NOW THAT I’M OLDER: MANAGING

ADULT ADHD

David W. Goodman, MD, LFAPA

Presented at 2023 NEI August Saturday Morning Live

 Learning Objectives

• Recognize and diagnose ADHD in adult patients to provide

appropriate treatment and optimize patient outcomes

• Discriminate between available treatments for adult ADHD for best

individual treatment and best patient outcomes

• Choose the best option for treatment of adult ADHD based on the
individual patient’s needs and personal goals for treatment,
improving the likelihood of desirable patient outcomes
 ADHD Persists into Adulthood

Measured ADHD
Sibley et al study - utilized symptoms, impairments, Spanned 16 years from
multi-informant childhood through young
treatment utilization, and
assessment comorbidities adulthood

“… the findings challenge the notion that approximately 50% of children with ADHD
outgrow the disorder by adulthood. Most cases demonstrated fluctuating symptoms
between childhood and young adulthood. Although intermittent periods of remission can be
expected in most cases, 90% of children with ADHD continued to struggle with residual
ADHD through young adulthood.”

Sibley MH et al. Am J Psychiatry 2022;179(2):142-51.

 ADHD Persists Into Adulthood
TRAJECTORY OF ADHD SYMPTOMS
Recovery
9%
Stable Data from the
Persistence Multimodal
11% Treatment of ADHD
(MTA) longitudinal
study

Stable Partial
Remission
16%
Fluctuating
64%

Sibley MH et al. Am J Psychiatry 2022;179(2):142-51.

Impact of Development on ADHD Symptoms

inattention SCHOOL-AGE:
- behavioral
disturbances
- academic
problems
- difficulty with
impulsivity social interactions
- self-esteem issues

comorbidity hyperactivity
recognized

Stahl's Essential Psychopharmacology. 5th ed. Cambridge University Press; 2021

Impact of Development on ADHD Symptoms

inattention SCHOOL-AGE:
- behavioral
disturbances
- academic
problems
- difficulty with
impulsivity social interactions
- self-esteem issues

comorbidity ADULTHOOD:
hyperactivity
recognized - occupational
failure
- self-esteem
issues
- relationship
problems
- injury/accidents
- substance abuse

Stahl's Essential Psychopharmacology. 5th ed. Cambridge University Press; 2021

 Manifestation of ADHD Symptoms in Adulthood
INATTENTIVE SYMPTOMS HYPERACTIVE-IMPULSIVE SYMPTOMS

• Starts task without reviewing instructions • Internal restlessness

• Poor follow-through on commitments • Difficulty sitting through meetings

• Inefficient at work • Works more than one job and/or has a very
active job
• Poor time and money management, trouble
doing things in proper order • Impulsive decisions (e.g., job changes)

• Appears not to listen, poor driving • Drives too fast

• Misses appointments or deadlines • Interrupts others, easily frustrated

Stahl SM, Mignon L. Stahl's Illustrated Attention Deficit Hyperactivity Disorder. Cambridge University Press; 2009;
Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. Cambridge University Press; 2013.
Prevalence Rates of Psychiatric Disorders in U.S. Adults: General
Population

Prevalence Percentage

Schizophrenia

Dementia

Bipolar Disorder

OA ADHD

GAD

Adult ADHD

Major Depression

0.0% 1.0% 2.0% 3.0% 4.0% 5.0% 6.0% 7.0%

Kessler RC et al. JAMA 2003;278(23):3095-105; Kessler RC et al. Am J Psychiatry 2006;63(4):415-24; Merikangas

KR et al. Arch Gen Psychiatry 2007;64(5):543-52; Polanczyk et al. Curr Opin Psychiatry. 2007 Jul;20(4):386-92
80% of Adults With ADHD Go Undiagnosed and Untreated

Ginsberg Y et al. Prim Care Companion CNS Disord 2014;16(3):PCC.13r01600.

