What is ADHD? Update on pharmacology and neuroimaging

NSFT Masterclass – ADHD in Adults, Dunston Hall / Norwich, 28 March 2014

What is ADHD? Update onpharmacology and neuroimaging

Dr Ulrich Müller([email protected] / [email protected])

Adult ADHD Service,Cambridgeshire & Peterborough NHS Foundation Trust (CPFT)

Mental Health Research Network (MHRN), East Anglia HubBehavioural and Clinical Neuroscience Institute (BCNI) /

Department of Psychiatry, University of Cambridge

Advisory board / consultancy Shire (2014) Heptares (2013-) Eli Lilly (2012) Janssen-Cilag (2008)

Speaker / workshop honorarium Birmingham & Solihull NHS FT (2013) UK Adult ADHD Network (2011-) British Association of Psychopharmacology (2008-) UCB Pharma (2008)

Travel expenses for educational meetings Astra Zeneca, Bristol-Myers Squibb (BMS),

Eli Lilly, Lundbeck, Pharmacia-Upjohn

Conflict of interest declaration

What is ADHD?

Catecholamine deficit model of ADHD

Efficacy of ADHD medication

Structural and functional MRI

Pharmacological MRI

SPECT/PET studies

Overview

What is ADHD?

DSM-5 criteria for ADHD≥5 symptoms per category in adults, ≥6 months; age of onset ≤12 years;noticeable in ≥2 settings; impact on social, academic or occupational

functioning; not better accounted for by another mental disorder

Inattention(a) Lack of attention to details /

careless mistakes(b) Difficulty sustaining attention(c) Does not seem to listen(d) Does not follow through on

instructions (easily side-tracked)(e) Difficulty organising tasks and

activities(f) Avoids sustained mental effort(g) Loses and misplaces objects(h) Easily distracted(i) Forgetful in daily activities

Hyperactivity / Impulsivity(a) Fidgetiness (hand or feet) /

squirms in seat(b) Leaves seat frequently(c) Running about / feeling

restless(d) Excessively loud or noisy(e) Always “on the go”(f) Talks excessively(g) Blurts out answers(h) Difficulty waiting his or her

turn(i) Tends to act without thinking

The prevalence of DSM-IV attention-deficit/hyperactivity disorder: a meta-analytic review

Willcutt, Neurotherapeutics 2012; 9: 490-499

Hyperactive Inattentive

How do different diagnostic criteria, age and gender affect theprevalence of attention deficit hyperactivity disorder in adults?

An epidemiological study in a Hungarian community sampleBitter et al., Eur Arch Psychiatry Clin Neurosci 2009; 260: 287-96

Crude prevalence estimates of adult ADHD, after correction for 'not interviewed‘subsample, stratified by gender and age

Is ADHD severity in adults associated with the lifetimeprevalence of … depressive episodes and anxiety disorder?

Simon et al., Eur Psychiatry 2013; 28: 308-14

Inverted-U model of arousal

Stahl2008

Efficacy of ADHD medicationin adults

1935 Amphetamine Benzedrine Sulfate®

1943 Methamphetamine Desoxyn®

1944 D-Amphetamine Dexedrine Sulfate®

1954 Methylphenidate Ritalin®

1994 Modafinil Provogil®

2004 Amphetamine salts Adderall®

2005 Desmethylphenidate Focalin®

2007 Armodafinil Nuvigil®

2008 Lisdexamphetamine Vyvanse®

2013 Elvanse®

…

Chronology of ADHD medication

Adults

AACAP 2001DGPPN 2003BAP 2006 / 2014*EuNetHyDis 2006NICE 2008*ENAA 2010CADDRA 2011

Children & Adolescents

NZ 2001AACAP 2001 / 2007EuNetHyDis 2004 / 2006DGKJP 2007NICE 2006 / 2008*SIGN 2009*CADDRA 2011AAP 2011

*British and international ADHD guidelines

0 1 2 3 4 5 6 7 8 9 10

Modafinil

Guanfacine

Clonidine

Buproprion

Tricyclic antidepressants

Lisdexamphetamine

Mixed amphetamine salts

Atomoxetine

Methylphenidate MR

Dexamphetamine

Methylphenidate IR

First-optionOther

First option and other treatment recommendations in10 national / international ADHD guidelines

