Update on Treating ADHD

Anthony L. Rostain, M.D., M.A

Professor of Psychiatry and Pediatrics

University of Pennsylvania Perelman School of Medicine

Co-Director, Developmental Neuropsychiatry Program

The Children’s Hospital of Philadelphia

Medical Director, Adult ADHD Treatment & Research Program

PENN Behavioral Health

ASCP Annual MeetingMiami Beach, FL May 31, 2018

• Book royalties (Routledge/Taylor Francis Group, St. Martin’s Press)

• Scientific advisory board honoraria (Shire, Ironshore, Arbor)

• Consultant honoraria for MLB, NFL, SUNY/Upstate (AHRQ grant)

• CME presentations for WebMD, NACE, Global Medical Education,

American Psychiatric Association

Disclosures

To review

• Current understandings about the neurobiology of ADHD

• Mechanisms of action of commonly prescribed ADHD medications

• Practical tips for prescribing and monitoring medications

• New medication options currently under investigation

Learning Objectives

PFC = prefrontal cortex.

Tripp G, et al. Neuropharmacology. 2009;57(7-8):579-589.

Neurobiology of ADHD

Noradrenalin Dopamine Serotonin

Genes

PFC Basal ganglia Cerebellum

Neural

Mechanisms

DBH HTR1B DAT1 D4 D5 SER T SNAP-25

Basic

Processes

ADHD

Executive Function

Working

memory

Behavioral

inhibition

Motivation

Delay

aversionReinforcement

Predominantly

inattentive

Predominantly

hyperactive–impulsiveCombined

Symptoms

Faraone SV, et al. Nat Rev Dis Primers. 2015;1:15020.

Clinical Progression PathophysiologyEtiology

Frontal–subcortical–cerebellar dysfunction via structural and functional brain abnormalities and

downregulation of catecholamine systems that regulate attention, reward, executive control and

motor functions

Different genetic risk factors affect the course of ADHD at different stages of the lifespan

Psychosocial influences, chaotic family environments, peer influences and mismatch with

school and/or work environments

Inattention persists and hyperactive–

impulsive symptoms wane

Substance abuse, low self-esteem

and social disability

Behavioral disinhibition, emotional ability

and emergence of diagnosis in preschool

years

Full expression of

ADHD, psychiatric

comorbidity, school failure,

peer rejection

and neurocognitive

dysfunction

Sm

ok

ing

in

itia

tio

n

Genetic

predisposition

Fetal exposures

and

epigenetic changes

Prodrome: hyperactivity; and speech,

language and motor coordination

problems

In utero Adolescence AdulthoodChildhood

Persistence of cortical thickness,

default-mode network and white matter

tract abnormalities

Schematic

representation

of functional

circuits involved

in the

pathophysiology

of ADHD

Purper-Ouakil D, et al. Pediatr Res. 2011;69(5 Pt 2):69R-76R.

Arnsten AF, et al. J Am Acad Child Adolesc Psychiatry. 2012;51(4):356-367.

Regulation of Attention and Emotion

Arnsten AF, et al. J Am Acad Child Adolesc Psychiatry. 2012;51(4):356-367.

Regulation of Attention and Emotion

Arnsten AF. J Pediatr. 2009;154(5):I-S43.

The Prefrontal Cortex Requires a Proper Level

of Catecholamines for Optimal Function

Increasing Levels of Catecholamine Release

Drowsy Alert Stressed

Unguided attention / responses

Distracted, poor impulse control

(eg, Untreated ADHD)

Misguided attention / responses

Mental inflexibility, stimulus bound

(eg, Excessive dose of stimulant)

Guided attention and responses

Focused, organized and flexible

(eg, Optimally treated ADHD)

NE a2A

Moderate D1

Too little

a2A/D1

NE a1, b1

Excess D1

Dulcan M. J Am Acad Child Adolesc Psychiatry. 1997;36(10 Suppl):85S-121S.

