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New Concepts in the Epidemiology, Diagnosis and Precision Treatment of ADHD in Children, Adolescents, and Adults


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This is the Grand Rounds Presentation at Saint Mary's Hospital here in Evansville, IN. In it, Dr. Cady covers the notable uptick in the diagnosis of ADHD, reviews societal effects contributing to the …

This is the Grand Rounds Presentation at Saint Mary's Hospital here in Evansville, IN. In it, Dr. Cady covers the notable uptick in the diagnosis of ADHD, reviews societal effects contributing to the increased diagnosis, and reviews the precision diagnosis and treatment of ADHD. He presents a rigorous grounding in diagnostic fundamentals, notes the contribution of SPECT imaging toward our understanding of ADHD, and reviews the precise pharmacotherapeutic treatment of ADHD to avoid side effects and control symptoms.

This presentation is the one that was actually presented (with updated title slide to reflect the weather outside this morning), and has the seven "true/false" questions at the end with the correct answers indicated.

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  • ADHD is recognized as a combination of 3 behavior types: inattention, impulsivity, and hyperactivity
    DSM-IV characterizes 3 subtypes of ADHD based on the preponderance of these behaviors [Biederman, 1998 p4]
    Combined inattentive and hyperactive-impulsive
    In many patients, hyperactive and impulsive symptomology tend to decrease with age; however, inattention is persistent throughout the lifespan [Biederman1998 p5, 7-8]
    Hyperactive-impulsive subtype occurs with the lowest frequency and in the youngest patients
    The inattentive subtype is most commonly recognized in older adults, but can occur at all ages
    The combined subtype occurs most frequently [Biederman, 1998 p4-5]
  • 237 boys 6 to 17 years old were followed prospectively for 4 years and into mid-adolescence
    Information on smoking history was determined using the Diagnostic Interview for Children and Adolescents/Parents’ version at the 4-year follow-up assessment only [Milberger 1997 p39]
    Information on frequency of cigarette smoking, age at onset/offset of smoking, and associated impairments were determined by trained interviewers blind to the subjects’ clinical status [Milberger 1997 p39]
    ADHD is a significant predictor of early smoking in adolescence
    At the end of 4 years 19% of ADHD boys were smoking compared with 10% of controls (P=0.003)
  • Onset of substance abuse in subjects with ADHD averaged 3 years earlier than controls (late adolescence/early adulthood)
    ADHD was a significant risk factor independent of comorbid diagnoses
  • The incidence of drug abuse was compared in 56 medicated ADHD patients, 19 non-medicated ADHD patients, and 137 non-ADHD control subjects [Biederman 1999 pe21]
    Non-medicated ADHD patients were at a significantly higher risk for substance abuse than controls or medicated ADHD patients [Biederman 1999 pe22-23]
    There was no significant difference between medicated ADHD patients and controls (chi-squared=3.7, P=0.15) [Biederman 1999 pe22-23]
    Medication is associated with an 85% reduction in the risk of substance abuse in ADHD patients [Biederman 1999 pe22-23]
    Poor compliance is often a more significant problem than addiction [Garland, 1998 p 387-388]
  • Studies comparing methylphenidate, dextroamphetamine, and pemoline have demonstrated equivalent efficacy.
    However, there is much individual variability in response to any one particular psychostimulant. That is, a particular patient may not respond to methylphenidate, but may respond well to an amphetamine medication. This slide shows results of a meta-analysis of six controlled within-subject comparisons of methylphenidate and amphetamine. Of the 174 subjects, 28% responded best to amphetamine, 16% responded better to methylphenidate, while the remaining 41% responded equally well to either stimulant.
    The response rate for any one particular stimulant medication is approximately 70%. No predictors of response have been identified; that is, there is no way to know whether a patient will respond to one stimulant vs another. Because patients may have a preferential response to one stimulant medication, different stimulants should be tried before considering a patient to be a stimulant nonresponder.
  • Stimulant medications have a very favorable benefit-risk ratio, with rapid, dramatic results and a low risk of long-term side effects. The Council on Scientific Affairs of the American Medical Association reviewed hundreds of trials involving thousands of patients, and concluded that “the risk-benefit ratio of stimulant treatment in ADHD must be evaluated and monitored on an on-going basis in each case, but in general is highly favorable” (Goldman et al. JAMA 1998;279:1100).
    Studies consistently show that approximately 70% of pediatric patients will show a positive response to the first trial of any one stimulant medication (Spencer et al. JAACAP 1996;35:409).
