Transcript Metabolism of Methylphenidate vs. Amphetamine

ADHD Across the Lifespan:
Presentation, Impact,
Diagnosis & Pharmacotherapy
Jefferson B. Prince, M.D.
Massachusetts General Hospital
Harvard Medical School
North Shore Medical Center
Metabolism of Methylphenidate
vs. Amphetamine
MPH
AMPH
Oxidative Deamination
Hydrolysis &
Deesterrifcation
Parahydroxymethylphenidate
Ring Hydroxylation
Ritalinic Acid
80%
unchanged
in urine
Hipuric Acid
Benzoic Acid
Hydroxyamphetamine
metabolite
MPH does not usually show on routine urine drug
screening
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, AMPgenerally 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
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 1999;340:40
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
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. N Eng J Med 1999;340:40
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
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 1999;340:40
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
Attention Deficit Hyperactivity Disorder
Pharmacological Treatment
Stimulants
Methylphenidate
Amphetamine compounds
Dextroamphetamine
Non-stimulant
Atomoxetine
Antidepressants
Recently
Approved
Treatment
for ADHD
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)
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; 1998:42-64.
Atomoxetine in ADHD
Background and Rationale
• 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
» Total
» >1 yr
Oct 2001 (NDA)
1,982
169
2003
>4,000
>1,000
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
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;
Studies of Non-Stimulant Treatments in ADHD
(controlled & uncontrolled)
N=2 N=1
N=7
N=1
Tricyclics
N=33
N=5
MAOIs
Includes RIMA
Bupropion
Venalfaxine
=4
Alpha-adrenergic
N=7
Tomoxetine
ABT-418
N= 1,829 subjects
Buspirone
Modafanil in Adults with ADHD
Response defined as >30% reduction in ADHD sympotoms
50
45
40
35
30
25
20
15
10
5
0
Placebo
D-Amphet Modafanil
Both
Neither
Optimal dosing in completers: Dex 22  9 mg/d; Modafanil 207  85 mg/d
Taylor et al., (2000) JCAP 10 (4): 311-20
45
40
35
Comorbid Conditions:
40%
Children and Adolescents
30-35%
30
(%) 25
20
15
20-25% 15-25%
15-20%
20%
19%
15%
10
5
0
Oppositional
defiant
disorder1
1MTA
Language
disorder2
Anxiety
Learning
Mood
Conduct Smoking4 Substance
disorders3 difficulties2 disorders2 disorder3
use
disorder5
Cooperative Group. Arch Gen Psychiatry. 1999;56:1076-1086.
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. 1991;148:565-577.
4Milberger S, et al. J Am Acad Child Adolesc Psychiatry. 1997;36:37-44.
5Biederman J, et al. J Am Acad Child Adolesc Psychiatry. 1997;36:21-29.
Lifetime Psychiatric Diagnoses in Adults
with ADHD
Substance Use Disorders
Anxiety Disorders
Bipolar
Major Depression
LD
Antisocial
0
10
20
30
40
50
60
Biederman et al., (1993) AJP 150(12): 1792-8
Shekim et al., (1990) Comprehensive Psychiatry 31(5): 416-25
Lifetime Comorbidity of ADHD with
Other Psychiatric Disorders
Substance
Abuse(4)
GAD(3)
Bipolar
Disorder(2)
Major
Depression(1)
0
10
20
1Alpert
2Nierenberg
3Pollack
30
40
et al., (1996) Psychiatric Research 62 (3): 213-9
et al., (2002) data presented at APA, Philadelphia, PA
et al., (1995) Psych Clinics of North America 18(4): 745-66
4Levin
& Kleber (1994) Harvard Rev Psych 2(5): 246-58
Is ADHD Pharmacotherapy
a Risk Factor for Subsequent
Substance 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 preclinical1,2
and human3,4 studies
• Evaluation of 674 medicated and 360 unmedicated patients
with ADHD followed into adolescence
(2 studies) or adulthood (4 studies)5
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.)
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 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.
ADHD+Substance Abuse
Treatment 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. 1998;37.
Riggs. Science and Clinical Perspectives. vol. 2 , in press.
Wilens TE. Alcohol Health Res World. 1998;22(2):127-130.
ADHD+Substance Abuse
Pharmacotherapy
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.
Bupropion in Adults With
ADHD+SUD
Frequency
40
•
Open study of adults with ADHD+mixed SUD
•
Referred out for SUD counseling
•
Dosing with bupropion to 200 mg SR bid by week 4
Retention in Trial
N=32
30
N=19
20
Dropout Rate= 41%
10
0
Baseline
Week 0
Week 1
Week 2
Week 3
Week 4
Week 5
Prince JB, et al. Presented at: 155th APA Annual Meeting; May 18-23, 2002; Philadelphia, Pa.
Week 6
Bupropion SR in Adults With
ADHD+SUD (cont.)
ADHD Sx
SUD
Baseline=34
0.0
Baseline=4
-5
(-46%)
-10
-15
-20
SUD CGI
ADHD RS
0
-0.5
-1.0
(-22%)
p.001
-1.5
p.001
-2.0
Reductions in Symptoms for Baseline to Endpoint (LOCF)
Prince JB, et al. Presented at: 155th APA Annual Meeting; May 18-23, 2002; Philadelphia, Pa.
ADHD+Substance Use Disorders
Treatment 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. J Am Acad Child Adoles Psychiatry. 1998;37.
Wilson & Levin. Curr Psych Rep. 2001;3:497-506.
Waxmonsky & Wilens. Adolesc SUD in Pediatric Psychopharmacology. 2003.
ADHD+Substance Use Disorders
Treatment 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. 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