Treatment Modalities for ADHD

Medical

Interventions

Educational / Workplace

Interventions

Psychosocial

Interventions

Pharmacologic Treatments for ADHD

Primary Agents Stimulants

Atomoxetine

adrenergic agonists

Secondary Agents Bupropion

Modafanil

Tricyclic antidepressants

Adjunctive agents Mood stabilizers

Anxiolytics

SSRIs

Neuroleptics

Combination regimens

Child and Adolescent ADHD:

Effect Sizes*

Medication Effect Size

Amphetamine 0.92

Methylphenidate 0.80

Atomoxetine 0.73

Modafinil 0.49

Bupropion 0.32

Faraone SV, Spencer TJ. Presented at APA Annual Meeting, Toronto, 2006.

*Drugs used to treat ADHD were evaluated for efficacy using 17 outcome measures. Effect sizes for stimulants

(amphetamine and methylphenidate) are significantly greater than are those for other medications.

29 controlled studies; N = 4465 children and adolescents

Adult ADHD: Effect Sizes (Stimulants)

Meta-analyses of 18 randomized controlled trials

5 RCT of ER stimulants in adults (2006 - 2008)

• Mean effect size (ES) = 0.73

• N=1 d-MPH ER; LDX; MAS XR; N=2 OROS MPH

• No heterogeneity of effect size

“documents the robust efficacy of stimulant medications in adult ADHD

similar to observed in children”

Faraone J Clin Psychiatry 2010

Neurotransmitters & ADHD Medications

dopamine

norepinephrineatomoxetine

Wilens TE, et al. Postgrad Med. 2010;122(5):97-109. Stevens JR, et al. In: Adler LA, et al (Eds). Attention-Deficit

Disorder in Adults and Children. Cambridge University Press: Cambridge, UK; 2015:245-258.

Pharmacologic Treatments Approved for ADHDAmphetamine-based Formulations Duration of Effect Peds/Adult

Adderall® (mixed amphetamine salts) 4-6 hours -/-

Adderall XR® (mixed amphetamine salts XR) ~12 hours +/+

Dexedrine® Spansule (dextroamphetamine) 6-8 hours +/-

VyvanseTM (lisdexamfetamine) ~12 hours +/+

Methylphenidate-based Formulations

Concerta® (MPH) ~12 hours +/+

Daytrana® (MPH patch) ~12 hours (worn for 9) +/-

Focalin® (dexMPH capsule) ~5 hours +/-

Focalin® XR (dexMPH XR capsule) 10-12 hours +/+

Metadate® CD (MPH controlled-release capsule) 8-10 hours +/-

Ritalin® (MPH) ~4 hours +/-

Ritalin® LA (MPH XR capsule) 8-10 hours +/-

Quillivant XRTM (MPH XR liquid) ~12 hours +/-

Nonstimulants

Strattera® (atomoxetine) 8-24 hours +/+

Intuniv® (guanfacine XR) ~12 hours +/-

Kapvay® (clonidine XR) ~12 hours +/-

Recent FDA Approved Medications

• Evekeo® (AMP racemic)

• Aptensio XR® (MPH)

• Oral Disintegrating

– Adzenys XR-ODT® (MPH)

• Liquids

– ProCentra® (AMP)

– Dyanavel XR® (AMP)

– Methylin® (MPH)

• Chewable

– QuillChew® ER (MPH)

AMPH = amphetamine; MPH = methylphenidate.

US Food and Drug Administration.

www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

Pharmacologic Treatments for ADHD

Primary Agents

Stimulants

Atomoxetine

adrenergic agonists

Secondary Agents

Bupropion

Modafanil

Tricyclic antidepressants

Adjunctive agents

Mood stabilizers

Anxiolytics

SSRIs

Neuroleptics

Combination regimens

• Psychostimulants first-line agents

– Multiple FDA approved agents (adult)

• Long-acting preparations preferable

– Better adherence, treat through the day

– Minimize potential for misuse or abuse

• May be useful to orient according to weight

– eg, 1–1.5 mg/kg/day MPH ~ 70–100 mg/day;

– 0.5–1.0 mg/kg/day MAS

Psychostimulants: Overview

MAS = mixed amphetamine salts.

Canadian Attention Deficit Hyperactivity Disorder Resource Alliance (CADDRA): Canadian ADHD

Practice Guidelines, Third Edition, Toronto ON; CADDRA, 2011.

www.caddra.ca/pdfs/caddraGuidelines2011.pdf. Accessed September 8, 2016.

