pharmcotherapy of adult adhd and co-morbid...

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

[email protected]

This activity is supported by an educational grant from Lilly USA, LLC. For further information concerning Lilly grant funding visit, www.lillygrantoffice.com


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


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


Pharmacotherapy in Adult ADHD

• Stimulants – Methylphenidate compounds– Amphetamine compounds

• Non-stimulants: Atomoxetine• Pharmacotherapy in Adult ADHD and Co-

Morbid Conditions


Suspected Neurochemical Pathophysiology of ADHD

Receptors

Synapse

Dopamine/Norepinephrine

Catecholamine Neuron

Transporter

Postsynaptic neuron

Courtesy T. Wilens

Presynaptic neuron


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


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


Studies of Stimulants in Adult 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

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _


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.


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.


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)


Study of OROS Methylphenidate in Adult ADHD

Biederman et al. (2006). Biological Psychiatry 59: 829-835.


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.


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


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


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


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:


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


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


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.


*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


†


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 (%)


Side Effect


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


Pharmacotherapy of Adult ADHD and Coexisting Psychiatric Disorders


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


Pharmacotherapy of ADHD and Bipolar Disorder

• 1 open label trial of buproprion

Wilens TE et al..(2003), Biol Psychiatry, 54(1):9–16.


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.


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)


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]


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.

pharmcotherapy of adult adhd and co-morbid...

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