Dr Ulrich Müller (ulrich.muller@cpft.nhs.uk / um207@cam.ac.uk) Adult ADHD Service, Cambridgeshire & Peterborough NHS Foundation Trust (CPFT) Mental Health Research Network (MHRN), East Anglia Hub Behavioural and Clinical Neuroscience Institute (BCNI) / Department of Psychiatry, University of Cambridge This presentation was presented at ADHD Training Day at Dunston Hall in Norwich on 28 March 2014. The day is free for all staff and is kindly sponsored by Eli Lilly Neuroscience plus is supported by the Trust NDD Steering Group and the Postgraduate Department.

1. NSFT Masterclass – ADHD in Adults, Dunston Hall / Norwich, 28 March 2014
What is ADHD? Update on
pharmacology and neuroimaging
Dr Ulrich Müller
(ulrich.muller@cpft.nhs.uk / um207@cam.ac.uk)
Adult ADHD Service,
Cambridgeshire & Peterborough NHS Foundation Trust (CPFT)
Mental Health Research Network (MHRN), East Anglia Hub
Behavioural and Clinical Neuroscience Institute (BCNI) /
Department of Psychiatry, University of Cambridge
Yasir
Hameed
(MRCPsych)
Digitally signed by Yasir Hameed
(MRCPsych)
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gn=Yasir Hameed (MRCPsych)
c=United Kingdom l=GB o=Norfolk
and Suffolk NHS Trust ou=Norfolk
and Suffolk NHS Trust
e=yasirmhm@yahoo.com
Reason: I have reviewed this
document
Location:
Date: 2014-05-06 19:46+01:00

2. 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

3.  What is ADHD?
 Catecholamine deficit model of ADHD
 Efficacy of ADHD medication
 Structural and functional MRI
 Pharmacological MRI
 SPECT/PET studies
Overview

4. What is ADHD?

5. 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

6. The prevalence of DSM-IV attention-deficit/
hyperactivity disorder: a meta-analytic review
Willcutt, Neurotherapeutics 2012; 9: 490-499
Hyperactive Inattentive

7. How do different diagnostic criteria, age and gender affect the
prevalence of attention deficit hyperactivity disorder in adults?
An epidemiological study in a Hungarian community sample
Bitter 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

8. Is ADHD severity in adults associated with the lifetime
prevalence of … depressive episodes and anxiety disorder?
Simon et al., Eur Psychiatry 2013; 28: 308-14

9. Inverted-U model of arousal
Stahl
2008

10. Efficacy of ADHD medication
in adults

11. 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

12. Adults
AACAP 2001
DGPPN 2003
BAP 2006 / 2014*
EuNetHyDis 2006
NICE 2008*
ENAA 2010
CADDRA 2011
Children & Adolescents
NZ 2001
AACAP 2001 / 2007
EuNetHyDis 2004 / 2006
DGKJP 2007
NICE 2006 / 2008*
SIGN 2009*
CADDRA 2011
AAP 2011
*British and international ADHD guidelines

13. 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-option
Other
First option and other treatment recommendations in
10 national / international ADHD guidelines
Seixas / Weiss / Müller, J Psychopharmacol 2012; 26: 753-6

14. BAP updated evidence-based guidelines for the
pharmacological management of ADHD
Consensus
1. 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 needs
1. 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 the
individual variations that may limit efficacy or cause side effects.
Bolea-Alamañac, …, Müller, et al., J Psychopharmacol 2014; 28: 179-203

15. BAP updated evidence-based guidelines for the
pharmacological management of ADHD
Bolea-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

16. Moderators of methylphenidate efficacy for
adults with ADHD: a meta-regression analysis
Castells et al., CNS Drugs 2011; 25: 157-69

17. Methylphenidate for ADHD and drug relapse in
criminal offenders with substance dependence:
a 24-week randomized placebo-controlled trial
Konstenius et al., Addiction 2014; 109: 440-49
Kaplan–Meier curve for retention in
treatment through to last visit at the clinic
(MPH=methylphenidate)
Change in self-rated attention deficit
hyperactivity disorder (ADHD) symptoms
(95% CI=−13.78 to −1.91, P = 0.011)

18. Methylphenidate for ADHD and drug relapse in
criminal offenders with substance dependence:
a 24-week randomized placebo-controlled trial
Konstenius et al., Addiction 2014; 109: 440-49
Proportion of negative urine-toxicology after release from prison (weeks 3–24) for the two
treatment 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

19. 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

20. Adler et al., Depression & Anxiety 2009; 26: 212-221
Chance of CAARS:inv:SV Total ADHD
Symptoms scores for all qualified patients
Chance of Liebowitz Social Anxiety Scale
(LSAS) Total scores for all qualified patients.
Atomoxetine treatment in adults with ADHD
and comorbid social anxiety disorder

21. 
 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 to
psychiatric and general
medicine medication
Leucht et al., Br J Psychiatry 2012;
200: 97-106

22. Figure 1. Extended Kaplan–Meier
curves for patients in the
Swedish patient register with a
diagnosis of ADHD who were
born no later than 1990,
according to sex and medication
status.
This analysis was based on 56,227
treatment or nontreatment periods and
23,693 convictions involving 16,087 men
(averaging 3.5 periods of treatment or
nontreatment and 1.5 convictions) and
23,533 treatment or nontreatment periods
and 4112 convictions involving 9569
women (averaging 2.5 treatment or
nontreatment periods and 0.4 convictions).
365: 2006-14, published 22 Nov 2012

