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How Do Drugs for ADHD
Work?
Jeffrey H. Newcorn, MD
Icahn School of Medicine at Mount Sinai
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Disclosure (Past 12 months)
Source Consultant Advisory
Board
Speaker
(Disease State)
Research
Support
Adlon X
Akili X
Arbor X X
Medice X
NFL X
NLS X
Otsuka X
Pfizer X (DSMB)
Rhodes X
Shire X X X
Sunovion X (DSMB)
Supernus X X
Additional research support provided by NIDA and NICHD
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What Is ADHD?
Inattention
• Difficulty sustaining attention
• Trouble initiating tasks; procrastination
• Trouble completing tasks
• Loses important items
• Seems not to listen
• Cannot organize
• Easily distractible
• Forgetful
• Poor attention to detail/careless mistakes
Hyperactivity/Impulsivity
• Intrudes/interrupts others
• “On the go”/“driven by motor”
• Runs/climbs excessively
• Cannot play/work quietly
• Squirms and fidgets
• Cannot stay seated
• Talks excessively
• Blurts out answers
• Cannot wait turn
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ADHD: DSM-5 Criteria
ADHD is classified as a neurodevelopmental disorder:
A. Threshold level of symptoms of Inattention and/or
Hyperactivity – impulsivity must be present for 6 months or more (5 in individuals > 17 years)
B. Several symptoms must be present before 12 years of age
- Current controversy – adult onset ADHD?
C. Impairment from symptoms must be present in 2 or more settings (e.g. school, work, home, other)
D. Significant impairment: social, academic, or occupational
E. Symptoms must not be better accounted for by other mental (or physical) disorders
American Psychiatric Association, 2013
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Locus Coeruleus
VTA
Substantia Nigra
PosteriorPParietal Cortex NET, ɑ2A
Sensory input
Prefrontal Cortex D1,
D4, D5 NET, ɑ2A
Striatum DAT, D2
NE enhances relevant signal;
regulates DA
DA suppresses irrelevant signal
NE enhances relevant signal
Cerebellum D3, D4
Neurobiological Basis of Attention and Inhibitory Control in ADHD
Modulators
Nicotinic/Cholinergic
5-HT1A, 1B
H3
Orexin
Synthesis/ metabolism
DƁH
COMT
MAO (A)
Interface with:
Glutamate
NMDA/ AMPA
GABA
Newcorn, NCDEU, 2008 Newcorn and Schulz, NCDEU, 2008
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Dual Pathway Model of ADHD: Implications for Mood Dysregulation and Aggression
Sonuga-Barke, Neurosci Biobehav Rev., 2003 Nov;27(7):593-604
ED*
*ED = Emotional Dysregulation
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Neurobiological Underpinnings of Dual Pathway Model of ADHD
Cubillo et al.,2012. Cortex, 48: 194-215
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Posner et al (JAACAP, 2011) showed higher activation of amygdala and greater amygdala-PFC connectivity in ADHD youth relative to controls when subjects were exposed to emotionally evocative stimuli – this difference was greatly reduced by administration of MPH
Increased Amygdala Activity and Amygdala-PFC Connectivity in Youth with ADHD
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CAARS Ratings of Impulsivity/Emotional Lability and Functional Connectivity of d,l-PFC
with Subgenual Cingulate Cortex
The CAARS impulsivity/emotional lability score was differentially associated
with the functional connectivity of the right dorsolateral prefrontal cortex
(DLPFC) with the right subgenual cingulate cortex (SCC) for cognitive control
Schulz et al., NeuroImage: Clinical, Vol 5:1-9, 2014
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Anti-correlated Task-Positive and Task-Negative Networks in Regulation of Attention
Lateral Parietal Cortex
Inferior Temporal
Lobule
Medial Prefrontal
Cortex
Posterior Cingulum/Precuneus
Task Negative
Inferior Parietal Lobule
Supplementary Motor areas
DLPFC
FEF
Task Positive
Sonuga-Barke and Castellanos, Neurosci Biobehav Rev, 31:977–986, 2007
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Motivation and Inattention Symptoms Are Correlated In Adults with ADHD
Volkow et al., Molecular Psychiatry advance online publication 21 September 2010.
