Tackling the Toxic Remainder: Addressing Challenges and Enhancing Outcomes in Adult ADHD

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Tackling the Toxic Remainder: Addressing Challenges and Enhancing Outcomes in Adult ADHD Supported by an educational

Rakesh Jain, MD, MPH Clinical Professor Department of Psychiatry Texas Tech Health Sciences Center, School of Medicine

Carolina School of Medicine Greenville, South Carolina Faculty Charles L.

1 Tackling the Toxic Remainder: Addressing Challenges and Enhancing Outcomes in Adult ADHD Supported by an educational grant from Shire. Rakesh Jain, MD, MPH Clinical Professor Department of Psychiatry Texas Tech Health Sciences Center, School of Medicine Midland, Texas Vladimir Maletic, MD, MS Clinical Professor of Psychiatry and Behavioral Science University of South Carolina School of Medicine Greenville, South Carolina Faculty Charles L. Raison, MD Mary Sue and Mike Shannon Chair for Healthy Minds, Children & Families Professor, Human Development and Family Studies, School of Human Ecology Professor, Department of Psychiatry, School of Medicine and Public Health University of Wisconsin-Madison Madison, Wisconsin

2 Faculty Disclosure Dr. Rakesh Jain: Paid Speaker Addrenex, Alkermes, Allergan (Actavis/Forest), Lilly, Lundbeck, Merck, Neos Therapeutics, Otsuka, Pamlab, Pfizer, Rhodes Pharmaceuticals, Shionogi, Shire, Sunovion, Takeda, Tris Pharmaceuticals; Advisory Board Addrenex, Alkermes, Forum, Lilly, Lundbeck, Merck, Neos Therapeutics, Otsuka, Pamlab, Pfizer, Shionogi, Shire, Sunovion, Takeda; Research AstraZeneca, Allergan (Actavis/Forest), Lilly, Lundbeck, Otsuka, Pfizer, Shire, Takeda; Spouse: Consultant Lilly, Otsuka, Pamlab. Dr. Maletic: Consultant Eli Lilly and Company, FORUM Pharmaceuticals Inc., H. Lundbeck A/S, Merck & Co., Inc., Otsuka America Pharmaceutical, Inc., Sunovion Pharmaceuticals Inc., Supernus Pharmaceuticals, Inc., Takeda Pharmaceutical Company Limited, Teva Pharmaceutical Industries Ltd.; Speakers Bureau Allergan, H. Lundbeck A/S, Merck & Co., Inc., Otsuka America Pharmaceutical, Inc., Sunovion Pharmaceuticals Inc., Takeda Pharmaceutical Company Limited. Dr. Raison: Scientific Advisory Board Usona Institute. Disclosure The faculty have been informed of their responsibility to disclose to the audience if they will be discussing offlabel or investigational use(s) of drugs, products, and/or devices (any use not approved by the US Food and Drug Administration). The off-label use of bupropion, tricyclic antidepressants, and modafinil for the treatment of ADHD will be discussed. Applicable CME staff have no relationships to disclose relating to the subject matter of this activity. This activity has been independently reviewed for balance. Learning Objectives Optimize use of validated screening tools for the accurate and timely diagnosis of adult attention-deficit/ hyperactivity disorder (ADHD) Distinguish between ADHD and other potential comorbid psychiatric disorders that may mimic or mask its symptoms Outline the latest clinical data pertaining to novel stimulant formulations that provide efficacious ADHD treatment while offering greater safety, patient adherence, and abuse deterrence Translate to practice the latest evidence regarding ADHD treatment, overcoming barriers to stimulant use, and challenges regarding the dual management of coexisting disorders

3 Disclaimer The points of view expressed by Drs. Jain and Maletic during the debate sections may or may not reflect their actual views. Dr. Raison has no adult children. Matt s Father Tells His Story An All Too Common Case of Burying the Lead What Matt s Dad Says about Matt Basically a normal child until entering college Struggled to keep up with academic requirements of college classes, which caused development of clinical levels of depression and anxiety. Binge drinking in freshman year had become full-blown alcohol use disorder by beginning of sophomore year Withdrew from college in first semester of sophomore year Entered inpatient alcohol program and started on an SSRI Depression and anxiety symptoms remitted Upon re-entering school next semester, no recurrence of full major depression but re-developed clinically significant anxiety and continued to struggle with classes SSRI = selective serotonin reuptake inhibitor.

