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Slide1
Recent Updates in ADHD:
Optimizing Outcomes in a Digital World
Slide2Please feel free to use, update and share some or all of these slides in your noncommercial presentations to colleagues or patients
When using our slides, please retain the source attribution:These slides may not be published, posted online, or used in commercial presentations without permission. Please contact pce@practicingclinicians.com for details
About These Slides
2
Slide credit: practicingclinicians.com:
Slide3Faculty
Greg W. Mattingly, MDJune 11; October 8Associate Clinical Professor, Washington University School of MedicinePresident,
Midwest Research GroupPresident Elect, American Professional Society for ADHD and Related Disorders (APSARD)
St Louis, Missouri Joel L. Young, MD
May 14; September 10; November 5Medical Director, Rochester Center for Behavioral MedicineRochester Hills, Michigan
Clinical Associate Professor of Psychiatry
Wayne State University School of Medicine
Detroit, Michigan
3
Slide4Faculty Disclosures
The faculty reported the following relevant financial relationships or relationships to products or devices they have with ineligible companies related to the content of this educational activity:Greg W. Mattingly, MD, has disclosed that he serves as a speaker for AbbVie, Alkermes, Corium, Eisai, Intracellular, Ironshore, Janssen, Lundbeck, Neurocrine,
Noven, Otsuka, Sunovion, Supernus, Takeda, and Trispharma; has received consulting fees from AbbVie, Acadia, Alkermes, Axsome
, Corium, Eisai, Ironshore, Intracellular, Janssen, Lundbeck, Neos, Neurocrine, Noven, Otsuka, Redax, Roche, Rhodes, Sage, Sirona, Sunovion, Supernus, Takeda, Teva, and
Trispharma; and funds for research support from AbbVie, Acadia, Alkermes, Akili, Axsome, Boehringer, Emalex, Idorsia, Janssen, Karuna, Lumos Labs, Medgenics, NLS-1 Pharma AG, Redax, Relmada, Roche, Sage, Sirtsei
, Sunovion, Supernus, Takeda, and Teva.
Joel L. Young, MD,
has disclosed that he has received consulting fees for Alkermes, Corium, Ironshore, Janssen, Noven, Otsuka, and Supernus and funds for research support from Janssen and Otsuka.
4
Slide5Learning Objectives
At the conclusion of this activity, learners should be able to:Interpret the impact of screen time and social media on processing speed and ADHD symptoms throughout the lifespanDiscuss the impact of unrecognized or untreated ADHD on mortality rates, school performance, job performance, and impact on daily social functionAssess strategies and options to optimize ADHD care within your practice
5
Slide6Life is a journey
—
you are never
quite sure what is next
Slide7Developmental Phases
Child
Teens
Young Adult
Older Adult
More
Less
Clinical presentation of ADHD changes across development and is related to interplay among environmental demands, available external supports, and typical symptom trajectories
Goodman
et al.
J Clin Psychiatry. 2012;73:192
.
Environmental Demands
7
Slide8Developmental Phases
External Supports
Goodman
et al.
J Clin Psychiatry. 2012;73:192
.
Child
Teens
Young Adult
Older Adult
Environmental Demands
More
Less
Clinical presentation of ADHD changes across development and is related to interplay among environmental demands, available external supports, and typical symptom trajectories
8
Slide9Developmental Phases
Hyperactivity
External Supports
Child
Teens
Young Adult
Older Adult
Environmental Demands
More
Less
Clinical presentation of ADHD changes across development and is related to interplay among environmental demands, available external supports, and typical symptom trajectories
Goodman
et al.
J Clin Psychiatry. 2012;73:192
.
9
Slide10Developmental Phases
Inattention
Hyperactivity
External Supports
Child
Teens
Young Adult
Older Adult
Environmental Demands
More
Less
Clinical presentation of ADHD changes across development and is related to interplay among environmental demands, available external supports, and typical symptom trajectories
Goodman
et al.
J Clin Psychiatry. 2012;73:192
.
10
Slide11Developmental Phases
Goodman
et al.
J Clin Psychiatry. 2012;73:192
.
Inattention
Hyperactivity
External Supports
Child
Teens
Young Adult
Older Adult
Environmental Demands
More
Less
Clinical presentation of ADHD changes across development and is related to interplay among environmental demands, available external supports, and typical symptom trajectories
11
Slide12Developmental Phases
Goodman
et al.
J Clin Psychiatry. 2012;73:192
.
