Jefferson B. Prince, M.D.

1
ADHD Across the Lifespan Presentation, Impact,
Diagnosis Pharmacotherapy
Jefferson B. Prince, M.D. Massachusetts
General Hospital Harvard Medical School North
Shore Medical Center
2
Metabolism of Methylphenidate vs. Amphetamine
MPH
AMPH
Oxidative Deamination Ring Hydroxylation
Hydrolysis Deesterrifcation
80 unchanged in urine
Hipuric Acid Benzoic Acid Hydroxyamphetamine
metabolite
Parahydroxy-methylphenidate
Ritalinic Acid
MPH does not usually show on routine urine drug
screening
3
Use of Stimulants to Treat ADHD

• The literature does not help the clinician
  choose the best stimulant for an individual
  patient. Group studies of psychostimulants-MPH,
  DEX, AMP-generally fail to show significant
  differences between MPH, DEX, AMP. Conversely,
  there are large individual differences in
  response to different drugs and doses.
  Therefore, the best order of their presentation
  for a particular patient is unknown. MPH, DEX,
  AMP may be used first, on the basis of the
  inclination of the physician and the parent.

Practice Parameter for the Use of Stimulant
Medication in the Treatment of Children,
Adolescents and Adults JAACAP (2002) 41 (2) suppl
26S-49S
4
Treating Adults with ADHD Using Stimulants

• Phase 1 Starting a Stimulant
• Choose MPH, DEX, AMP
• Immediate Release or Extended Delivery (varies
  per circumstance)
• ? Rating Scales vs Anchor points
• (baseline and follow-up vs significant other
  info)
• (CAARS, ADHD-RS, SNAP-IV, WRAADDS)

Zametkin Ernst. N Eng J Med 199934040 Wilens,
Biederman Spencer Attention Deficit
Hyperactivity Disorder Ann Rev Med (2002) 53
113-31 Practice Parameter for the Use of
Stimulant Medication in the Treatment of
Children, Adolescents and Adults JAACAP (2002) 41
(2) suppl 26S-49S
5
Treating Adults with ADHD Using Stimulants

• Phase 2 Titrating to Optimal Effect
• Forced Titration or Titrate to optimal effect
  (inverted U)
• MTA or Childrens Texas Medication Algorithm
• Adjust dose often?
• Medication should be given 7 days/week during
  initiation of therapy and through titration to
  optimal effect
• This strategy allows significant others of adult
  receiving medication to observe medication
  effects, benefits, side effects in multiple
  settings (e.g., home, work)

Zametkin Ernst. N Eng J Med 199934040 Wilens,
Biederman Spencer Attention Deficit
Hyperactivity Disorder Ann Rev Med (2002) 53
113-31 Practice Parameter for the Use of
Stimulant Medication in the Treatment of
Children, Adolescents and Adults JAACAP (2002) 41
(2) suppl 26S-49S
6
Treating Adults with ADHD Using Stimulants

• Phase 3 Monitoring the Stimulant
• ? N of 1 with alternative stimulant (MPH, DEX,
  AMP)
• If choose IR then consider switch to Extended
  Delivery
• ? Rating Scales (baseline and follow-up vs
  caregiver info)
• (CPRS-R, CTRS-R, ADHD-RS, SNAP-IV, IOWA-CTRS)
• After titration to optimal dose then continue 7
  days/wk or or sculpt to situation?
• Monitor for
• side effects (frequency severity)
• adherence
• comorbidity (adjust stimulant as necessary)

Zametkin Ernst. N Eng J Med 199934040 Wilens,
Biederman Spencer Attention Deficit
Hyperactivity Disorder Ann Rev Med (2002) 53
113-31 Practice Parameter for the Use of
Stimulant Medication in the Treatment of
Children, Adolescents and Adults JAACAP (2002) 41
(2) suppl 26S-49S
7
Attention Deficit Hyperactivity Disorder
Pharmacological Treatment
Stimulants Methylphenidate
Amphetamine compounds Dextroamphetamine
Non-stimulant Atomoxetine Antidepressants
Tricyclics Bupropion Antihypertensives
Clonidine Guanfacine Miscellaneous
Combined pharmacotherapy Magnesium Pemoline
(monitor for hepatic toxicity) Modafanil
Venlafaxine Cholinergic agents (i.e.
donezepil) Neuroleptics (only in severe
cases with monitoring)
Recently Approved Treatment for ADHD
Updated 2003 from Wilens T, Biederman J, Spencer
T. ADHD, In Annual Review of Medicine, 2002 53.
And Greenhill L. Childhood attention deficit
hyperactivity disorder pharmacological
treatments. In Nathan PE, Gorman J, eds.
Treatments That Work. Philadelphia, Pa Saunders
199842-64.
8
Background and Rationale
Atomoxetine in ADHD

