1 ADHD: Transition From Adolescence to AdulthoodLarry Suess, DO, PhD, FACN June 10, 2017 No disclosures to report

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3 Am I ADHD? 2. What type of ADHD am I?

4 Objectives By the end of todays lecture,-you should be able to understand the DSM5 Diagnostic Criteria for ADHD? -be able to provide a complete work-up to the patient? -understand ADHD neural mechanisms? -have a cursory understanding of treatment protocol? -understand red flags?

5 Fidgety Phillip Dr. Heinrich Hoffmann, 1844Let me see if Philip can Be a little gentleman Let me see, if he is able To sit still for once at table: Thus Papa bade Phil behave; And Mamma look'd very grave. But fidgety Phil, He won't sit still; He wriggles and giggles, And then, I declare Swings backwards and forwards And titlts up his chair, Just like any rocking horse; - "Philip! I am getting cross!"

6 Johnny Head-in-Air Dr. Heinrich Hoffmann, 1844Once, with head as high as ever, Johnny walk'd beside the river. Johnny watch'd the swallows trying Which was cleverest at flying. Oh! What fun! Johnny watch'd the bright round sun Going in and coming out; This was all he thought about. To the rivers very brink, Where the bank was high and steep, And the water very deep; And the fishes, in a row, Started to see him coming so.  One step more! Oh! sad to tell! headlong in poor Johnny fell. And the fishes, in dismay, Wagg'd their tails and ran away.

7 Epidemiology

8 Brief History Legal Medical Year Event Year Event 1848Dr. Heinrich Hoffman wrote Fidgety Phil 1902 Dr. George Frederic Still first comprehensive observations in ADHD encephalitis epidemic Still’s symptoms seen “brain damage” 1937 amphetamines were helpful in reducing hyperactive and impulsive behavior 1950s and 60s increase in psychiatric drug intervention 1968 Dr. Stella Chess described "Hyperactive Child Syndrome Year Event 1973 Rehabilitation Act of Section 504 2002 No Child Left Behind Act, Public Law 2004 Individuals with disabilities Education Act (IDEA) 2008 Americans with Disabilities Act Amendments Act of 2008 (ADAAA) 2009 Forest Grove School District v. T.A.

9 DSM-1 Minimal Brain Dysfunction 1952Hyperkinetic Reaction of Childhood 1968 DSM-1 ADD with or without hyperactivity 1980 ADHD , Undifferentiated ADD 1987 ADHD combined subtypes 1994 ADHD Adult 2013

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21 ADHD: Defined

22 Three presentations of ADHD are defined in DSM-5™ based on the predominant symptom pattern for the past 6 months: Combined presentation – all three core features are present and ADHD is diagnosed when ≥6 symptoms of hyperactivity/impulsivity and ≥6 symptoms of inattention have been observed for ≥6 months.

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25 with functioning or development, as characterized by (1) and/or (2):A. A persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning or development, as characterized by (1) and/or (2): . (1) (2) Note: The symptoms are not solely a manifestation of oppositional behavior, defiance, hostility, or failure to understand tasks or instructions. For older adolescents and adults (age 17 and older), at least five symptoms are required. https://www.psychiatry.org/psychiatrists/practice/dsm

26 Several inattentive or hyperactive-impulsive symptoms were present prior to age 12 years.C. Several inattentive or hyperactive-impulsive symptoms are present in two or more settings (e.g., at home, school, or work; with friends or relatives; in other activities). D. There is clear evidence that the symptoms interfere with, or reduce the quality of, social, academic, or occupational functioning. E. The symptoms do not occur exclusively during the course of schizophrenia or another psychotic disorder and are not better explained by another mental disorder (e.g., mood disorder, anxiety disorder, dissociative disorder, personality disorder, substance intoxication or withdrawal). https://www.psychiatry.org/psychiatrists/practice/dsm