    Up to 78% of adult patients respond to a single stimulant (Spencer et al. Arch Gen Psych 1995;52:434).
    The response rate for stimulant medications increases to approximately 90% when two different stimulant medications are tried (Goldman et al. JAMA 1998;279:1100).
  • Atomoxetine represents the first of a new generation of compounds treating ADHD through blockade of norepinephrine reuptake, as opposed to dopamine. Several other companies have similar products under development. Atomoxetine was FDA-approved on November 26, 2002.
  • Most patients are treated with an antidepressant that works on a single neurotransmitter system, either serotonin or norepinephrine. This includes 11 prominent agents that are widely prescribed.
  • Plasma MPH Concentrations
    To assess whether different delivery patterns affected efficacy, the efficacy of BID dosing was compared with flat and ascending release profiles
    BID dosing: 2 large bolus doses
    Flat release: a large bolus followed by small constant doses
    Ascending release: a large bolus followed by small increasing doses
    As expected, BID dosing of MPH resulted in dual peaks, ascending release gave a slow steady increase in plasma levels, and flat release provided continuous plasma concentrations of MPH
    N=38 with clinical diagnosis of ADHD and receiving current treatment with MPH doses of 5 to 15 mg/d
    Age range: 7 to 12 years of age (mean: 9.2 years)
  • An extended-release formulation of Adderall® (Adderall XR™) is now available for the treatment of ADHD. This capsule formulation contains equal proportions of immediate release and extended release beads and the active ingredients are identical to Adderall® (equal mg portions of d-amphetamine sulfate, amphetamine sulfate, d-amphetamine saccharate, and amphetamine aspartate monohydrate). The IR beads are designed to release medication upon ingestion, and the extended-release beads are designed to release the drug approximately 4 hours post-dose. Thus, a single 20-mg ADDERALL XR™ dose is designed to release medication similar to a 10 mg IR Adderall tablet dosed BID given approximately 4 hours apart.
    The contents of the capsule may be sprinkled onto food for patients who have difficulty swallowing pills.
  • Key Point: Vyvanse is a new chemical entity, a prodrug for the treatment of ADHD. After
    ingestion, Vyvanse is converted (via enzymatic reaction [rate-limited hydrolysis]) to
    l-lysine, a naturally occurring essential amino acid, and to active d-amphetamine. (Please read 2nd communication objective discussing enzyme responsible for metabolism)
    Communication Objectives:
    [Reminder] Vyvanse is a new chemical entity with a different chemical structure than that of Adderall XR or Dexedrine Spansules.
    Vyvanse is a prodrug, in which d-amphetamine is covalently bonded to l-lysine. It is therapeutically inactive until it is converted (via enzymatic reaction [rate-limited hydrolysis]) to active d-amphetamine in the body. The specific enzyme(s) responsible for this enzymatic reaction (rate-limited) has not been fully identified. The bond linking d-amphetamine to l-lysine is an amide bond, more specifically a peptide bond. Enzymes responsible for the breakdown of peptide bonds are peptidases. OVERALL, PEPTIDE BONDS ARE BROKEN BY PEPTIDASE ENZYMES.
    How does Vyvanse become active where it is metabolized?
    Activation: Vyvanse is a prodrug that is therapeutically inactive until it is converted to active d-amphetamine in the body. Cleavage occurs at the amino-terminal group of d-amphetamine. An enzymatic reaction occurs converting (metabolizing) inactive lisdexamfetamine to its active form, d-amphetamine. This enzymatic reaction occurs via rate-limited hydrolysis.
    Vyvanse is rapidly absorbed from the gastrointestinal tract and converted to d-amphetamine, which is responsible for the drug’s activity. Vyvanse is converted to d-amphetamine and l-lysine, which is believed to occur by gastrointestinal and/or hepatic metabolism.
    Release of the active ingredient in Vyvanse does not rely on gastrointestinal factors such as GI transit time or gastric pH.
