adhd across the lifecycle: definitions and...
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ADHD Across the Lifecycle: Definitions and Overview
Joseph Biederman, MD Professor of Psychiatry Harvard Medical School
Chief, Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD
Massachusetts General Hospital
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Disclosures
• My spouse/partner and I have the following relevant financial relationship with a commercial interest to disclose: – Research support: DOD, FDA, AACAP , Alcobra, Forest Research
Institute, Ironshore, Lundbeck, Magceutics Inc., Merck, PamLab, Pfizer, Shire Pharmaceuticals Inc., SPRITES, Sunovion, Vaya Pharma/Enzymotec, and NIH.
– Royalties paid to the Department of Psychiatry at MGH, for a copyrighted ADHD rating scale used for ADHD diagnoses: Ingenix, Prophase, Shire, Bracket Global, Sunovion, and Theravance
– US Patent Application (Provisional Number #61/233,686) through MGH corporate licensing, on a method to prevent stimulant abuse.
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1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010
Still describes ‘Defect of Moral Control’ in
The Lancet
Bradley shows that benzedrine
reduces hyperactivity
ADHD symptoms described as Minimal
Brain Dysfunction
Methylphenidate indicated for behavioral
disorders in children
Twin studies document high heritability
DSM III operationalizes diagnostic criteria
DSM II Hyperkinetic
Reaction
CDC describes ADHD as a serious public health problem
Long- acting stimulants developed
DSM IV refines criteria
Similar correlates of ADHD in boys
& girls
Non-stimulants approved
DSM-5 extends age at
onset to 12 & adjusts
criteria for adults
CBT for
adult ADHD
Neuroimaging documents structural and functional brain
anomalies
ADHD in adults recognized as valid
disorder
Comorbidity with anxiety/mood/autism spectrum disorders & executive
dysfuntion confirmed
Rare genomic insertions and deletions discovered
Molecular polygenic background confirmed Faraone et al, Nature Reviews Disease Primers (In Press)
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0 5 10 15 20 Prevalence of ADHD (%)
Puerto Rico
New York City
Pittsburgh
Iowa
Tennessee
Minnesota
Oregon
Missouri
Virginia
North Carolina
N.Y., Mich., Wis.
India China
Netherlands New Zealand
Japan Brazil
Ukraine Germany
Netherlands/Belgium Switzerland
Israel United Kingdom
Ireland Canada
New Zealand Spain
0 5 10 15 20 Prevalence of ADHD (%)
Worldwide Prevalence of ADHD in Children
Faraone SV et al. (2003), World Psychiatry 2(2):104-113
USA Ex USA
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Akinbami et al. NCHS Data Brief No. 70, August 2011
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www.mghcme.org Zuvekas al. Am J Psychiatry 2012; 169:160-166
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Poor Adherence to Treatment in ADHD
• Despite the well documented morbidity of ADHD and the marked efficacy and safety of stimulants, the failure to adhere to medications after one year is as high as 87%!! (Safren 2007)
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Long Delays in the Initiation of Treatment (n=1498)
3.3
7.8
0
1
2
3
4
5
6
7
8
9
Age of Onset of Diagnosis Age of Onset of Treatment
p < 0.001
MGH Pediatric Psychopharmacology Clinic
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Inattention
Impulsivity/Hyperactivity
ADHD: Core Symptom Areas
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Course of ADHD Symptoms Over Time by Sex: A Growth Curve Model
Age by Sex Interaction: NS
Biederman et al. 2009
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ADHD: Course of the Disorder
Inattention
Time
Hyperactivity
Impulsivity
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Faraone et al. Psychol Med. 2006;36:159-165.
Full Diagnosis
Residual Diagnosis
0
10
20
30
40
50
60
70
80
90
100
12 15 17 21 26
Age at Follow-up
Pe
rsis
ten
ce R
ate
Loss of full diagnostic status is not equivalent to remission.