 Breakdown of Comorbidities Among those with ADHD
Comorbidities in Adult ADHD

MDD

Substance Use Disorder 87% of adults

with ADHD
Anxiety Disorders have at least
one comorbid
psychiatric
Developmental Disability condition*

Bipolar Disorder

0% 10% 20% 30% 40% 50% 60% 70%

Percentage of Adult ADHD Patients With This Comorbidity

Data from the U.S. National Comorbidity Survey Replication (NCSR) Data from O ther Countries - Norway, Japan, Switzerland

Kessler et al. Am J Psychiatry. 2006;163(4):716-23 (United States, General Population, 12-month comorbidity prevalence)
*Torgersen T et al. Nord J Psychiatry 2006;60(1):38-43 (Norway, Clinical population, lifetime comorbidity prevalence)
Ohnishi T et al. Innov Clin Neurosci 2019:16(9-10);11-6 (Japan, Clinical population, 12-month comorbidity prevalence)
Quenneville AF et al. Psychiatry Res 2022;310:114423 (Switzerland, lifetime comorbidity prevalence)
 ADHD and Rising Mortality with Comorbidities
Mortality Rate per 10,000 Person-Years

90.96

51.60

30.05

12.68

2.16 3.79

No ADHD ADHD ADHD ADHD ADHD ADHD

or comorbidity only +1 +2 +3 +≥4
Sun S et al. JAMA Psychiatry 2019;76(11):1141-9.
 Recent FDA Update (May 2023)

The FDA is requiring updates to the Boxed Warning for prescription stimulants to include up-to-date
warnings on harms of misuse and abuse, and particularly that most individuals who misuse
prescription stimulants get the drugs from other family members or peers.

Updated Boxed Warning Updated Patient Counseling Information

 Recent FDA Update (May 2023)
What should health care professionals do?
§ Assess patient risk of misuse, abuse, and addiction before
prescribing stimulant medicines.
§ Counsel patients not to share their prescribed stimulant with
anyone else.
§ Educate patients and their families on these serious risks, proper
storage of the medicine, and proper disposal of any unused
medicine.
§ Throughout treatment, regularly assess and monitor them for
signs and symptoms of nonmedical use, addiction, and potential
diversion, which may be evidenced by more frequent renewal
requests than warranted by the prescribed dosage.
 Misuse and Diversion on College Campuses

• According to two national studies: Most people (regardless of age) received

stimulants from a friend/relative and were more likely to obtain them for free
than to purchase them.
>35% of students prescribed medication diverted at least once.
In a study of 483 students who were prescribed a medication, 35.8% had diverted a medication
at least once in their lifetime.
>46% of students prescribed stimulants reported having been approached in
the past year to divert medication.
Results from a 2014 survey of over 21,000 undergraduates at a large, public university in the
Midwest.21
Sharing is the most common method of diversion with students.

Center for Behavioral Health Statistics and Quality. (2018)

Garnier et al., J Clin Psychiatry. 2010;71(3):262-269.
McCabe et al., Addict Behav. 2014;39(7):1176-82.
TREATMENT OF ADULT ADHD
International Adult ADHD Treatment Guidelines
and Consensus
• Australian Evidence-Based Clinical Guideline for ADHD (Australian ADHD
Professionals Association – AADPA), 2022
• ADHD International Consensus Statement (World ADHD Federation), 2020
• European Consensus by the European Network of Adult ADHD, 2019
• Canadian Attention Deficit Hyperactivity Disorder Resource Alliance
(CADDRA), 2018
• National Institute for Health and Clinical Excellence (NICE) UK, 2018
• U.S Guidelines currently in development by the American Professional
Society for ADHD and Related Disorders (APSARD.org)

Guideline for Attention Deficit Hyperactivity. Melbourne: Australian ADHD Professionals Association; 2022; Faraone SV et al. Neurosci Biobehav Rev 2021;128:789-818;
Kooij JJS et al. Eur Psychiatry 2019;56:14-34; Canadian ADHD Resource Alliance (CADDRA): Canadian ADHD Practice Guidelines, 4th ed, Toronto ON; CADDRA, 2018;
National Institute for Health and Care Excellence. Attention Deficit Hyperactivity Disorder: Diagnosis and Management (NG87), 2018; www.APSARD.org
 Treatment Guidelines

“If stimulant medication is prescribed, a

positive response does not confirm the
diagnosis of ADHD.”

Medication response does not make a diagnosis

Up to 30% of adults with ADHD do not have a

beneficial response to the first stimulant. They
may respond to an alternative stimulant.

