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Making Exam Room DecisionsAdults with ADHD
Pharmcotherapy of Adult ADHD and Co-Morbid Conditions:
A Guide for Primary Care Providers
Lenard A. Adler MD
Director, Adult ADHD ProgramProfessor of Psychiatry and
Child and Adolescent PsychiatryNYU School of Medicine
http://psych.med.nyu.edu//patient-care/adult-adhd-screening-test212-263-3580
This activity is supported by an educational grant from Lilly USA, LLC. For further information concerning Lilly grant funding visit, www.lillygrantoffice.com
Making Exam Room DecisionsAdults with ADHD
Faculty Disclosure• Grant/Research Support
Bristol-Myers Squibb, Pfizer, Shire, Eli Lilly, Ortho McNeil/Jannsen/Johnson and Johnson, National Instiitute of Drug Abuse
• Speakers Bureau– None
• Advisory Board and Consultant– Eli Lilly, Major League Baseball, Mindsite, Organon, Ortho McNeil/Jannsen/Johnson and
Johnson, Shire, i3 Research, Epi-Q, INC Research, AstraZeneca Pharmaceuticals
• Consultant– Otsuka Pharmaceuticals
In prior years have received grant/research support or consulted with orserved on advisory boards, or speaker’s bureau from:
– Abbott, Bristol-Myers Squibb, Cephalon, Cortex Pharmaceuticals, Eli Lilly, Major League Baseball, Merck & Co, Mindsite, NIDA, New River Pharmaceuticals, Novartis Pharmaceuticals, Organon, Other McNeil/Jannsen/Johnson and Johnson, Pfizer, Psychogenics, Sanofi-Aventis Pharmceuticals, Shire.
– Have receive royalty payments (as inventor) from NYU for license of adult ADHD scales and training materials since 2004
Making Exam Room DecisionsAdults with ADHD
Learning Objectives
• After completing this module, participants will be able to:– discuss pathophysiology of ADHD
– discuss safety and efficacy of treating adults with ADHD with stimulant and non-stimulant medications
– identify options for pharmcotherapy in adults with simple ADHD and ADHD plus comorbid psychiatric disorders
Making Exam Room DecisionsAdults with ADHD
Pharmacotherapy in Adult ADHD
• Stimulants – Methylphenidate compounds– Amphetamine compounds
• Non-stimulants: Atomoxetine• Pharmacotherapy in Adult ADHD and Co-
Morbid Conditions
Making Exam Room DecisionsAdults with ADHD
Suspected Neurochemical Pathophysiology of ADHD
Receptors
Synapse
Dopamine/Norepinephrine
Catecholamine Neuron
Transporter
Postsynaptic neuron
Courtesy T. Wilens
Presynaptic neuron
Making Exam Room DecisionsAdults with ADHD
Wilens TE, Spencer TJ. (1998), In: Handbook of Substance Abuse, New York: Plenum Press. Solanto MV. (2002), Behavioral Brain Research,130:65-67.