Persistence of Full and Residual Diagnoses in Prospective Studies
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Persistent Controversy BMJ | 3 april 2010 | Vol 340
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Changes in DSM-V ADHD
• “Neurodevelopmental” - not “disruptive” • ≥ 6/9 inattentive or ≥ 6/9 impulsive/hyperactive
symptoms over last six months (>5 for adults) • Symptoms caused impairment by age 12 (no
longer 7) • ASDs no longer exclusionary • No more “subtypes”; Inattentive / Hyperactive-
impulsive / Combined are now “Presentations” • Restricted inattentive subtype: In Appendix,
worthy of further study
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ADHD as a Brain Disorder: Neuroimaging Findings
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Developmental Trajectories of Brain Volume Abnormalities in Youth w/ADHD
• Design: MRI case control study
• N=152 youth w/ ADHD and 139 controls of both genders
• Objective: assess volumetric changes overtime in medicated vs unmedicated youth w/ADHD and controls
Castellanos et al. JAMA. 2002 Oct;288(14):1740-8
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Developmental Trajectories of Brain Volume Abnormalities in Youth w/ADHD
• Main Findings: – Smaller brain volumes in all regions independently
of medication status
– Smaller total cerebral (-3.2%) and cerebellar (-3.5%) volumes
– Volumetric abnormalities (except caudate) persisted with age
– No gender differences
– Volumetric findings correlated with severity of ADHD
Castellanos et al. JAMA. 2002 Oct;288(14):1740-8
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Brain Volumes and ADHD M
illili
ters
Non-ADHD Controls
Unmedicated Medicated
Unadjusted Total Cerebral Brain Volume for Unmedicated and Medicated Children and Adolescents With ADHD and Controls
N=103
N=49
N=139
*p=0.001 by 2-way analysis of variance (group [medicated vs. unmedicated vs. control] by sex); Castellanos FX et al. (2002), JAMA 288(14):1740-1748
1,000
1,020
1,040
1,060
1,080
1,100
1,120
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Developmental Trajectories of Brain Volume Abnormalities in Youth w/ADHD
• Conclusions:
– Genetic and or early environmental influences on brain development in ADHD are fixed, nonprogressive and unrelated to stimulant treatment
Castellanos et al. JAMA. 2002 Oct;288(14):1740-8
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Dorsolateral prefrontal
cortex
Ventromedial prefrontal
cortex
Parietal cortex
Figure 4a
Faraone et al, Nature Reviews Disease Primers (In Press)
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Cerebellum
Ventral anterior cingulate cortex
Putamen
Amygdala
Nucleus caudatus
Nucleus accumbens
Figure 4b
Dorsal anterior cingulate cortex
Faraone et al, Nature Reviews Disease Primers (In Press)
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MRI findings in Adult with ADHD
Seidman et al. Biol Psychiatry, 2006; 60: 1071-1080
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Volumetric reductions in light blue (frontal and cerebellar regions)
Superior frontal gyrus
Anterior cingulate gyrus
Cerebellar cortex
Seidman et al. Biol Psychiatry, 2006; 60: 1071-1080
Volume Reductions in Adult ADHD
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•Dorsolateral Frontal Cortex (BA 8, 9)
•Supramarginal Gyrus
(BA 40)
•Superior Temporal Gyrus
(BA 22)
•Angular Gyrus
(BA 39)
•Middle Temporal Gyrus
(BA 21)
Makris et al. Cerebral Cortex June 2007; 17:1364-1375
Cortical Thickness Analysis in Adult with ADHD
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•Anterior Cingulate Gyrus (BA 24)
•Orbital Frontal Cortex
((BA 11, 12, 13, 14)
•Orbital Frontal Cortex
((BA 11, 12, 13, 14)
Makris et al. Cerebral Cortex June 2007; 17:1364-1375
Cortical Thickness Analysis in Adult with ADHD
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www.mghcme.org Reproduced from Makris N, et al. Cerebral Cortex. 2007; doi:10.1093/cercor/bhm156.
A DTI-MRI Study of Connections in ADHD
Makris et al. Cerebral Cortex 2008 May;18(5):1210-20
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MGH-NMR Center & Harvard- MIT CITP Bush et al, Biological Psychiatry 1999
1 x 10 -3
1 x 10 -2
y = +21 mm
Normal Controls
1 x 10 -2
1 x 10 -3
y = +21 mm
ADHD
Dorsal Anterior Cingulate Cortex (Cognitive Division) Fails to Activate in ADHD
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0
0.5
1
1.5
2
2.5
Baseline 6 Weeks
OROS MPH
Placebo
• 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
Methylphenidate Activates Dorsal Anterior Midcingulate Cortex
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Cortical Thickness Differences
Functional ROI
DTI ROI
Volumetric ROI
Dorsal ACC (dACC) “Cognition”
Perigenual ACC (pACC) “Emotion”
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Nakao et al. Am J Psychiatry 2011
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Resting-State Functional Connectivity in a Longitudinal
Sample of ADHD Children Grown Up
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Adult ADHD: Decreased Positive Correlations Between PCC-MPFC
• 20 ADHD participants (mean age = 34.9; 16 male)
– Ascertained retrospectively
• 20 Controls (mean age = 31.2; 14 male)
Castellanos et al., 2008
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Reduced MPFC-PCC Coupling Reflects Current Diagnostic State of ADHD
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Neural Basis of Persistent ADHD
• Persistent ADHD alters intrinsic functional organization of the brain
• Findings supports the idea that adult ADHD diagnosis reflects a true brain difference (vs. controls & vs. remitting ADHD)
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Spencer et al. J Clin Psychiatry 2013 Sep;74(9):902-17.