  • Transcript

    • 1. New Concepts in the Epidemiology, Diagnosis and Precision Treatment of ADHD in Children, Adolescents, and Adults (Slideshare users: this is an updated cover slide) Grand Rounds – Saint Mary’s Hospital February 5, 2014 Louis B. Cady, MD – CEO & Founder – Cady Wellness Institute Adjunct Clinical Lecturer – Indiana University School of Medicine Department of Psychiatry Child, Adolescent, Adult & Forensic Psychiatry – Evansville, Indiana
    • 2. Continuing Medical Education Commercial Disclosure Requirement for Louis B. Cady, M.D. I, Louis B. Cady, MD, have the following commercial relationships to disclose: •Speaker honoraria received from: • Immunolaboratories, Great Plains Diagnostic Labs, LABRIX •Speaker’s bureaus (active) for: • Forest Pharmaceuticals, Sunovion •Historical data – speaker’s bureau for Bristol-Myers Squibb, Celltech, Cephalon, Eli Lilly, Glaxo-Smith Kline, Janssen, McNeil, Pfizer-Roerig, Sanofi!~aventis, Sepracor, Shire, McNeil, Takeda, Janssen, Searle, Shire, Takeda, Wyeth-Ayerst This CME presentation is not being underwritten by any pharmaceutical company, and Dr. Cady is not receiving a fee or honorarium for presenting it.
    • 3. This is where to follow along on your tablets and smart phones, or access the presentation slides later… md Note – the 7 True/False “Q & A” for CME documentation of learning are attached at the end of this presentation with the correct answer indicated.
    • 4.
    • 5. “Truth is a constant variable.” – William Mayo, MD. “Dr. Will” Gonda extension, Mayo Clinic Building 2004. © Louis B. Cady,
    • 6. Prevalence: how much, and ―why so much‖?
    • 7. Prevalence & diagnosis
    • 8. (NYT, 12 14 2013)
    • 9. Increased methylphenidate usage for attention deficit disorder in the 1990’s. Safer DJ et al. Pediatrics. 1996 Dec; 98(6 Pt 1):1084-8} • 2.5 X increase in MPH tx between 1990 and 1995 – 2.8% (1.5 million) US youths aged 5-18 received this medication in mid-1995 • “The increase in methylphenidate…appears largely related to – an increased duration of treatment; – More girls, adolescents and inattentive youths on the medication – And a recent improved public image of medication treatment.”
    • 10. Prevalence data of parent report of ADHD “CURRENT Dx” by provider 2007 2011 IL 4.8% 7.2% IN 9.3% 13.0% KY 10.2% 14.8% Rates of ADHD diagnosis increased an average of 3% per year from 1997 to 2006 (CDC Vital & Health Statistics) accessed 01 26 2014
    • 11. ADHD Stats at 317 years of age. • 5 million children (9% for this age group) – Boys 12% – Girls 5% • Children with fair/poor health status 2½ X more likely to have dx. (8% vs 21%)
    • 12. What does it ―look like‖? A section for kinesthetic and visual learners…
    • 13. ADHD – not concentrating Inferior Orbital pre-frontal cortex Images courtesy of Daniel Amen, MD – Amen Clinics, Inc., Newport Beach, CA
    • 14. ADHD - concentrating
    • 15. ADHD – concentrating, on RX
    • 16. ADD – inattentive, without Rx ADD – inattentive, on Amph Images courtesy of Daniel Amen, MD – Amen Clinics, Inc., Newport Beach, CA
    • 17. Diagnostic criteria
    • 18. DIAGNOSIS: FOUR FLAVORS OF ADHD 314.00 ADHD Predominantly Inattentive Type* 314.01 ADHD Predominant HyperactiveImpulsive Type* 314.04 ADHD, Combined Type 314.9 ADHD – Not Otherwise Specified 6 of 9 symptoms required for 314.00 & 314.01
    • 19. PATIENT NAME: ___________________________ DATE: __________ Medication status: ( ) pre-treatment? ( ) on Rx? ( ) OFF of Rx? PATIENT STATUS: CHILD Check off the symptoms which are unusually troublesome for your child (or YOU, if you are an adult patient) which are clearly different from what other children or adults typically experience. PLEASE USE THE BACK SIDE OF THIS FORM TO AMPLIFY ON ANY OF THE "CHECKED" SYMPTOMS WHICH YOU FEEL I SHOULD KNOW MORE ABOUT. ATTENTION PROBLEMS displays failure to give close attention to details; makes careless mistakes has difficulty with sustained attention doesn't listen even when spoken to directly has REAL trouble following through on instructions; fails to finish tasks difficulty organizing tasks/activities avoids, dislikes, or reluctant to engage in tasks requiring sustained mental effort (homework, work projects, etc.) loses things necessary for tasks/activities easily distracted by extraneous stimuli (sounds or sights in the environment) often forgetful in daily activities For physician use only RECENT CLINICAL HISTORY: HYPERACTIVITY, "WIGGLESOMENESS" PROBLEMS fidgets with hands or feet, squirms in seat