Holze F et al. Neuropsychopharmacology 2020;45(3):462-71; Zametkin AJ, Ernst M. N Engl J Med 1999;340(1):40-6;
Rapoport JL et al. Science 1978;199(4328):560-3; Rapoport JL et al. Arch Gen Psychiatry 1980;37(8):933-43.
 Neuropharmacology of Stimulants

Methylphenidate Amphetamine

D-Methylphenidate D-amphetamine
(d-MPH) (d-AMP)
L-Methylphenidate L-amphetamine
(l-MPH) (l-AMP)

D-enantiomer has greater CNS effects.

 Neuropharmacology of Prodrug Stimulants

• Prodrug of d-AMP covalently bound to l-

lysine.
• LDX half-life = 50 minutes
• d-AMP half-life = ~8 hours

• Does not cross blood brain barrier.

Lisdexamfetamine (LDX)

• Prodrug of dexmethylphenidate
• Serine ring attached to d-MPH
• SDX half-life: 5.7 hours
• Dexmethylphenidate half-life: 11.7 hours

Serdexmethylphenidate (SDX)
FDA-Approved Medications for Adults With ADHD

Methylphenidate (MPH)
based Amphetamine (AMP) based Nonstimulants

d-MPH XR Lisdexamfetamine Viloxazine ER

OROS MPH XR MAS XR double bead Atomoxetine

MPH DR/ER MAS triple bead

SDX/d-MPH
 Medications Approved for Adults With ADHD –
Dosage and Duration of Action
Methylphenidate- Amphetamine-
based Duration of based Duration of
Medication Adult Dosage Action Medication Adult Dosage Action

d-MPH XR 10-20 mg/day 12 hours

Lisdexamfetamine 30-70mg/day 14 hours

OROS MPH XR 18-72 mg/day 10-12 hours

MAS XR triple
12.5-50mg/day 16 hours
Up to 16 bead
MLR (PRC-063) 25-85 mg/day
hours

Up to 12
26.1/5.2mg- MAS XR 20-60 mg/day
SDX/d-MPH 13 hours hours
52.3/10.4mg/day

Non-Stimulants Adult Dosage

Viloxazine ER 200-600 mg/day

Atomoxetine 40-100 mg/day

 Methylphenidate Mechanism of Action

Dopamine Norepinephrine

VMAT VMAT

DAT NET
MPH binds to NET and blocks
MPH binds to DAT and
norepinephrine reuptake à
blocks dopamine reuptake à
Increased dopamine availability Increased norepinephrine
availability
NET - Norepinephrine
Transporter
DAT – Dopamine
Transporter
VMAT – Vesicular
Monoamine Transporter
 Amphetamine Mechanism of Action
Dopamine
• Unlike MPH, AMP is a
competitive inhibitor of DAT.

• It is also a competitive inhibitor of

VMAT.
VMAT2
• At high levels, AMP leads to the
displacement of DA from the
vesicles into the terminal.

Amphetamine has these same

actions at Noradrenergic neurons.
Competes for reuptakeà
Increased DA/NE availability

Loaded into vesicles through VMAT2 à DAT DAT – Dopamine

Increased DA availability Transporter
VMAT2 – Vesicular
Monoamine Transporter 11-32
 Differential Response to Stimulants

Meta-Analysis of Within-Subject Comparative Trials

Evaluating Response to Stimulant Medications

Amphetamine 28%

Methylphenidate 16%

Equal Response 41%

No response to either 15%

0% 10% 20% 30% 40% 50%

Best Response (percent)

Arnold LE. J Atten Disord 2000;3(4):200-11.

 How Many Stimulant Preparations Are There?

Methylphenidates Amphetamines

>30
stimulant
preparations
Number of Stimulant Compounds?

Methylphenidate MAS
mixed amph salts

Amphetamine
(racemic) d-Amph

d-MPH Ser-d-MPH
(prodrug) Lis-d-Amph
(prodrug)
 Primary Considerations for Dosing?

