update on treating adhd...2018/06/04 · update on treating adhd anthony l. rostain, m.d., m.a...
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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)