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ADHD Imaging Studies Summary
• Neuroimaging studies confirm that brain abnormalities in fronto-subcortical networks are associated with ADHD
• But neuroimaging techniques are not valid tools for ADHD diagnosis; imaging measures are not sensitive or specific enough to be used for diagnostic purposes
Spencer et al. J Clin Psychiatry 2013 Sep;74(9):902-17.
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ADHD as a Neurobiological Disorder: Catecholamine Dysregulation
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Frontosubcortical Networks and Catecholamines
• Dopaminergic and noradrenergic dysregulation abnormalities in fronto subcortical pathways
• Medications that are effective in ADHD are either dopaminergic or noradrenergic
Zametkin. J Am Acad Child Adolesc Psychiatry. 1987;26(5):676-686.
Zametkin. J Am Acad Child Adolesc Psychiatry. 1987;26(5):676-686
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MESENCEPHALON
PONS
MEDULLA Raphe nuclei (serotonin)
Substantia nigra tegmentum (dopamine)
Locus ceruleus (norepinephrine)
to cerebellum
to cord
to diencephalon and cerebrum
Brain Stem
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ADHD as a Neurobiological Disorder: Genetic Findings
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Genetic Basis
of ADHD
ADHD: Genetics
Twin Studies Family Studies
Adoption Studies Molecular Genetics
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www.mghcme.org Mean heritability of ADHD = .75 Faraone et al. Biol Psychiatry. 2005;57:1313-23.
ADHD
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
Matheny 1971
Willerman 1973
Goodman 1989
Gillis 1992
Edelbrock 1992
Stevenson 1992
Schmitz 1995
Thapar 1995
Gjone 1996
Silberg 1996
Sherman 1997
Levy 1997
Nadder 1998
Hudziak 2000
Willcutt 2000
Thapar 2000
Coolidge 2000
Kuntsi 2001
Martin 2002
Rietveld 2003
Laarson 2004
Heritability
Panic Disorder Schizophrenia Height
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Effe
ct s
ize
Allele frequency
High
Intermediate
Modest
Low
Very rare Rare Low frequency Common
Rare & Low frequency
copy number variants
Common variants
explain about 40% of
heritability
Rare chromosomal
anomalies
- 22q11.2 deletion syndrome - Jacobsen syndrome (deletions of end of 11q) - Turner’s syndrome (X0) - Klinefelter’s syndrome (XXY)
- Monoamine system genes - Neurite outgrowth genes
Gene finding in ADHD
- 16p13.11 - 15q11-13 region containing nicotinic alpha-7 acetylcholine receptor subunit gene -Rare point mutations expected from sequencing studies
Faraone et al, Nature Reviews Disease Primers (In Press)
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Dopamine Transporter
(DAT)
Dopamine
Receptor
(DRD4)
Presynaptic Neuron
Methylphenidate
(MPH)
Dopamine
The Dopamine Story...
