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
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
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
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
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
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
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
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.
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
• 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
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;
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)
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
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
(%)
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
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
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.
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
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.
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.
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.
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
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.
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).
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
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