Oh, By the Way On closer questioning, parents were told by teachers in elementary school that Matt might have ADHD and suggested an evaluation Mom and dad believed that ADHD was a fad diagnosis that

4 Oh, By the Way On closer questioning, parents were told by teachers in elementary school that Matt might have ADHD and suggested an evaluation Mom and dad believed that ADHD was a fad diagnosis that pathologized normal childhood behavior and so elected not to have Matt evaluated Matt got in occasional trouble at school for misbehaving and occasional anger outbursts, but overall got through Mom very invested in Matt as an only child and held off on returning to work so that she could help Matt with his homework through high school ADHD = attention-deficit/hyperactivity disorder. ADHD: Not so different after all? Attention and/or Vigilance Working Memory Executive Function Episodic Memory 0 = essentially absent; 0/+ = poorly documented, ambiguous, mild and/or variable; + = consistently present but not pronounced; ++ = a common, marked characteristic; +++ = a core, severe and virtually universal characteristic of the disorder; M = cognitive domain specified in the MATRICS program; brackets around (symbols) = an intermediate magnitude of deficit. Millan MJ, et al. Nat Rev Drug Discov. 2011;11(2): Semantic Memory Visual Memory Verbal Memory Fear Extinction Processing Speed Procedural Memory Social Cognition (Theory of Mind) Major depression +(+) (+) 0/+? ++(+) + +(+) + Bipolar disorder ++(+) ? Schizophrenia +++ M +++ M +++ M (+) M +++ M M M +++ ASD (+) +(+) / ADHD / /+ OCD +++( ) +(+) /+ + 0/ /+ PTSD +++( ) +(+) +(+) (+) /+ 0 Panic disorder +++( ) + 0/+ + 0/+ 0/ GAD /+ 0 Parkinson s ++ ++(+) ? (+) +(+) disease Alzhemier s +(+) +(+) +(+) (+) 0? disease Language No Evidence That Prevalence of ADHD is Increasing When Rigorously Diagnosed Prevalence Estimate Prevalence Estimate North America Europe Oceania South America Asia Africa Middle East Year Year of Publication Estimates of ADHD prevalence are significantly variable Geographical location and year of study are not associated with variability of prevalence estimates No evidence to suggest an increase in prevalence of ADHD in children over last 30 years when standardized diagnostic procedures are followed Polanczyk GV, et al. Int J Epidemiol 2014;43(2):

DSM-5 Criteria for ADHD: Inattentive Symptoms (6/9 age < 17 years; 5/9 17 years) Are forgetful in daily activities Are easily distracted Lose things necessary for tasks Avoid tasks requiring

5 DSM-5 Criteria for ADHD: Inattentive Symptoms (6/9 age < 17 years; 5/9 17 years) Are forgetful in daily activities Are easily distracted Lose things necessary for tasks Avoid tasks requiring sustained mental effort Fail to give close attention to details Inattentive Symptoms/ Patients Often: Have difficulty sustaining attention Do not seem to listen Do not follow through on instructions Have difficulty organizing tasks or activities American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; DSM-5 Criteria for ADHD: Hyperactive/Impulsive Symptoms (6/9 age < 17 years; 5/9 17 years) Interrupt or intrude on others Have difficulty awaiting turn Are easily distracted Blurt out answers before questions are completed Talk excessively Hyperactive /Impulsive Symptoms/ Patients Often: Fidget with hands or feet or squirms in seat Leave seat in classroom inappropriately Run about or climb excessively (or internal restlessness) Have difficulty playing quietly Are on the go or acts as if driven by a motor Criterion items now include examples specific to adult presentation highlighting lifespan (eg, paying bills, keeping appointments) American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; Prevalence and Persistence of ADHD Prevalence 18- to 44-year-olds: 4.4% Percentage of adults with ADHD who received treatment within the previous 12 months: 11% High degree of psychiatric comorbidities, eg, major depression, anxiety disorders, bipolar disorder, SUD, etc. Impairment in multiple domains (home, social, school, work) Approximately 15% of children with a childhood diagnosis show persistence across childhood and adolescence and still meet diagnostic criteria for ADHD in adulthood, while only approximately 35% achieve full remission. SUD = substance use disorder. Froehlich TE, et al. Arch Pediatr Adolesc Med. 2007;161(9): Kessler RC, et al. Am J Psychiatry. 2006;163(4): Wilens TE, et al. Postgrad Med. 2010;122(5): Riglin et al, 2016, JAMA Psychiatry ;73(12):