leaves seat in classroom in which remaining in seat was expected, or can't stay put at work runs about; climbs excessively in inappropriate situations difficulty playing or engaging in leisure activities quietly often was "on the go" as if "driven by a motor" talks excessively - a "chatterbox" PROBLEMS BEING IMPULSIVE blurts out answers before questions are completed difficulty waiting your turn interrupts or intrudes on others (butts into conversations) PARENTS: Please feel in your child's CURRENT DRUG THERAPY... PLEASE LIST! medication TAKEN ____________ ____________ ____________ ____________ ____________ ____________ ____________ size of dose WHEN _________ _________ _________ _________ _________ _________ _________ ____________ ____________ ____________ ____________ ____________ ____________ ____________ physician use... ADHD Diagnostic Symptom Checklist, adapted from DSM-IV, by: Louis B. Cady, M.D. - 611 Harriet Street - Suite 304 - Doctors Plaza Evansville, IN 47710 – Symptoms present before age 7 (now 12 in DSM-5) years – Impairment from symptoms present in 2 or more settings – Significant social, academic, or occupational impairment – Exclude other mental disorders
    • 20. DSM-5 update • 6 symptoms before age 7 • 6 symptoms for adults • 6 symptoms before age 12 • 5 (FIVE) symptoms for adults
    • 21. ―The Total Picture‖ diagnostic pearls [from Steven Grcevich, MD] • Read comments on report cards! • Ask siblings: “What’s (s)he like to live with?” • Ask patient: “When was the last time you got invited to someone else’s house to play?” • Ask parents: “Is (s)he involved with any activities in the community?”
    • 22. Different symptom manifestation: children through adults
    • 23. Continuation of Impairment of ADHD Childhood  Adulthood School failure / underachievement Becomes Job failure or underemployment Multiple injuries Becomes Fatal car wrecks / risk taking Drug experimentation Becomes Drug dependence ODD / CD Becomes ASPD, criminal involvement Impulsivity and carelessness Becomes Unwanted pregnancy, STDs, etc Repetitive failure Becomes Hopelessness, frustration, giving up Courtesy of William Dodson, MD – Denver, Colorado
    • 24. ADHD: Course of the Disorder Inattentio n —Age—
    • 25. Earlier Initiation of Smoking with ADHD Smoking probability 0.6 0.5 ADHD n=128 Control n=109 0.4 237 6 to 17-year-old boys 0.3 0.2 0.1 0 0 P<0.003 2 4 6 8 10 12 14 16 18 20 4 year follow-up Milberger S, et al. J Am Acad Child Adolesc Psychol. 1997;36:37-44. 22 24
    • 26. Increased Lifetime Substance Abuse in Untreated Adults with ADHD Lifetime rate of substance abuse in referred ADHD adults ADHD (n=239) 60 50 55% Control (n=268) P<0.001 40 30 27% 20 10 0 Biederman, et al. Biol Psychiatry. 1998;44:269273.
    • 27. Pharmacotherapy Significantly Reduces Substance Abuse in Adults with ADHD % of study population 40 32 3fold! 30 P<0.001 20 12 10 Unmedicated ADHD Medicated ADHD Control (N=19) (N=56) 10 0 (N=137) Biederman J, et al. Pediatrics. 1999;104:e20-e25.
    • 28. Horrigan J, et al. Presented at 47th Annual AACAP Meeting: October 24-29, 2000. New York, NY.
    • 29. What happens if ADHD isn’t treated?
    • 30. Driving behavior and results in 27 clinically referred German adults • N=27, with initial screen – 19 studied – initial testing then either: • 10- kept medication free • 9 – tx’ed for 6 weeks with MPH Sobanski E, et al. Driving-related risks and impact of metylphendiate treatment on driving in adtuls with attenion-deficit/hyperactivity disorder (ADHD). J Neural Trasm. 2008; 115(2):347-56.
    • 31. Driving behavior and results in 27 clinically referred German adults • Background findings: – All ADHD subjects: drove significantly more kilometers per year – More often registered by traffic authorities – Fined more frequently – Involved in more MVA’s – Self described driving style as “more insecure and hectic” than controls. • A high risk group was delineated with: – 3-6 MVA’s per ADHD subject Sobanski E, et al. Driving-related risks and impact of metylphendiate treatment on driving in adtuls with attenion-deficit/hyperactivity disorder (ADHD). J Neural Trasm. 2008; 115(2):347-56.
    • 32. Do you want to treat them? STUDY CONCLUSIONS: MPH tx improved information processing and sustained visual attention compared to baseline and untreated control groups. Sobanski E, et al. Driving-related risks and impact of metylphendiate treatment on driving in adtuls with attenion-deficit/hyperactivity disorder (ADHD). J Neural Trasm. 2008; 115(2):347-56.
