Addressing Treatment Gaps in Adult Patients with ADHD

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1 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, Pfizer, Shionogi, Shire, Sunovion, Takeda; Speakers Bureau Addrenex, Allergan, Lilly, Lundbeck, Merck, Otsuka, Pamlab, Pfizer, Shionogi, Shire, Sunovion, Takeda; Research Support AstraZeneca, Allergan, Lilly, Lundbeck, Otsuka, Pfizer, Shire, Takeda Dr. Saundra Jain: Consultant Lilly, Otsuka, and Pamlab 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). Brand names are included in this presentation for participant clarification purposes only. No product promotion should be inferred. Applicable CME staff have no relationships to disclose relating to the subject matter of this activity. This activity has been independently reviewed for balance.

2 ADHD: An Enormously Common and Impairing Disorder 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) Chronic course ~75% persistence from childhood into adolescence ~5% persistence from childhood into adulthood SUD = substance use disorder. Froehlich TE, et al. Arch Pediatr Adolesc Med. 27;161(9): Kessler RC, et al. Am J Psychiatry. 26;163(4): Wilens TE, et al. Postgrad Med. 21;122(5): Adam Levine?? Dr. Hallowell Michael Phelps Jim Carrey ADHD Symptom Evolution: Childhood to Adulthood 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. 27;2(4): Adler LA. J Clin Psychiatry. 24;65 Suppl 3:8-11.

3 ADHD: Lifetime Symptom Progression Behavioral disturbance Academic difficulties Self-esteem issues Legal issues Smoking Injuries Occupational failure Self-esteem Relationship problems Injuries/accidents Preschool School-age Adolescent College-age Adult Behavioral disturbance Academic difficulties Peer relationships Self-esteem issues Academic failure Occupational difficulties Self-esteem Substance abuse Injuries/accidents Pliszka S; AACAP Work Group on Quality Issues. J Am Acad Child Adolesc Psychiatry. 27;46(7): Brown TE, et al. Postgrad Med. 21;122(5): Spencer TJ, et al. J Pediatr Psychol. 27; 32(6): Biederman J. Biol Psychiatry. 25;57(11): What s Different between DSM-IV and DSM-5? The Highlights Age of onset (symptoms) DSM-IV: Some symptoms that caused impairment present before age 7; DSM-5: Several symptoms that caused impairment present prior to age 12 New specifiers In partial remission Mild, moderate, severe Criterion items now include examples specific to adult presentation highlighting lifespan (eg, paying bills, keeping appointments) Older adolescents and adults (age 17) at least 5 of 9 symptoms required; <17 years old at least 6 of 9 symptoms required American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; 213. DSM-5 Criteria for ADHD: Inattentive Symptoms (6/9 age <17 years; 5/9 17 years) Fail to give close attention to details Are forgetful in daily activities Are easily distracted Lose things necessary for tasks Inattentive Symptoms/ Patients Often: Have difficulty sustaining attention Do not seem to listen Do not follow through on instructions Avoid tasks requiring sustained mental effort Have difficulty organizing tasks or activities American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; 213.

4 DSM-5 Criteria for ADHD: Hyperactive/Impulsive Symptoms (6/9 age <17 years; 5/9 17 years) Interrupt or intrude on others Fidget with hands or feet or squirms in seat Have difficulty awaiting turn Are easily distracted Blurt out answers before questions are completed Hyperactive /Impulsive Symptoms/ Patients Often: Leave seat in classroom inappropriately Run about or climb excessively (or internal restlessness) Have difficulty playing quietly Talk excessively Are on the go or acts as if driven by a motor American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; 213. Adult ADHD Ring of Fire NCS-R: Psychiatric Comorbidities Panic Disorder 3.* Any Substance Use Disorder 3.* Specific Phobias 2.8* Adult ADHD Comorbidities Major Depression 2.7* OCD 1.5 Bipolar Disorder 7.4* GAD 3.2* PTSD 3.9* Social Phobias 4.9* Odds Ratio (95% CI). *P <.5. 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. 26;163(4): Impairment is Significant with Undiagnosed ADHD 35% 3% Non-ADHD Controls (n = 199) Undiagnosed ADHD (n = 752) P <.5 Undiagnosed ADHD 25% 2% 15% 1% 5% P <.1 P <.1 P <.5 % Post-College Degree Unemployed 1 Traffic Citation (past 5 yrs) Problem Drinking Able SL, et al. Psychol Med. 27;37(1):97-17.