Inattention
Hyperactivity
External Supports
Child
Teens
Young Adult
Older Adult
Environmental Demands
More
Less
Clinical presentation of ADHD changes across development and is related to interplay among environmental demands, available external supports, and typical symptom trajectories
12
Slide13Adult-Onset or Adult Diagnosis of ADHD
Risk factors for adult diagnosis of ADHD:Female sexHigher IQMore years of education
Breda
et al.
Br J Psychiatry. 2021;218:43. Horrigan
et al.
AACAP. 2000
.
Full-Scale IQ
Age at Initial Diagnosis (Yr)
150
140
130
120
110
100
90
80
70
50
0
10
20
30
40
Age at Initial Diagnosis vs Full-Scale IQ
(314.00)
13
KEY TAKE HOME:
IQ can compensate for the impairments of ADHD and forestall diagnosis
Slide14Impact of Social Media on ADHD
Ra et al. JAMA. 2018;320:255
.
Estimated mean prevalence of ADHD symptoms across follow-ups by baseline modern digital media use frequency index
derived from the primary unadjusted repeated measures logistic regression model among baseline ADHD symptom–negative students
Mean ADHD Symptom Prevalence Across Follow-ups, % (+95% CI)
Baseline No. of Digital Media Activities Used at a High Frequency Rate
0
2
4
6
8
10
12
14
16
18
20
0
n = 495
1
n = 337
2
n = 313
3
n = 321
4
n = 268
5
n = 243
6
n = 167
7
n = 114
8
n = 91
9
n = 66
10
n = 54
11
n = 34
12
n = 17
13
n = 16
14
n = 51
KEY TAKE HOME:
In the top decile of social media use, 14% of high school juniors
now meet criteria for ADHD
14
Slide15What About Memory and Aging?
Schaie et al. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. 2004;11:304
.
Mean T-Scores
Age (Yr)
35
40
45
50
55
25
32
39
46
53
60
67
74
81
88
Inductive reasoning
Spatial orientation
Perceptual speed
Numeric ability
Verbal ability
Verbal memory
15
Slide16Risk of Cognitive Impairment
Odds Ratio (95% CI)Digit Symbol Substitution Test
Relative Risk for Impairment
Impact of Television and Exercise After 25 Yr
Hoang et al. JAMA Psychiatry. 2016;73:73
.
Most active
Intermediate
Least active
1
16
Slide17MTA Study Followed Into Adulthood
9.1%
of demonstrated recovery (sustained remission)
10.8%
demonstrated stable ADHD persistence
63.8%
had fluctuating periods of remission and recurrence over time
KEY TAKE HOME:
90% continued to
have ADHD symptoms into adulthood
Sibley et al. Am J Psychiatry. 2022;179:142.
Total Sample (%)
Years After Baseline
100
90
80
70
60
50
40
30
20
10
0
16
0
2
3
6
8
10
12
14
DSM ADHD (persistent)
Partially remitted
Fully remitted
Recovered
Stable partial remission
Stable persistence
Fluctuating status
17
Slide18Common Myths of ADHD
Only in boysTwice as common in boys but equally prevalent in adultsAnd girls are more likely to be missedYou eventually grow out of itRecent data shows that only 10% of children diagnosed with ADHD do not have ADHD issues as adultsHyperactivity is the outward marker
Two thirds of boys have hyperactivity, but the majority of girls do notTry a test dose of a stimulant to see if you focus betterMost individuals feel that they focus better with a stimulant, but over time they quickly build a tolerance and need higher and higher doses
18
Slide19Suicide, Homicide, and Unintentional Injury
Outcome or Subgroup
Adjusted Model 1
HR (95% CI)
P
Value
All cause
Total
1.32 (1.22-1.43)
<.001
Male
1.26 (1.15-1.39)
<.001
Female
1.52 (1.28-1.79)
<.001
Suicide
Total
2.71 (2.16-3.4)
<.001
Male
2.48 (1.88-3.28)
<.001
Female
3.18 (2.13-4.75)
<.001
Unintentional injury
Total
1.32 (1.12-1.54)
.001
Male
1.29 (1.09-1.53)
.003
Female
1.44 (0.92-2.26)
.11
Homicide
Total
2.10 (1.14-3.84)
.02
Male
1.93 (0.98-3.79)
.06
Female
3.06 (0.77-12.17)
.11
Natural causes
Total
1.14 (1.02-1.27)
.02
Male
1.09 (0.96-1.24)
.17
Female
1.28 (1.04-1.58)
.02
Chen et al. JAMA Netw Open. 2019;2:e198714
.
