How Do Drugs for ADHD Work?

Jeffrey H. Newcorn, MDIcahn School of Medicine at Mount Sinai

Disclosure (Past 12 months)Source Consultant Advisory

BoardSpeaker

(Disease State)Research Support

Adlon XAkili XArbor X XMedice XNFL XNLS XOtsuka XPfizer X (DSMB)Rhodes XShire X X XSunovion X (DSMB)Supernus X X

Additional research support provided by NIDA and NICHD

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

ADHD: DSM-5 CriteriaADHD 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

Locus Coeruleus

VTA

SubstantiaNigra

PosteriorPParietalCortexNET, ɑ2A

Sensory input

Prefrontal Cortex D1,

D4, D5NET, ɑ2A

StriatumDAT, D2

NE enhances relevant signal;

regulates DA

DA suppresses irrelevant signal

NE enhances relevant signal

CerebellumD3, D4

Neurobiological Basis of Attention and Inhibitory Control in ADHD

ModulatorsNicotinic/Cholinergic

5-HT1A, 1BH3Orexin

Synthesis/ metabolismDƁH

COMT

MAO (A)

Interface with: Glutamate

NMDA/ AMPA

GABA

Newcorn, NCDEU, 2008Newcorn and Schulz, NCDEU, 2008

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

Neurobiological Underpinnings of Dual Pathway Model of ADHD

Cubillo et al.,2012. Cortex, 48: 194-215

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

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

Anti-correlated Task-Positive and Task-Negative Networks in Regulation of Attention

LateralParietalCortex

InferiorTemporal

Lobule

MedialPrefrontal

Cortex

PosteriorCingulum/Precuneus

Task Negative

InferiorParietalLobule

SupplementaryMotor areas

DLPFC

FEF

Task Positive

Sonuga-Barke and Castellanos, Neurosci Biobehav Rev, 31:977–986, 2007

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

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

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

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

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 ActingIntermediate

Dextrostat†Dexedrine tabs†

Dexedrine Spansule†Adderall‡Evekio ‡ Adderall XR

‡

Vyvanse †(tablets/chewable)Adzenys (ODT) ‡

Dyanavel (liquid) ‡Mydayis ‡

Methylphenidate

Short Acting Long ActingIntermediate

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

DasotralineCentanafadineMazindolViloxazineFasoracetamMolindoneMisc. early phase

Jornay PM #Adhansia XR #

Emerging Formulations

*Not all drugs and/or formulations available in all countries

Novel stimulant formulations

PresenterPresentation NotesA wide array of medications are used in treating ADHD. Stimulants have the longest history of use with demonstrated efficacy and long-term safety record. Nonstimulants are more recent arrivals on the scene and have also shown efficacy and safety in recent long-term studies.

As the graph shows, the clinician has a wide range of choices within the stimulant class, with both methylphenidate and amphetamine-based drugs available in short, intermediate, and long-acting formulations. The nonstimulant class is likely to expand as other agents are investigated for their utility in treating ADHD.

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 studiesTime-action properties complicate response

PresenterPresentation NotesAdministration of stimulants to most patients with ADHD results in significant improvements in behavior These improvements are observed in the core symptoms of inattention, hyperactivity, and impulsivity, which improves compliance, social interaction, academic efficiency, and accuracy

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 neuronIncreased neurotransmitter

Transporter

Stimulants and Atomoxetine: Neurochemical Mechanisms of Action

Amphetamines and methylphenidate block

reuptake

Atomoxetine blocks NE

transporterAmphetamine increases

meurotransmitterrelease

X

Amphetamines block reuptake

X

PresenterPresentation NotesWhat happens when you add ADHD medications to the picture? Stimulant medications, bupropion, tricyclic antidepressants, and atomoxetine bind to the dopaminergic or noradrenergic reuptake protein and block the transporter.

Blocking the transporter results in accumulation of dopamine and norepinephrine in the synaptic cleft. A consequence is that more neurotransmitter is made available there to potentiate the neuronal impulse.

signal

PET Studies of Dopamine Transporter Occupancy by Methylphenidate (MPH)*

DA

DA

DADA DA

MAO A

[11C]cocaine

without drug

with drug*Illustration of methodology

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

ccup

ancy

Dopamine Transporters

Plac

ebo

2.5

mg

10 m

g40

mg

Norepinephrine Transporters

Therapeutic doses occupy 70-80% of NET

Volkow et al., J Neurosci, 2001Volkow et al., Synapse, 2002Hannestad et al., Biol Psychiatry, 2010

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.