• Initially tested as Antidepressant (1200 adults)
• High affinity for norepinephrine reuptake
  inhibition
• Low affinity for other receptors
• (cholinergic, histaminic, serotonergic, a-1,2
  adrenergic)
• Minimal direct cardiac effect
• No apparent effect on lab values, no need to
  monitor level
• Metabolized through 2D6 (but does not inhibit)
• Plasma half-life 5 hours but CNS effects much
  longer
• enables QD dosing in most pts
• Patient Experience Oct 2001 (NDA)
  2003
• Total 1,982 gt4,000
• gt1 yr 169
  gt1,000

9
Dosing of Atomoxetine in Adults with ADHD

• PDR Recommendations
• Not controlled so can give samples, refills
  call in prescriptions
• Start 0.5 mg/kg/d
• Target 1.2 mg/kg/d with max of 1.4 mg/kg/d or
  100 mg/d
• 185 man
• Start 18, 25 or 40 mg for 4-7 days in AM after
  food
• 25 mg for 4-7 days then increase to 40 mg for 4-7
  days then 60 mg
• If already on stimulant, typically stop
  stimulant, introduce ATMX then reevaluate need
  for stimulant
• Available in 10mg, 18mg, 25mg, 40mg, 60mg
• Sprinkling not formally tested and may irritate
  GI tract
• Drug Interactions (contraindicated with MAOIs)
• Decrease dose if coadminister with strong 2D6
  inhibitor (fluoxetine, quinidine)
• Coadministration with iv Albuterol (600 ug over 2
  hours) associated with mild increases in HR and
  BP
• Coadministration with methlyphenidate appears
  well tolerated but not fully studied
• Cost 3/capsule

10
Tolerability of Atomoxetine in Combined Adult
Studies
Event Atomoxetine (N269) Placebo (N263) P Value Discontinuations
Dry Mouth 21 6 lt.001 0
Insomnia 13 6 .013 3
Nausea 12 5 .005 1
Constipation 10 4 .009 0
? Appetite 10 3 lt.001 0
Dizziness 6 2 .015 0
? Libido 6 2 .010 1
Erectile Disturbance 7 1 .006 1
Dysmennorhea 7 3 .331 0
Urinary Retention 3 0 .015 2
Events reported by gt2 of pts treated with ATMX
and at least twice rate of placebo Nausea
Dyspepsia, fatigue observed significantly more
often in QD compared to BID trials
11
Studies of Non-Stimulant Treatments in ADHD
(controlled uncontrolled)
N1
N2
Tricyclics
N7
N1
MAOIs Includes RIMA
N33
N5
Bupropion
Venalfaxine
N4
Alpha-adrenergic
N7
Tomoxetine
ABT-418
Buspirone
N 1,829 subjects
12
Modafanil in Adults with ADHD
Response defined as gt30 reduction in ADHD
sympotoms
Responders
Optimal dosing in completers Dex 22 ? 9 mg/d
Modafanil 207 ? 85 mg/d
Taylor et al., (2000) JCAP 10 (4) 311-20
13
Comorbid ConditionsChildren and Adolescents
45
40
40
30-35
35
30
20-25
15-25
25
()
15-20
20
19
20
15
15
10
5
0
Oppositional defiant disorder1
Anxiety disorders3
Learning difficulties2
Mood disorders2
Conduct disorder3
Smoking4
Substance use disorder5
Language disorder2
1MTA Cooperative Group. Arch Gen Psychiatry.
1999561076-1086. 2Barkley R. Attention-deficit
Hyperactivity Disorder. A Handbook for Diagnosis
and Treatment, ed 2.New York Guilford Pr,
1993. 3Biederman J, et al. Am J Psychiatry.
1991148565-577. 4Milberger S, et al. J Am Acad
Child Adolesc Psychiatry. 19973637-44. 5Biederma
n J, et al. J Am Acad Child Adolesc Psychiatry.
19973621-29.
14
Lifetime Psychiatric Diagnoses in Adults with ADHD
Biederman et al., (1993) AJP 150(12)
1792-8 Shekim et al., (1990) Comprehensive
Psychiatry 31(5) 416-25
15
Lifetime Comorbidity of ADHD with Other
Psychiatric Disorders
1Alpert et al., (1996) Psychiatric Research 62
(3) 213-9 2Nierenberg et al., (2002) data
presented at APA, Philadelphia, PA 3Pollack et
al., (1995) Psych Clinics of North America 18(4)
745-66 4Levin Kleber (1994) Harvard Rev Psych
2(5) 246-58
16
Is ADHD Pharmacotherapy a Risk Factor for
SubsequentSubstance Abuse?
Summary of Meta-analysis

• Concerns linger as to the ultimate risk that
  stimulant pharmacotherapy begets on the
  development of SA in ADHD youths growing up
• Discordant findings in the literature for
  preclinical1,2and human3,4 studies
• Evaluation of 674 medicated and 360 unmedicated
  patients with ADHD followed into adolescence(2
  studies) or adulthood (4 studies)5

1. Kollins SH, et al. Pharmacol Biochem Behav.
200168(3)611-627. 2. Garasimov, et al. J Clin
Pharm Ther. 2001. 3. Biederman J, et al.
Pediatrics. 1999104(2)20. 4. Lambert NM,
Hartsough CS. J Learn Disabil. 199831(6)533-544.
5. Wilens TE, et al. Pediatrics.
2003111179-185.
17
Is ADHD Pharmacotherapy a Risk Factor for
SubsequentSubstance Abuse? (cont.)
Summary of Results of Meta-analysis

• 5/6 studies do not support that stimulants
  increase SA
• 4/6 studies indicate reduced risk for SA in
  treated vs untreated ADHD individuals (odds
  ratio1.9)
• No difference in drug or alcohol disorder risk
  reduction
• Risk reduction greater in adolescents than adults

Treatment of ADHD reduces the risk for SA by
one-half
Wilens TE, et al. Pediatrics. 2003111179-185.
18
ADHDSubstance AbuseTreatment Strategies
Pharmacotherapy
Initiating Pharmacotherapy How Soon?