• Adverse effects are generally well tolerated

– Reduced appetite and consequent weight loss

– Abdominal pain, nausea, constipation

– Difficulty falling asleep

– Mild increase in heart rate and blood pressure

– Jitteriness, jumpiness

– Motor tics

– Dysphoria, moodiness, irritability

– Rebound effects

Psychostimulants: Overview

Pliszka SR. J Am Acad Child Adolesc Psychiatry. 2006;46(7):894-921. Daughton J, et al. In: Martin A, et

al (Eds). Pediatric Psychopharmacology: Principles and Practice. Second Edition. New York, NY:

Oxford Press; 2011.

Methylphenidate

Blocks reuptake of transmitter into pre-synaptic terminal

Amphetamine

Releases transmitter from vesicle

Blocks reuptake of transmitter into vesicle

Blocks reuptake of transmitter into pre-synaptic terminal

Induces release of transmitter when it is absorbed into the pre-synaptic terminal

D- form acts on DA neurons; L-form acts on NE neurons

Summary of

Stimulant Action

Methylphenidate Activates Dorsal

Anterior Mid-cingulate Cortex

Bush et al. Arch Gen Psychiatry. 2008:65:102-114.

0

0.5

1

1.5

2

2.5

Baseline 6 Weeks

OROS MPH

Placebo

• fMRI at baseline and again at week 6

• OROS MPH group showed higher daMCC activation at 6 weeks vs placebo

• N=21 adults with ADHD; dosing to 1.3 mg/kg/day OROS MPH or placebo

P = 0.02 vs PBO

• Trust your patient – if you are concerned about potential

substance abuse or misuse do not prescribe stimulants

• Explain the principle of a “medication trial” and the need

for patient to keep a medication response log

• Up to 30% of patients respond better to either AMPH or

MPH, while 30% respond equally well to both

• Start with MPH at varying doses – once the optimal dose

is determined, can adjust the schedule with longer acting

preparations

• If MPH is not optimally effective, switch to AMPH and

determine responses to variable doses

Psychostimulant Use Guidelines

Daughton J, et al. In: Martin A, et al (Eds). Pediatric Psychopharmacology: Principles and Practice. Second

Edition. New York, NY: Oxford Press; 2011. Prince JB, et al. In: Barkley RA (Ed). Attention-Deficit

Hyperactivity Disorder: A Handbook for Diagnosis and Treatment. New York, NY: Guilford Press; 2015.

16%Responded

better to MPH than

AMPH28%

Responded

better to AMPH

than MPH

1) Mattingly G, Wilson J, Rostain A. A clinician’s guide to ADHD treatment options. Postgraduate Medicine, 2017

2) Arnold LE. J Attention Disorders 2000;3:200-11.

▪

Methylphenidate vs Amphetamine1,2

41%

Responded to

both AMPH and MPH

(‘double responders’)

13%

Did not respond to either medication

Most patients (n=152/174; 87%) responded to either

methylphenidate and/or amphetamine1

In Pediatric Studies

• Some patients report a need for additional medication at

specific times

– Stimulant dose may be increased when there is a need

for increased focus

– Patients who need evening treatment may benefit from

• Combination of extended-release and immediate-

release stimulant

• Atomoxetine or a combination of atomoxetine and a

daytime stimulant

Adjusting Medication

Adler LA, et al. Curr Psychiatry Rep. 2006;8(5):409-415. Hazell P. CNS Drugs. 2007;21(1):37-46.

Extended-release stimulants, lisdexamfetamine, MPH transdermal system

Atomoxetine, bupropion, tricyclic antidepressant

0800 1200 1600 2000 2400Time (h)

Combination treatment: long-acting stimulant and nonstimulant

Long-acting stimulant Immediate-release stimulant

Morning Evening

Stimulants may be prescribed in combination with a nonstimulant to

ensure coverage into the evening

Long-acting stimulant

Long-acting stimulant (1/2 AM dose)

Adapted from Hazell P. CNS Drugs. 2007;21(1):37-46.

Medication Dosing Options

• Patience

• Usually improves after a few days

• Eat a big breakfast and dinner

• Absorption ?