Same Problem, Different Manifestations Inattention Disorganized Forgetfulness affects work/ home/financial/personal life Hyperactivity Impulsivity Fidgets or squirms in seat Blurts out answers Can t

Course of ADHD may not be as we believed? Moffit et al 2015: 1,037 individuals born in Dunedin, New Zealand, in 1972 and 1973 and followed to age 38, with 95% retention.

Agnew-Blais et al 2016: birth cohort of 2232 twins born in England and Wales from 1994 to 1995. Among 166 individuals with adult ADHD, 112 (67.

6 Same Problem, Different Manifestations Inattention Disorganized Forgetfulness affects work/ home/financial/personal life Hyperactivity Impulsivity Fidgets or squirms in seat Blurts out answers Can t sit still in business meetings, restlessness Excessive spending Polanczyk G, et al. Curr Opin Psychiatry. 2007;20(4): Adler LA. J Clin Psychiatry. 2004;65 Suppl 3:8-11. Course of ADHD may not be as we believed? Moffit et al 2015: 1,037 individuals born in Dunedin, New Zealand, in 1972 and 1973 and followed to age 38, with 95% retention. Unexpectedly, the childhood and adult ADHD groups had virtually nonoverlapping sets; 90% of adult ADHD cases lacked a history of childhood ADHD. Agnew-Blais et al 2016: birth cohort of 2232 twins born in England and Wales from 1994 to Among 166 individuals with adult ADHD, 112 (67.5%) did not meet criteria for ADHD at any assessment in childhood. Caye et al, 2016: PelotasBirthCohort Study, including 5249 individuals born in Pelotas, Brazil, in They were followed up to 18 to 19 years of age, with 81.3% retention. Only 60 young adults (12.6%) with ADHD had the disorder in childhood, (87% had no childhood ADHD). Moffit et al., 2015, Am J Psychiatry; 172: , Agnew-Blais et al.,2016, JAMA Psychiatry.;73(7): , Caye et al., 2016, JAMA Psychiatry Determinants of ADHD persistence Researchers collected data on children from Avon, England, including 9757 with data on symptoms of ADHD at multiple time points, since Data analysis was conducted in The proportion of children with multimorbidity was highest in those in the persistent trajectory (42.5%; 95% CI, 33.9%-51.1%; P <.001) Riglin et al, 2016, JAMA Psychiatry ;73(12):

ADHD trajectories are diverse Probability of Being in the High-Scoring Range for Attention-Deficit/Hyperactivity Disorder Symptoms by Latent Class.

inattentive symptoms (score range, 0-10). Riglin et al, 2016, JAMA Psychiatry ;73(12):1285-1292 ADHD Doesn t Live Alone: Multiple Comorbidities are the Norm Panic Disorder 3.