19
Slide20Comorbidities in College-Age Adults:
Important Considerations in Our Differential N = 443 (214 men and 229 women), aged 18-22 yr (Median = 18.2 yr),
recruited from 9 colleges involved in a large-scale, multisite longitudinal investigation
College students with ADHD:
55% had ≥1 and 31.8% had ≥
2 comorbid conditions
College students without ADHD:
11.2% and 4.0%, respectively
Comorbid
and Non-ADHD Disorders by Group
Disorder
ADHD, %
Comparison, %
P
OR
Depressive
32.3
5.4
<.001
8.4
Anxiety
28.63.6<.00110.8
GAD15.51.8<.001
10.0Trauma and stressor7.30.9.0018.7
Learning disorder
10.0
0.4<.00124.7
Anastopoulos et al. J Clin Child Adolesc Psychol. 2018;47:236.20
Slide21Psychiatric Comorbidities Increase the
Risk of Premature Mortality in Adults With ADHD
Outcome or Subgroup
Deaths, n
Person-Yr
Mortality Rate per 10,000 Person-Yr
HR (95% CI)
Model 1
Overall
3821
16,206,949
2.36
NA
ADHD only
39
102,989
3.79
1.56 (1.11-2.18)
ADHD plus 1 comorbidity
73
57,575
12.68
4.21 (3.27-5.42)
ADHD plus 2 comorbidities9029,952
30.058.57 (6.73-10.92)ADHD plus 3 comorbidities
7314,14651.6015.69 (12.08-20.37)ADHD plus ≥4 comorbidities94
10,334
90.96
29.29 (22.77-37.66)None of the above345215,991,9532.161 [Reference]
Sun et al. JAMA Psychiatry. 2019;76:1141
.21
Slide22Polygenic Risk for ADHD and Associated Traits
(A) target phenotypes and (B) items on the neuroticism scale. Values displayed next to each bar represent
the
P
value for significance for the most predictive models.
BMI
General cognitive ability
Alcohol intake
Risk taking
Neuroticism
Tobacco use
Depression
Alcohol dependency
Anxiety disorder
Bipolar disorder
Schizophrenia
Phenotype (Best Fit)
Mood swings
Fed-up feelings
Miserableness
Irritability
Tense/high strung
Guilty feelings
Sensitivity/hurt feelings
Suffer from nerves
Worry after embarrassment
Nervous feeling
Worrier/anxious feelings
Phenotype (Best Fit)
Loneliness/isolation
6.7 x 10
-44
6.9 x 10
-42
4.5 x 10
-34
5.4 x 10
-29
3 x 10
-18
3.5 x 10
-13
3.4 x 10
-12
6 x 10
-12
0.002
0.009
0.042
0.267
0
0.0005
0.0010
0.0015
0.0020
0.0025
Variance Explained: R
2
0
Variance Explained: R
2
0.002
0.004
0.162
0.007
2.9 x 10
-4
4.5 x 10
-6
2.2 x 10
-13
4.2 x 10
-21
2.2 x 10
-24
9.3 x 10
-25
8.1 x 10
-29
4.5 x 10
-36
4.5 x 10
-129
-log
10
model
P
value
40
30
20
10
-log
10
model
P
value
40
30
20
10
Du
Rietz
et al.
Biol Psychiatry Cogn Neurosci Neuroimaging. 2018;3:635.
A
B
22
Slide23ADHD Treatment Reduces the Risk of Suicidality
in Patients With Comorbid ADHD and BD/SZDWithin 6 mo after treatment initiation, SA and NSSI events decreased significantly in terms of: Number of patients having SA/NSSI (P = .013)Numbers of SA/NSSI events experienced (
P = .004)Hospitalizations decreased from 31 to 19 (P
= .029)OR: 0.63 with stimulant treatment
ADHD and comorbid BD/SZD
19%
of patients (206)
met the criteria for
KEY TAKE HOME:
Appropriate ADHD treatment may decrease SA/NSSI in patients with BD/SZD
who have ADHD
Of 1564
patients with
BD/SZD:
Öhlund et al. Ther Adv Psychopharmacol. 2020;10:2045125320947502
.
23
Slide24Motor Vehicle Trauma and ADHD Medication Usage
Chang et al. JAMA Psychiatry. 2017;74:597
.
Reduction in Trauma Rates (%)
27
34
49
60
50
40
30
20
10
0
Women: 2-Yr Follow-up
Men: 2-Yr
Follow-up
Motorcyclists
During Mo Taking Medication
Reduction in MVA Trauma Rates
While Taking ADHD Medications
24
Slide25The Benefits of Treating ADHD
Treatment of adult ADHD with licensed medications may lead to benefits across a range of outcomes—including core symptoms, executive function, and quality of life—within a relatively short period of timeIn a systematic analysis of 48 studies and 76 outcome measures in patients with ADHD, treatment of ADHD was associated with benefit in numerous areas
Treatment benefit by outcome group in treated patients with ADHD vs untreated ADHD
25
Collective clinical opinion of Steering Group members. Shaw et al. BMC Med 2012;10:99.