Ratings of motivation derived from the MPQ Achievement subscale are negatively correlated with ratings of inattention on the CAARS and SWAN scales
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Current View of ADHD: Multiple Cognitive and Emotional Processes and Interacting Brain Networks
Faraone S, et al. Nat Rev Dis Primers 2015; 6:1.
a. Cortical brain regions; b. Subcortical brain regions; c. Catecholamine (DA + NE) mechanisms; d. Executive control networks; e. Reward network; f. Alerting network; g. Default mode network
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Summary: ADHD Diagnosis, Clinical Presentation and Pathophysiology
• The DSM diagnosis of ADHD is narrowly defined
– Focus on inattention and hyperactive/impulsive symptoms
– Consistent with a fronto-striatal model of the disorder
• Recent models of ADHD highlight the importance of several other symptomatic/functional domains
– Expanded view of executive dysfunction
– Mood dysregulation
– Important roles of motivation and salience
• Studies of ADHD pathophysiology are consistent with an expanded conceptualization of ADHD
– Important implications for diagnosis and treatment
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Why Do We Treat ADHD?
▶ Decrease level of core symptoms
▶ Minimize impairment from core symptoms
– Improvement over time is likely linked to improved functional status that follows treatment of symptoms
– Examples: academic and/or occupational problems related to attention, task completion, time management, etc.; relationship problems, self-esteem
▶ Alter course of other disorders?
– Treat symptoms commonly associated with other axis I or axis II disorders, including personality disorders
– Decrease risk for the emergence of other disorders
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ADHD Medications Worldwide* (approved and investigational)
Approved Not Approved
Non-Stimulant
Strattera¶
Intuniv ‡‡
Kapvay¶
TCAs§
Provigil**
Wellbutrin, Zyban††
Tenex‡‡
Catapres¶¶
Effexor/Pristiq§§
Duloxetine/Reboxetine
Stimulants
Amphetamine
Short Acting Long Acting Intermediate
Dextrostat†
Dexedrine tabs†
Dexedrine Spansule†
Adderall‡
Evekio ‡
Adderall XR‡
Vyvanse †
(tablets/chewable)
Adzenys (ODT) ‡
Dyanavel (liquid) ‡
Mydayis ‡
Methylphenidate
Short Acting Long Acting Intermediate
Ritalin #
Focalin*
Ritalin SR #
Metadate ER #
Concerta #
Metadate CD #
Ritalin LA #; Focalin XR*
Daytrana (patch) #
Aptensio XR #;
Quillivant (liquid) # Quillichew #; Cotempla-XR-ODT #
#d,l-methylphenidate
*dexmethylphenidate †dextroamphetamine sulfate ‡mixed amphetamine salts ¶atomoxetine
§tricyclic antidepressants
(many brands) **modafinil ††bupropion ‡‡guanfacine ¶¶clonidine §§venlafaxine
Investigational Drugs
Dasotraline
Centanafadine
Mazindol
Viloxazine
Fasoracetam
Molindone
Misc. early phase
Jornay PM #
Adhansia XR #
Emerging Formulations
*Not all drugs and/or formulations
available in all countries
Novel stimulant
formulations
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ADHD Practice Parameters. J Am Acad Child Adolesc Psychiatry. 1997;36:85S.
Greenhill LL, et al. J Am Acad Child Adolesc Psychiatry. 1999;38:503-512.
Benefits of Acute Stimulant Treatment
▶ Core Symptoms
– Inattention
– Impulsivity
– Hyperactivity
• Associated Features
– Noncompliance
– Impulsive aggression
– Social interactions
– Academic efficiency
– Academic accuracy
– Family dynamics
– Self-esteem
ES for core symptoms is
~0.8-1.1 across studies
Time-action properties
complicate response
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Adapted from: Wilens TE and Spencer TJ. In: Handbook of Substance Abuse; 1998; Solanto MV. Behavioral Brain Research. 2002;130:65-67.