7 ADHD trajectories are diverse Probability of Being in the High-Scoring Range for Attention-Deficit/Hyperactivity Disorder Symptoms by Latent Class. The primary outcome was ADHD symptoms assessed repeat- edly across time using the parent-rated 5-item Strengths and Difficulties Questionnaire (SDQ)26 subscale designed to mea- sure hyperactive and inattentive symptoms (score range, 0-10). Riglin et al, 2016, JAMA Psychiatry ;73(12): ADHD Doesn t Live Alone: Multiple Comorbidities are the Norm Panic Disorder 3.0* Any Substance Use Disorder 3.0* Specific Phobias 2.8* Adult ADHD Comorbidities Major Depression 2.7* OCD 1.5 Bipolar Disorder 7.4* GAD 3.2* Drug Dependence 7.9* PTSD 3.9* Social Phobias 4.9* Odds Ratio (95% CI). *P <.05. GAD = generalized anxiety disorder; NCS-R = National Comorbidity Survey Replication; OCD = obsessive-compulsive disorder; PTSD = posttraumatic stress disorder. Kessler RC, et al. Am J Psychiatry. 2006;163(4): Undiagnosed Adult ADHD Comes at a High Price in Terms of Impairment 35% 30% Non-ADHD Controls (n = 199) Undiagnosed ADHD (n = 752) P <.05 Undiagnosed ADHD 25% 20% 15% 10% P <.001 P <.01 P <.05 5% 0% Post-College Degree Unemployed Able SL, et al. Psychol Med. 2007;37(1): Traffic Citation (past 5 yrs) Problem Drinking

9 million person-years), 5580 cohort members died Mortality risk ration (MRR) was 4.25 (3.05 5.78) for those aged 18 years or older MRR was higher in girls and women (2.85, 1.

8 ADHD can be life threatening Danish national registers, followed up 1.92 million individuals, including with ADHD, from their first birthday through to 2013 During follow-up (24.9 million person-years), 5580 cohort members died Mortality risk ration (MRR) was 4.25 ( ) for those aged 18 years or older MRR was higher in girls and women (2.85, ) than in boys and men (1.27, ). Dalsgaard et al, 2015, Lancet, 385 (14): Matt s Dad Asks Any way we could get a sense of whether Matt has Adult ADHD? Adult ADHD Self-Report Scale (ASRS-v1.1) How to Use Patients check 1 of the 5 boxes in response to each of the 6 questions. Kessler RC, et al. Psychol Med. 2005;35(2):

Adult ADHD Self-Report Scale (ASRS-v1.1) How to Score If 4 marks appear in the darkly shaded boxes within the questionnaire, the patient has symptoms highly consistent with ADHD in adults.

What Matt s Dad Says When We Meet Again 6 Months Later Matt taken to see family physician who dismisses adult ADHD as a made up disorder Matt continued to struggle with anxiety and class assignments

and is started on extended-release methylphenidate, while continuing his SSRI Ability to complete school assignments improves dramatically and anxiety is reduced All is well except for Matt s

9 Adult ADHD Self-Report Scale (ASRS-v1.1) How to Score If 4 marks appear in the darkly shaded boxes within the questionnaire, the patient has symptoms highly consistent with ADHD in adults. Kessler RC, et al. Psychol Med. 2005;35(2): What Matt s Dad Says When We Meet Again 6 Months Later Matt taken to see family physician who dismisses adult ADHD as a made up disorder Matt continued to struggle with anxiety and class assignments for 3 months, finally prompting parents to get him in to see a child psychiatrist with experience in adult patients Based on childhood history and current symptoms, Matt is diagnosed with adult ADHD and is started on extended-release methylphenidate, while continuing his SSRI Ability to complete school assignments improves dramatically and anxiety is reduced All is well except for Matt s struggle to perform on his evening waiter job that brings him extra spending money Why Adult ADHD Needs Coverage across All Waking Hours Go to bed on time Plan logistics for next day Balance checkbook Sleep soundly Wake up Interact with significant other Help kids with homework Finish work accurately & on time Drive carefully to home Organize kids for school Organize themselves for work Drive carefully to work Pay attention at work

Common Unmet Needs in Adults with ADHD No coverage of symptoms in evening/ late evening/ before bedtime Negative impact on sleep

that Matt is being fully adherent with his medications.