Outcome
25
Slide26Whom Should You Screen?
Patients presenting with:Family history or children with ADHD Treatment-resistant MDD, bipolar disorder, or anxiety disordersDrug abuse or drug dependence Poor school performance as a child (not reaching potential) Poor occupational performance as an adult (not reaching potential) Motor vehicle issuesForgetfulness (missed appointments, trouble with adherence to medications)
Screening: PDF
P
rocrastinationD
istractibility
F
orgetfulness
Canadian ADHD Resource Alliance (CADDRA). 4th Edition. 2018. Bond et al. Ann Clin Psychiatry. 2012;24:23.
Lam et al. J Affect Disord. 2009;117(suppl 1):S26. Mattingly et al. CNS Spectr. 2016;21:45.
26
Slide27Reduction in ADHD-RS
Reduction in Functional Impairment
ADHD Diagnosis
Average ADHD-RS: 30-40
ADHD patient
before diagnosis
ADHD-RS: 0-54 (
18 symptoms rated 0-3
)
Standard reduction
of symptoms
Standard Reduction
Average ADHD-RS: 20-30
Optimal Improvement Average ADHD-RS: <18
Goal:
Minimal functional impairment
Optimizing ADHD Symptom Reduction
Can Minimize Functional Impairment
Mattingly et al. CNS Spectr. 2016;21:45.
27
Slide2816%
Responded
better to MPH than AMPH
28%
Responded
better to AMPH
than MPH
Methylphenidate vs Amphetamine?
41%
Responded to
both AMPH and MPH (“double responders”)
13%
Did not respond to either medication
Most patients (n = 152/174; 87%) responded to
MPH and/or AMPH
In Pediatric Studies
Mattingly et al. Postgrad Med. 2017;129:657. Arnold et al. J Atten Disord. 2000;3:200.
28
Slide29Network Meta-analysis: Results of ADHD Treatment
Mean Change in ADHD Symptoms, Rated by Healthcare Professionals
Favors Placebo
Favors Drug
Favors Placebo
Favors Drug
Children and Adolescents
Adults
SMD (95% CI)
SMD (95% CI)
Amphetamines
-1.02 (-1.19 to -0.85)
-0.79 (-0.99 to -0.58)
Atomoxetine
-0.56 (-0.66 to -0.45)
-0.45 (-0.58 to -0.32)
Bupropion
-0.96 (-1.69 to -0.22)
-0.46 (-0.85 to -0.07)
Clonidine
-0.71 (-1.17 to -0.24)
Guanfacine
-0.67 (-0.85 to -0.50)
Methylphenidate
-0.78 (-0.93 to -0.62)
-0.49 (-0.64 to -0.35)
Modafinil
-0.62 (-0.84 to -0.41)
0.16 (-0.28 to 0.59)
0.5
-1
-0.5
0
Favors Placebo
Favors Drug
0.5
-1
-0.5
0
Favors Placebo
Favors Drug
Cortese et al. Lancet Psychiatry. 2018;5:727.
29
Slide30Transition from Methylphenidate to
Amphetamine Occurs in Adolescence
US Stimulant Prescriptions
Methylphenidate
Amphetamine
IMS NPA Market Dynamics
—
RETAIL Rx ONLY. Mattingly et al. CNS Spectr. 2016;21:45.
Age (
yr
)
30
Slide31Currently Approved ADHD Medications Reflect
Limited Distinct Approaches for Adult Patients
Stimulants
Nonstimulants
Atomoxetine
Viloxazine XR
(kids and adults)
ER
α
2 adrenergic agonists
Stimulants
Methylphenidate
Short acting
Short acting
Long acting
(kids and adults)
Amphetamine
Approved
Investigational
Several MoAs under investigation
Long acting
(kids and adults)
adhdmedicationguide.com. accessdata.fda.gov/scripts/cder/daf/. De Sousa et al. Mens Sana Monogr. 2012;10:45. Spencer et al. J Clin Psychiatry. 2002;63:16. Stahl et al. Prim Care Companion J Clin Psychiatry. 2004;6:159. Chang et al. J Experiment Clin Med. 2013;5:210. clinicaltrials.gov/.
31
Slide32Methylphenidate Preparations
Adapted from Mattingly et al. CNS Spectr. 2021;26:104.