• Adjust timing of medication

• Adjust timing of meals

• Encourage snacks (including bedtime)

• Consider changing dose, regimen, or medication

Managing Common Side Effects:

Appetite Loss

Pliszka SR. J Am Acad Child Adolesc Psychiatry. 2006;46(7):894-921. Daughton J, et al. In: Martin A, et

al (Eds). Pediatric Psychopharmacology: Principles and Practice. Second Edition. New York, NY:

Oxford Press; 2011.

• For stimulant-induced insomnia

– Melatonin

– Clonidine, guanfacine

– Trazodone

– Mirtazapine

– Antihistamine (acutely)

– Tricyclic antidepressant

Managing Common Side Effects:

Insomnia

The use of these medications for this indication is off-label.

Pliszka S; AACAP Work Group on Quality Issues. J Am Acad Child Adolesc Psychiatry.

2007;46(7):894-921. Weiss MD, et al. J Am Acad Child Adolesc Psychiatry. 2006;45(5):512-519. Tjon

Pian Gi CV, et al. Eur J Pediatr. 2003;162(7-8):554-555. Kratochvil CJ, et al. J Am Acad Child Adolesc

Psychiatry. 2005;44(5):499-501.

• Direct vs indirect effect

– Medication vs hunger

– Determine time of day

• Patience

– Often resolve after the first few days of treatment

• Lower daily dose

• Try a different medication

Managing Common Side Effects:

Stomachaches

• Stimulant-exacerbated tics

– Examine severity of tics

– Re-challenge to examine if tics are stimulant-induced

– Switch to atomoxetine, α2-adrenergic agonists, or

atypical or typical antipsychotics (pimozide – FDA

approved)

– Combination therapies

• Atomoxetine plus stimulant

• Clonidine plus methylphenidate (3 studies)

• Atypical plus other treatment

Managing Common Side Effects: Tics

The use of these medications for this indication is off-label.

Pliszka S; AACAP Work Group on Quality Issues. J Am Acad Child Adolesc Psychiatry. 2007;46(7):894-921.

Palumbo DR, et al. J Am Acad Child Adolesc Psychiatry. 2008;47(2):180-188. Hazell PL, et al. J Am Acad Child

Adolesc Psychiatry. 2003;42(8):886-94. The Tourette’s Syndrome Study Group. Neurology. 2002;58(4):527-536.

• Current FDA language stipulates that sudden death can

occur at usual doses in patients with a pre-existing

structural cardiac abnormality or other serious heart

problem

• Careful history of heart-related problems must be

obtained and documented before starting stimulant

medication

Recent Concerns about Stimulants

and Cardiac Disease

Important screening questions:

• Patient-related factors: history of murmur, syncope, or

other CVD illness

• Family-related factors: history of early or sudden cardiac

death

• Other health considerations that increase CVD risk

– Smoking history, caffeine use, over-the-counter

sympathomimetic medications

• If cardiac screening is negative, EKG is NOT required

prior to initiating treatment

Screening Adults with ADHD

for Cardiovascular Safety

CVD = cardiovascular disease; EKG = electrocardiogram.

• Spontaneous syncope

• Exercise-induced syncope

• Exercise-induced chest pain

• Sudden death in family member under age 30

• History of cardiac abnormalities (structural or electrical) in

self or family members

• EKGs are not routinely required

Clinical Assessment of Cardiac Risk

Cava JR, et al. Pediatr Clin N Am. 2004;51(5):1401-1420. Paterick TE, et al. JAMA. 2005;294(23):3011-

3018.

• Possible causes for concern

– History of palpitations or arrhythmia

– Recent myocardial infarction

– Syncopal episodes, dizziness

– Multiple risk factors, such as smoking, high body mass

index, hypertension, metabolic syndrome

• Maximize cardiac medications and address risk factors;

patients with ADHD may find it difficult to make necessary

lifestyle changes

• Introduce ADHD medication at a low dose and titrate up

slowly

• Monitor symptoms, blood pressure/heart rate regularly

• Longer term effects of ADHD medications on cardiovascular

status unclear

Treating ADHD Patients with

Heart Disease

Gutgesell H, et al. Circulation. 1999;99(7):979-982.