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Measuring Changes in Dopamine
T Y R O S I N E
D A
D O P A
D A
D A
D A
M A O
D O P A C
D A
T Y R O S I N E
D A
D O P A
D A
D A
D A
M A O
D O P A C
D A
D A D A D A D A
D A
D A D A
m e t h y l p h e n i d a t e
C O N H C H 2
C l C l
O 1 1
C H 3 H O
N C 2 H 5
H
[ 1 1 C ] r a c l o p r i d e
C O N H C H 2
C l C l
O 1 1
C H 3 H O
N C 2 H 5
H
[ 1 1 C ] r a c l o p r i d e
R R R R R R
Dopamine Stress Test
Volkow, Swanson. Am J Psychiatry. 2003 Nov;160(11):1909-18
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After Oral MPH Baseline
DAT PET Imaging (Altropane) with and without oral MPH
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DAT Binding (age-corrected) in Right Caudate by Diagnosis
2.7
2.8
2.9
3
3.1
3.2
3.3
3.4
3.5
ADHD Controls
DAT
Bin
din
g p <0.008
N=21 N=26
15 %
Spencer et al Biol Psychiatry 2007
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ADHD Genetics
• The literature is predominated by candidate gene studies
• Genome-wide association studies are emerging
• CNV studies are emerging
0
20
40
60
80
100
120
19
87
19
88
19
89
19
90
19
91
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
20
01
20
02
20
03
20
04
20
05
20
06
20
07
20
08
“ADHD Genetics” Publications
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Maternal Smoking During Pregnancy: Results in Children
22%
8%
0%
5%
10%
15%
20%
25%
ADHD Controls
* P=0.04, controlling for SES,
parental ADHD, and parental IQ
P=0.002
N=140 N=120
His
tory
of
Mat
ern
al
Smo
kin
g (%
)
Milberger et al. Am J Psychiatry 1996;153:1138.
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1.5
1.7
1.9
2.1
Nicotine (6) Control (6)
Volu
me (
x10
9 m
m3)
(14% reduction, P<0.001)
Cingulate Cortex
Prenatal nicotine exposure reduces the volume of the cingulate cortex
*
Bhide et al 2009
Prenatal Nicotine Exposure: Effects on Brain Structure
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Prenatal Exposure (PNE (F1) Mice Have Increased Spontaneous Locomotor Activity
F1 - Female
F1 - Male
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www.mghcme.org Zhu et al. J Neuroscience 2012; 32(27):9410-9418
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ADHD Diagnostic Considerations
Inattention
Impulsivity/Hyperactivity
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0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Cu
mu
lati
ve M
orb
idit
y R
isk
Control ADHD
P ≤ .009 for all categories
Biederman et al. Psychological Medicine, 2006, 36, 167–179.
Cumulative Morbidity Risks for Psychiatric Disorders in ADHD and Control Probands
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Biederman et al. AJP. April 2010
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Parental Support at the 16-Year Follow-Up
13.3% 15.9%
26.6%
38.0%
0%
5%
10%
15%
20%
25%
30%
35%
40%
Financially Dependent on Parents Lives with Parents
Controls ADHD
z=2.13 p=0.03
z=2.45 p=0.01
Biederman et al. JCP 2012
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84.6%
37.9%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Controls ADHD
z=-4.78 p<0.001
Biederman et al. JCP 2012
College Graduate at the 16-Year Follow-Up
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1.9
2.5
0.0
1.0
2.0
3.0
4.0
5.0
Controls ADHD
z=3.47 p=0.001
Biederman et al. JCP 2012
Ho
llin
gsh
ead
Mea
n S
core
(Hig
her
Sco
re =
Hig
her
SES
Overall SES at the 16-Year Follow-Up
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Biederman et al. JCP 2012
6.1 6.6
5.1 5.2
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
9.0
Educational Level (1 to 7) Occupational Level (1 to 9)
Controls ADHD
Ho
llin
gsh
ead
Mea
n S
core
(Hig
her
Sco
re =
Hig
her
SES
z=-5.36 p<0.001
z=-3.12 p=0.002
Educational and Occupational Level at the 16-Year Follow-Up
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Biederman et al. Pediatrics 2009 Jul;124(1):71-8.
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Protective Effect of Stimulants on Comorbidity
Biederman et al. Pediatrics 2009
2(1) =19.7, p<0.001 2
(1) =17.8, p<0.001
2(1) =3.5, p=0.063
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Protective Effect of Stimulants on Comorbidity
2(1) =21.4, p<0.001
2(1) =19.9, p<0.001
2(1) =1.3, p=0.258
Biederman et al. Pediatrics 2009
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Protective Effect of Stimulants
2(1) =18.4, p<0.001
Biederman et al. Pediatrics 2009
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72
ADHD and Substance Abuse
Wilens et al. J Nerv Ment Dis. 1997;185(8): 475-482.
