Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.
NSFT Masterclass – ADHD in Adults, Dunston Hall / Norwich, 28 March 2014
What is ADHD? Update on
pharmacology and neuroima...
Advisory board / consultancy
 Shire (2014)
 Heptares (2013-)
 Eli Lilly (2012)
 Janssen-Cilag (2008)
Speaker / worksho...
 What is ADHD?
 Catecholamine deficit model of ADHD
 Efficacy of ADHD medication
 Structural and functional MRI
 Phar...
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; ...
The prevalence of DSM-IV attention-deficit/
hyperactivity disorder: a meta-analytic review
Willcutt, Neurotherapeutics 201...
How do different diagnostic criteria, age and gender affect the
prevalence of attention deficit hyperactivity disorder in ...
Is ADHD severity in adults associated with the lifetime
prevalence of … depressive episodes and anxiety disorder?
Simon et...
Inverted-U model of arousal
Stahl
2008
Efficacy of ADHD medication
in adults
1935 Amphetamine Benzedrine Sulfate®
1943 Methamphetamine Desoxyn®
1944 D-Amphetamine Dexedrine Sulfate®
1954 Methylphenid...
Adults
AACAP 2001
DGPPN 2003
BAP 2006 / 2014*
EuNetHyDis 2006
NICE 2008*
ENAA 2010
CADDRA 2011
Children & Adolescents
NZ 2...
0 1 2 3 4 5 6 7 8 9 10
Modafinil
Guanfacine
Clonidine
Buproprion
Tricyclic antidepressants
Lisdexamphetamine
Mixed ampheta...
BAP updated evidence-based guidelines for the
pharmacological management of ADHD
Consensus
1. Stimulants are first-line tr...
BAP updated evidence-based guidelines for the
pharmacological management of ADHD
Bolea-Alamañac, …, Müller, et al., J Psyc...
Moderators of methylphenidate efficacy for
adults with ADHD: a meta-regression analysis
Castells et al., CNS Drugs 2011; 2...
Methylphenidate for ADHD and drug relapse in
criminal offenders with substance dependence:
a 24-week randomized placebo-co...
Methylphenidate for ADHD and drug relapse in
criminal offenders with substance dependence:
a 24-week randomized placebo-co...
Atomoxetine for ADHD in the adulthood:
a meta-analysis and meta-regression
Cunill et al., Pharmacoepidemiol Drug Saf 2013;...
Adler et al., Depression & Anxiety 2009; 26: 212-221
Chance of CAARS:inv:SV Total ADHD
Symptoms scores for all qualified p...

 Amphetamines Castells et al., Cochrane Database Syst Rev 2011
Methylphenidate Castells et al., CNS Drugs 2011
Atomoxet...
Figure 1. Extended Kaplan–Meier
curves for patients in the
Swedish patient register with a
diagnosis of ADHD who were
born...
promising negative
Dopaminergic MK-0929, Selegeline
Noradrenergic Desipramine, Venlafaxine
Duloxetine,
Guanfacine,
Reboxet...
A 9-week, randomized, double-blind, placebo-controlled,
parallel-group, dose-finding study to evaluate the efficacy
and sa...
Structural MRI studies
Results of the ALE meta-analysis showing clusters with significant ALE maxima (Z > 3; pcorrected < 0.05)
superimposed on a...
Neuroanatomical abnormalities and cognitive
impairments are shared by adults with ADHD
and their unaffected first-degree r...
Neuroanatomical abnormalities and cognitive
impairments are shared by adults with ADHD
and their unaffected first-degree r...
Gray matter volume abnormalities in ADHD:
voxel-based meta-analysis exploring the effects
of age and stimulant medication
...
Functional and pharmacological
MRI studies
Ventral-striatal responsiveness during reward anticipation
in ADHD: meta-analysis of fMRI studies
Plichta & Scheres, Neuro...
Meta-analysis of functional fMRI studies in ADHD
Hart et al., Arch Gen Psychiatry 2013; 70: 185-98
21 data sets (287 patie...
>
<
>
>
>
BEEP
This task measures the
participant’s ability to inhibit a
pre-potent response
Stop-signal
occurs on 25%
tri...
Methylphenidate, modafinil, and
atomoxetine improve stop-signal
inhibition in adults with ADHD
Aron et al.,
Biol Psychiatr...
Scatter plots showing plasma
atomoxetine levels against mean RIFG
activation during successful inhibition
Atomoxetine 40mg...
Atomoxetine modulates right inferior frontal
activation during inhibitory control
– a pharmacological fMRI study
Chamberla...
Effects of stimulants in ADHD: Meta-analysis of fMRI studies
Rubia et al., Biol Psychiatry 2013 [Epub ahead of print]
Meta...
SPECT / PET studies
 Dopamine synthesis
 Ernst et al. 1998 [18F-dopa]; Forssberg et al. 2006 [11C-levodopa],
Ludolph et al. 2008 [18F-dopa]
...
 Single dose of MPH displaces
[18F]fallypride
 No displacement differences
between ADHD patients and
healthy controls
(A...
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
mech...
Evaluating dopamine reward pathway in ADHD:
Clinical implications
Volkow et al., JAMA 2009; 302: 1084-91
[11C]cocaine PET:...
Logan et al., Nucl Med Biol 2007; 34: 667-679
Hannestad et al., Biol Psychiatry 2010, 68: 854-860
Displacement of [11C]MRB...
Thank you for your attention !
 Prof. Philip Asherson (IoP, London)
 Dr Marios Adamou (Wakefield)
 Dr Muhammad Arif (Leicester)
 Dr Ovais Badat (Bris...
What is ADHD? Update on pharmacology and neuroimaging
What is ADHD? Update on pharmacology and neuroimaging
Upcoming SlideShare
Loading in …5
×

What is ADHD? Update on pharmacology and neuroimaging

4,961 views

Published on

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.

Published in: Health & Medicine

What is ADHD? Update on pharmacology and neuroimaging

  1. 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) DN: cn=Yasir Hameed (MRCPsych) 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. 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. 3.  What is ADHD?  Catecholamine deficit model of ADHD  Efficacy of ADHD medication  Structural and functional MRI  Pharmacological MRI  SPECT/PET studies Overview
  4. 4. What is ADHD?
  5. 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. 6. The prevalence of DSM-IV attention-deficit/ hyperactivity disorder: a meta-analytic review Willcutt, Neurotherapeutics 2012; 9: 490-499 Hyperactive Inattentive
  7. 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. 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. 9. Inverted-U model of arousal Stahl 2008
  10. 10. Efficacy of ADHD medication in adults
  11. 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. 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. 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. 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. 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. 16. Moderators of methylphenidate efficacy for adults with ADHD: a meta-regression analysis Castells et al., CNS Drugs 2011; 25: 157-69
  17. 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. 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. 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. 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. 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. 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. 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. 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. 25. Structural MRI studies
  26. 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. 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. 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. 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. 30. Functional and pharmacological MRI studies
  31. 31. Ventral-striatal responsiveness during reward anticipation in ADHD: meta-analysis of fMRI studies Plichta & Scheres, Neurosci Biobehav Rev 2014; 38: 125-34
  32. 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. 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. 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. 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. 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. 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. 38. SPECT / PET studies
  39. 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]
  40. 40.  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
  41. 41. 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
  42. 42. 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)
  43. 43. 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
  44. 44. Thank you for your attention !
  45. 45.  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

×