Dosing in mgs for ADHD medication is primarily based on:

Weight/Height
No weight or height correlations for optimal dosing
Pediatrics has weight guidelines but there is tremendous dose variability
with patients
Delivery system
No delivery system is consistently better for all patients
Symptom reduction
Easily assessed clinically and with symptom rating scales
Impairment reduction
Impairment arise from both ADHD and executive symptoms
Observer reports
Helpful but only observed behavior that is context specific
 Delivery System Technology
Beaded (IR/ER ratio, double/triple beaded) OROS (osmotic release)

Patch
Microparticles (liquid, dissolvable
tabs, chewables) impermeable
covering
membrane drug
adhesive

capillary

Stahl SM, Mignon L. Stahl’s Illustrated Attention Deficit Hyperactivity Disorder 2009.
Serdexmethylphenidate (SDX) – Prodrug of d-MPH

• Serine ring attached to d-MPH

• Half-life: 5.7 hours

• Decreased potential for

misuse

• FDA-designated Controlled
Substance Class IV (not II)
 SDX - Oral Human Abuse Liability Study

• Three randomized, double-blind, placebo- and active-controlled crossover studies –

a. Oral SDX (120 and 240mg)vs. Extended Release

(ER) d-MPH (80mg)
and phentermine (60 mg)

b. Intranasal (IN) SDX (80mg) vs. d-MPH (40mg)

c. Intravenous (IV) SDX (30mg) vs. d-MPH (15 mg)

• SDX resulted in lower maximal & overall d-MPH exposure than pure d-MPH across all routes

• Lower abuse potential than d-MPH

• SDX - lower frequency of stimulant-related adverse events compared to d-MPH

Shram MJ et al, Curr Med Res Opin. 2022 Jul;38(7):

SDX/d-MPH: Pharmacokinetics
SDX/d-MPH

SDX/d-MPH 52.3/10.4 mg

Adapted from Azstarys Prescribing Information 2021.

 Serdexmethylphenidate/d-Methylphenidate
(SDX/d-MPH)
• Controlled class II designation

• Approved 02 March 2021 for ages 6 and older 30% d-MPH

• Efficacy study – 70% SDX

ØChildren ages 6–12 with ADHD

ØRandomized, double-blind, dose-optimized laboratory classroom study

ØSDX/d-MPH demonstrated significant improvement in ADHD symptoms versus

placebo

ØBoth rapid onset and long-lasting treatment effects compared to placebo

Kollins SH et al. J Child Adolesc Psychopharmacol 2021;31(9):597-609.
 SDX/d-MPH Efficacy
Behavioral symptoms

KP415: serdexmethylphenidate Cl and d-methylphenidate d-MPH capsules (70/30 molar ratio)

Kollins SH et al. 2021 APSARD Virtual Conference; January 15, 2021.

SDX/d-MPH Efficacy: Permanent Product Measure of Performance
(PERMP)
Sustained Attention Measure

Kollins SH et al. J Child Adolesc Psychopharmacol 2021;31(9):597-609.

 SDX/d-MPH Adverse Events

• Generally well-tolerated with adverse events (AEs) typical of

stimulant therapy
• AEs mild to moderate in severity; no serious AE

Adverse event (≥2%) SDX/d-MPH (%) Placebo (%)

Headache 5.41 1.32
Abdominal pain 4.05 1.32
Insomnia 2.70 1.32
Upper respiratory tract
2.70 5.26
infection
Pharyngitis 2.70 0.00
https://investors.kempharm.com/news-releases/news-release-details/kempharm-announces-top-line-results-kp415e01-efficacy-and-
safety; https://investors.kempharm.com/news-releases/news-release-details/kempharm-submits-kp415-nda-fda-treatment-adhd;
clinicaltrials.gov [NCT03292952].
 SDX/d-MPH – Capsule Sizes

Equivalent dexmethylphenidate
Serdexmethylphenidate (SDX)/d-Methylphenidate (d-MPH)
hydrochloride
26.1 mg SDX / 5.2 mg d-MPH 20 mg
39.2 mg SDX / 7.8 mg d-MPH 30 mg
52.3 mg SDX / 10.4 mg d-MPH 40 mg

https://investors.kempharm.com/news-releases/news-release-details/kempharm-announces-top-line-results-kp415e01-efficacy-and-safety
https://investors.kempharm.com/news-releases/news-release-details/kempharm-submits-kp415-nda-fda-treatment-adhd
Amphetamine (AMP ER) Chewable Tablet

Composition and pharmaco-kinetics

• d-to l- AMP ratio of 3.2:1

• Bioequivalent to AMP ER oral

suspension

• Tmax 5 hours (range 3 to 7 hours)