5 ADHD and SUD: Increased Risks across the Board Population-based sample of Swedish adult twins (N = 18,167) Associations of ADHD Symptoms with SUD (Adjusted for Sex, Age, and Education and Controlled for the Random Effect of Twins) Compared with Controls/Twins with No ADHD Symptoms Substance Abuse All Twins, n (%) ADHD OR Alcohol Alcohol abuse 543 / 17,94 (3.6) 1.88 Alcohol dependence 17 / 17,734 (6.3) 3.58 Drugs ADHD Sxs and subtypes are associated with Stimulants 688 / 17,779 (3.87) 2.45 Opiatesincreased risks for all SUD1912 outcomes; / 17,779 (1.75) no difference1.97 Cannabis between ADHD subtypes, no 2751 substance / 17,779 (15.47) preference, 2.19 Illicit drug and useno sex differences for 294 the comorbidity / 17,779 (16.54) 2.27 Poly-substance use 1425 / 17,779 (8.2) 2.54 Poly-substance use including alcohol 174 / 18,27 (9.42) 2.78 Nicotine (smoke and/or snus ) Regular nicotine use 3115 / 18,167 (17.15) 1.33 P.1. Calculated from multilevel logistic regression adjusted for sex, age, and education and controlled for the random effect of twins. Capusan AJ, et al. J Atten Disord. 216;[Epub ahead of print]. Do Adults with ADHD Experience Just a Cluster of Symptoms, or are There Elements of Shame, Failure, Loss of Well-Being Involved Too? Maladaptive Schemata d 21 =.43*** Perceived Stress a 1 =.975*** a 2 =.62*** b 1 =.19 b 2 =.79*** ADHD Symptoms c =.54* N = 24; *P <.5, **P <.1, ***P <.1 Well-Being Indirect effect 1 = a 1b 1 ADHD symptoms Maladaptive schemata Well-being Indirect effect 2 = a 1d 21b ADHD symptoms Maladaptive schemata Perceived stress 2 Well-being Indirect effect 3 = a 2b 2 ADHD symptoms Perceived stress Well-being Direct effect of ADHD symptoms on well-being = c Noteworthy Points 1. Adults with ADHD have 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 Study of 24 adults with ADHD, 52 men, Miklósi M, et al. J Nerv Ment Dis. 216;[Epub ahead of print]. 152 women The 24-Hour Day of a Typical Adult and Why the Adult with ADHD Needs Longer than 8- to 12-Hour Coverage of Symptoms / Day Organize kids for school

6 Adult ADHD: Screening Tools Distractibility: A Shared Symptom of Multiple Psychiatric Conditions Distractibility Depressive Disorders Bipolar Disorders Anxiety Disorders ADHD Psychotic Disorders SUDs Task Force on DSM-IV. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (Textbook Revision). Arlington, VA; American Psychiatric Association: 2. ASRS-VI.I How to Use Patients simply check 1 of the 5 boxes in response to each of the 6 questions. Kessler RC, et al. Psychol Med. 25;35(2):

7 ASRS-VI.I 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. 25;35(2): ADHD-RS How to Use The ADHD Rating Scale-IV obtains parent ratings regarding the frequency of each ADHD symptom based on DSM-IV criteria. Parents are asked to determine symptomatic frequency that describes the child s home behavior over the previous 6 months. The ADHD Rating Scale-IV is completed independently by the parent and scored by a clinician. The scale consists of 2 subscales: inattention (9 items) and hyperactivity-impulsivity (9 items). If 3 items are skipped, the clinician should use extreme caution in interpreting the scale. Results from this rating scale alone should not be used to make a diagnosis. Adult ADHD: Nonpharmacologic Options