• Evaluate blood pressure/pulse prior to initiating ADHD

treatment

• Address hypertension before treating ADHD

• Once hypertension is controlled, treat ADHD and monitor

blood pressure

• Stimulants have a clinically insignificant effect on blood

pressure in treated, normotensive adults

Treating ADHD Patients with

Hypertension

Wilens TE, et al. J Clin Psychiatry. 2006;67(5):696-702. Pliszka S; AACAP Work Group on Quality

Issues. J Am Acad Child Adolesc Psychiatry. 2007;46(7):894-921. Nutt DJ, et al. J Psychopharmacol.

2007;21(1):10-41. Canadian Attention Deficit Hyperactivity Disorder Resource Alliance (CADDRA):

Canadian ADHD Practice Guidelines, Third Edition, Toronto ON; CADDRA, 2011.

www.caddra.ca/pdfs/caddraGuidelines2011.pdf. Accessed September 8, 2016.

Pharmacologic Treatments for ADHD

Primary Agents

Stimulants

Atomoxetine

adrenergic agonists

Secondary Agents

Bupropion

Modafanil

Tricyclic antidepressants

Adjunctive agents

Mood stabilizers

Anxiolytics

SSRIs

Neuroleptics

Combination regimens

Atomoxetine: Mechanism of Action

NA = Noradrenaline Bymaster FP, et al. Neuropsychopharmacology. 2002;27(5):699-711. Arnsten AF, et al.

Pharmacol Biochem Behav. 2011;99(2):211-216.

• Posterior Attention System

– Increased NE

• Improved alerting and orienting

• Reduced “startle” and over-reactivity

• Anterior Attention System

– Increased NE and DA

• Improved focusing

• Improved executive functioning

Atomoxetine: Mechanism of Action

DA = dopamine; NE = norepinephrine.

Bymaster FP, et al. Neuropsychopharmacology. 2002;27(5):699-711. Arnsten AF, et al. Pharmacol

Biochem Behav. 2011;99(2):211-216.

• Downstream increase in DA activity in the prefrontal

cortex

– Consistent with improved executive functioning

• No increase in DA activity in the nucleus accumbens

– Not associated with abuse liability

• No increase in DA in the striatum

– Not associated with motor activity (tics)

Atomoxetine: Effects on Dopamine

Bymaster FP, et al. Neuropsychopharmacology. 2002;27(5):699-711. Arnsten AF, et al. Pharmacol

Biochem Behav. 2011;99(2):211-216.

• Dizziness, high blood pressure

• Headache, irritability, nervousness

• Abdominal pain, nausea, vomiting, loss of appetite,

weight loss

• Dry mouth, constipation, urinary hesitancy

• Decreased sexual desire

• Very slight chance of hepatic insufficiency

Atomoxetine: Side Effects

US Food and Drug Administration. www.accessdata.fda.gov/scripts/cder/drugsatfda/. Michelson D, et

al. Biol Psychiatry. 2003;53(2):112-120.

Pharmacologic Treatments for ADHD

Primary Agents

Stimulants

Atomoxetine

adrenergic agonists

Secondary Agents

Bupropion

Modafanil

Tricyclic antidepressants

Adjunctive agents

Mood stabilizers

Anxiolytics

SSRIs

Neuroleptics

Combination regimens

• Mechanism of action: partial agonist of NE

• Decreases erratic activity of locus coeruleus

• Increases neurotransmission in prefrontal cortex

• First introduced as anti-hypertensive agents

• Helpful for patients who are highly aroused, impulsive,

emotionally labile, irritable and explosive

• Reduces anxiety, defiance, and aggression

• Useful in controlling tics

α2-Adrenergic Agonists(Clonidine, Guanfacine)

US Food and Drug Administration. www.accessdata.fda.gov/scripts/cder/drugsatfda/. Newcorn JH, et

al. In: Martin A, et al (Eds). Pediatric Psychopharmacology: Principles and Practice. Second Edition.

New York, NY: Oxford Press; 2011. Prince JB, et al. In: Barkley RA (Ed). Attention-Deficit Hyperactivity

Disorder: A Handbook for Diagnosis and Treatment. New York, NY: Guilford Press; 2015.

Guanfacine: How does it work ?