Receptors
Synapse
Dopamine/Norepinephrine
Catecholamine Neuron
X
Amphetamines and methylphenidate block reuptake
Presynaptic neuron
Postsynaptic neuron
Increased neurotransmitter
Amphetamine increases dopamine release
Atomoxetine blocks transporter
Transporter
Suspected Neurochemical Pathophysiology of ADHD
Making Exam Room DecisionsAdults with ADHD
Stimulant Medications Studied for ADHDGeneric Name Brand Name Form Approximate
Duration of Action
Approved for Adults with ADHD
methylphenidate (MPH)
Ritalin® Metadate®Daytrana®
Varies with brand 3 to 4 hours No
mixed amphetamine salts (MAS)
Adderall® 5 mg, 7.5 mg, 10 mg, 12.5, mg, 15 mg, 20 mg, 30 mg
4 to 6 hours No
Oros methylphenidate (Oros MPH)
Concerta® 18 mg, 27 mg36 mg, 54 mg
Up to 10 hours Yes
dexmethylphenidate extended release (D-mph XR)
Focalin XR®(isomer of MPH)
5 mg, 10 mg15 mg, 20 mg30 mg
10 to 12 hours Yes
mixed amphetamine salts extended release (MAS XR)
Adderall XR® 5 mg, 10 mg15 mg, 20 mg, 25 mg, 30 mg
10 to 12 hours Yes
lisdexamfetamine dimesylate (LDX)
Vyvanse®(pro-drug)
20 mg, 30 mg40 mg, 50 mg60 mg, 70 mg
12 to 13 hours Yes
Making Exam Room DecisionsAdults with ADHD
Studies of Stimulants in Adult ADHD
Making Exam Room DecisionsAdults with ADHD
Study of Methylphenidate (MPH®)
Use in Adult ADHD DSM-IV ADHD Symptom Checklist
Spencer, T. et al. (2006). Am J Psychiatry
ADH
D R
atin
g Sc
ale
0
10
20
30
40
50
SubthresholdADHD
N=26
N=56
Baseline 1 2 3 654
** *** *** ***
MPHPlacebo
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Making Exam Room DecisionsAdults with ADHD
ADH
D R
atin
g Sc
ale
Study of Mixed Amphetamine Salts in Adult ADHD
(first 4 wks)DSM-IV ADHD Symptom Checklist
10
20
30
40
Baseline wk 1 wk 2 wk 3
SubthresholdADHDN=27
MAS
P<.001
Placebo
P<.001
Spencer et al. (2001). Arch Gen Psychiatry. 58, 775-782.
Making Exam Room DecisionsAdults with ADHD
Study of Mixed Amphetamine Salts Extended Release in Adult ADHD
Dose-ranging, multicenter, double-blind study, N=248Findings Once-daily extended-release mixed amphetamine
effective and well tolerated Statistically significantly lower scores by 12 hours on
Conner Adult Attention Rating Scale (CAARS) Statistically significant improvement in ADHD Rating Scale
(ADHD-RS) Dose-related improvement in Clinician Global Impression
of Severity (CGI) scores
Weisler, R. et al. (2006). CNS Spectr., 8:625-39.
Making Exam Room DecisionsAdults with ADHD
ADHD Rating Scale: Mean Total Score at Endpoint (ITT)
-20
-10
0
10
20
30
40
Baseline Endpoint Change (Endpoint – Baseline)
Mea
n AD
HD
-RS
Tota
l Sco
re
Placebo MAS XR 20 mg
MAS XR 40 mg
MAS XR 60 mg
33.0
26.4
–6.6
31.1
18.5*
–12.6
31.3
18.4*
–12.9
32.9
18.5*
–14.4
*P≤.001, adjusted Dunnett test compared with placebo after ANCOVA with baseline score as covariate.
Endpoint = LOCF
Data on file, Shire and Weisler R et al. CNS Spectr. 2006 Aug;11(8):625-39.
4 week study
N=248 adults ( ≥18 years)
Making Exam Room DecisionsAdults with ADHD
Study of OROS Methylphenidate in Adult ADHD
Biederman et al. (2006). Biological Psychiatry 59: 829-835.
Making Exam Room DecisionsAdults with ADHD
Open Label Study of Dexmethylphenidate Extended Release in Adult ADHD
Adler LA et al. (2009). J Attn Disorders, 12, 449-459.
ADHD-RS Total Score All d-MPH-XR (N = 82) Placebo (N = 20)
Baseline 36.5 ± 7.94 37.0 ± 7.10
Final DB 19.0 ± 11.52 24.9 ± 13.58
Change Base to final DB
–17.5 ± 11.39 –12.2 ± 11.84
Final open-label 10.6 ± 8.27 14.7 ± 10.78
Change final DBto final open-label
– 8.4 ± 10.14 –10.2 ± 10.19
Conclusion:
Once-daily d-MPH-ER 20 to 40 mg is safe and effective for long-term treatment of adult ADHD.