    • 33. - Reviving American Manufacturing, accessed 1 27 2014
    • 34. accessed 01 27
    • 35. Unemployment, underemployment are contemporary problems…
    • 36. Psychiatric disorders (lifetime) in adults with ADHD [multiple sources, % is estimated; N.B. – this is WITHOUT TREATMENT GROWING UP] • Substance use disorders (all) 50% • Anxiety disorders 40% • Major depression 35% • Learning disabilities 20% • Bipolar disorder 10% • Antisocial disorder 10%
    • 37. Adult ADHD’ers: • Lower self esteem as adults • Lower educational achievements • Greater use of ancillary educational resources • Greater tobacco and recreational drug use • A lifelong pattern of “consistent inconsistency.” Source: David Goodman, MD – Johns Hopkins Adult ADHD treatment center
    • 38. 105 Adult ADHD Drivers vs. 64 Controls (CC) • ADHD’ers self reported: – More citations (esp. for SPEEDING), crashes & license suspensions than CC • ADHD’ers: Barkley RA, et al. J Int. Neuropsychol Soc. 2002 (5):655762. – less attentive, made more errors on visual reaction task – Lower scores on driving rules test. • Driving difficulties: not related to “ODD”, depression, anxiety, or frequency of substance use.
    • 39. Drug, drug... who's got the drug?
    • 40. We are not there yet.
    • 41. Response to Psychostimulants Meta-analysis of Within-Subject Comparative Trials Evaluating Response to Stimulant Medications 50 41% 40 Best Response (Percent) Betting odds: Amph – 69% MPH 57% 28% 30 16% 20 10 0 AMP . MPH Equal response to either stimulant Arnold et al. J Attention Dis. 2000;3:200.
    • 42. Benefit-Risk Ratio and Efficacy of Psychostimulants • Very favorable benefit-risk ratio – rapid, dramatic results – low risk of long-term side effects • Approximately 70% of patients with ADHD will show a positive response on the first trial of any one stimulant medication • If two different stimulant medications are tried, the response rate increases to ~90% Greenhill. Child Adolesc Psychiatr Clin North Am. 1995;4:123; Spencer et al. JAACAP. 1996;35:409; Goldman et al. JAMA. 1998;279:1100.
    • 43. Amphetamines, methylphenidate, and antidepressants - important differences: Amphetamine - increases release and decreases uptake at the DOPAMINE uptake transporter (Seiden, et al., 1993) –effects release of DA from vesicles. –also allows dopamine to be released from newly synthesized pools inside the cell. –also activates 5-HT receptors (Sloviter, et al., 1978) –L-amphetamine = 50/50 NERI/DRI (Stahl, 2013) Methylphenidate - effects release of DA from vesicles only – inhibits dopamine reuptake, as well. Antidepressants: inhibit reuptake of NE and DA; do not cause release. [Atomoxetine = “NRI”]
    • 44. Atomoxetine • Superior to placebo (but slightly less effective than MPH) in large, double-blind, placebocontrolled trial-Heiligenstein, 2000 • Spencer et al. (JCAP 2001)-open study, 30 patients, 75% improved >25%. HCl O N H CH3 CH3 SE’s: rhinitis, headache, anorexia, dizziness, nervousness, somnolence • Michaelson (Pediatrics, 2001) ATX>PLB, best response at 1.2 mg/kg/day • Kratchovil (JAACAP, 2002) ATX=generic MPH, open-label study, inadequately powered Heiligenstein et al. Presented at AACAP, October 24-29, 2000 Spencer et al. J. Child Adolesc Psychopharmacol 2001: 11(3) 229-238
    • 45. ―Strattera* [coupled with fluoxetine or paroxetine] has been great for our admissions.‖ -Dr. William Beute, MD Pine Rest Campus Clinic Grand Rapids, MI * Brand name used in this slide because this is a direct quote April 21, 2004 [quoted with permission]
    • 46. “2P, or not 2P… …that is interaction.” NB: Cytochrome p450 2D6: - This is where atomoxetine is metabolized - It is inhibited by
    • 47. ―Alpha 2a agents‖ • Concept of SUSTAINED RELEASE AGENTS – generic instant release agents not the same • Extended release guanfacine – “1,2,3 or 4 mg at bedtime” • Extended release clonidine – “0.1 – 0.2mg (ER) twice daily (a.m. and pm)” • Both are approved for monotherapy or for add-on therapy. • Stimulants seem more potent; alpha-2 Rx seems to be better for oppositional/defiant symptoms, either by themselves or in combination therapy.