8 CBT in Adult ADHD Its Potential Role as Augmentation Therapy 23 participants randomized to CBT and DEX vs 25 participants randomized to CBT and PLB. Manualized CBT in a series of weekly telephone conference calls with the principal investigators. 4 ADHD RS-Inv CBT+DEX CBT+PLB ADHD RS-Inv Time Treatment Mean n P Baseline CBT+DEX CBT+PLB Week 15 CBT+DEX CBT+PLB Week 2 CBT+DEX CBT+PLB Baseline Week 15 Week 2 Time CBT = cognitive-behavioral therapy; DEX = dextroamphetamine; PLB = placebo. Weiss M, et al. BMC Psychiatry. 212;12:3. Physical Exercise for Adults with ADHD Its Potential Role as Augmentation Therapy Study: 32 young men with unmedicated adult ADHD. Single bout of moderately intense, 2 minutes of stationary cycling Results: In young men reporting elevated symptoms of ADHD, a 2-minute bout of moderate intensity cycle exercise transiently enhances motivation for cognitive tasks, increases feelings of energy and reduces feelings of confusion, fatigue, and depression, but has no effect on the behavioral measures of attention or hyperactivity employed Noteworthy Points 1. Physical exercise, even very brief, if done at least at moderate intensity, can positively impact symptoms that negatively affect adults with ADHD 2. However, physical exercise appears not to impact the core attentional difficulties of ADHD. Therefore, it s best reserved as augmentation therapy Fritz KM, et al. Med Sci Sports Exerc. 216;[Epub ahead of print]. Mindful Meditation in Adult ADHD Its Potential Role as Augmentation Therapy (Hedges g) ASRS-Inattention ASRS-Hyperactivity-Impulsivity BDI-Depression STAI-Anxiety PANAS-X-Negative Affect PANAS-X-Positive Affect Affective Measures PANAS-X-Fear PANAS-X-Sadness PANAS-X-Joviality PANAS-X-Self-Assurance PANAS-X-Attentiveness PANAS-X-Shyness PANAS-X-Fatigue PANAS-X-Serenity AAQoL-Life Productivity AAQoL-Psychological Health AAQoL-Life Outlook AAQoL-Relationships Attentional Measures AAQoL-Total Quality of Life ANT-Hit RT Block Change CPT-II-Commission Errors CPT-II-Detectability Noteworthy Points 1. Mindfulness practices, when combined with medication treatment, can be added as an augmentation agent 2. The effects of mindfulness on adults with ADHD cover both core symptoms of ADHD, as well as elements of anxiety, mood, and positive psychiatry Brazilian study of 21 adult ADHD patients and 8 controls underwent 8 weekly MAP sessions. MAP = mindful awareness practices. Bueno VF, et al. Biomed Res Int. 215;215:

9 Adult ADHD: Brief Neurobiology Update Overlapping Monoamine Innervation of Prefrontal Cortex A Possible Reason for Comorbidities in Adult ADHD A B Robbins TW, et al. Annu Rev Neurosci. 29;32: Examining the Cognition and Emotional Dysregulation Pathways in Adults with ADHD (Stressed vs Non-Stressed Situations) Prefrontal Regulation during Alert, Non-Stress Conditions Amygdala Control during Stress Conditions DMPFC = dorsal medial prefrontal cortex; DLPFC = dorsal lateral prefrontal cortex; rlpfc = rostral lateral prefrontal cortex; VMPFC = ventral medial prefrontal cortex; NA = noradrenaline; DA = dopamine. Arnsten AF. Nat Rev Neurosci. 29;1(6):

10 ADHD is Associated with Structural Changes in DLPFC and ACC White matter: red Gray matter (cortex and nuclei): blue Volume Decrease NAc: red DLPFC: blue CGa: blue Volume Increase MRI study of 24 adults with ADHD and 18 healthy controls ACC = anterior cingulate cortex; CGa = anterior cingulate gyrus; NAc = nucleus accumbens. Seidman LJ, et al. Biol Psychiatry. 26;6(1): Adult ADHD Brain Brain Volumetric Differences between Those with Current ADHD, Remitted ADHD, and Controls Noteworthy Points 1. Children with ADHD start out with thinner cortexes 2. If ADHD remits in adult years, the cortical thinning is less, but still not the same thickness as adults without ADHD 3. The thinnest cortexes are in adults with current ADHD Jadidian A, et al. J Neuropsychiatry Clin Neurosci. 215;27(3): Adult ADHD Brain Brain Volumetric Differences between Those with Current ADHD, Remitted ADHD, and Controls Noteworthy Points 1. Adults with ADHD have notably less connectivity in multiple areas (eg, left putamen, left inferior parietal gyrus, bilateral subgenual cortex), but connectivity is not correlated with symptom severity 2. Persistent adult ADHD have worse connectivity as compared to both controls and remitted ADHD Jadidian A, et al. J Neuropsychiatry Clin Neurosci. 215;27(3):

