Update on Treating ADHD

Home , Atomoxetine, Centanafadine, Dasotraline, Guanfacine

ASCP Annual Meeting Miami Beach, FL May 31, 2018

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 Disclosures

• 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 Learning Objectives

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 Neurobiology of ADHD

Symptoms

Predominantly Predominantly Combined ADHD inattentive hyperactive–impulsive

Basic Executive Function Motivation Working Behavioral Delay Reinforcement Processes memory inhibition aversion

PFC Basal ganglia Cerebellum Neural Mechanisms Noradrenalin Dopamine Serotonin

Genes DBH HTR1B DAT1 D4 D5 SER T SNAP-25

PFC = prefrontal cortex. Tripp G, et al. Neuropharmacology. 2009;57(7-8):579-589. Behavioral disinhibition, emotional ability Full expression of Inattention persists and hyperactive– and emergence of diagnosis in preschool ADHD, psychiatric impulsive symptoms wane years comorbidity, school failure, peer rejection Prodrome: hyperactivity; and speech, and neurocognitive Substance abuse, low self-esteem language and motor coordination dysfunction and social disability

problems Smoking initiation Smoking

In utero Childhood Adolescence Adulthood

Genetic Psychosocial influences, chaotic family environments, peer influences and mismatch with predisposition school and/or work environments

Different genetic risk factors affect the course of ADHD at different stages of the lifespan Fetal exposures and epigenetic changes Frontal–subcortical–cerebellar dysfunction via structural and functional brain abnormalities and downregulation of catecholamine systems that regulate attention, reward, executive control and motor functions

Persistence of cortical thickness, Clinical Progression Etiology Pathophysiology default-mode network and white matter tract abnormalities

Faraone SV, et al. Nat Rev Dis Primers. 2015;1:15020. 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. 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, et al. J Am Acad Child Adolesc Psychiatry. 2012;51(4):356-367. The Prefrontal Cortex Requires a Proper Level of Catecholamines for Optimal Function

Guided attention and responses Focused, organized and flexible (eg, Optimally treated ADHD)

NE a2A Moderate D1

Unguided attention / responses Misguided attention / responses Distracted, poor impulse control Mental inflexibility, stimulus bound (eg, Untreated ADHD) Too little NE a1, b1 (eg, Excessive dose of stimulant) a2A/D1 Excess D1

Drowsy Alert Stressed Increasing Levels of Catecholamine Release

Arnsten AF. J Pediatr. 2009;154(5):I-S43. Treatment Modalities for ADHD

Educational / Workplace Interventions

Medical Psychosocial Interventions Interventions

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

Primary Agents Adjunctive agents  Stimulants  Mood stabilizers  Atomoxetine  Anxiolytics   adrenergic agonists  SSRIs Secondary Agents  Neuroleptics  Bupropion  Combination regimens  Modafanil  Tricyclic antidepressants Child and Adolescent ADHD: Effect Sizes* Medication Effect Size Amphetamine 0.92 Methylphenidate 0.80 Atomoxetine 0.73 Modafinil 0.49 Bupropion 0.32

29 controlled studies; N = 4465 children and adolescents *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. Faraone SV, Spencer TJ. Presented at APA Annual Meeting, Toronto, 2006. 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

norepinephrine atomoxetine Pharmacologic Treatments Approved for ADHD

Amphetamine-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 +/- 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. Recent FDA Approved Medications

• Evekeo® (AMP racemic) • Liquids • Aptensio XR® (MPH) – ProCentra® (AMP) – Dyanavel XR® (AMP) – Methylin® (MPH) • Oral Disintegrating – Adzenys XR-ODT® (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

• 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

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. Psychostimulants: Overview

• 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

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. Summary of Stimulant Action

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 Methylphenidate Activates Dorsal Anterior Mid-cingulate Cortex

2.5

OROS MPH P = 0.02 vs PBO 2 Placebo

1.5

0.5

0 Baseline 6 Weeks

• 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

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

• 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

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. Methylphenidate vs Amphetamine1,2 In Pediatric Studies

Most patients (n=152/174; 87%) responded to either methylphenidate and/or amphetamine1

Responded Responded 16% better to AMPH better to MPH than 41% 28% AMPH than MPH Responded to both AMPH and MPH (‘double responders’)

13% Did not respond to either medication

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. ▪ Adjusting Medication

• 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

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

Morning Evening

Long-acting stimulant Immediate-release stimulant

Extended-release stimulants, lisdexamfetamine, MPH transdermal system

Atomoxetine, bupropion, tricyclic antidepressant

Combination treatment: long-acting stimulant and nonstimulant

Long-acting stimulant Long-acting stimulant (1/2 AM dose) Time (h) 0800 1200 1600 2000 2400

Stimulants may be prescribed in combination with a nonstimulant to ensure coverage into the evening

Adapted from Hazell P. CNS Drugs. 2007;21(1):37-46. Managing Common Side Effects: Appetite Loss

• 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

• For stimulant-induced insomnia – Melatonin – Clonidine, guanfacine – Trazodone – Mirtazapine – Antihistamine (acutely) – Tricyclic antidepressant

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. Managing Common Side Effects: Stomachaches

• 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: Tics

• 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

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. Recent Concerns about Stimulants and Cardiac Disease

• 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 Screening Adults with ADHD for Cardiovascular Safety

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

CVD = cardiovascular disease; EKG = electrocardiogram. Clinical Assessment of Cardiac Risk

• 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

Cava JR, et al. Pediatr Clin N Am. 2004;51(5):1401-1420. Paterick TE, et al. JAMA. 2005;294(23):3011- 3018. Treating ADHD Patients with Heart Disease • 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 Gutgesell H, et al. Circulation. 1999;99(7):979-982. Treating ADHD Patients with Hypertension

• 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

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

NA = Noradrenaline Bymaster FP, et al. Neuropsychopharmacology. 2002;27(5):699-711. Arnsten AF, et al. Pharmacol Biochem Behav. 2011;99(2):211-216. Atomoxetine: Mechanism of Action

• 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

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. Atomoxetine: Effects on Dopamine

• 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)

Bymaster FP, et al. Neuropsychopharmacology. 2002;27(5):699-711. Arnsten AF, et al. Pharmacol Biochem Behav. 2011;99(2):211-216. Atomoxetine: Side Effects

• 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

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

• 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

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 ?

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

HCN = hyperpolarization-activated cyclic nucleotide-gated channels α2-Adrenergic Agonists: Side Effects (Clonidine, Guanfacine)

• Sedation, fatigue • Dizziness • Dry mouth, indigestion, nausea • Nightmares, insomnia • Anxiety, depression • Hypertensive crisis with sudden discontinuation

• 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%

• 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

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. Managing Inadequate Response

• 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

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

• Dasotraline - DNRI • Mazindol CR - TRI + Orexin • Fasoracetam NFC1 - mGluR activator* • Centanafadine - TRI • Viloxazine – NRI

*gene mutation predicts response Dasotraline Pediatric ADHD Study

Goldman R, et al. APSARD, 2017 Dasotraline for ADHD in Adults: RCT Proof of Concept Trial Inhibits 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 RS

SAGA Change in ADHD-RS (N=96) THANK YOU!!

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