Extended DAT Occupancy Following Administration of OROS MPH

Spencer TJ, et al. Am J Psychiatry. 2006;163:387-395.

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

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

Lisdexamfetamine Targets Amygdala Mechanisms That Bias Cognitive Control in ADHD

Schulz et al., Biological psychiatry : cognitive neuroscience and neuroimaging, 2018

MPH Increases Suppression of Default-mode Activity in Children with ADHD

Peterson et al., Am J Psychiatry 2009

- Decreased activation in Precuneus and mPFCwith 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

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

PresenterPresentation Notes Phasic DMN deactivation in each motivational condition for ADHD participants (off and on methylphenidate) and controls (collapsed across days). Brain images show the extent of DMN deactivation (cool colours show deactivation, warm colours activation) weighted by the probabilistic DMN masks. The bar‐charts show the weighted mean beta values across all ROIs (error bars represent standard errors). 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

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”

Rationale for Non-stimulantTreatment 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

Time (Hours)

-1 0 1 2 3 4

% o

f Bas

eline

150

200

250

300

350

400Dopamine Norepinephrine

MPH 3 mg/kg, ip ATX 1 mg/kg, ip

*P

MPH and ATX: Differential Effects on Extracellular Dopamine Levels in Striatum

Bymaster FP et al., Neuropsychopharmacology 2002; 27( 5): 699–711.

P

Atomoxetine Increases Right IFG Activation in Association with Improved Inhibitory Control

Chamberlain et al., Biol Psychiatry, 2009;65:550–555

OROS Methylphenidate vs. Atomoxetine Comparator Study: Response+

Newcorn JH, et al. Am J Psychiatry, 2008

+Funded by Eli Lilly

% R

espo

nder

s

0

20

40

60

80

100 AtomoxetineOROSPlacebo

P=.016P=.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

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 atomoxetineOverall ES across clinical trials is ~0.7

Newcorn et al., JAACAP, 2009 ,48(5):511-8

Mechanisms of Action and Predictors of Response to Methylphenidate (Stimulant) and Atomoxetine

(Non-Stimulant) Medications

35

Randomize

Methylphenidate6-8 weeks

Atomoxetine6-8 weeks

Atomoxetine6-8 wks

Open-labeltreatment

2 weekwashout

2 weekwashout

Methylphenidate6-8 weeks

The MACRO Study

MACRO Study: Comparative Response Model Estimated Means for ADHD-RS Total Score

Block 1

39.56 (.91)

17.03(1.01)

38.90(.91)

19.27(1.03)

05

1015202530354045

Baseline 1 End of Block

MPH (n = 124) ATX (n = 108)

d = -.17

Block 2

33.40(1.18)

17.56(1.19)

33.34(1.11)

21.87(1.20)

05

1015202530354045

Baseline 2 End of Block

MPH (n =108) ATX (n = 124)

d = -.34*

N = 232 randomized; all randomized subjects included in analysis; baseline 2 is ~15% lower than baseline 1, and is not different by drug; correlation of block 2 and block 1 response (adjustment for carryover)

*p < .05

PresenterPresentation NotesThe number needed to treat indicates that you need to treat between 4-5 people, but only when you consider dropout as a “bad” response. You need to treat more in block 2 because all dropouts are considered bad and dropout is more equivalent in block 2 than in block 1, thus these numbers might not be the most easily interpreted.

Chart1

Baseline 1Baseline 1

End of BlockEnd of Block

d = -.17

MPH (n = 124)

ATX (n = 108)

39.56 (.91)

17.03(1.01)

38.90(.91)

19.27(1.03)

39.56

38.9

17.03

19.27

Sheet1

MPH (n = 124)ATX (n = 108)

Baseline 139.5638.9

End of Block17.0319.27

To resize chart data range, drag lower right corner of range.

Chart1

Baseline 2Baseline 2

End of BlockEnd of Block

d = -.34*

MPH (n =108)

ATX (n = 124)

33.40(1.18)

17.56(1.19)

33.34(1.11)

21.87(1.20)

33.4

33.34

17.56

21.87

Sheet1

MPH (n =108)ATX (n = 124)

Baseline 233.433.34

End of Block17.5621.87

To resize chart data range, drag lower right corner of range.