11 Adult ADHD: Pharmacologic Options ADHD: Options Pharmacologic Treatment Stimulants Methylphenidate Dexedrine Amphetamine (compounds) 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. 21;122(5): 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 +/- Vyvanse TM (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) 1-12 hours +/+ Metadate CD (MPH controlled-release capsule) 8-1 hours +/- Ritalin (MPH) ~4 hours +/- Ritalin LA (MPH XR capsule) 8-1 hours +/- Quillivant XR TM (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. 21;122(5): Stevens JR, et al. In: Adler LA, et al (Eds). Attention-Deficit Disorder in Adults and Children. Cambridge University Press: Cambridge, UK; 215:

12 Recent FDA Approvals in ADHD Aptensio-XR (MPH extended-release capsules): approved for ages 6 (no adult studies available) Evekeo (amphetamine sulphate): 5 and 1 mg tablets Adzenys XR-ODT (amphetamine extended-release orally disintegrating tablet) Several other new options for treatment of ADHD thought to be arriving soon US Food and Drug Administration. Improvement Mean Change from Baseline ATX n PLA n Atomoxetine in Adult ADHD Results from a Long-Term Study (with evening measures of ADHD symptom prevalence) Randomized, multicenter, double-blind, placebo-controlled, 26-week study AISRS Total Score Week ** *** *** *** Atomoxetine Placebo ** * Most common side effects were nausea, dry mouth, fatigue, decreased appetite, urinary hesitation, and erectile dysfunction *P.5, **P.1, ***P.1. ATX = atomoxetine; AISRS = Adult ADHD Investigator Symptom Rating Scale; CAARS-Inv = Conners Adult ADHD Rating Scale Investigator Administered Screening Version; PLA = placebo. Adler LA, et al. J Clin Psychopharmacol. 29;29(1):44-5. Improvement Mean Change from Baseline ATX n PLA n CAARS-Inv: SV Evening Total Score Week Atomoxetine -2 Placebo ** -8 *** -9 *** -1 ** ** OROS MPH in Adult ADHD Another Effective and Generally Well-Tolerated Treatment Option 4 35 AISRS Score OROS-MPH mg/day Placebo mg/day OROS-MPH Placebo Week (LOCF) ± ± 12.8 P =.4* 72.6 ± ± 22.4 P =.3 P =.1 P < ± ± ± ± ± ± 25.9 Randomized, multicenter, double-blind, placebo-controlled, with 72 participants randomized to OROS MPH and 77 to placebo OROS-MPH mg/kg Placebo mg/kg.47 ± ± ± ±.3.98 ± ± ± ± ± ± ± ±.18 Most common side effects were anorexia, dry mouth, gastrointestinal problems, tension/jitteriness, insomnia, cardiovascular complaints, depression, anxiety, and dizziness OROS = osmotic release oral system. Biederman J, et al. Biol Psychiatry. 26;59(9):

13 d-mph-er in Adult ADHD Another Effective and Generally Well-Tolerated Treatment Option DSM-IV ADHD-RS DSM-IV ADHD-RS Inattentive Subscale Score Total Score Placebo n = 53 Placebo n = 53 P =.6 P =.12 P <.1 d-mph-er d-mph-er d-mph-er 2 mg 3 mg 4 mg n = 57 n = 54 n = 54 P =.21 P =.11 P <.1 d-mph-er d-mph-er d-mph-er 2 mg 3 mg 4 mg n = 57 n = 54 n = 54 DSM-IV ADHD-RS Hyperactive/Impulsive Subscale Score Placebo n = 53 Baseline Final Visit P =.5 d-mph-er 2 mg n = 57 P =.37 P <.1 d-mph-er 3 mg n = 54 Randomized, multicenter, double-blind, placebocontrolled, with 168 participants randomized to d-mph-er and 53 to placebo d-mph-er 4 mg n = 54 Most common side effects were headache, decreased appetite, insomnia, dry mouth, and jitteriness d-mph-er = extended-release dexmethylphenidate. Spencer TJ, et al. Biol Psychiatry. 27;61(12): Triple-Bead Formulations of MAS A Potential New Treatment Option for Adult ADHD Greater Improvement 7-week, Phase 3, randomized, double-blind, placebo-controlled, dose optimization study of triple-bead MAS in adults with ADHD (137 randomized to active treatment, 137 randomized to placebo) Least Squares Mean Change from Baseline in AIM-A Subscale Score * Living with ADHD General Well-Being Performance and Daily Functioning Relationships/ Communication Most common side effects were insomnia, dry mouth, decreased appetite, headache, and decreased weight *P <.1 vs placebo; P =.1 vs placebo; P =.3 vs placebo. AIM = Adult ADHD Impact Module; MAS = mixed amphetamine salts. Spencer TJ, et al. J Clin Psychiatry. 28;69(11): * * * Placebo (n = 132) Triple-Bead MAS (n = 136) Bothersomeness/ Concern Daily Interference Adult ADHD: Special Issues / Concerns with Stimulant Use