    • 48. STIMULANTS: Time Course Considerations 2 Classes: MPH or Amph Amphetamines MPH ~4 hrs MPH dexMPH 8 hrs 12 hrs MPH LA MPH ―CD‖ OROS-MPH D-amp Dex-MPH SR 4-5 hrs MPH Patch (12+) SR Liquid MPH-12 hrs 7-8 hrs 8-10-12 Dex spans AMP salts XR Mixed Lisamph salts dexamph Cady diagram, 2014 – includes current stimulants
    • 49. KEY TAKE HOME POINT! The drug level must Plasma Concentration Profiles Associated ASCEND during the day in order to keep the withtherapeutic effect STEADY. Different MPH Delivery Patterns Concentration (ng/mL) MPH TWICE DAILY MPH Oros 6 Flat – MPH sips 5 4 3 2 1 0 0 5 10 15 Time (h) Simulated plasma methylphenidate concentrations for 20-mg total daily dose delivered by twicedaily (BID), flat, and ascending dosing regimens. from Swanson J, et al. Clin Pharmacol Ther. 1999;66:295-305.
    • 50. ―Mixed salts of amphetamines, "handedness,‖ and efficacy Amphetamine mixed salts contains: –d - amphetamine sulfate (aka "Dexedrine") –d,l - amphetamine sulfate –d,l - amphetamine saccharate –D,l – amphetamine aspartate Dextro-amphetamine 2x as effective as lamphetamine –Smith & Davis, 1977; Janowsky & Davis, 1976
    • 51. The Arnold studies Randomized, double-blind, placebo controlled 31 children with “MBD” (1976) Rx: 5 mg of d-AMP; 7 mg l-AMP [difference d.t. MW's] CONCLUSIONS (replicated previous 1972 study of n=11): –Both agents found effective –Typically one agent was more effective than the other for individual children [Arnold LE, Huestis RD, Smeltzer DJ, et al. Levoamphetamine vs dextroamphetamine in minimal brain dysfunction. Arch Gen Psychiatry 33:292-301, 1976 Arnold LE, et al. Levoamphetamine and dextroamphetamine: Differential effects on aggression and hyperkinesis in children and dogs. Am J Psychiatry 130:165-170, 1973]
    • 52. Typically one agent was more effective than the other for individual children • d-AMP "appeared non-significantly more effective" • slightly better for "over-anxious" children • l-isomer - 2/3 of children improved • seemed to be of more benefit to "unsocialized-aggressive" kids • 28% of responders preferred the l-AMP form • “decreased tendency to blunt affect and produce the „amphetamine look‟ [sic]”
    • 53. Substance Use Disorders: Drugs of Abuse vs Meds for ADHD Drugs of Abuse Medications for ADHD Used to feel good Feel nothing or feel bad in overdose Users crave the drug Patients commonly forget to take medication Large and ready market exists Readily available but long-term use is rare A “struggle” to get kids to stop taking them A “struggle” to get kids to take them Courtesy of William Dodson, MD – Denver, Colorado
    • 54. Drug Delivery & Dosing adjustments
    • 55. OROS MPH – the first player GI liquid absorbed into osmotic matrix pump MPH pushed out the laser drilled hole at end of tablet
    • 56. Peaks & troughs… OROS MPH & OROS MPH – 18 mg Illustration from Alza promotional literature
    • 57. Mixed amphetamine salts “XR” system Immediate-Release Bead Delayed-Release Bead Bead Core Bead Core Drug Layer Drug Layer Overcoating Release-Delaying Polymer Overcoating 50% 50% Overcoating Capsule Available in 5, 10, 15, 20, 25, and 30 mg dosing forms
    • 58. Chemical Structure of Lis-dexamfetamine O O CH 3 H2 N H2 N N H Rate-limited OH + Hydrolysis CH3 H2 N Site of cleavage NH 2 Lisdexamfetamine (Prodrug) NH 2 l-lysine d-amphetamine (active)  Lis-dexamfetamine is a prodrug that is therapeutically inactive until it is converted to active d-amphetamine in the body
    • 59. Charged polymer sustained delivery technology 12 hour sustained release LIQUID MPH
    • 60. Basic MPH 101 • How much to Rx?! • Old dosing charts show 0.3 – 0.7 mg/kg/dose – But only “1.5 mg/kg/day”…. • But THREE doses of 0.3 – 0.7 mg/kg/dose = 0.9 – 2.1mg/kg/day • THEREFORE, theoretical maximum should be ―2.1 mg/kg/day‖ (the ―Biederman max‖) • But what is that really, in “Hoosier-speak”?