Delivery Mechanism and Formulation
Generic Name
Approved Ages
Doses/d
Onset
Duration
Comments
Short acting
Dexmethylphenidate
tablet
Dexmethylphenidate HCl
Children ≥6 yr
2
NA
6 hr
At least 4 hr between doses
Methylphenidate tablet
Methylphenidate HCl
Children ≥6 yr, adults
2-3
1-2 hr
4 hr
Methylphenidate chewable tablet and liquid
Methylphenidate HClChildren ≥6 yr, adults2-31 hr
4 hr
Chewable tablet: take with 8 oz of water before meals
Oral solution: take 30-45 min before mealsLast dose before 6 PMIntermediate acting
Methylphenidate tabletMethylphenidate HClChildren ≥6 yr, adults1NA
8 hr
Methylphenidate capsule
Methylphenidate HCl
Children 6-15 yr
1
1.5 hr
8-9 hr
May be sprinkled on applesauce
Long acting
Dexmethylphenidate capsule
Dexmethylphenidate HCl
Children ≥6 yr, adults
1
30 min
12 hr
May be sprinkled
Methylphenidate chewable tablet (3 preparations)
Methylphenidate HCl
Children ≥6 yr, adults
1
45 min
8 hr
Methylphenidate chewable tablet
Methylphenidate HCL
Children 6-12 yr
1
30 min to
1 hr
12 hr
May be sprinkled
Methylphenidate chewable tablet
Methylphenidate HCL
Children ≥6 yr, adults
1
1-2 hr
10-12 hr
Methylphenidate liquid
Methylphenidate HCl
Children ≥6 yr, adults
1
45 min
12 hr
Shake bottle vigorously for 10 s before dispensing
Methylphenidate ODT
Methylphenidate HCl
Children ≥6 yr
1
1 hr
12 hr
No crushing or chewing
Allow to disintegrate in saliva before swallowing
Methylphenidate transdermal patch
Methylphenidate
Children ≥6 yr
1
2 hr
12 hr
Wear for ≤9 hr
Methylphenidate capsule
(3 preparations)
Methylphenidate HCl
Children ≥6 yr, adults
1
1 hr
12 hr
May be sprinkled
Methylphenidate capsule
Methylphenidate HCL
Children ≥6 yr, adults
1
1 hr
13-16 hr
May be sprinkled and consumed within 10 min
Methylphenidate capsule
Methylphenidate HCL
Children ≥6 yr, adults
1
8-10 hr
12+ hr
Take in the evening between 6:30 and 9:30 PM for early morning symptom control; may be sprinkled
32
Slide33Amphetamine Preparations
Adapted from Mattingly et al. CNS Spectr. 2021;26:104.
Delivery Mechanism
and Formulation
Generic Name
Approved Ages
Doses/d
Onset
Duration
Comments
Short acting
Amphetamine tablet
Amphetamine mixed salts
Children ≥3 yr
1-3
1.5 hr
4-6 hr
Elimination half-life 9.77-11 hr for the D-isomer and
11.5-13.8 hr for L-isomer
Dextroamphetamine tablet
(2 preparations)
Dextroamphetamine sulfate
Children 3-16 yr
1-2
NA4-6 hr
Dextroamphetamine tabletDextroamphetamine sulfateChildren 3-16 yr1-3NA
4-6hr
Dextroamphetamine liquid
Dextroamphetamine sulfateChildren 6-16 yr1-2NA6-10 hrPlasma half-life of approximately 12 hr
Methamphetamine tabletMethamphetamine HClChildren ≥6 yr1-2NA
NA
Not readily available
Intermediate acting
Amphetamine tablet and ODT
Racemic amphetamine sulfate
Children ≥3 yr (tablet); Children
6-17 yr (ODT)
1-2
45 min
9.25 hr
Elimination half-life 10.0-11.7 hr
Dextroamphetamine capsule
Dextroamphetamine sulfate
Children 6-16 yr
1-2
NA
6-10 hr
Plasma half-life of approximately 12 hr
Long acting
Amphetamine capsule
(2 preparations)
Amphetamine mixed salts
Children ≥6 yr, adults
1
1.5 hr
10.5-12 hr
May be sprinkled on applesauce
Amphetamine capsule
Amphetamine mixed salts
Children ≥13 yr, adults
1
2 hr
14 hr
May be sprinkled on applesauce
Amphetamine liquid
(2 preparations)
Amphetamine
Children ≥6 yr
1
1 hr
12
Amphetamine liquid
Children ≥6 yr, adults
1
1.5 h
10-12 h
Do not add to food or other liquids
Amphetamine ODT
Amphetamine
Children ≥6 yr, adults
1
1.5 h
10-12 h
Allow tablet to disintegrate in saliva before swallowing
Amphetamine prodrug capsule and chewable tablet
Lisdexamfetamine dimesylate
Children ≥6 yr, adults
1
1.5-2 hr
12-14 hr
Capsule: may be sprinkled in water, orange juice, or yogurt
Chewable tablet: chew thoroughly before swallowing
33
Slide34Nonstimulant Options
*
Adapted from Mattingly et al. CNS Spectr. 2021
;26:104.