Making Exam Room DecisionsAdults with ADHD
Lisdexamfetamine Dimesylate Chemistry
Lisdexamfetamine (prodrug)
Site of cleavage
l-lysine d-amphetamine (active)
+
H N2
O
NH
NH2
CH3H N2
O
OH
NH2
H N2
CH3
LDX is a prodrug that is therapeutically inactive until it is converted to active d-amphetamine in the body
Rate-limitedHydrolysis
Making Exam Room DecisionsAdults with ADHD
Lisdexamfetamine Dimesylate in Adult ADHD
Patients and Methods• Double-blind, placebo-controlled, randomized, parallel-group,
4-week study with forced-dose escalation in adults aged 18 to 55 years with primary diagnosis of ADHD by DSM-IV-TR® criteria
Week 4Week 3Week 2Week 1
Placebo
30 mg/d
50 mg/d
70 mg/d
Placebo
30 mg/d
50 mg/d
70 mg/d
Adler LA et al. (2009), J. Clin Psychiatry
Making Exam Room DecisionsAdults with ADHD
ADHD-RS Total Scores: ITT Population
A more negative change in ADHD-RS total score indicates greater improvement.LS=least squares; SE=standard error of the mean.*P<.0001 (adjusted Dunnett’s test compared with placebo following ANCOVA with baseline score as covariate).
Baseline Endpoint Change from baseline (LS mean ± SE)
30 mg/d LDX 50 mg/d LDX 70 mg/d LDXPlacebo
-20
-10
0
10
2030
40
50
60
-16.2* -17.4* -18.6*
-8.2
ADH
D-R
S To
tal S
core
Cha
nge
in
ADH
D-R
S To
tal S
core
Making Exam Room DecisionsAdults with ADHD
Side Effects in Stimulant Studies
• Dry mouth
• Insomnia
• Appetite suppression
• Headache
• Edginess
• Cardiovascular– AHA guidelines established for children
Side effects are similar for all stimulants:
Making Exam Room DecisionsAdults with ADHD
Prescribing InformationFDA Approved Stimulants for Adult ADHDGeneric Name Form Recommended
Start DoseRecommended Maximum Daily Dose
Approximate Duration of Action
Oros methylphenidate (Oros MPH)
18 mg, 27 mg36 mg, 54 mg
Start with18 mg or 36 mg each morning
Maximum recommended daily dose is 72 mg
Up to 10 hours
dexmethylphenidate extended release (D-mph XR)
5 mg, 10 mg15 mg, 20 mg30 mg
Start with 10 mg/day
10 to 12 hours
mixed amphetamine salts extended release (MAS XR)
5 mg, 10 mg15 mg, 20 mg, 25 mg, 30 mg
Start with 20 mg/day
Maximum daily recommended dose is 30 mg/day.
10 to 12 hours
lisdexamfetamine dimesylate (LDX)
20 mg, 30 mg40 mg, 50 mg60 mg, 70 mg
Start with 30 mg once daily in the morning
Recommended maximum dose 70 mg once daily in the morning
12 to 13 hours
Making Exam Room DecisionsAdults with ADHD
Studies of FDA Approved Non-Stimulant Medication for ADHD in Adults
Generic Name Brand Name Form Approximate Duration of Action
Approved for Adults with ADHD
atomoxetine Strattera® 10 mg, 18 mg25 mg, 40 mg60 mg, 80 mg100 mg
24 hours Yes
Making Exam Room DecisionsAdults with ADHD
Study of Atomoxetine in Adult ADHD
• FDA-approved noradrenergic agent
• Two combined multisite, randomized, placebo-controlled studies
• Pivotal trials for FDA approval
• Ns = 280 + 256 = 536 adults
• Target dosage to 120 mg/d
– mean dose circa 92 mg/d
• 10 wk study duration
Michelson et al. (2003). Biol Psychiatry, 53:112-120.
Making Exam Room DecisionsAdults with ADHD
*P<0.003; **P<0.05; †P≤0.001.
Efficacy of Atomoxetine in Adults with ADHD
22
24
26
28
30
32
Baseline Week 2 Week 4 Week 6 Week 8 Week 10
CA
AR
S-In
v AD
HD
Tot
al
*
**
†
†
PlaceboAtomoxetine
Michelson et al. (2003). Biol Psychiatry, 53:112-120.
†
Making Exam Room DecisionsAdults with ADHD
Side Effects of Atomoxetine in Adults with ADHD*
Dry mouth 21 7Insomnia 21 9Nausea 12 5Decreased appetite 12 3Decreased libido 7 2Erectile difficulty 10 1Dizziness 6 2Increased BP (systolic, diastolic): 1-3 mm HgIncreased HR: 5 bpm
*All significant versus placebo.