MACRO Study: Medication Preference X Responder Status*

Χ2(4)= 44.62, p < .001

24.5% 38.2%

9.8%25.0%

n=5 17.2%

42.1%11.8%

n=8 27.6%

23.5%

25.0%

n=14 48.3%

0%

10%

20%

30%

40%

50%

60%

N=102 Chose MPH N=68 Chose ATX N=29 Chose Neither

Responds to Both Responds to ATX Only Responds to MPH Only Non-Responder

n=24

n=43

n=10

n=25

n=17

n=8

n=17

N=26

*Responder: > 50% change in ADHD-RS

Preference primarily determined by response to chosen treatmentNewcorn et al., AACAP annual meeting, 2013

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

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)

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

MACRO fMRI Predictor Study:Increased Baseline Caudate Activation Predicts

Differential Response to MPH Over ATX

p < .005Schulz et al., JAACAP, 2017

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

Cellular Mechanisms of Alpha-2a Agonist Medications

Wang et al., Cell, 2007.

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.

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

http://eresources.library.mssm.edu:2080/science?_ob=MiamiCaptionURL&_method=retrieve&_udi=B6T4S-4WH0JV6-1&_image=fig1&_ba=1&_user=30742&_coverDate=08/15/2009&_rdoc=1&_fmt=full&_orig=search&_cdi=4982&view=c&_acct=C000000333&_version=1&_urlVersion=0&_userid=30742&md5=561020bc93ed40918026049bc66d6254http://eresources.library.mssm.edu:2080/science?_ob=MiamiCaptionURL&_method=retrieve&_udi=B6T4S-4WH0JV6-1&_image=fig1&_ba=1&_user=30742&_coverDate=08/15/2009&_rdoc=1&_fmt=full&_orig=search&_cdi=4982&view=c&_acct=C000000333&_version=1&_urlVersion=0&_userid=30742&md5=561020bc93ed40918026049bc66d6254

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.

Schulz et al., Eur Neuropsychopharmacol, 2014

Guanfacine Moderates the Influence of Emotion onAmygdala-Prefrontal Connectivity for Response Inhibition

x = -44 y = 32 z = -10

Left Amygdala Right Amygdala

LR

Parameter Estimates for Inferior Frontal Gyrus Signal

0-1.5 1.50-1.5 1.5 0-1.5 1.5

Par

amet

er E

stim

ates

for A

myg

dala

Sig

nal Happy Sad Neutral

0

-1.5

1.5No-goGo

Placebo

No-goGo

Guanfacine

IFG regulation of amygdala activity in association with improvement in negative bias for sad response

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

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?

Common and Unique Effects of Medications for ADHD

Attention/ ExecutiveControl

Inhibitory Control

Mood Regulation/ Limbic

Reward/ Motivation

Alerting/Salience

Default Mode

Stimulants +++ +++ ++ ++ ++ +++

Atomoxetine ++ ++ (?) + (?) (?) +

Guanfacine + ++ +/++ (?) ? ++ (?)

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 finding

• 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

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

Back-up Slides

MTA Study: Normalization Following Treatment

DBD Cumulative Distributions(Parent Teacher Average)

0

10

20

30

40

50

60

70

80

90

100

0 0.25 0.5 0.75 1 1.25 1.5 1.75 2 2.25 2.5 2.75 3Score

Perc

ent LNCG

CombMedBehCC

Comb67.6%

Med55.6%

Beh33.8%

CC25.3%

(Not at All) (Just a Little) (Pretty Much) (Very Much)

LNCG87.6%

Swanson et al. for the MTA Cooperative Group, JAACAP, 2001

Atomoxetine Selectively Binds to Norepinephrine Transporters

Seneca et al; Psychophamacology 2005

Therapeutic doses occupy 38-82% of NET in non-human

primates

Newcorn et al., JAACAP, 2009 ,48(5):511-8

Temporal Course of Response to Atomoxetine: Excellent Responders Respond Quicker and at Lower Dose