Delivery Mechanism
and Formulation
Generic Name
Approved Ages
Doses
per Day
Onset Effect
Duration of Effect
Comments
Long acting
Norepinephrine transporter reuptake inhibitor capsule
Atomoxetine
Children ≥6 yr, adults
1-2
3-4 wk
NA
Dosed by body weight
α
2
-adrenergic receptor agonist tablet
Clonidine HClChildren ≥6 yr22 wkNAAn antihypertensive agent may be prescribed in addition to a stimulant
Discontinuation must be gradualα2-adrenergic receptor agonist tabletGuanfacineChildren ≥6 yr 1
3 wkUp to 24 hr
per dose
An antihypertensive agent may be prescribed in addition to a stimulantDosed by body weightSerotonin norepinephrine modulating agent capsuleViloxazine HClChildren 6-17 yr11 wk24 hr
34
Slide35Nonmedical Use of Prescription
Stimulants Among College Students
Butler et al. Front Psychiatry.
2021;12:667118.
*Results based on an online survey conducted in 2016 with 3379 respondents aged 18-26 yr. The current study includes a subsample of
486 respondents who met the inclusion criteria (aged 18-26 yr, currently enrolled in college, and reported prescription stimulant NMU at any time in their lifetime).
Patterns of NMU of Prescription Stimulant Medications*
100
80
60
40
20
0
College Students (%)
Polysubstance
Use
IS Other Than Marijuana
IS Prior to Rx Stimulant
IS and Prescription Stimulant Simultaneously
NMU of Prescription Stimulant Prior to IS
Lifetime
Diagnosis of ADHD
91.4
55.0
43.0
23.6
32.0
43.0
35
Slide36FDA-Approved Medications With
Clinical Data for Adults With ADHD *Now also includes delayed-release/extended-release methylphenidate, time-release methylphenidate, prodrug methylphenidate, and viloxazine XR.
Medication
Molecule
Hr
Adult Dosing
Atomoxetine
Nonstimulant
24
40-100 mg
Dexmethylphenidate XR
2 beads
Methylphenidate
12*
10-40 mg
OROS methylphenidate
OROS capsule
Methylphenidate
12*
18-72 mg
Mixed amphetamine XR
2 beads
Amphetamine
12
10-20 mg
Lisdexamfetamine
Prodrug
Amphetamine
14
20-70 mg
Mixed amphetamine ER
3 beads
Amphetamine
16
12.5-50 mg
Mattingly et al. CNS Spectr. 2016;21:45.
36
Slide37What About the New Kids on the Block?
Slide38Serdexmethylphenidate C-IV/d-Methylphenidate C-II:
A 70/30 Prodrug/d-MPH Combination
70/30 combination:
70% prodrug d-MPH;30% d-MPH
Serdex prodrug is C-IVDoses:
26.1 mg/5.2 mg
39.2 mg/7.8 mg
52.3 mg/10.4 mg
Starting dose is
39.2 mg/7.8 mg
Serdexmethylphenidate/Dexmethylphenidate PI.
Placebo
d-MPH/Serdex
LS Mean SKAMP-Combined Change From Baseline
Hr
0
0.5
1
2
4
8
10
12
13
-12
-10
-8
-6
-4
-2
0
2
4
38
Slide39Serdex/d-MPH: Long-term Efficacy, 1-Yr Open-Label Study
Childress et al. APSARD 2021. Poster.
Mean ADHD RS-5 Total Score
0
5
10
15
20
25
30
35
40
45
Baseline
30
60
90
120
150
180
210
240
270
300
330
360
Day of Treatment
*
P <.001
41.5
16.1*
15.3*
14.7*
14.2*
14.3*
13.8*
14.3*
13.9*
13.9*
12.4*
13.1*
12.6*
39
Slide4070/30 Serdex/d-MPH: Adverse Events
Reported at ≥5%: Gastrointestinal: decreased appetite, decreased weight, nausea, abdominal pain, dyspepsia, vomitingNeurologic/psychiatric: insomnia, anxiety, affect lability, irritability, dizzinessCardiovascular: increased blood pressure, tachycardiaData from 1-wk treatment phase of 150 patients 6-12 yr with ADHD:
Serdexmethylphenidate/Dexmethylphenidate PI.