23. promising negative
Dopaminergic MK-0929, Selegeline
Noradrenergic Desipramine, Venlafaxine
Duloxetine,
Guanfacine,
Reboxetine
Cholinergic ABT-418, AZD-1446, Galantamine,
ABT-894 Pozanicline
Glutamatergic ORG-26576
Histaminergic Bavisant, MK-0249
Serotinergic Buspirone, Paroxetine
Mixed Metadoxine Lithium, Modafinil,
NS-2359
Investigational drugs in adult ADHD
(published studies only)

24. A 9-week, randomized, double-blind, placebo-controlled,
parallel-group, dose-finding study to evaluate the efficacy
and 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 score
AISRS = Adult ADHD Investigator Symptom Rating Scale.
 The only phase 3 study
in adults with ADHD
(n = 338, 9 weeks)
 No effects of modafinil
255-510 mg on ADHD
symptoms
 High rate of
side effects (86%)
and drop out (47%)

25. Structural MRI studies

26. 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 ADHD
van Ewijk et al., Neurosci Biobehav Rev 2012; 36: 1093-1106

27. Neuroanatomical abnormalities and cognitive
impairments are shared by adults with ADHD
and their unaffected first-degree relatives
Pironti, Lai, Müller, et al., Biol Psychiatry 2013 [Epub ahead of print]

28. Neuroanatomical abnormalities and cognitive
impairments are shared by adults with ADHD
and their unaffected first-degree relatives
Pironti, Lai, Müller, et al., Biol Psychiatry 2013 [Epub ahead of print]

29. Gray matter volume abnormalities in ADHD:
voxel-based meta-analysis exploring the effects
of age and stimulant medication
Nakao et al., Am J Psychiatry 2011;
168: 1154-63
FIGUR E 2 . Results o f the
meta-regression analysis
showing independent
associations of mean age and
percentage of patients
receiving stimulant
medication with more normal
gray matter volumes in the
right basal ganglia

30. Functional and pharmacological
MRI studies

31. Ventral-striatal responsiveness during reward anticipation
in ADHD: meta-analysis of fMRI studies
Plichta & Scheres, Neurosci Biobehav Rev 2014; 38: 125-34

32. Meta-analysis of functional fMRI studies in ADHD
Hart 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 networks
Reduced / increased activation in
attentional networks

33. >
<
>
>
>
BEEP
This task measures the
participant’s ability to inhibit a
pre-potent response
Stop-signal
occurs on 25%
trials.
Stop-signal reaction time task
(SSRT)
Horse-race model

34. Methylphenidate, modafinil, and
atomoxetine 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 Drug
Placebo Drug
SSRT(ms)
0
50
100
150
200
250
300
p=0.016
Placebo Drug
Chamberlain et al.,
Biol Psychiatry
2007
Atomoxetine 60mg
* *
ADHD
unmedicated
Controls
unmedicated
ADHD
medicated
>>

35. Scatter plots showing plasma
atomoxetine levels against mean RIFG
activation during successful inhibition
Atomoxetine 40mg
enhances 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

36. Atomoxetine modulates right inferior frontal
activation during inhibitory control
– a pharmacological fMRI study
Chamberlain, Hampshire, Müller, et al., Biol Psychiatry 2009; 65: 550-55
Aston-Jones & Gold
2009

37. Effects of stimulants in ADHD: Meta-analysis of fMRI studies
Rubia et al., Biol Psychiatry 2013 [Epub ahead of print]
Meta-analysis at p < .005: Relative to placebo, increased
activation is shown with acute stimulant medication in right
inferior prefrontal cortex extending deep into the insula and
bordering superior temporal lobe and decreased activation
in anterior cingulate cortex and supplementary motor area.
(B) Meta-analysis results in two-dimension at peak Montreal
Neurological Institute coordinates: 38, 18, 4 (corresponding to
Talairach coordinates: 42, 20, 12) at p < .005, showing right
inferior frontal cortex reaching into insula and anterior cingulate
cortex/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 Montreal
Neurological Institute coordinates: 38, 18, 4 (corresponding to
Talairach coordinates: 42, 20, 12) at a more lenient p < .05,
showing in addition a cluster in right putamen and rostral
anterior cingulate.

38. SPECT / PET studies

39.  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]

41.  Single dose of MPH displaces
[18F]fallypride
 No displacement differences
between ADHD patients and
healthy controls
(A and B) Coronal planes through an AC–PC aligned MPRAGE image
showing 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-commissural
caudate (10, 11). (C) Midbrain region of interest defined on a T2 scan
co-registered to the MRAC-PC.
A PET study of nigro-striatal dopaminergic
mechanisms underlying attention:
implications of ADHD and its treatment
Del Campo, ..., Müller, Brain 2013; 136: 3252-70

42. 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 dopaminergic
mechanisms underlying attention:
implications of ADHD and its treatment
Del Campo, ..., Müller, Brain 2013; 136: 3252-70

43. Evaluating dopamine reward pathway in ADHD:
Clinical implications
Volkow et al., JAMA 2009; 302: 1084-91
[11C]cocaine PET:
DA transporter
ADHD patients [53]
< controls [44] in L
midbrain,
N. accumbens,
caudate
Meta-regression showing effect of stimulant exposure on striatal dopamine transporter (DAT) density
in ADHD Circle size reflects the weight a study obtained in the meta-regression. Lower effect sizes
were detected in studies involving drug-naive ADHD patients (Fusar-Poli et al., Am J Psychiatry 2012)

44. Logan et al., Nucl Med Biol 2007; 34: 667-679
Hannestad et al., Biol Psychiatry 2010, 68: 854-860
Displacement of [11C]MRB by methylphenidate
(MPH) and atomoxetine (ATX)
MPH
Plc
2.5
10
40
mg

45. Thank you for your attention !

47.  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 Network
www.ukaan.org