27 Specify whether: (F90.2) Combined presentation: If both Criterion A1 (inattention) and Criterion A2 (hyperactivity-impulsivity) are met for the past 6 months. (F90.0) Predominantly inattentive presentation: If Criterion A1 (inattention) is met but Criterion A2 (hyperactivity-impulsivity) is not met for the past 6 months. (F90.1) Predominantly hyperactive/impulsive presentation: If Criterion A2 (hyperactivityimpulsivity) is met but Criterion A1 (inattention) is not met over the past 6 months. Specify if: In partial remission: When full criteria were previously met, fewer than the full criteria have been met for the past 6 months, and the symptoms still result in impairment in social, academic, or occupational functioning. https://www.psychiatry.org/psychiatrists/practice/dsm

28 Specify current severity: Mild: Few, if any, symptoms in excess of those required to make the diagnosis are present, and symptoms result in only minor functional impairments. Moderate: Symptoms or functional impairment between “mild” and “severe” are present. Severe: Many symptoms in excess of those required to make the diagnosis, or several symptoms that are particularly severe, are present, or the symptoms result in marked impairment in social or occupational functioning. https://www.psychiatry.org/psychiatrists/practice/dsm

29 ADHD Symptom Manifestation by AgeCHILDHOOD ADOLESCENCE ADULTHOOD Hyperactivity Easily distracted, inattentive Inattentiveness Low frustration tolerance Easily bored Poor organization of time/money Aggression Impatient Missing deadlines or appointments Easily distracted Emotionally immature compared to peers Poor bill tracking Difficulty developing routines Shifts activities Restlessness Impulsiveness Poor driving Emotional reactivity Some specific symptoms of ADHD by age are shown here. Any individual with ADHD can exhibit any of these symptoms regardless of age; however, in general, younger patients are more likely to display hyperactive and impulsive symptoms than adults. In childhood, symptoms of ADHD may manifest as low frustration tolerance and aggression. Children with ADHD may be easily distracted and have difficulty developing routines such as regular homework time or bedtime rituals. In adolescence, symptoms may remain the same but manifest differently, or symptoms may begin to change at this stage with hyperactivity lessening. Symptoms may be exhibited in adolescence by poor driving (distraction), and it may become apparent that these patients are emotionally immature compared to their peers. In adulthood, inattentive symptoms generally predominate, and may manifest as missed appointments or deadlines, poor organization of time and money, and poor bill tracking. Wasserstein. JCLP Wilens et al. Ann Rev Psychiatry Millstein et al. J Atten Disord 1997.

30 ADHD Developmental Trends by AgeINATTENTION IMPULS IVITY HYPER ACTIV ITY RECOGNIZED COMORBIDITY The trends of ADHD symptoms by age are shown here. In general, hyperactive and impulsive symptoms may lessen as an individual ages, possibly beginning in adolescence. However, inattentive symptoms seem to persist through adulthood. Adults are also more likely to have comorbid disorders be recognized than children. This may be because the comorbidities develop later, but could also be because of changes in symptom expression, ability of patients to express themselves, and other factors. Childhood Adolescence Adulthood Wasserstein. JCLP Mick et al. Psychiatr Clin N Am 2004.

31 ADHD: Differential Diagnosis (Drives the work-up)

32 Language and Learning Disability (10-15%) Comorbid Conditions Language and Learning Disability (10-15%) 1.Usually less hyperactive and more inattentive B. Tourette's Syndrome (70% with tics have ADHD) C. Oppositional Defiant Disorder (35-65% of ADHD patients) D. Conduct Disorder (10-20% of ADHD patients) E. Major Depression (20% of ADHD patients) F. Anxiety Disorder (25% of ADHD patients) G. Substance Abuse (20-40% of ADHD patients)

33 Differential Diagnosis: Psychiatric Conditions Low self esteem Major Depression Bipolar Disorder Dysthymia Anxiety Disorder Obsessive Compulsive Disorder Separation Anxiety Conduct Disorder Oppositional Defiant Disorder Poor Social skills Substance Abuse Consider if symptom onset in adolescence