Receptors
Synapse
Dopamine/ Norepinephrine
Catecholamine Neuron Presynaptic
neuron
Postsynaptic neuron Increased neurotransmitter
Transporter
Stimulants and Atomoxetine: Neurochemical Mechanisms of Action
Amphetamines and methylphenidate block
reuptake
Atomoxetine blocks NE
transporter Amphetamine increases
meurotransmitter release
X
Amphetamines block reuptake
X
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signal
PET Studies of Dopamine Transporter Occupancy by Methylphenidate (MPH)*
DA
DA
DA
DA DA
MAO A
[11C]cocaine
without drug
with drug
*Illustration of methodology
Slide courtesy of Nora Volkow
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Methylphenidate Occupies Dopamine and Norepinephrine Transporters
Placebo 20 mg 40 mg
Therapeutic
doses occupy
>50% of DAT
0
20
40
60
80
100
0.0 0.2 0.4 0.6 0.8 1.0
Dose (mg/kg)
% D
AT O
ccupancy
Dopamine Transporters
Pla
cebo
2.5
mg
10
mg
40 m
g
Norepinephrine Transporters
Therapeutic doses
occupy 70-80% of NET
Volkow et al., J Neurosci, 2001 Volkow et al., Synapse, 2002 Hannestad et al., Biol Psychiatry, 2010
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Low DA Activity Extends Beyond Striatum and Is Increased By MPH in Adults with ADHD
Volkow, N. D. et al. Arch Gen Psychiatry 2007;64:932-940.
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Extended DAT Occupancy Following Administration of OROS MPH
Spencer TJ, et al. Am J Psychiatry. 2006;163:387-395.
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Meta-Analysis of fMRI Findings in ADHD and Normalization with MPH
Main areas implicated in
ADHD are right inferior frontal
(increased activity) and right
rostral/dorsal anterior cingulate
(decreased activity)
Rubia et al., Biol Psychiatry, 2014
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MPH Attenuation of mPFC Activity During an Emotional Stroop Task*
Positively valenced distraction interactions Negatively valenced distraction interactions
Posner et al., Psychiatry Research: Neuroimaging, 2011
*Using a different task to show an alternative
effect of a treatment
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Lisdexamfetamine Targets Amygdala Mechanisms That Bias Cognitive Control in ADHD
Schulz et al., Biological psychiatry : cognitive neuroscience and neuroimaging, 2018
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MPH Increases Suppression of Default-mode Activity in Children with ADHD
Peterson et al., Am J Psychiatry 2009
- Decreased activation in
Precuneus and mPFC
with MPH vs. Placebo
- This decreased activity
was associated with
reduced symptom
severity
- Method: discontinuation
design in youth on MPH
who were scanned and
then taken off medication
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Task‐related Default Mode Network Modulation and Inhibitory Control in ADHD: Effects of Motivation and MPH
Liddle et al. (2011). J Child Psychol Psychiat, Jul;52(7):761-71. ):761-771, 2013
DMN deactivation was
significantly modulated by
motivational incentive only in the
ADHD participants off-
methylphenidate.
For the on-methylphenidate day,
there was no significant
difference between diagnostic
groups, nor any significant
effects of motivational incentive,
and net deactivation across
groups was significantly below
zero
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Decreased Brain Glucose Utilization During Numerical Calculations Test with MPH Treatment
Volkow et al., PLoS One, 2008
Greater glucose utilization
on placebo than MPH
Scans (PET)
Obtained While Performing
Numerical Calculations
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Summary: Stimulant Mechanisms of Action
▶ Bind to DA and NE transporters
– Increase synaptic DA and NE
▶ Modulate activity in front-striatal network
– IFG – inhibitory control
– dACC – cognitive control
▶ Suppress default mode network activity
– Quiets noise, thereby enhancing signal
– Brain works more efficiently
▶ Alter limbic-prefrontal connectivity
– Increased for attention to emotional stimuli
– Decreased for emotional cues
▶ Enhance activity in reward network
– Increased motivation and sensitivity to reward
– Tasks seem “more interesting”
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Rationale for Non-stimulant
Treatment of ADHD
▶ Stimulants are extremely effective, but:
– Poor response or tolerability in some patients
• Affective blunting can be problematic
– Sub-optimal response is not uncommon
• Consider alternative treatments
• Consider combination treatment
– Time-action effects are often problematic
– Relative or labeled contraindicatons for some
comorbid conditions (e.g., tics, anxiety, SUD)
– Some patients will not take stimulants
– Risk for diversion or abuse of Schedule II drugs
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Time (Hours)
-1 0 1 2 3 4
% o
f B
asel
ine
150
200
250
300
350
400 Dopamine Norepinephrine
MPH 3 mg/kg, ip ATX 1 mg/kg, ip
*P<.05 vs baseline
-1 0 1 2 3 4
% o
f B
ase
line
0
100
200
300
400
150
250
300
50
Dopamine Norepinephrine
*P<.05 vs baseline
Bymaster FP et al., Neuropsychopharmacology 2002; 27( 5): 699–711.