    • 61. Cady/Desiderato Factor-Label, DownHome, Good-Ole Boy MPH Calculation: 1 Kg 2.1mg MPH = X Kg ONE milligram 2.2 lbs Lys-dexamph, amphetamine salts, dex amph, dex-MPH = ½ the typical amount of methylphenidate pound of kid 1mg / lb of kid / day spread out over 12 hours, OR About ½ that for amphetamines or dex-MPH
    • 62. So how much to dose? • No correlation between plasma level and therapeutic response: – Big levels in small kids – Small levels in big kids • All medication titrations should be made by informed, observant clinicians with good solid follow-up and examinations • Titrations should be based on DYSFUNCTION
    • 63. M.D. does not stand for ―minor deity‖ • Start lower than you think you probably should. • Push it carefully until you get results – a “just right” therapeutic effect – absent side effects • Use the “Biederman max” as a rough rule of thumb to calculate the “ceiling,” NOT TO START! • If you have to “break through the ceiling” – think carefully, document your rationale, monitor carefully for side effects, HTN, cardiac issues • Explain both the “Goldilocks” and the “Cinderella” aspects to patients/parents
    • 64. How to screw it up: a case study • 1/28/14 – 7 year old child presents for tx • Oct 2013 – dx’ed with ADHD • RX: – Started on 30 mg lys-dexamph from start • Zombied out for two days – Dosage reduced to 15 mg. Worked well for 3 weeks. “I like the way my brain is working.” – Began hearing voices in his head at night. • Medication stopped • Voices persisted over the next 2 weeks, then d/c
    • 66. Case of the ―disorganized daughter‖ • 7/18/12 – 29 yo MWF presents with classic hypomania, sleep deprivation and psychosis. – Known history of opioid abuse and dependence. • Per mother: “severe insomnia, mood swings, periodic fits of rage followed by sadness/crying; difficulty concentrating; flight of ideas, trouble managing daily activities; little impulse control” • Noted to have elevated symptoms of ADHD on initial rating scales
    • 67. TREATMENT COURSE • By 8/28/2012, stabilized on: – Paloperidone 6 mg daily + Benztropine 1 mg three times daily – Lamotrigine started with plan to cross titrate. – Started on PNV with Fe and DHA due to low iron. • Further history: used opioids to sleep. • Essentially psychiatrically stable. Euthymic. • Viewed as stable enough to take Quotient test.
    • 69. STATS: • ATTENTIVE • Impulsive • Distracted • Disengaged 7.5% (!!!) of the time 47.5% of the time 32.5% of the time 12.5% of the time
    • 70. Patient’s response to the Quotient results: • “Wow, that’s really bad isn’t it?!” • Asked if she had had severe problems with attention in school. • “Well, there’s actually something I’ve never told you…”
    • 71. More history, more treatment • “I actually used cocaine [therapeutically] before school( in high school) to concentrate.” – Set the curve in all of her finals in her junior year. – Stopped it in her senior year – Used opioid (Lortabs) throughout college to study and focus. (“It made me awake and helped me do stuff.”). • Now concerned about her ability to focus. • Brother, in law school, recently dx’ed with ADD. On mixed amphetamine salts. Doing much better.
    • 72. Current status: disorganized daughter • RX: – Lurasidone – 80 mg HS (bipolar) – Lamotrigine – 50 mg per day (bipolar - & couldn’t go up) – Vilazodone – 30 mg in the a.m.(for OCD symptoms) – Lisdexamphetamine – 50 mg capsule in a.m. for ADHD • Supplements: – L-tyrosine, PNV with Fe and DHA • Status – perfect function and focus.
    • 73. Key take-aways from this case • Don’t let a substance abuse disorder give you a constricted field of logic. • Affective disorders and ADHD can coexist. • Frequently ADHD’ers have used illegal drugs or tried their kid’s stimulant. • Avoid Puritanical blame/self-righteousness: – Many ADHD’ers (and affective disorder patients) fall into alcohol, marijuana, and other drugs in an attempt to self-treat • Treat the primary problem first.
    • 74. Need for systems approach
    • 75. At home: Two great ―how to do it‖ books
    • 76. Therapy Axioms: who needs it, when to do it • The later a child (or adult) is diagnosed, the more complications (s)he has had, and the more conflict – the higher the likelihood of need for psychotherapy • The converse applies. • The higher the level of family dysfunction, the more the need for: – “parent training” – Behavioral therapies, etc.
