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Jefferson B. Jefferson B. Prince, M.D. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical ADHD Across the Lifespan: Presentation, Impact, Diagnosis & Pharmacotherapy
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Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center ADHD Across the Lifespan: Presentation, Impact,

Dec 16, 2015

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Page 1: Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center ADHD Across the Lifespan: Presentation, Impact,

Jefferson B. Prince, M.D.Jefferson B. Prince, M.D.

Massachusetts General HospitalHarvard Medical SchoolNorth Shore Medical Center

ADHD Across the Lifespan: Presentation, Impact, Diagnosis & Pharmacotherapy

Page 2: Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center ADHD Across the Lifespan: Presentation, Impact,

Metabolism of Methylphenidate vs. Amphetamine

MPH AMPH

Hydrolysis & Deesterrifcation

Parahydroxy-methylphenidate

Ritalinic Acid

Oxidative Deamination

Ring Hydroxylation

80% unchanged

in urine

Hipuric Acid

Benzoic Acid

Hydroxyamphetamine metabolite

MPH does not usually show on routine urine drug MPH does not usually show on routine urine drug screeningscreening

Page 3: Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center ADHD Across the Lifespan: Presentation, Impact,

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 Practice Parameter for the Use of Stimulant Medication in the Treatment of Children, Adolescents and Adults JAACAP (2002) 41 (2) suppl 26S-49SChildren, Adolescents and Adults JAACAP (2002) 41 (2) suppl 26S-49S

Page 4: Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center ADHD Across the Lifespan: Presentation, Impact,

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. Zametkin & Ernst. N Eng J MedN Eng J Med 1999;340:40 1999;340:40

Wilens, Biederman & Spencer Attention Deficit Hyperactivity Disorder Ann Rev Med (2002) 53: 113-31Wilens, 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 Practice Parameter for the Use of Stimulant Medication in the Treatment of Children, Adolescents and Adults JAACAP (2002) 41 (2) suppl 26S-49SAdults JAACAP (2002) 41 (2) suppl 26S-49S

Page 5: Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center ADHD Across the Lifespan: Presentation, Impact,

Treating Adults with ADHD Using Stimulants

• Phase 2: Titrating to Optimal Effect– Forced Titration or Titrate to optimal effect (inverted U)

• MTA or Children’s 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. Zametkin & Ernst. N Eng J MedN Eng J Med 1999;340:40 1999;340:40

Wilens, Biederman & Spencer Attention Deficit Hyperactivity Disorder Ann Rev Med (2002) 53: 113-31Wilens, 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 Practice Parameter for the Use of Stimulant Medication in the Treatment of Children, Adolescents and Adults JAACAP (2002) 41 (2) suppl 26S-49SAdults JAACAP (2002) 41 (2) suppl 26S-49S

Page 6: Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center ADHD Across the Lifespan: Presentation, Impact,

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. Zametkin & Ernst. N Eng J MedN Eng J Med 1999;340:40 1999;340:40

Wilens, Biederman & Spencer Attention Deficit Hyperactivity Disorder Ann Rev Med (2002) 53: 113-31Wilens, 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 Practice Parameter for the Use of Stimulant Medication in the Treatment of Children, Adolescents and Adults JAACAP (2002) 41 (2) suppl 26S-49SAdults JAACAP (2002) 41 (2) suppl 26S-49S

Page 7: Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center ADHD Across the Lifespan: Presentation, Impact,

Attention Deficit Hyperactivity DisorderPharmacological TreatmentStimulants Methylphenidate Amphetamine compounds Dextroamphetamine Non-stimulant

AtomoxetineAntidepressants 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 Updated 2003 from Wilens T, Biederman J, Spencer T. ADHD, In Annual Review of MedicineAnnual Review of Medicine, 2002: 53. And , 2002: 53. And

Greenhill L. Childhood attention deficit hyperactivity disorder: pharmacological treatments. In: Nathan PE, Greenhill L. Childhood attention deficit hyperactivity disorder: pharmacological treatments. In: Nathan PE,

Gorman J, eds. Gorman J, eds. Treatments That Work. Treatments That Work. Philadelphia, Pa: Saunders; 1998:42-64.Philadelphia, Pa: Saunders; 1998:42-64.