Differential Therapeutic Effects of MPH and ATX on fMRI Activation*

*Counting stroop task; n= 42 drug-naïve youth with ADHD

ATX: ↓ activations in the dACC and d,l-PFC correlated with ↑ focused attention

MPH: ↑ activation in IFG correlated with ↓ severity of impulsivity

Chou et al., Eur Neuropsychopharmacol, 2015

MACRO fMRI Predictor Study:Differential Response to MPH Over ATX and Pre-

Treatment Caudate Activation

NNT for MPH > ATXEntire sample: n = 6High caudate activation: n = 2

Schulz et al., JAACAP, 2017

Guanfacine Moderates the Influence of Emotion onDorsolateral Prefrontal Cortex for Response Inhibition

Trial Type Face Emotion Trial Type x Face Emotion Trial Type x Face Emotion x Drug

z = -10 z = 25 z = 30 z = 35

Happy Sad Neutral

0

0.5

1

-0.5

-1

GuanfacinePlacebo

0

0.5

1

-0.5

-1

Par

amet

er E

stim

ates No-go

Go

Happy Sad Neutral

Schulz et al., Psychopharmacology, 2013Negative response bias for sad faces is reversed by GUAN, in association with increased dl-PFC activation

Methylphenidate Treatment Activates Dorsal Anterior Mid-cingulate Cortex

Bush et al. Arch Gen Psychiatry. 2008:65:102-114.

0

0.5

1

1.5

2

2.5

Baseline 6 Weeks

OROS MPHPlacebo

• fMRI at baseline and again at week 6• OROS MPH group showed higher daMCC activation at 6 weeks vs placebo• N=21 adults with ADHD; dosing to 1.3 mg/kg/day OROS MPH or placebo

P = 0.02 vs PBO

Bush et al. Arch Gen Psychiatry. 2008:65:102-114.

PresenterPresentation NotesSummary21 adults with ADHD were randomized to 6 weeks of OROS MPH or placebo.fMRIs were done at baseline and at 6 weeks while the participants were performing the Multi-Source Interference Task (MSIT), a test of executive function. (In a previous study, people with ADHD were compared with a control population. fMRIs of both populations, done while They were performing the MSIT found differences in activation in the brain, particularly in the anterior cingulate cortex.)In this study, the group taking OROS MPH showed greater activation of the dorsal anterior midcingulate cortex (daMCC) than the placebo group at six weeks.

From Bush, 2008:fMRI RESULTSBaseline Group ComparisonThe methylphenidate OROS and placebo groups did notsignificantly differ at baseline in any a priori region of interest.In fact, a GLM contrasting methylphenidate OROSMSITInterference vs placebo MSITInterference during baseline scan1 showed that only 1 cortical area differed between groups(the precuneus [area 31]: x, y, z=13, −51, 34), and it isnot part of the CFP cognitive/attention network.Group Comparison at 6 WeeksAs predicted, the main group-averaged contrast of interestshowed that, compared with placebo, 6 weeks of methylphenidateOROS significantly increased daMCC activation(Figure 2-part of this figure is shown in the slide, at left). Two separate areas in the daMCC, athird posteriorly adjacent to the daMCC, and a fourth insularregion passed a rigorous, multistep, masked, random-effects,repeated-measures ANOVA GLM analysis, showinga significant treatment group (methylphenidate OROSvs placebo)scan (scan 1 [baseline] vs scan 2 [6 weeks])interaction and a confirmatory t test indicating significantlyhigher scan 2 activation during MSIT Interference trialsin the methylphenidate OROS group than in the placebogroup (corrected P

The use of modafinil is an off-label use in the treatment of ADHD

Volkow ND, et al. JAMA. 2009;301:1148-1154.

Modafinil Binds to DAT in Striatum (Including NAcc) in Humans

Modafinil Increases Activation in dACCDuring Working Memory

The use of modafinil is an off-label use in the treatment of ADHD

Spence SA, et al. Br J Psychiatry. 2005;187:55-61.

Neural Correlates of Improved Inhibitory Control and Visual Processing with ATX *

Inhibitory Control: Greater activation in right IFG and right ACC with ATX treatment for the incongruent condition vsthe congruent condition (RVP test: CANTAB)

Visual Processing:Greater activation in the left precuneus with ATX treatment for the larger vsfewer number of words (DMS test: CANTAB).