increasing the dose of his long-acting methylphenidate If not sufficient, consider switching to another class of agent with a

(long-/short-acting) Dexedrine Amphetamine (long-/short-acting) Atomoxetine Alpha-agonists Guanfacine XR Clonidine XR Guan XR /

10 Common Unmet Needs in Adults with ADHD No coverage of symptoms in evening/ late evening/ before bedtime Negative impact on sleep Rebound symptoms Potency of intervention not sufficient Onset of action is too slow Friendly Suggestions for Matt s Dad Ensure that Matt is being fully adherent with his medications. Confirm ongoing abstinence from alcohol and no use of drugs of abuse that might impact his functioning late in the day Consider increasing the dose of his long-acting methylphenidate If not sufficient, consider switching to another class of agent with a long half-life for prolonged symptom benefit Pharmacologic Treatment Options for ADHD Stimulants Methylphenidate (long-/short-acting) Dexedrine Amphetamine (long-/short-acting) Atomoxetine Alpha-agonists Guanfacine XR Clonidine XR Guan XR / Clon XR + stimulants Antidepressants Bupropion Tricyclics Modafinil Combinations FDA Approved (all in Peds, some in Adults) FDA Approved FDA Approved (Peds only) Not FDA Approved Wilens TE, et al. Postgrad Med. 2010;122(5):

11 NNT for Each Drug ABT-418 Atomoxetine Bupropion SR Bupropion XL LDX MAS MAS-XR MPH Modafinil OROS MPH Dextroamphetamine d-mph-er Short-Acting Stimulant Long-Acting Stimulant Nonstimulant Number Needed to Treat d-mph-er = dexmethylphenidate extended release; LDX = lisdexamfetamine dimesylate; MAS = mixed amphetamine salts; MAS-XR = mixed amphetamine salts extended release; MPH = methylphenidate; OROS MPH = osmotic-release oral system methylphenidate; SR = sustained release; XL = extended release. Faraone SV, et al. J Clin Psychiatry. 2010;71(6): Current and Investigational Methylphenidate Medications Jain R, et al. Prim Care Companion CNS Disord. 2016;18(4). Current and Investigational Amphetamine Medications Jain R, et al. Prim Care Companion CNS Disord. 2016;18(4).

12 Current and Investigational Non-stimulant Medications Jain R, et al. Prim Care Companion CNS Disord. 2016;18(4). Formulations of Methylphenidate-Based ADHD Medications and Potential Administration Restrictions Jain R, et al. Postgrad Med. 2016;128(7): Formulations of Amphetamine-Based ADHD Medications and Potential Administration Restrictions Jain R, et al. Postgrad Med. 2016;128(7):

ADHD Medications are Not Associated with Adverse Cardiovascular Outcomes in Adults Relevant Point: Stimulant use in this study was not associated with an increased risk of serious cardiovascular

Matt s Dad Comes for One More Piece of Advice After last discussion, Matt s dad confronted Matt about adherence and Matt admitted to missing his medicine on some days Adherence improved and symptoms

13 ADHD Medications are Not Associated with Adverse Cardiovascular Outcomes in Adults Relevant Point: Stimulant use in this study was not associated with an increased risk of serious cardiovascular events Habel LA, et al. JAMA. 2011;306(24): Matt s Dad Comes for One More Piece of Advice After last discussion, Matt s dad confronted Matt about adherence and Matt admitted to missing his medicine on some days Adherence improved and symptoms improved, but still difficulty with late-in-the-day loss of medication so psychiatrist switched agents Matt doing better, but now really wants to get his life in shape, wants to know what else he can do to help manage his ADHD Dad notes that Matt is no longer clinically depressed or anxious, but still has a hard time handling stress and is unrealistically hard on himself and prone to shame and giving up too easily when confronting difficulties Adult ADHD is Far More Than Inattention and Impulsivity Maladaptive Schemata d 21 =.043*** Perceived Stress a 1 =.975*** a 2 =.062*** b 1 =.019 b 2 =.709*** ADHD Symptoms c =.054* N = 204; *P <.05, **P <.01, ***P <.001 Well-Being Indirect effect 1 = a 1 b 1 ADHD symptoms Maladaptive schemata Well-being Indirect effect 2 = a 1 d 21 b 2 ADHD symptoms Maladaptive schemata Perceived stress Well-being Indirect effect 3 = a 2 b 2 ADHD symptoms Perceived stress Well-being Direct effect of ADHD symptoms on well-being = c Key Summary Points 1. Adults with ADHD suffer considerable shame, guilt, perceived stress, maladaptive schemata, lowered sense of well-being 2. When treating adults with ADHD, symptom reduction AND addressing these various elements is critical Miklósi M, et al. J Nerv Ment Dis. 2016;204(5):