14 Differentiating ADHD from Bipolar Disorder in Adults: Overlapping and Non-Overlapping Symptoms King s College, Institute of Psychiatry, London Study with total 6 adult women were recruited (2 with ADHD, 2 with bipolar disorder, and 2 controls) Std Mean Scores (+/- Std Err) BAARS-IV Self-Report ADHD BD Control ADHD Symptoms Mania and Dep Symptoms Emotional Lability Inatt Hyp-Imp Impairment Inatt Hyp-Imp Impairment Total Inatt Hyp-Imp Total Total Change (last 48h) No. Sym Past No. Sym Pres Total Total AnxDep ElaDep Anger Last Month Last 5 Years BAARS-IV Informant DIVA ASRM YMRS DI ALS CNS-LS Clinical Implication for the Treatment of Adult ADHD The distinction between sustained traits and episodic symptoms that reflect a change in the premorbid mental state are best at discriminating ADHD from bipolar disorder in adults Kitsune GL, et al. J Affect Disord. 216;192: Cognitive and Executive System Dysfunction in ADHD What are the Impairments? (and what this means to clinical decision-making) University College of Dublin Study of 51 adults diagnosed with combined ADHD compared with 28 adult controls Results: ADHD individuals have the following Executive Function Impairments: 1. Divided Attention (P =.4) 2. Sustained Attention higher number of omissions (P =.1) AND higher number of commission errors (P =.5) 3. Executive Function Test Hotel task is comprised of 5 distinct activities that would plausibly be completed in the course of running a hotel (ie, checking guests bills, proofreading a leaflet on the hotel s facilities, sorting money, etc). Results: Significantly lower number of attempted tasks (P =.4) Clinical Implication for the Treatment of Adult ADHD Attentional Problems and Executive Dysfunction are prominent issues and therefore coverage of symptoms for maximum number of hours/day is a clinical necessity Salomone S, et al. J Atten Disord. 216;[Epub ahead of print]. With Stimulants FDA Package Insert Directs Clinicians to Exercise the Following Care US Food and Drug Administration.

15 Adult ADHD and Car Accidents: What is Known about the Disorder s Impact, and Its Treatment s Impact on Outcomes Relevant Points - Males with ADHD had a 1.47 hazard ratio of serious car accidents - Females had a hazard ratio of 1.45 of serious car accidents - In males, taking medications for ADHD lead to a 58% risk reduction (in females it was statistically insignificant) Chang Z, et al. JAMA Psychiatry. 214;71(3): MPH for ADHD and Drug Relapse in Criminal Offenders with Substance Dependence: A 24-Week Randomized Placebo-Controlled Trial Sample: 54 incarcerated males (Mean age = 42) Dose: Start dose 18 mg MPH/placebo titrated over a period of 19 days to max dose of 18 mg/day CBT: Individual CBT once weekly for 12 weeks Measurements: Change in selfreported ADHD symptoms, urine tox, retention to treatment Findings: MPH-treated group showed reduced ADHD symptoms (P =.11), significantly higher proportion of negative urine screens (P =.47), and better retention (P =.32) CAARS-Score Change in self-rated ADHD symptoms (95% CI: to -1.91, P =.11) Baseline Placebo MPH Weeks Konstenius M, et al. Addiction. 214;19(3): 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. 211;36(24):

16 Potential and Common Unmet Needs in Adult ADHD Potency of intervention not sufficient In Conclusion: What is an Optimum Response to Treatment in Adults with ADHD? Optimum would be early, full, and sustained control over ALL symptoms of ADHD, for AS MANY hours in the day as possible (with great tolerability, of course!) Attention Impulsive Emotional Hyperactivity Behavior