How Do Drugs for ADHD

Work?

Jeffrey H. Newcorn, MD

Icahn School of Medicine at Mount Sinai

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

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 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

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

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

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

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 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

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

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

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

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

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 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

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

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-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

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

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

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

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

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

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

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

MACRO Study: Medication Preference X Responder Status*

n=24

n=43

n=10

n=25

n=17

n=8

n=17

N=26

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 < .005 Schulz 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

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 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

ram

ete

r E

stim

ate

s

fo

r A

myg

da

la S

ign

al Happy Sad Neutral

0

-1.5

1.5

No-go

Go

Placebo

No-go

Go

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?

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

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