Seixas / Weiss / Müller, J Psychopharmacol 2012; 26: 753-6

BAP updated evidence-based guidelines for thepharmacological management of ADHD

Consensus1. Stimulants are first-line treatment for adults with ADHD (A)2. Atomoxetine is considered first-line treatment in patients with substance

use disorders (S)3. Drug treatment should be continued as long as clinically useful (S)4. Careful titration and monitoring of side effects is required, particularly

when using stimulants (A)5. Drug holidays may be useful to ascertain the need of continuation of

treatment (S)6. Co-administration of drugs is relatively common in clinical practice for

resistant cases but there is a lack of studies investigating its efficacy (S)

Research needs1. More studies are required to elucidate the effects of ‘flexible’ dosing and

co-administration of drugs.2. More pharmacological studies in humans are necessary to understand

the full range of actions of ADHD medications in the brain and theindividual variations that may limit efficacy or cause side effects.

Bolea-Alamañac, …, Müller, et al., J Psychopharmacol 2014; 28: 179-203

BAP updated evidence-based guidelines for thepharmacological management of ADHDBolea-Alamañac, …, Müller, et al., J Psychopharmacol 2014; 28: 179-203

ADHD drugs – relationship between primary pharmacology, efficacy, safety and recreational abuse potential.BP=blood pressure, HR=heart rate

Moderators of methylphenidate efficacy foradults with ADHD: a meta-regression analysis

Castells et al., CNS Drugs 2011; 25: 157-69

Methylphenidate for ADHD and drug relapse incriminal offenders with substance dependence:

a 24-week randomized placebo-controlled trialKonstenius et al., Addiction 2014; 109: 440-49

Kaplan–Meier curve for retention intreatment through to last visit at the clinic

(MPH=methylphenidate)

Change in self-rated attention deficithyperactivity disorder (ADHD) symptoms

(95% CI=−13.78 to −1.91, P = 0.011)

Methylphenidate for ADHD and drug relapse incriminal offenders with substance dependence:

a 24-week randomized placebo-controlled trialKonstenius et al., Addiction 2014; 109: 440-49

Proportion of negative urine-toxicology after release from prison (weeks 3–24) for the twotreatment groups; methylphenidate (MPH) and placebo over 24 weeks of treatment:

(a) amphetamines only, mean difference 95% CI = 0.07–0.36; and(b) other drugs, mean difference 95% CI = 0.02–0.25.

(a) amphetamines only (b) other drugs

Atomoxetine for ADHD in the adulthood:a meta-analysis and meta-regression

Cunill et al., Pharmacoepidemiol Drug Saf 2013; 22: 961-9

Investigator-rated ADHD severity

• Atomoxetine was modestly more efficacious than placebo in reducing ADHD symptoms.• Atomoxetine was associated with higher all-cause discontinuation than placebo.• Atomoxetine was associated with higher discontinuation due to adverse events than placebo.

-0.40

Adler et al., Depression & Anxiety 2009; 26: 212-221

Chance of CAARS:inv:SV Total ADHDSymptoms scores for all qualified patients

Chance of Liebowitz Social Anxiety Scale(LSAS) Total scores for all qualified patients.

Atomoxetine treatment in adults with ADHDand comorbid social anxiety disorder

Amphetamines Castells et al., Cochrane Database Syst Rev 2011

Methylphenidate Castells et al., CNS Drugs 2011

Atomoxetine Cunill et al., Pharmacoepidemiol Drug Saf 2013

Adult ADHD compared topsychiatric and general

medicine medicationLeucht et al., Br J Psychiatry 2012;

200: 97-106

Figure 1. Extended Kaplan–Meiercurves for patients in theSwedish patient register with adiagnosis of ADHD who wereborn no later than 1990,according to sex and medicationstatus.

This analysis was based on 56,227treatment or nontreatment periods and23,693 convictions involving 16,087 men(averaging 3.5 periods of treatment ornontreatment and 1.5 convictions) and23,533 treatment or nontreatment periodsand 4112 convictions involving 9569women (averaging 2.5 treatment ornontreatment periods and 0.4 convictions).