Kollins
et al. J Child Adolesc Psychopharm. 2021;31:597.
n (%)
Serdex/
d-MPH
N = 74
Placebo
N = 76
Any TEAE
23 (31.1)
11 (14.5)
Headache
4 (5.4)
1 (1.3)
Abdominal pain, upper
3 (4.1)
1 (1.3)
Insomnia
2 (2.7)
1 (1.3)Pharyngitis
2 (2.7)0 (0.0)40
Slide41Transdermal d-Amphetamine Patch
5 mg/9 hr
10 mg/9 hr
15 mg/9 hr
20 mg/9 hr
n (%)
7 (7)
35 (33)
42 (39)
23 (21)
Day 28
Wk 1
2
3
4
5
6
7
8
Dose-Optimization Period
Randomized, Double-Blind Treatment Period With Crossover
Screening and washout
Safety
follow-up
Optimal dose
Placebo
Placebo
Optimal dose
5 mg/
9 hr
5 mg/
9 hr
10 mg/
9 hr
5 mg/
9 hr
10 mg/
9 hr
15 mg/
9 hr
5 mg/
9 hr
10 mg/
9 hr
15 mg/
9 hr
20 mg/
9 hr
Cutler et al. APA 2021. Abstr P9-066.
41
Slide42Transdermal d-AMPH Patch
Cutler et al. APA 2021. Abstr P9-066.
160
140
120
100
80
d-AMPH transdermal patch
Placebo
Hr Post Dose
LS Mean (SE) Number Correct
12
0
2
4
6
8
10
*
*
*
*
*
*
*
*
*Statistically significant difference.
42
Slide43Allows Flexible Wear Time on Weekends
Mattingly et al. APSARD. 2022.
Treatment
d-ATS 20 mg
Time After Steady-state Dose (Hr)
Plasma Amphetamine Concentration (ng/mL)
150
0
50
100
60
40
20
150
0
50
100
2-Hr Weekend Wear Time
4-Hr Weekend Wear Time
43
Slide44Transdermal d-AMPH Patch
No dropouts due to patch issues
Cutler et al. APA 2021. Abstr P9-066.
n (%)
Double-Blind Period
Randomized treatment phase
(1 week)
d-ATS (All Doses)
(N = 105)
Placebo
(N = 105)
Decreased appetite
13 (12)
2 (2)
Insomnia
6 (6)
5 (5)
Headache
6 (6)
4 (4)
Hyperkalemia
5 (5)
4 (4)
Vomiting
4 (4)
0 (0)Nasopharyngitis3 (3)2 (2)
Abdominal pain, upper
3 (3)
1 (1)Nausea3 (3)1 (1)Affect lability3 (3)0 (0)Tic
2 (2)0 (0)Irritability2 (2)1 (1)44
Slide45Viloxazine XR
Approved for children aged 6-18 yr and now
for adults with ADHD
Yu et al. J Exp Pharmacol. 2010:12;285. Viloxazine PI.
PFC:
NE > DA > 5-HT
Nucleus Accumbens:
5-HT > NE > DA
Neurotransmitter Levels (% of Baseline)
Min
900
800
700
600
500
400
300
200
100
PFC
-90
-60
-30
0
30
60
90
120
150
180
210
240
270
NE (n = 5)
DA (n = 3)
5-HT (n = 5)
Glu (n = 6)
His (n = 6)
GABA (n = 5)
ACh (n = 3)
#
#
#
#
**
**
Neurotransmitter Levels (% of Baseline)
Min
Acb
500
400
300
200
100
270
240
210
180
150
120
90
60
30
0
-30
-60
-90
#
#
**
**
NE (n = 5)
DA (n = 5)
5-HT (n = 5)
Glu (n = 6)
His (n = 6)
GABA (n = 6)
ACh (n = 6)
45
Slide46Viloxazine XR: 100-400 mg Daily
Pediatric data, 6-12 yr of ageImproved symptoms in 1 wkEqual improvement in inattentive and hyperactive symptoms
Nasser et al. Clin Ther. 2020;42:1452.