• If adolescent engaged in substance
  treatment/motivated with good alliance and
  evidence of abstinence or significant reduction
  in use (UA and self report)
• May initiate pharmacotherapy early in treatment
  if mechanism to closely monitor
• compliance with meds, target symptom response
• substance treatment and progress
• urine toxicology results

Riggs, et al. J Am Acad Child Adolesc Psychiatry.
199837.Riggs. Science and Clinical
Perspectives. vol. 2 , in press. Wilens TE.
Alcohol Health Res World. 199822(2)127-130.
19
ADHDSubstance AbusePharmacotherapy

• Choose Medications with lowest abuse potential
• Antidepressants
• Bupropion
• Other
• Atomoxetine ?
• Stimulants
• Magnesium pemoline
• Methylphenidate
• Amphetamine compounds
• Alternatives
• Antihypertensives (juveniles)
• Combined pharmacotherapy

Riggs, et al. J Am Acad Child Adolesc Psychiatry.
199837. Waxmonsky Wilens. Adolesc SUD in
Pediatric Psychopharmacology. 2003.
20
Bupropion in Adults With ADHDSUD

• Open study of adults with ADHDmixed SUD
• Referred out for SUD counseling
• Dosing with bupropion to 200 mg SR bid by week 4

Retention in Trial
N32
N19
Frequency
Dropout Rate 41
Prince JB, et al. Presented at 155th APA Annual
Meeting May 18-23, 2002 Philadelphia, Pa.
21
Bupropion SR in Adults WithADHDSUD (cont.)
ADHD Sx
SUD
Baseline4
Baseline34
(-22)
(-46)
SUD CGI
ADHD RS
p?.001
p?.001
Reductions in Symptoms for Baseline to Endpoint
(LOCF)
Prince JB, et al. Presented at 155th APA Annual
Meeting May 18-23, 2002 Philadelphia, Pa.
22
ADHDSubstance Use DisordersTreatment
Strategies Pharmacotherapy

• Pharmacotherapyimportant aspect of multimodal
  treatment
• Pharmacotherapyfirst-line treatment for ADHD
• Weigh risk/benefit of pharmacotherapy for
  ADHD/comorbidity
• Adverse interactions-medications with drugs of
  abuse versus
• Delay in diagnosis treatment ADHD (other
  comorbidity) may
• Result in poor substance treatment
  retention/outcomes
• Legal consequences vs treatment

Riggs, et al. J Am Acad Child Adoles Psychiatry.
199837.Wilson Levin. Curr Psych Rep.
20013497-506.Waxmonsky Wilens. Adolesc SUD
in Pediatric Psychopharmacology. 2003.
23
ADHDSubstance Use DisordersTreatment
Considerations

• If no improvement in 2 months (or clinical
  deterioration), consider
• Medication change
• adverse effects of medication / interaction with
  substances of abuse?
• ? efficacy
• ? compliance with medication/other psychiatric
  treatment?
• Reassess psychiatric diagnostic formulation
  (e.g., ADHD vs bipolar?)
• Reassess substance abuse
• ? escalation in use polydrug use
• Compliance with substance treatment?
• Deterioration in psycosocial functioning?
• More intensive treatment
• Increased frequency of therapy, monitoring
• Increased level of care (e.g., residential
  inpatient)
• Consultation/referral to treatment specialist

Riggs and Davies, 2002 Riggs. Science Clinical
Perspectives. 2003vol 2 (in press).
24
Diagnosis Assessment of ADHDSummary

• ADHD
• affects millions of people of both genders
• persists through adolescence and adulthood in a
  high percentage of cases
• Adversely Impact Development across lifespan
• Family
• Academics/Occupation
• Behavior
• Diagnosis relies strongly on DSM-IV criteria in
  domains of
• inattention
• impulsivity
• hyperactivity
• Diagnostic assessment includes a thorough
  gathering of information from multiple sources

25
Summary Update on Pharmacotherapy of ADHD

• Stimulants and Atomoxetine are FDA approved
  first line agents
• Antidepressants (TCAs Bupropion) are second
  line agents
• Antihypertensives are alternative agents
• typically used adjunctly with other meds
• Combined pharmacotherapy for incomplete
  response or comorbid cases
• Current research
• New stimulant delivery systems (patch)
• Modafanil
• Cholinergic agents Achetylcholinesterase
  inhibitors