365: 2006-14, published 22 Nov 2012

promising negativeDopaminergic MK-0929, SelegelineNoradrenergic Desipramine, Venlafaxine

Duloxetine,Guanfacine,Reboxetine

Cholinergic ABT-418, AZD-1446, Galantamine,ABT-894 Pozanicline

Glutamatergic ORG-26576Histaminergic Bavisant, MK-0249Serotinergic Buspirone, ParoxetineMixed Metadoxine Lithium, Modafinil,

NS-2359

Investigational drugs in adult ADHD(published studies only)

A 9-week, randomized, double-blind, placebo-controlled,parallel-group, dose-finding study to evaluate the efficacyand safety of modafinil as treatment for adults With ADHD

Arnold et al., J Atten Disorder 2012 [Epub ahead of print]

Change from baseline to final visit in the AISRS total scoreAISRS = Adult ADHD Investigator Symptom Rating Scale.

The only phase 3 studyin adults with ADHD(n = 338, 9 weeks)

No effects of modafinil255-510 mg on ADHDsymptoms

High rate ofside effects (86%)and drop out (47%)

Structural MRI studies

Results of the ALE meta-analysis showing clusters with significant ALE maxima (Z > 3; pcorrected < 0.05)superimposed on a structural scan in Talairach space. Top row: coronal view, bottom row: axial view

Meta-analysis of diffusion tensor imaging (DTI) in ADHDvan Ewijk et al., Neurosci Biobehav Rev 2012; 36: 1093-1106

Neuroanatomical abnormalities and cognitiveimpairments are shared by adults with ADHD

and their unaffected first-degree relativesPironti, Lai, Müller, et al., Biol Psychiatry 2013 [Epub ahead of print]

Neuroanatomical abnormalities and cognitiveimpairments are shared by adults with ADHD

and their unaffected first-degree relativesPironti, Lai, Müller, et al., Biol Psychiatry 2013 [Epub ahead of print]

Gray matter volume abnormalities in ADHD:voxel-based meta-analysis exploring the effects

of age and stimulant medicationNakao et al., Am J Psychiatry 2011;

168: 1154-63FIGUR E 2 . Results o f themeta-regression analysisshowing independentassociations of mean age andpercentage of patientsreceiving stimulantmedication with more normalgray matter volumes in theright basal ganglia

Functional and pharmacologicalMRI studies

Ventral-striatal responsiveness during reward anticipationin ADHD: meta-analysis of fMRI studies

Plichta & Scheres, Neurosci Biobehav Rev 2014; 38: 125-34

Meta-analysis of functional fMRI studies in ADHDHart et al., Arch Gen Psychiatry 2013; 70: 185-98

21 data sets (287 patients with ADHD / 320 controls13 data sets (171 patients with ADHD / 178 controls

Reduced activation in inhibitory networksReduced / increased activation in

attentional networks

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BEEP

This task measures theparticipant’s ability to inhibit a

pre-potent response

Stop-signaloccurs on 25%trials.

Stop-signal reaction time task(SSRT)

Horse-race model

Methylphenidate, modafinil, andatomoxetine improve stop-signal

inhibition in adults with ADHD

Aron et al.,Biol Psychiatry

2003

Methylphenidate 30mg Modafinil 200mg

Turner et al.,Biol Psychiatry

2004

Placebo DrugPlacebo Drug

SS

RT

(ms)

0

50

100

150

200

250

300p=0.016

Placebo Drug

Chamberlain et al.,Biol Psychiatry

2007

Atomoxetine 60mg

* *

ADHDunmedicated

Controlsunmedicated

ADHDmedicated

>>

Scatter plots showing plasmaatomoxetine levels against mean RIFGactivation during successful inhibition

Atomoxetine 40mgenhances the inhibition-related

BOLD signal(second level CamBA analysis of drug effect:

cluster wise, permutational ANOVA)

>>Atomoxetine modulates right inferior

frontal activation during inhibitory control– a pharmacological fMRI study

Chamberlain, Hampshire, Müller, et al., Biol Psychiatry 2009; 65: 550-55

Atomoxetine modulates right inferior frontalactivation during inhibitory control

– a pharmacological fMRI studyChamberlain, Hampshire, Müller, et al., Biol Psychiatry 2009; 65: 550-55

Aston-Jones & Gold2009

Effects of stimulants in ADHD: Meta-analysis of fMRI studiesRubia et al., Biol Psychiatry 2013 [Epub ahead of print]

Meta-analysis at p < .005: Relative to placebo, increasedactivation is shown with acute stimulant medication in rightinferior prefrontal cortex extending deep into the insula andbordering superior temporal lobe and decreased activationin anterior cingulate cortex and supplementary motor area.