HCN = hyperpolarization-activated cyclic nucleotide-gated channels

Stimulation of α2A-adrenergic

receptors

• Inhibits cAMP production which closes

nearby HCN channels

• Increases pyramidal excitability

• Strengthens connectivity of DLPFC

microcircuits

• Reduces distractibility and improves working

memory in monkeys and humans

• Enhances DLPFC perfusion in monkeys

during working memory tasks

• Sedation, fatigue

• Dizziness

• Dry mouth, indigestion, nausea

• Nightmares, insomnia

• Anxiety, depression

• Hypertensive crisis with sudden discontinuation

α2-Adrenergic Agonists: Side Effects(Clonidine, Guanfacine)

US Food and Drug Administration. www.accessdata.fda.gov/scripts/cder/drugsatfda/. Newcorn JH, et

al. In: Martin A, et al (Eds). Pediatric Psychopharmacology: Principles and Practice. Second Edition.

New York, NY: Oxford Press; 2011. Prince JB, et al. In: Barkley RA (Ed). Attention-Deficit Hyperactivity

Disorder: A Handbook for Diagnosis and Treatment. New York, NY: Guilford Press; 2015.

• Start with ½ tablet at bedtime (0.05 mg clonidine, 0.5 mg

guanfacine)

• Add ½ tablet in the morning as tolerated (5–15 days)

• Continue incremental increases by ½ tablet q weekly

• Titrate upwards as tolerated to maximum of 0.4/4 mg daily

• Extended-release preparation is approved for children

and adolescents; need to increase dose by 33%

α2-Adrenergic Agonists: Dosing(Clonidine, Guanfacine)

US Food and Drug Administration. www.accessdata.fda.gov/scripts/cder/drugsatfda/. Newcorn JH, et

al. In: Martin A, et al (Eds). Pediatric Psychopharmacology: Principles and Practice. Second Edition.

New York, NY: Oxford Press; 2011. Prince JB, et al. In: Barkley RA (Ed). Attention-Deficit Hyperactivity

Disorder: A Handbook for Diagnosis and Treatment. New York, NY: Guilford Press; 2015.

• Stimulants may be combined with atomoxetine when

patients do not respond adequately to either medication

alone

• Clinical trials have been conducted on the following

combination therapies:

– Atomoxetine and MPH

– Clonidine and MPH

– Guanfacine and MPH

Combining Agents

Wilens TE, et al. Presented at: 159th Annual Meeting of the American Psychiatric Association; May 2006;

Toronto, Canada. Palumbo DR, et al. J Am Acad Child Adolesc Psychiatry. 2008;47(2):180-188. Hazell PL, et

al. J Am Acad Child Adolesc Psychiatry. 2003;42(8):886-94. The Tourette’s Syndrome Study Group.

Neurology. 2002;58(4):527-536. Cohen LG, et al. Pharmacotherapy. 1999;19(6):746-752. Rapport MD, et al. J

Am Acad Child Adolesc Psychiatry. 1993;32(2):333-342.

• Newly diagnosed patients may take 2 to 3 months to be

stabilized on medication

• Adjust the dose or consider switching medications

• Ensure that comorbid conditions are treated

• Try combination treatment

• Manage side effects

• Reconsider the diagnosis and possible presence of

confounding comorbid psychiatric conditions

Managing Inadequate Response

Pliszka S; AACAP Work Group on Quality Issues. J Am Acad Child Adolesc Psychiatry.

2007;46(7):894-921.

• Dasotraline - DNRI

• Mazindol CR - TRI + Orexin

• Fasoracetam NFC1 - mGluR activator*

• Centanafadine - TRI

• Viloxazine – NRI

*gene mutation predicts response

Non-Stimulants in Development

Dasotraline Pediatric ADHD Study

Goldman R, et al. APSARD, 2017

Dasotraline for ADHD in Adults:

RCT Proof of Concept TrialInhibits Dopamine and Norepinephrine Transporters more than Serotonin

• N=331 with post baseline

efficacy assessment

• Discontinuation due to

adverse events: 10.3% (4

mg), 27.8% (8 mg), and

1.8% (placebo)

Koblan et al., Neuropsychopharm, 2015

Mazindole-CR for Adult ADHD:

TRI Plus Orexin Modulation

Comparative Analysis of 9-Gene/CNTN4

Subset from the SAGA Trial: ∆ in ADHD RSSAGA

Change in ADHD-RS (N=96)

rostain@pennmedicine.upenn.edu www.med.upenn.edu/add

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