Page 8: Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center ADHD Across the Lifespan: Presentation, Impact,

Background and Rationale

• Initially tested as Antidepressant (≈1200 adults)• High affinity for norepinephrine reuptake inhibition• Low affinity for other receptors

– (cholinergic, histaminic, serotonergic, -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 >4,000» >1 yr 169 >1,000

Atomoxetine in ADHD

Page 9: Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center ADHD Across the Lifespan: Presentation, Impact,

• PDR Recommendations – Not controlled so can give samples, refills & call in prescriptions

Start ≈ 0.5 mg/kg/dTarget 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

Dosing of Atomoxetine in Adults with ADHD

Page 10: Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center ADHD Across the Lifespan: Presentation, Impact,

Tolerability of Atomoxetine in Combined Adult Studies

Event Atomoxetine

(N=269)

Placebo

(N=263)

P Value Discontinuations

Dry Mouth 21 6 <.001 0

Insomnia 13 6 .013 3

Nausea 12 5 .005 1

Constipation 10 4 .009 0

Appetite 10 3 <.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 >2% 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;

Page 11: Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center ADHD Across the Lifespan: Presentation, Impact,

Tricyclics

MAOIs Includes RIMA

Bupropion

Tomoxetine

ABT-418

N=33

N=1

N=7

N=5

N=2

Alpha-adrenergic

N=7

N=4

N=1

Venalfaxine

BuspironeN= 1,829 subjects

Studies of Non-Stimulant Treatments in ADHD (controlled & uncontrolled)

Page 12: Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center ADHD Across the Lifespan: Presentation, Impact,

Modafanil in Adults with ADHD

05

10152025303540

4550

Placebo D-Amphet Modafanil Both Neither

Taylor et al., (2000) JCAP 10 (4): 311-20Taylor et al., (2000) JCAP 10 (4): 311-20

% R

esp

ond

ers

Response defined as >30% reduction in ADHD sympotoms

Optimal dosing in completers: Dex 22 Optimal dosing in completers: Dex 22 9 mg/d; Modafanil 207 9 mg/d; Modafanil 207 85 mg/d 85 mg/d

Page 13: Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center ADHD Across the Lifespan: Presentation, Impact,

11MTA Cooperative Group. MTA Cooperative Group. Arch Gen Psychiatry.Arch Gen Psychiatry. 1999;56:1076-1086. 1999;56:1076-1086.22Barkley R. Barkley R. Attention-deficit Hyperactivity Disorder. A Handbook for Diagnosis and TreatmentAttention-deficit Hyperactivity Disorder. A Handbook for Diagnosis and Treatment , ed 2., ed 2.

New York: Guilford Pr, 1993.New York: Guilford Pr, 1993.33Biederman J, et al. Biederman J, et al. Am J Psychiatry.Am J Psychiatry. 1991;148:565-577. 1991;148:565-577.44Milberger S, et al. Milberger S, et al. J Am Acad Child Adolesc Psychiatry.J Am Acad Child Adolesc Psychiatry. 1997;36:37-44. 1997;36:37-44.55Biederman J, et al. Biederman J, et al. J Am Acad Child Adolesc Psychiatry.J Am Acad Child Adolesc Psychiatry. 1997;36:21-29. 1997;36:21-29.

Oppositional

defiantdisorder1

Anxietydisorders3

Learningdifficulties2

Mooddisorders2

Conduct disorder3

Smoking4 Substanceuse

disorder5

Language disorder2

Comorbid Conditions:Children and Adolescents40%

30-35%

20-25% 15-25%

15-20% 20% 19%15%

0

5

10

15

20

25

30

35

40

45

(%)

Page 14: Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center ADHD Across the Lifespan: Presentation, Impact,

Lifetime Psychiatric Diagnoses in Adults with ADHD

0 10 20 30 40 50 60

Antisocial

LD

Major Depression

Bipolar

Anxiety Disorders

Substance Use Disorders

Biederman et al., (1993) AJP 150(12): 1792-8Biederman et al., (1993) AJP 150(12): 1792-8

Shekim et al., (1990) Comprehensive Psychiatry 31(5): 416-25Shekim et al., (1990) Comprehensive Psychiatry 31(5): 416-25

Page 15: Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center ADHD Across the Lifespan: Presentation, Impact,

Lifetime Comorbidity of ADHD with Other Psychiatric Disorders

0 10 20 30 40

MajorDepression(1)

BipolarDisorder(2)

GAD(3)

SubstanceAbuse(4)

11Alpert et al., (1996) Psychiatric Research 62 (3): 213-9Alpert et al., (1996) Psychiatric Research 62 (3): 213-9

22Nierenberg et al., (2002) data presented at APA, Philadelphia, PANierenberg et al., (2002) data presented at APA, Philadelphia, PA

33Pollack et al., (1995) Psych Clinics of North America 18(4): 745-66Pollack et al., (1995) Psych Clinics of North America 18(4): 745-66

44Levin & Kleber (1994) Harvard Rev Psych 2(5): 246-58 Levin & Kleber (1994) Harvard Rev Psych 2(5): 246-58

Page 16: Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center ADHD Across the Lifespan: Presentation, Impact,

Is ADHD Pharmacotherapy a Risk Factor for Subsequent

Substance Abuse?