(B) Meta-analysis results in two-dimension at peak MontrealNeurological Institute coordinates: 38, 18, 4 (corresponding toTalairach coordinates: 42, 20, 12) at p < .005, showing rightinferior frontal cortex reaching into insula and anterior cingulatecortex/supplementary motor area.

Red / orange: Stimulants increase activation; Blue: Stimulants decrease activation(14 data sets, total of 212 children with ADHD)

(C) Meta-analysis results in two-dimension at peak MontrealNeurological Institute coordinates: 38, 18, 4 (corresponding toTalairach coordinates: 42, 20, 12) at a more lenient p < .05,showing in addition a cluster in right putamen and rostralanterior cingulate.

SPECT / PET studies

Dopamine synthesis Ernst et al. 1998 [18F-dopa]; Forssberg et al. 2006 [11C-levodopa],

Ludolph et al. 2008 [18F-dopa] Ernst et al. 1999 [18F-dopa]

Striatal dopamine transporter (DAT) availability Dougherty et al. 1999 [123I-altropane];

Krause et al. 2000 [99mTc-TRODAT-1]; Cheon et al. 2003 [123I-IPT];Larisch et al. 2006 [123I-FP-CIT]; Spencer et al. 2007 [11C-altropane]

van Dyck et al. 2002 [123I-β-CIT]; Jucaite et al. 2005 [11C-PE2I] Volkow et al. 2007a, 2009 [11C-cocaine]; Hesse et al. 2009 [123I-FP-CIT]

Striatal D2/D3 dopamine receptor density Volkow et al. 2007b, 2009 [11C-raclopride] Jucaite et al. 2005 [11C-raclopride]; Del Campo et al. 2013 [18F-fallypride]

Dopamine release (D2/D3 radiotracer displacement) Volkow et al. 2007b [11C-raclopride] Del Campo et al. 2013 [18F-fallypride] Cherkazowa et al. 2014 [11C-raclopride]

Imaging of the DA system in ADHD with SPECT/PET[published studies with healthy controls only]

Single dose of MPH displaces[18F]fallypride

No displacement differencesbetween ADHD patients andhealthy controls

(A and B) Coronal planes through an AC–PC aligned MPRAGE imageshowing striatal regions of interest. (A) Ventral striatum (2, 3), pre-commissural dorsal putamen (4, 5), pre-commissural dorsal caudate(6, 7); (B) post-commissural putamen (8, 9) and post-commissuralcaudate (10, 11). (C) Midbrain region of interest defined on a T2 scanco-registered to the MRAC-PC.

A PET study of nigro-striatal dopaminergicmechanisms underlying attention:

implications of ADHD and its treatmentDel Campo, ..., Müller, Brain 2013; 136: 3252-70

r= -0.516, p=0.020

r= -0.542, p=0.019

r=-0.126, p=0.320

R= -0.596, p=0.010

A PET study of nigro-striatal dopaminergicmechanisms underlying attention:

implications of ADHD and its treatmentDel Campo, ..., Müller, Brain 2013; 136: 3252-70

Evaluating dopamine reward pathway in ADHD:Clinical implications

Volkow et al., JAMA 2009; 302: 1084-91

[11C]cocaine PET:DA transporterADHD patients [53]< controls [44] in Lmidbrain,N. accumbens,caudate

Meta-regression showing effect of stimulant exposure on striatal dopamine transporter (DAT) densityin ADHD Circle size reflects the weight a study obtained in the meta-regression. Lower effect sizeswere detected in studies involving drug-naive ADHD patients (Fusar-Poli et al., Am J Psychiatry 2012)

Logan et al., Nucl Med Biol 2007; 34: 667-679Hannestad et al., Biol Psychiatry 2010, 68: 854-860

Displacement of [11C]MRB by methylphenidate(MPH) and atomoxetine (ATX)

MPH

Plc

2.5

10

40mg

Thank you for your attention !

Prof. Philip Asherson (IoP, London)

Dr Marios Adamou (Wakefield)

Dr Muhammad Arif (Leicester)

Dr Ovais Badat (Bristol)

Dr David Coghill (Dundee)

Prof. Gisli Gudjohnsson (IoP, London)

Dr James Kustow (London)

Dr Ulrich Müller (Cambridge)

Mark Pitts (SLAM, London)

Dr Susan Young (IoP, London)

UK Adult ADHD Networkwww.ukaan.org