• No food effect

Pardo A et al. CNS Spectr 2020;25(6):774-81

 AMP ER Chewable Tablet: Efficacy Study

• Randomized, double-blind, placebo-controlled, parallel study

• Adults with ADHD aged 18 to 60 years
• Of 130 randomized subjects, 127 were in the intent-to-treat (ITT) population
and 91 completed the study.
• Primary endpoint: mean Permanent Product Measure of Performance total
(PERMP-T) score over all post-dose time points
• Statistically significant vs. placebo at 30 min and 1, 2, 4, 8, 13 hours
• AMPH ER tablet (302.8) vs. placebo (279.6) (p=0.0043)
• Most common adverse events (>2%): insomnia, irritability, initial insomnia, and
decreased appetite

Cutler AJ et al. APSARD 2021 [Poster Presentation].

 Amphetamine Transdermal System (d-ATS)

• A d-AMP transdermal patch

• Efficacy study
• Double-blind, placebo-controlled, crossover laboratory classroom
study

• 110 subjects aged 6–17 years

• d-ATS significantly better than placebo on primary endpoint,
SKAMP total score (least-squares mean difference -5.87, p<0.001)

• Most common adverse events (>15%): decreased appetite,

headache, insomnia, irritability, and application site reaction

Cutler AJ et al. J Child Adolesc Psychopharm 2022;10.1089/cap.2021.0107.

 Triple-Bead Mixed Amphetamine Salt (MAS)

• May help with improved attention, with once-daily dosing

vDosing: 12.5 to 25 mg once a day (>13 yo) or 50 mg (adults)

vCapsules: 12.5, 25, 37.5, 50 mg
vDuration of action: 16 hours (onset at 2–4 hours)

Product Name Daily Dosage Tmax (mean, hours) T1/2 (mean, hours)

Triple-bead mixed 1 d-l-amphetamine: 7–10 d-amphetamine: 10–11

amphetamine salt (in children) (in children & adults)

d-l-amphetamine: 8 l-amphetamine: 10–13

(in adults) (in children & adults)

Frick G et al. J Atten Disord 2017;1087054717696771;

Brams M et al. J Child Adolesc Psychopharmacol 2018;28(1):19-28.
 Side Effects With Stimulant Medication

Insomnia GI Upset Decreased Weight Loss Headache

appetite

Dry mouth Constipation Hand tremors Jitters

Goodman DW et al. CNS Spectr 2005;10(Suppl 20):26-34; Weisler RH et al. CNS Spectr 2006;11(8):625-39;
Adler L et al. Presented at the 158th Meeting of the American Psychiatric Association, May 21-25, 2005.
 CYP450 Inhibitory Effects of
ADHD Medications
Cytochrome P450 Isoenzymes
Medication 1A2 2C9 2C19 2D6 3A4
Amphetamine 0 0 0 0 0
Methylphenidate 0 0 0 0 0
Atomoxetine 0 0 0 0* 0
Viloxazine +++ 0 0 0* 0
Bupropion ? ? ? +++ ?
Desipramine 0 0 0 0 0
Guanfacine 0 0 0 0 0*
Clonidine 0 0 0 0 0*
* substrate

Adapted from: Goodman D. ADHD across the lifespan. In Mental Disorders in Primary Care, 2017; Flockhart DA et al. Arch
Intern Med 2002;162(4):405-12; Steingard R et al. J Child Adolesc Psychopharmacol 2019; 29(5):324-39; Viloxzaine PI 2021.
 Side Effects With Stimulant Medication

• No RCT has assessed AEs in older ADHD adults on

psychostimulants

• Side effect ramifications in older adults may be very clinically

significant

• Some research has shown side effects may be more likely in

stimulant-naïve patients

Goodman DW et al. CNS Spectr 2005;10(Suppl 20):26-34; Weisler RH et al. CNS Spectr 2006;11(8):625-39;
Adler L et al. Presented at the 158th Meeting of the American Psychiatric Association, May 21-25, 2005.
 Non-Stimulants

General
• Atomoxetine
• Viloxazine
Child/Adolescent only
• Guanfacine ER
• Clonidine ER
Off-label
• Bupropion
• Desipramine
• Modafinil
Moderate Efficacy of Stimulants and Atomoxetine for
Emotional Lability in Adults With ADHD

Standardized mean difference: -0.41

Moukhtarian TR et al. Eur Psychiatry 2017;44:198-207.