34 Differential Diagnosis: Medications Anticonvulsants Antihistamines Decongestants Beta agonists Differential Diagnosis: General Medical Conditions Hypothyroidism Severe Anemia Lead Poisoning Chronic illness Hearing Impairment or vision Impairment Obstructive Sleep Apnea in Children

35 Differential Diagnosis: Neurologic Conditions Sleep disorders Obstructive Sleep Apnea Restless Leg Syndrome Periodic Limb Movement disorder Tourette's Syndrome Seizure disorder (e.g. Absence Seizure) Sensory disorders Vision disorder Hearing Loss Intellectual Disability (Mental Retardation) Fragile X Syndrome Fetal Alcohol Syndrome Phenylketonuria Neurofibromatosis 522q11 Deletion Syndrome Other learning disabilities Autism Spectrum Disorders Speech or language disorders

36 Differential Diagnosis: Environmental Unsafe or disruptive learning environment School curriculum not well matched to child's ability Family dysfunction or poor parenting Child Abuse or neglect Parental Psychopathology

37 H&P LABWORK CBC w/ diff Comprehensive chemistry Urine Drug screen EKG Thyroid panel (TSH, free T4) Pregnancy test EEG-if needed SUPPORTIVE DATA School records Work records Family information/History KASPER ADHD Scale FUTURE Pharmacogenomic Testing

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40 As of May, 2017 1. How often do you have difficulty concentrating on what people say to you, even when they are speaking to you directly? (DSM-5 A1c) 2. How often do you leave your seat in meetings or other situations in which you are expected to remain seated? (DSM-5 A2b) 3. How often do you have difficulty unwinding and relaxing when you have time to yourself? (DSM-5 A2d) 4. When you’re in a conversation, how often do you find yourself finishing the sentences of the people you are talking to before they can finish them themselves? (DSM-5 A2g) 5. How often do you put things off until the last minute? (not in the DSM) 6. How often do you depend on others to keep your life in order and attend to details? (not in the DSM)

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44 ADHD:Treatment

51 How Neurotransmission Works

52 How ADHD Affects Neurotransmission

53 How ADHD Medication Works

54 Two types of ADHD Medications

55 https://www. washingtonposthttps://www.washingtonpost.com/apps/g/page/national/your-brain-on-adhd/1716/

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59 Schools' response to academic failure is to change the child to fit the school environment“retain children in a grade with hopes that they will catch up to the prescribed learning sequence the next time around”

60 Americans with Disabilities Act Amendments Act of 2008 (ADAAA)Amends the the meaning of "disability" in the ADA and the Rehabilitation Act of 1973, Section 504

61 Americans with Disabilities Act Amendments Act of 2008 (ADAAA)restores the original definition of "substantially limited" - that the impairment simply be a substantial limitation rather than a "significant" or "severe" restriction.  broadens the definition of "major life activities" and provides that the impairment only needs to limit one major life activity in order to be considered a disability under the ADA. Districts must now make their Section 504 determinations based upon the child’s disability as it presents itself without mitigating measures (i.e.,hearing aids, medications, learned behavioral adaptations). There is one exception, ordinary eyeglasses on contact lenses

62 Americans with Disabilities Act Amendments Act of 2008 (ADAAA)a student shall not be “regarded as” having a disability (one of the prongs that would allow a student to be protected under Section 504) if the disability is“transitory and minor.” It defines transitory as “an impairment with an actual or expected duration of 6 months or less.” OCR also clarified that a Section 504 re-evaluation is similar to an IDEA re-evaluation Section 504 specifies that re-evaluations in accordance with the IDEA is one means of compliance with Section 504 and that regulations require that re-evaluations be conducted periodically. Re-evaluation must occur prior to a significant change of placement.