14 Cognitive-Behavioral Therapy Benefits Symptoms of Adult ADHD Control Forest Plot of Comparison: CBT vs Waitlist, Outcome: ADHD Symptoms CBT Study or Subgroup Mean SD Total Mean SD Total Weight (%) Std. Mean Difference IV, Random, 95% CI Emilsson, (0.29, 1.73) Pettersson, (-0.46, 0.94) Safren, (-0.12, 1.32) Stevenson, (0.98, 2.39) Virta, (-0.69, 1.06) Total (0.21, 1.31) Heterogeneity: Tau 2 = 0.25; Chi 2 = 10.94, df = 4 (P = 0.03); i 2 = 63% Test for overall effect: Z = 2.72 (P = 0.006) Forest Plot of Comparison: CBT vs Active Control, Outcome: ADHD Symptoms Control CBT Study or Subgroup Mean SD Total Mean SD Total Weight (%) Std. Mean Difference IV, Fixed, 95% CI Estrada, (-0.82, 0.57) Safren, (0.06, 0.97) Solanto, (0.12, 1.01) Total (0.14, 0.71) Std. Mean Difference IV, Random, 95% CI Std. Mean Difference IV, Fixed, 95% CI Heterogeneity: Chi 2 = 2.91, df = 2 (P = 0.23); i 2 = 31% Test for overall effect: Z = 2.89 (P = 0.00) Favors Control Favors CBT Large effect size advantage of CBT vs waitlist (SMD =.76); medium effect size advantage vs active control conditions (SMD =.43) CI = confidence interval; CBT = cognitive-behavioral therapy; SMD = standard mean difference. Young Z, et al. J Atten Disord. 2016;[Epub ahead of print]. Elements of an Adult ADHD Coaching Program Target Area Academics Time management Organization Career planning Health habits Life skills Problem solving Psychoeducation Social Medication Motivation Handling stress and anxiety Specific Components Studying, note taking, memory skills, writing, paying attention and focusing in class, accessing accommodations Setting and keeping goals, scheduling, overcoming procrastination, setting reminders, using calendars and planners, being on time Organizing home and study areas, finding places for everything Evaluating and identifying a career. Planning steps in reaching that career goal Maintaining healthy eating, sleeping, and exercise routines Maintaining finances, managing a home or apartment, becoming independent from parents Breaking down tasks, identifying barriers, making good decisions Educating oneself about ADHD, engaging in self-advocacy Managing and establishing health relationships, communication, emotional control, and self-esteem Managing medication Utilizing self-reinforcement to accomplish goals Managing life skills so that anxiety and depression associated with impairments is lessened In 148 college students with ADHD, an 8-week coaching program markedly improved multiple domains of school and social functioning, as well as self-esteem and emotional distress. Prevatt F. Curr Psychiatry Rep. 2016;18(12):110. Prevatt F, et al. J Atten Disord. 2015;19(8):

Addressing Treatment Gaps in Adult Patients with ADHD

Addressing Treatment Gaps in Adult Patients with ADHD Supported by an educational grant from Shire. Faculty Disclosure Dr. Rakesh Jain: Consultant Addrenex, Allergan, Lilly, Lundbeck, Merck, Otsuka, Pamlab,