 Viloxazine ER

• Norepinephrine Reuptake Inhibitor

• Also has affinity for 5HT2B, 5HT2C,

and 5HT7

• Increases serotonin in PFC in

preclinical studies

• FDA approved for child/adolescent

April 2021 and for adults April 2022

• Strong CYP 1A2 inhibitor

Yu C et al. J Exp Pharmacol 2020;12:285-300;

 Viloxazine ER

• ADHD symptom improvement in children

• Separated from placebo by week 1

• 100 mg dose (p=0.0004) and 200 mg dose (p=0.0244)
• Greater than placebo at end of study (primary endpoint)
• 100 mg dose (p=0.0004) and 200 mg dose (p<0.0001)

• ADHD symptom improvement effect size vs. placebo by mg dose

• 200 mg: 0.547 300 mg: 0.596 400 mg: 0.623

Nasser A et al. Clin Ther 2020;42(8):1452-66; Johnson JK et al. J Atten Disord

2020;24(2):348-58.
 Viloxazine ER: Adult

Nasser A et al. CNS Drugs 2022;36(8):897-915.

 Adverse Effects of Viloxazine ER
• Child/Adolescent AEs in ≥5% of • Adult AEs in ≥5% of patients
patients receiving Viloxazine ER (100 – receiving Viloxazine ER (200 – 600
400 mg) mg):
• Insomnia (14.8%)
• Somnolence (8.9%–14%)
• Fatigue (11.6%)
• Decreased appetite (6.0%–7.7%)
• Nausea (10.1%)
• Headache (5.4%–6.8%)
• Decreased appetite (10.1%)
• Fatigue (4.9%–7.2%)
• Dry mouth (9.0%)
• Nausea (4.9%)
• Headache (9.0%).
• Upper abdominal pain (4.8%)

Nasser A et al. Clin Ther 2020;42(8):1452-66; Nasser A et al. Clin Ther 2021;43(4);684-700;
Nasser A et al. J Clin Psychopharmacol 2021;41(4):370-80.
 Decision Process: Medication
Stimulants - Methylphenidate vs Amphetamine; Non-
Compound stimulants

Pill, liquid, orally disintegrating tablet (ODT), chewable,

Form of administration patch

Immediate Release (IR), Sustained Release (SR), Extended

Duration of action Release (ER/XR)

Tablet with excipients, beads, osmotic-controlled release

Delivery system/technology (OROS), ion exchange beads/particles, DELEXIS, patch

Based on symptom reduction, delivery system, weight/height (dosing

Dosing of stimulants is not by weight/height), impairment reduction

Patient preference Prior patient medication history

Insurance coverage, cost of medication

Access

Slide content provided courtesy of David W. Goodman, M.D

 Summary

• ADHD very often persists into adulthood, causing serious personal and professional dysfunction.

• Comorbidity is the rule and is often the presenting issue. Treatment must consider both ADHD
and comorbidity.

• There are several treatment options - stimulant medications are the most effective – data suggests
that AMP may work best for adults with ADHD.

• Non-stimulants can be used as monotherapy or adjunctive to a stimulant preparation.

• While developing a treatment plan, it is important to consider factors tailored to the patient,
including prior medical history and cost/insurance concerns.
 Posttest Question 1
FDA maximum daily dose of stimulant medication is set by…

1. Safety parameters
2. Weight
3. Age
4. Registration trials
5. Abuse dosing potential
6. Optimal dose response
7. I’d be guessing
 Posttest Question 2
Which of the following Mixed Amphetamine Salts (MAS) has the
longest duration of action?

1. MAS Immediate Release (MAS IR)

2. Triple-bead MAS
3. MAS Extended Release (MAS ER)
 Posttest Question 3
Which of the following statements is true about viloxazine ER?

1. Its primary mechanism of action involves the inhibition of the dopamine

transporter (DAT).
2. It is a norepinephrine reuptake inhibitor.
3. It was approved for the treatment of ADHD in adults by the FDA in 2022.
4. 2 & 3 are true.