63 International System of electrode placement for EEG Recordinghttps://www.researchgate.net/figure/ _fig2_Figure international-System-for-EEG-Recording-the-electrodes-inside-hexagonal

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65 Brain mapping takes EEGand Pictographs it

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67 Pharmacogenomics DefinedPharmacogenomics uses information about a person’s genetic makeup, or genome, to choose the drugs and drug doses that are likely to work best for that particular person. National Institutes of Health National Human Genome Research Institute What We Do: Pharmacogenomics is defined as the study of how a person’s individual DNA affects their response to medications. This technology is currently available to all clinicians and is as simple as collecting a sample, sending to our laboratory and within a matter of days receiving a clear, clinically actionable and easy to interpret report to better inform your decision making process in appropriate medication selection uniquely to each patient.

68 Genetic Linkage of ADHD 16p13https://www.ncbi.nlm.nih.gov/pubmed/

69 Genes that may be linked to ADHDDopaminergic neurotransmission system: DRD4, DRD5, DAT1/SLC6A3, DBH, DDC. Noradrenergic system: NET1/SLC6A2, ADRA2A, ADRA2C). Serotonergic system: 5-HTT/SLC6A4, HTR1B, HTR2A, TPH2. Neurotransmission and neuronal plasticity: SNAP25, CHRNA4, NMDA, BDNF, NGF, NTF3, NTF4/5, GDNF.

70 Dopaminergic neurotransmissionDRD4 DRD5 DAT1/SLC6A3 DBH DDC Serotonergic system 5-HTT/SLC6A4 HTR1B, HTR2A TPH2

71 Metabolic pathways of amphetamine in humansThe primary active metabolites of amphetamine are 4-hydroxyamphetamine and norephedrine;[143] at normal urine pH, about 30–40% of amphetamine is excreted unchanged and roughly 50% is excreted as the inactive metabolites (bottom row).[1] The remaining 10–20% is excreted as the active metabolites.[1] Benzoic acid is metabolized by XM-ligase into an intermediate product, benzoyl-CoA,[145] which is then metabolized by GLYAT into hippuric acid.[146]

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75 Personalized Medication Selection FactorsAdverse Effects Adherence Patient Experience Family History Illness Cost Pharmacogenomics With pharmacogenomics, clinicians have an objective tool that can be used in concert with other factors known to influence medication selection in order to better identify the “right” medication for each individual. Pharmacogenomics is an additional “tool” in clinicians’ “toolboxes” to provide personalized medication selection for each individual. It’s not a magic bullet, but Personalized Medication Selection MISDU Z

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77 Pharmacogenomics DefinedPharmacogenomics uses information about a person’s genetic makeup, or genome, to choose the drugs and drug doses that are likely to work best for that particular person. National Institutes of Health National Human Genome Research Institute What We Do: Pharmacogenomics is defined as the study of how a person’s individual DNA affects their response to medications. This technology is currently available to all clinicians and is as simple as collecting a sample, sending to our laboratory and within a matter of days receiving a clear, clinically actionable and easy to interpret report to better inform your decision making process in appropriate medication selection uniquely to each patient.

78 KEY POINTS Polymorphisms affect pharmacokinetics and pharmacodynamics of specific drugs are common. Testing for certain polymorphisms before prescribing certain drugs could help avoid adverse drug effects and improve efficacy. Pharmacogenomic testing has only recently begun to enter clinical practice, and routine testing is currently limited to a few clinical scenarios. However, additional applications may be just around the corner. Many pharmacogenomic tests are available, but testing has not yet been recommended for most drugs. Needed are large-scale trials to show that routine testing improves patient outcomes.

79 Personalized Medication Selection FactorsAdverse Effects Adherence Patient Experience Family History Illness Cost Pharmacogenomics With pharmacogenomics, clinicians have an objective tool that can be used in concert with other factors known to influence medication selection in order to better identify the “right” medication for each individual. Pharmacogenomics is an additional “tool” in clinicians’ “toolboxes” to provide personalized medication selection for each individual. It’s not a magic bullet, but Personalized Medication Selection

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81 Am I ADHD? 2. What type of ADHD am I?

82 Am I ADHD? NO-didn’t meet criteria 2. What type of ADHD am I?