    • 77. Inventor of NASDAQ screen – Strong family hx of ADHD – Dx’ed at 48 yoa – Interviewed in Time Square – “Don’t you feel proud?” –―Not really – all my life, people were telling me I would never amount to anything.‖ Quote & identity used by specific permission of David Goodman, MD & his patient
    • 78. Note: unstandardized co-efficients • Prospective 33 year follow up of 135 white boys with ADHD (w/p CD) in childhood & 136 matched comparators w/o ADHD • ―Development of CD/APD accounted for the relationship between ADHD & risk-taking.‖ from: Olazagasti MAR, et al J Am Child Adolesc Psychiatry 2014, Feb 1. published online 2013 January 5 doi:10.1016/j.aaac.2012.11.012
    • 79. Integrated: how to avoid over-reliance on meds • Smart prescribing! • School: – Excellent working relationships with school – Good teaching • HOME: – – – – – Diminish “electronic screens” effect Good home discipline Good sleep/wake schedules Good diet Adequate exercise • Parent training: parenting, stress tips
    • 80. “There are things known and there are things unknown, and in between are the doors.” - Jim Morrison
    • 81. ―Probably the most interesting period of medicine has been that of the last few decades. So rapid has been this advance, as new knowledge developed, that the truth of each year was necessarily modified by new evidence, making the truth an ever-changing factor.‖ Plummer Building lobby. Photo: © Louis B. Cady, MD 2004
    • 82. Contact information: Louis B. Cady, M.D. Office: 812-429-0772 E-mail: 4727 Rosebud Lane – Suite F Interstate Office Park Newburgh, IN 47630 (USA)
    • 83. Q & A – and answers • Previous epidemiological data suggested prevalence of ADHD in 3 – 7% of school-aged children. According to more recent CDC data (2009) the prevalence is probably around 9% for this group. – TRUE • Actually, the reported dx of ADHD by current providers is much higher in the TriState (Indiana, Illinois, & Kentucky), ranging from approximately 7 – 15%. (per CDC Vital & Health Statistics, 1997-2006) - TRUE • SPECT imaging, as well as PET and functional MRI, may be a useful way to look at the living brain and observe functioning. – TRUE
    • 84. Q & A – and answers • Here is a comparison and contrast of DSM-IV (in use until January 1, 2014, and DSM-5 (FIVE) in current use.) Either ALL of the following statements are true, or ALL of them are false. - There are nine symptoms in each domain – nine for inattentiveness and nine for hyperactivity and impulsivity – In DSM-IV, the previous diagnosis criteria specified that any symptoms used for diagnosis much be present before the age of 7 (SEVEN) – In DSM-V, the current diagnostic criteria specify that the child (or adult) must have the requisite number of symptoms before the age of 12 (TWELVE). – The difference between the “cutoff” for diagnosis for ADULTS between DSM-IV and DSM-5 (FIVE) is that in DSM-IV, for the full diagnosis, you had to have at least 6 symptoms in either domain, and now in DSM-5 (FIVE) you just have to have FIVE symptoms as an adult to qualify. ALL of these statements TRUE
    • 85. Q & A – and answers • According to common dosing guidelines and the presented “Cady/Desiderato Good Old Boy Down-Home Guide to Dosing Stimulants,” the theoretical MAXIMUM of methylphenidate products should be 1 mg of methylphenidate per pound of kid per day, and amphetamines should be half that: e.g., ½ mg per lb of kid per day. – • TRUE 30 mg of Lisdexamfetamine (brand name = Vyvanse ®)* = 30 mg of amphetamine equivalents for dosing calculations. [*note – brand name is cited here for this medication because this medication is not in generic circulation at this time, and most practitioners will not recognize the generic name.] – FALSE (oops – this was not covered this a.m.) • • Explanation: 30 mg of Vyvanse = 10 mg amphetamine; 50 mg Vyvanse = 20 mg amphetamine; 70 mg of Vyvanse = 30 mg of amphetamine. This is a common dosing error by well meaning pediatricians – confusing Vvanse and amphetamine doses. Sorry for not presenting this. According to presented data and recommendation, the two longest acting and smoothest agents in class are lisdexamfetamine and liquid 12 hour sustained release methylphenidate. – TRUE It was a great pleasure to present to you this morning! Hope the “Q & A” was helpful. I will be back on April 2nd to present another CME lecture on the use of TMS (transcranial magnetic stimulation) and depression.