week to a target of ~80 mg

Administered either as:• Single daily dose in the morning • Evenly divided doses in the morning and late

afternoon/early evening (bid dosing in adult trials)

After 2 to 4 additional weeks, dose may be increased to a maximum of 100 mg daily (patients without an optimal response)

Full benefits often not seen until 4 – 6 weeks of steady treatment!

Strattera® [package insert]. Indianapolis, Ind: Eli Lilly; 2003.

Comparative Study of ATX vs OROSComparative Study of ATX vs OROS

492 patients with ADHD (6-16 yrs) randomized to ATX (0.8-1.8 mg/kg/d)

OROS (18-54 qd) or PBO for 6 wks Response (≥40% sx improvement)

ATX: 45% OROS: 56% PBO: 24% Of 70 Non-responders to OROS 43% + Of 69 Non-responders to ATX 42% +

(Newcorn, Kratochvil, et al, 2008)

Types of non-pharmacological Types of non-pharmacological treatmentstreatments

1. Psychoeducation about ADHD and its treatment to address prejudices/fears

2. Cognitive-behavioral treatments to modify maladaptive attitudes

3. Remedial instruction/coaching to modify deficits or maladaptive behaviors

Non-Pharmacological TreatmentsNon-Pharmacological Treatmentsare important to ADHD treatmentare important to ADHD treatment

ADHD/ADD results from impairment brain chemistry and medication is most effective treatment

BUT, medication is not effective if not taken

cannot fully alleviate some symptoms

Some ADHD patientsSome ADHD patientsdo not take their ADHD medicationsdo not take their ADHD medications

Because they:

have prejudices about the disorder

fear and don’t understand ADHD meds

Primary Primary PrejudicePrejudice about ADHD about ADHD

“It’s essentially a simple problem, a matter of willpower” because….

“It’s just being too hyper and not listening”

“Everyone with ADHD can pay attention very well for certain specific activities”

Primary Primary fearsfears about ADHD medications about ADHD medications

“This will make problems for me”

“make me too hyper or too slow”

“take away my personality”

“get me dependent or addicted”

Patient Education is needed about Patient Education is needed about medicationsmedications

Need to be “fine-tuned” in collaboration with each patient

Set patient expectations to collaborate adjust med, dose or timing to individual

needs and body chemistry prevent stimulant “rebound” Need to report any side effects

Home Interventions Home Interventions for ADD/LD School Problemsfor ADD/LD School Problems

daily parental reading with child daily parental help with organization/study early computer training and use supplementary audio or videos remedial tutoring avoid micro-managing homework for teens protect non-academic strengths

Parent Training for Management of Parent Training for Management of ADHD Behavior ProblemsADHD Behavior Problems

positive attending rewards for appropriate behavior planned ignoring transition management target behaviors & point systems use of “time out” & “response cost”(Cunningham, 1998; Teeter, 1998)

Improving Interactions of ADHD Teens Improving Interactions of ADHD Teens and Their Parentsand Their Parents

recognize aims & limits of parental control facilitate appropriate independence seeking maintain adequate structure & supervision establish & enforce “bottom line” rules negotiate all “non-bottom line” issues use consequences wisely to influence focus on positives, practice forgiveness(A.Robin, 1998, C.Dendy, 1995)

School AccommodationsSchool Accommodationsfor ADD/LDfor ADD/LD

Daily check of assignments & organization preferential seating reduced volume of work weekly/daily progress reports alternative test delivery (oral/written) extended time for tests (as needed)(S.Rief, 2005, C.Dendy, 2000)

Cognitive Behavioral Treatments for:Cognitive Behavioral Treatments for:

Defensive attitudes about self & others: “Everyone expects too much from me.” “I may seem smart, but I’m really stupid.” “High goals just bring disappointment.” “It’s not worth trying; the world is unfair.” “I’m just destined to be a loser.”

These attitudes have cognitive & emotional aspects

Remedial instruction or Coaching for: Remedial instruction or Coaching for:

Skill deficiencies that persist Study skills and academic deficits Organization of ideas and stuff Priority setting & time management Budgeting income and spending Monitoring self in conversations

Pills don’t teach skills.

Clinical Tips for Psychosocial Treatment Clinical Tips for Psychosocial Treatment of Adult ADHD of Adult ADHD

(Ramsay & Rostain, 2005, 2007)(Ramsay & Rostain, 2005, 2007)

Assess patients’ “readiness for change” (motivation and resources)

Provide psychoeducation about ADHD

Maintain an active therapeutic stance and collaboration with patients

Pay attention to the quality of the therapeutic relationship

Maintain focus on specific functional problems faced by patients

Clinical Tips for Psychosocial Treatment Clinical Tips for Psychosocial Treatment of Adult ADHD of Adult ADHD

(Ramsay & Rostain, 2005, 2007)(Ramsay & Rostain, 2005, 2007)

Implement cognitive modification and foster resilient attitudes

Normalize trial-and-error nature of the therapy process for adult ADHD

Encourage individualized coping strategies for “living with ADHD”

Maintain ongoing case conceptualization Consider referrals for additional clinical services

(e.g., medications, coaching)

Cognitive Model of PsychotherapyCognitive Model of Psychotherapy (Ramsay & Rostain, 2005, 2007)(Ramsay & Rostain, 2005, 2007)

• Based on cognitive model of psychopathology

• Time efficient • Structured, active• Collaborative problem-solving• Regular homework

Interventions to ProvideInterventions to ProvideTherapy & SupportTherapy & Support

relevant articles, books and websites support groups: CHADD, ADDA on-site support: for patient, teachers psychotherapy- individual, conjoint parent support/training mgmnt skills crisis intervention “realistic hope” vs. “optimism”

Levels of Care for ADHDLevels of Care for ADHDtailor to pt & family needstailor to pt & family needs

Comprehensive assessment for ADHD,

comorbid disorders, and context Family Education re: ADHD and its tx PE, “fine-tuning” of meds, monitoring Parent support & behavior mgmnt training Accommodations/Interventions in school Psychotherapy: individual, family