Methylphenidate Atomoxetine*
MPH and ATX: Common Effects on Extracellular Monoamine Levels in PFC
* Promiscuous NET clears both norepinephrine and dopamine when DAT is absent in prefrontal cortex
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MPH and ATX: Differential Effects on Extracellular Dopamine Levels in Striatum
Bymaster FP et al., Neuropsychopharmacology 2002; 27( 5): 699–711.
P<.05 vs baseline
Prefrontal cortex
Nucleus accumbens
Striatum
MPH 3 mg/kg, ip
Prefrontal cortex
Nucleus accumbens
Striatal dopamine
ATX 1 mg/kg, ip
P<.05 vs baseline
Time (Hours)
-1 0 1 2 3 4 -1 0 1 2 3 4
% o
f B
ase
line
0
100
200
300
400
150
250
300
50
Methylphenidate Atomoxetine
* Robust DAT but few NET in striatum
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Atomoxetine Increases Right IFG Activation in Association with Improved Inhibitory Control
Chamberlain et al., Biol Psychiatry, 2009;65:550–555
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OROS Methylphenidate vs. Atomoxetine Comparator Study: Response+
Newcorn JH, et al. Am J Psychiatry, 2008 +Funded by Eli Lilly
% R
esp
on
de
rs
0
20
40
60
80
100 Atomoxetine
OROS
PlaceboP=.016
P=.423
P=.026
All Patients (N=492)
Prior Stimulant (N=301)
Stimulant Naïve (N=191)
*
* *
*
*
+ 40% Reduction in ADHD-RS Score
* Significantly different from placebo
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Bimodal Response to Atomoxetine in 6 Pre-marketing Clinical Trials
(and why we need personalized treatment approaches)
0%5%
10%15%20%25%30%35%40%45%50%
Non-response(< 25%)
Intermediateresponse(25 - 40%)
Excellentresponse(> 40%)
N = 1,069 youth ages 6 – 18 years; 618 treated with atomoxetine
Overall ES across clinical trials is ~0.7
Newcorn et al., JAACAP, 2009 ,48(5):511-8
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Mechanisms of Action and Predictors of Response to Methylphenidate (Stimulant) and Atomoxetine
(Non-Stimulant) Medications
35
Randomize
Methylphenidate 6-8 weeks
Atomoxetine 6-8 weeks
Atomoxetine 6-8 wks
Open-label treatment
2 week washout
2 week washout
Methylphenidate 6-8 weeks
The MACRO Study
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MACRO Study: Comparative Response Model Estimated Means for ADHD-RS Total Score
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MACRO Study: Medication Preference X Responder Status*
n=24
n=43
n=10
n=25
n=17
n=8
n=17
N=26
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Common and Unique Activation Profiles in Association with Response to MPH and ATX in Youth with ADHD
Schulz et al., Arch Gen Psychiatry, In Press
- Pre and post-treatment (7 weeks) scans in 18 subjects treated with MPH and 18 subjects treated with ATX in randomized clinical trials - Regression analysis incorporates change in regional activation and change in ADHD-RS ratings in the same model
Schulz et al. Arch Gen Psychiatry, 2012
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MACRO fMRI Predictor Study: Objectives and Hypotheses
• Primary aim: Examine whether off-drug fMRI profile can predict differential response to MPH vs. ATX
• Hypothesis: Differences in striatal activation off drug predict differential response to MPH over ATX
• Method: – Study 36 youth who completed treatment with both
medications for 6-8 weeks
– Double-blind treatment with MPH or ATX titrated to optimal response
– Examine fMRI main effects (i.e., profile associated with response to
each drug) and interactions (i.e., profile associated with differential response)
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MACRO fMRI Predictor Study: Increased Baseline Activation of Motor Cortex
Predicts Response to ATX (Main Effect)
Schulz et al., JAACAP, 2017
Method: Off treatment scans obtained in 36 youth with ADHD treated with both MPH and ATX, randomized for order
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MACRO fMRI Predictor Study: Increased Baseline Caudate Activation Predicts
Differential Response to MPH Over ATX
p < .005 Schulz et al., JAACAP, 2017
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Summary: Atomoxetine Mechanisms of Action
• Increases synaptic DA in PFC and NE diffusely
• Drives prefrontal activity
– Increase attention and responsiveness to signal
• Enhances inhibitory control via activity at IFG
• No direct activity in caudate, ventral striatum
– Minimal effects on motivation/reward
• Uncertain effects on default mode network
– Findings in both directions (likely task dependent)
• Due to high level of non-response, ATX would benefit from a biomarker-informed strategy
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Cellular Mechanisms of Alpha-2a Agonist Medications
Wang et al., Cell, 2007.