Change From Baseline in ADHD RS-5 Total Score LS Mean ± SE
Wk of Treatment
0
-2
-4
-6
-8
-10
-12
-14
-16
-18
-20
-22
Baseline
1
2
3
4
5
6
Placebo (n = 155)
100 mg/day viloxazine (n = 147)
200 mg/day viloxazine (n = 158)
*
*
ꝉ
ꝉ
ꝉ
*
ꝉ
ꝉ
ꝉ
ꝉ
*
*
ADHD RS-5 Measure
Placebo (n = 155)
Viloxazine
100 mg/day (n = 147) 200 mg/day (n = 158)
CFB, LS mean (SE)
Total score
-10.9 (1.14)
-16.6 (1.16)
-17.7 (1.12)
Inattention subscale
-5.7 (0.60)
-8.6 (0.62)
-9.2 (0.60)
Hyperactivity/impulsivity subscale
-5.5 (0.59)
-8.0 (0.60)
-8.7 (0.58)
46
Slide47Viloxazine 200-600 mg Daily in Adult ADHD
Nasser et al. Psych Congress 2021. Poster.
Placebo
Viloxazine ER
-18
0
-2
-4
-6
-8
-10
-12
-14
-16
AISRS Total Score Change From BL
Wk of Treatment
BL
1
2
3
4
5
6
47
Slide48Improvement in Both Inattentive and Hyperactive/Impulsive Symptoms
Nasser et al. Psych Congress. 2021.
Placebo
Viloxazine ER
-10
0
-2
-4
-6
-8
Inattention Score Change From BL
Wk of Treatment
BL
1
2
3
4
5
6
Placebo
Viloxazine ER
-10
0
-2
-4
-6
-8
Hyperactivity/Impulsivity Score
Change From BL
Wk of Treatment
BL
1
2
3
4
5
6
48
Slide49Viloxazine XR Long-term Adult Data
Avg Dose:
400 mg daily
Nasser et al. Psych Congress. 2021.
Pivotal
Open-Label Extension
Mean CFB in AISRS Total Score (SEM)
0
-2
-4
-6
-8
-10
-12
-14
-16
-18
-20
-22
-24
-26
-28
BL
DW1
DW2
DW3
DW4
DW6
OW2
OW4
OW12
OW20
OW28
OW36
OW44
OW52
Pivotal
—
placebo
Pivotal
—
viloxazine ER
49
Slide50Improvement
Nasser et al. Psych Congress. 2021.
Viloxazine XR ADHD Score and BRIEF-A
55
95
90
85
80
75
70
65
60
55
50
45
40
BRIEF-A GEC T-Score at Baseline
AISRS Total Score at Baseline
100
25
30
35
40
45
50
15
5
-5
-15
-25
-35
-45
-55
CFB BRIEF-A GEC T-Score at EoS (%)
AISRS Total Score at Baseline
25
-110
-100
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
20
30
40
50
Slide51Other Groups With Executive Function Deficits?
P
<.001 change from baseline.
*
New-Onset Executive Function Difficulties at Menopause:
A Possible Role for Lisdexamfetamine
Epperson et al. Psychopharmacology. 2015;232:3091.
50.0
45.0
40.0
35.0
30.0
25.0
20.0
15.0
10.
5.0
0.0
BADDS Total Score
Baseline
Active
Placebo
51
Slide52Tools in the “Toolbox”
Get to know 1 or 2 long-acting MPHs, 1 or 2 long-acting AMPHs and 1 or 2 nonstimulantsConsider onset and durationTitrate to optimal effect vs side effectsWatch for breakthrough symptoms throughout the day, especially in mornings and eveningsUse short-acting stimulants sparingly and avoid in College studentsMonotherapy in adultsWhen concerned about abuse, misuse or diversion
52
Slide53Digital Therapeutics?
Lumosity, Akili, Atentiv, Pear, and othersPotential cognitive enhancers in children and adults with ADHD?53
Slide54Digital Therapeutics
EndeavorRx
54
Slide55Digital Therapeutics
Examples of Lumos “Games”
Attention
Attention
and
Flexibility
Attention
and
Flexibility
Lumos Labs.
Activities target attention and/or flexibility
55
Slide56Digital Therapeutics
Lumosity, Akili, Atentiv, and othersPotential cognitive enhancers in children and adults with ADHDQuestionsDo they work with ADHD medications?Akili adult trial to evaluate effects with and without ADHD medicationsDo they improve core ADHD symptoms or just specific cognitive aspects?
Lumosity to look at ADHD-RS, BRIEF, WFIRSDo they work with comorbidities: ASP, MDD, post COVID-19?Akili with pilot data in these conditions
Do they work in adults?Controlled data thus far only in childrenLumosity with large “big data” set in adults with ADHD
56
Slide57Key Summary Points
Excessive screen time and social media use have been shown to worsen processing speed and increase ADHD symptoms Recent data from the MTA study show that 90% of children with ADHD will continue to have symptoms into adulthood Unrecognized or untreated ADHD dramatically increases mortality rates, worsens school and job performance, and impacts overall daily functionHolistic ADHD treatment has some of the biggest treatment effects of any intervention in medicine 57
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