Atomoxetine (%) Placebo (%)
Michelson et al. (2003). Biol Psychiatry, 53:112-120.
Side Effect
Making Exam Room DecisionsAdults with ADHD
Prescribing InformationFDA Approved Non-Stimulant for Adult ADHD
Generic Name Form Recommended Start Dose
Recommended Maximum Daily Dose
Approximate Duration of Action
atomoxetine 10 mg, 18 mg25 mg, 40 mg60 mg, 80 mg100 mg
Start with 40 mg Maximum recommended daily dose is 100 mg
24 hours
Making Exam Room DecisionsAdults with ADHD
Pharmacotherapy of Adult ADHD and Coexisting Psychiatric Disorders
Making Exam Room DecisionsAdults with ADHD
Pharmacotherapy of ADHD and Major Depression
• 1 double-blind study of desipramine1
• 1 placebo controlled trial of paroxetine vs. dextroamphetamine2
• 1 open label trial of venlafaxine +/-stimulants3
• 1 open label trial of sertraline or fluxoxetine + stimulants4
1. Wilens T et al. (1996). Am J Psychiatry, 153(9):1147–1153.2. Weiss M et al. . (2006). J Clin Psychiatry, 67(4):611–619.3. 3. Hornig-Rohan M, Amsterdam JD. (2002). Prog Neuropsychopharmacol Biol Psych., 26(3):585–589.4. Findling Rl. (1996). J Child Adolesc Psychopharmacol., 6(3):165–175
Making Exam Room DecisionsAdults with ADHD
Pharmacotherapy of ADHD and Bipolar Disorder
• 1 open label trial of buproprion
Wilens TE et al..(2003), Biol Psychiatry, 54(1):9–16.
Making Exam Room DecisionsAdults with ADHD
Pharmacotherapy of ADHD and Social Anxiety Disorder
• Controlled trial of atomoxetine— 40 -100 mg/day (n=224) vs. placebo
(n=218) for 14 weeks• Significant improvement of ADHD and
social anxiety symptoms on atomoxetine
Adler LA et al. (2009). Depress Anxiety, 26(3):212-21.
Making Exam Room DecisionsAdults with ADHD
Pharmacotherapy of ADHD and Executive Function Deficits
Executive functioning refers to those neuro-cognitive processes needed to organize behavior across time and sustain problem-solving toward future goals1
• Effects of Stimulant on Neuropsychological Tests2
- Examined neuropsychological test results in group of transitional adults (15-25 years)
• Atomoxetine Treatment of Executive Function Deficits3
- Examined effects on executive function during 6 month trial of atomoxetine via Brown Adult Attention Deficit Scale
- Results: Improvement in all measures of executive functioning
1. Welsh MC, Pennington BF. (1988). Developmental Neuropsychology, 4(3),199-230.2. Biederman et al. (2008). J. Clinical Psychiatry,69 (7): 1150-56. 3. Brown et al. (In Press)
Making Exam Room DecisionsAdults with ADHD
Pharmacotherapy of ADHD and Substance Use Disorders (SUD)
• Atomoxetine (Strattera®) in patients with ADHD and Alcohol Use Disorders1
• Atomoxetine in patients with ADHD and Cocaine Abuse2
• OROS Methylphenidate in patients with ADHD smokers (nicotine)3
1. Wilens TE et al. (2008), Drug Alcohol Depend., Jul 1;96(1-2):145-54.2. Levin FR et al. (2009), J Dual Diagn, Jan 1;5(1):41-56.3. Winhusen TM et al. (2010), J Clin Psychiatry, May 18. [Epub ahead of print]
Making Exam Room DecisionsAdults with ADHD
Summary of Pharmacotherapy for Treating Adult ADHD
• There are five drugs approved by the FDA to treat adult ADHD. Four are long-acting stimulants and one is a long-acting non-stimulant.
• Research has shown these drugs to have long-term safety and efficacy in the treatment of adult ADHD.
• Adults with complicated ADHD (ADHD plus comorbid conditions) such as Major Depression, Bipolar Disorder, Anxiety, Executive Function Deficits, and Substance Use Disorder can also be treated with combination therapy.