• 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 preclinical1,2

and human3,4 studies

• Evaluation of 674 medicated and 360 unmedicated patients with ADHD followed into adolescence(2 studies) or adulthood (4 studies)5

Summary of Meta-analysis

1. Kollins SH, et al. Pharmacol Biochem Behav. 2001;68(3):611-627. 2. Garasimov, et al. J Clin Pharm Ther. 2001. 3. Biederman J, et al. Pediatrics. 1999;104(2):20. 4. Lambert NM, Hartsough CS. J Learn Disabil. 1998;31(6):533-544. 5. Wilens TE, et al. Pediatrics. 2003;111:179-185.

Page 17: Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center ADHD Across the Lifespan: Presentation, Impact,

Is ADHD Pharmacotherapy a Risk Factor for Subsequent

Substance Abuse? (cont.)

• 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 ratio=1.9)

• 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. 2003;111:179-185.

Summary of Results of Meta-analysis

Page 18: Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center ADHD Across the Lifespan: Presentation, Impact,

ADHD+Substance AbuseTreatment Strategies: Pharmacotherapy

• 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

Initiating Pharmacotherapy: How Soon?

Riggs, et al. J Am Acad Child Adolesc Psychiatry. 1998;37.Riggs. Science and Clinical Perspectives. vol. 2 , in press.Wilens TE. Alcohol Health Res World. 1998;22(2):127-130.

Page 19: Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center ADHD Across the Lifespan: Presentation, Impact,

ADHD+Substance 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. 1998:37.Waxmonsky & Wilens. Adolesc SUD in Pediatric Psychopharmacology. 2003.

Page 20: Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center ADHD Across the Lifespan: Presentation, Impact,

0

10

20

30

40

Baseline Week 0 Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Bupropion in Adults With ADHD+SUD

Retention in TrialRetention in Trial

Fre

qu

en

cy

N=19

N=32

Dropout Rate= 41%

• Open study of adults with ADHD+mixed SUD

• Referred out for SUD counseling

• Dosing with bupropion to 200 mg SR bid by week 4

Prince JB, et al. Presented at: 155th APA Annual Meeting; May 18-23, 2002; Philadelphia, Pa.

Page 21: Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center ADHD Across the Lifespan: Presentation, Impact,

Bupropion SR in Adults WithADHD+SUD (cont.)

Reductions in Symptoms for Baseline to Endpoint (LOCF)

-20

-15

-10

-5

0

ADHD Sx

AD

HD

RS

Baseline=34

p.001

(-46%)

Prince JB, et al. Presented at: 155th APA Annual Meeting; May 18-23, 2002; Philadelphia, Pa.

-2.0

-1.5

-1.0

-0.5

0.0

p.001

(-22%)

SUD

Baseline=4

SU

D C

GI

Page 22: Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center ADHD Across the Lifespan: Presentation, Impact,

ADHD+Substance Use DisordersTreatment Strategies: Pharmacotherapy

• Pharmacotherapy—important aspect of multimodal treatment

• Pharmacotherapy—first-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. Riggs, et al. J Am Acad Child Adoles Psychiatry.J Am Acad Child Adoles Psychiatry. 1998;37. 1998;37.Wilson & Levin. Wilson & Levin. Curr Psych RepCurr Psych Rep. 2001;3:497-506.. 2001;3:497-506.

Waxmonsky & Wilens. Waxmonsky & Wilens. Adolesc SUD in Pediatric Psychopharmacology.Adolesc SUD in Pediatric Psychopharmacology. 2003. 2003.

Page 23: Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center ADHD Across the Lifespan: Presentation, Impact,

ADHD+Substance 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. Riggs and Davies, 2002; Riggs. Science & Clinical Perspectives.Science & Clinical Perspectives. 2003;vol 2 (in press). 2003;vol 2 (in press).

Page 24: Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center ADHD Across the Lifespan: Presentation, Impact,

Diagnosis & Assessment of ADHD

Summary• 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

Page 25: Jefferson B. Prince, M.D. Massachusetts General Hospital Harvard Medical School North Shore Medical Center ADHD Across the Lifespan: Presentation, Impact,

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