Design: 24 adults with ADHD; ATX vs placebo

Fan, Chou, and Gau, Hum Brain Mapp, 2017

Clinical Implications• All known effective drugs impact catecholaminergic front-

striatal mechanisms in one way or other – Effective drugs for ADHD have at least some effects in common

• Medications for ADHD each have divergent activity– Unique mechanisms of action helps to explain differential effects of

existing drugs within and across individuals– Provides a rationale for combined pharmacologic treatment

• To date, no drugs that uniquely target novel neurotransmitters or neuromodulators have been successfully developed

• 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

�How Do Drugs for ADHD Work?Disclosure (Past 12 months)What Is ADHD?ADHD: DSM-5 CriteriaNeurobiological Basis of Attention and Inhibitory Control in ADHDDual Pathway Model of ADHD:�Implications for Mood Dysregulation and Aggression Neurobiological Underpinnings of Dual Pathway Model of ADHDSlide Number 8CAARS Ratings of Impulsivity/Emotional Lability and Functional Connectivity of d,l-PFC with Subgenual Cingulate CortexAnti-correlated Task-Positive and Task-Negative Networks in Regulation of AttentionMotivation and Inattention Symptoms Are Correlated In Adults with ADHDCurrent View of ADHD: Multiple Cognitive and Emotional Processes and Interacting Brain Networks Summary: ADHD Diagnosis, Clinical Presentation and PathophysiologyWhy Do We Treat ADHD? ADHD Medications Worldwide* �(approved and investigational) Benefits of Acute Stimulant Treatment Stimulants and Atomoxetine: Neurochemical Mechanisms of ActionSlide Number 18Methylphenidate Occupies Dopamine and Norepinephrine TransportersLow DA Activity Extends Beyond Striatum and Is Increased By MPH in Adults with ADHD �Extended DAT Occupancy Following Administration of OROS MPH Meta-Analysis of fMRI Findings in ADHD and Normalization with MPH MPH Attenuation of mPFC Activity During an Emotional Stroop Task*Lisdexamfetamine Targets Amygdala Mechanisms That Bias Cognitive Control in ADHD Slide Number 25Task‐related Default Mode Network Modulation and Inhibitory Control in ADHD: Effects of Motivation and MPHSlide Number 27Summary: Stimulant Mechanisms of ActionRationale for Non-stimulant�Treatment of ADHDMPH and ATX: Common Effects on Extracellular Monoamine Levels in PFCMPH and ATX: Differential Effects on Extracellular Dopamine Levels in StriatumAtomoxetine Increases Right IFG Activation in Association with Improved Inhibitory Control OROS Methylphenidate vs. Atomoxetine Comparator Study: Response+Bimodal Response to Atomoxetine in 6 �Pre-marketing Clinical Trials �(and why we need personalized treatment approaches)Mechanisms of Action and Predictors of Response to Methylphenidate (Stimulant) and Atomoxetine �(Non-Stimulant) MedicationsMACRO Study: Comparative Response Model Estimated Means for ADHD-RS Total ScoreMACRO Study: �Medication Preference X Responder Status*Common and Unique Activation Profiles in Association with Response to MPH and ATX in Youth with ADHD MACRO fMRI Predictor Study:�Objectives and HypothesesMACRO fMRI Predictor Study:�Increased Baseline Activation of Motor Cortex Predicts Response to ATX (Main Effect) MACRO fMRI Predictor Study:�Increased Baseline Caudate Activation Predicts Differential Response to MPH Over ATX Summary: Atomoxetine Mechanisms of ActionCellular Mechanisms of Alpha-2a �Agonist MedicationsGUAN Increases SPECT Measured rCBF in �d,l-PFC in Monkeys Doing a Working Memory TaskGuanfacine Enhances Activation of dl-PFC During a Cued Alerting Task Guanfacine Extended Release Treatment of Oppositional Symptoms in Children with ADHDSlide Number 47Slide Number 48Summary: Guanfacine Mechanisms of ActionCommon and Unique Effects of Medications for ADHD Discussion and Take Home MessagesSlide Number 52�Back-up SlidesMTA Study: �Normalization Following TreatmentAtomoxetine Selectively Binds to �Norepinephrine TransportersSlide Number 56Differential Therapeutic Effects of MPH and ATX on fMRI Activation*MACRO fMRI Predictor Study:�Differential Response to MPH Over ATX and Pre-Treatment Caudate Activation Slide Number 59Slide Number 60Modafinil Binds to DAT in Striatum (Including NAcc) in Humans Modafinil Increases Activation in dACC During Working MemoryNeural Correlates of Improved Inhibitory Control and Visual Processing with ATX *�Clinical Implications