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GUAN Increases SPECT Measured rCBF in d,l-PFC in Monkeys Doing a Working
Memory Task
Avery RA, et al. Neuropsychopharmacology. 2000;23:240-249.
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Guanfacine Enhances Activation of dl-PFC During a Cued Alerting Task
Clerkin et al., Biol Psychiatry, 2009
METHODS:
-Healthy adults ages (n = 16)
-Cued alerting task
-Single dose challenge of 1 mg guanfacine and placebo
-Randomized for order
-1 week between challenges
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Guanfacine Extended Release Treatment of Oppositional Symptoms in Children with ADHD
Connor et al., Effects of guanfacine extended release on oppositional symptoms in children aged 6-12 years with
attention-deficit hyperactivity disorder and oppositional symptoms: a randomized, double-blind, placebo-controlled
trial. CNS Drugs. 2010 Sep 1;24(9):755-68.
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Schulz et al., Eur Neuropsychopharmacol, 2014
Guanfacine Moderates the Influence of Emotion on Amygdala-Prefrontal Connectivity for Response Inhibition
x = -44 y = 32 z = -10
Left Amygdala Right Amygdala
L R
Parameter Estimates for Inferior Frontal Gyrus Signal
0 -1.5 1.5 0 -1.5 1.5 0 -1.5 1.5
Pa
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stim
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Placebo
No-go
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Guanfacine
IFG regulation of amygdala activity in association with improvement in negative bias for sad response
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Neural Mechanisms Underlying the Therapeutic Actions of Guanfacine Extended Release in
Treatment of Youth with ADHD
Bedard, Schulz et al., Psychiatry Research: Neuroimaging, 2015
METHODS: -Children and adolescents ages 8 – 15 (n=25)
-Randomized treatment with GXR or placebo for 6 weeks
- Spiderman Go/nogo task obtained at baseline and end of treatment
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Summary: Guanfacine Mechanisms of Action
• Binds to post-synaptic ion channel and facilitates signal transmission
• Increases activation in PFC
– Enhances alerting mechanisms
– Effects on attention and EF uncertain in humans
• Decreases limbic activity and limbic – PFC connectivity
– Modulates emotional reactivity
• Decreases activation in mid-cingulate in association with clinical improvement
– Common mechanism with stimulants?
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Discussion and Take Home Messages
• ADHD is a multi-faceted neurodevelopmental disorder that has a strong biological basis – Expanding conceptualization of the disorder highlights several new
clinical domains of interest
• Effective treatments impact multiple brain regions: – Attention/executive control, default mode, reward/motivation,
emotion regulation networks
• Effective medications for ADHD have both common and unique effects – Unique effects provide a rationale for combination
pharmacotherapy and neurobiological basis of differential response
• Are there biomarker predictors of response? – Not yet, though there are interesting preliminary findings
• Clinical observations regarding a broader ADHD phenotype line up with findings from neuroimaging studies – The current definition of ADHD – which maps most closely onto a
restrictive, fronto-striatal model - is not fully adequate
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Iliyan Ivanov MD
Jeffrey Halperin PhD
Juan Pedraza MD
Jeffrey Newcorn MD Kurt Schulz PhD A-C Bedard PhD
Beth Krone PhD Amanda Kirschenbaum BSc
Erica Pazmino MA
Stephanie Duhoux PhD
ADHD Clinical - Translational Studies Team
Collaborators:
Mark Stein PhD James Blair PhD Lenard Adler MD Stuart White PhD
Jin Fan PhD