Risk for Substance Use Disorder (SUD) Onset in Adults With Untreated ADHD
Control
ADHD
P ≤0.05, ADHD vs control at end point
Ris
k fo
r SU
D (
%)
0
10
20 30 40
50 60 70 80
90
100
Age at onset (years) 0 10 20 30 40 50 60
Earlier onset
Higher risk
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SUD in ADHD Youth Growing Up: Overall Rate of Substance Use Disorder
0
5
10
15
20
25
30
35
Control
(n=344)
Medicated
(n=117)
Unmedicated
(n = 45)
Pe
rce
nt
of
Gro
up
p < 0.001
Biederman, Wilens, Mick et al., Pediatric 1999
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0 10 30 20
25
50
75
100
Age
*p<0.05 vs. Controls
%
Biederman et al. Am J Psychiatry. 2008 Mar 3
No Stimulant Therapy*
Controls
Stimulant Therapy*
*p<0.05 vs. Controls
Stimulant Therapy and Subsequent Risk for Substance Dependence Disorders
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0 4 8 12 16 20
0
0.1
0.3
0.4
0.5
0.6
Age (years)
Su
rviv
al
Prob
ab
ilit
y
Milberger S, et al. J Am Acad Child Adolesc Psychiatry. 1997:36;37-44.
P<.003
Onset of Nicotine Use in Children and Adolescents with ADHD
ADHD
Control
0.2
2 6 10 14 18 22
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Hammerness et al. J Pediatr 2012
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Prospective Study of OROS MPH vs. non-ADHD and ADHD
Omnibus test, chi-squared(1)=8.44, p=0.04
8.67.1 8.3
20.8
0
5
10
15
20
25
Non-ADHD (n=177)
OROS MPH (n=154)
ADHD Current Meds (n=36)
ADHD Not Current Meds
(n=49)
% current smoking according to Fagerstrom Tolerance Questionnaire
p=0.02
p=0.007
Not significant (all p>0.60)
Hammerness and Biederman, Jounal of Pediatrics 2012
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Novel Comorbidities
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Emotional Dysregulation
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(Kim 2011 Behavioral Brain Research)
Amgydala-Prefrontal Circuitry
Amygdala: Red Ventromedial prefrontal cortex: Blue Dorsomedial prefrontal cortex: Green
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Deficient Emotional Self Regulation in Youth with ADHD
2%
44%
0
10
20
30
40
50
60
Controls ADHD
2(1)=108.4, p<0.001 %
% subjects with ADHD-associated severe impairment
32%
50%
0
10
20
30
40
50
60
ADHD ADHD+DESR
z=2.49, p=0.01
%
Spencer et al. Postgrad Med. 2011
Sep;123(5):50-9.
Rates of DESR
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Autistic Traits
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Autism
From Autism to Autistic Traits
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Autistic Traits in ADHD Children
18.0%
1.0%
0%
5%
10%
15%
20%
25%
ADHD Probands Control Probands
p <0.001
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PTSD and TBI
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•For each comparison, the
dot gives the relative risk
and the horizontal line
gives the 95% confidence
interval
•The center of the
diamond at the bottom
gives the weighted relative
risk across all studies and
the width of the diamond
gives its 95% confidence
interval
NORMAL CONTROLS
Antshel 2013
Ruhl 2009
Kessler 2006
Bernardi 2012
Park 2010
Biederman 2012
Hurtig 2007
Smalley 2007
Wozniak 1999
Subtotal
PSYCHIATRIC CONTROLS
McLeer 1994 (PSY)
Ford 2000
Subtotal
TRAUMA CONTROLS
Daud 2009 (non-TP)
Daud 2009 (TP)
McLeer 1994 (SA)
Husain 2008
Subtotal
Citation
Adult
Adult
Adult
Adult
Adult
Adult
Child
Child
Child
Child
Child
Child
Child
Child
Child
Age
ADHD
Population
Population
Population
Population
ADHD
ADHD
ADHD
ADHD
Population
ADHD
Population
Population
Population
Population
Sample
1 .01 .5 1 10 100
Relative Risk for PTSD
Spencer-Kimchi et al. 2014 submitted
Forest Plot of Studies Examining the ORs of PTSD in ADHD
PSY=psychiatric sample. SA=Sexually abused sample. TP=Sample of refugee
children with tortured parents. Non-TP=Sample of refugee children with non-
traumatized parents.
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Forest Plot of Studies Examining the ORs of ADHD after mTBI
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www.mghcme.org Man et al. Pediatrics. 2014 Dec 15.
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www.mghcme.org Mikolajczyk et al. JAMA Pediatr. 2015; doi: 10.1001/jamapediatrics.2014.3275
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Functional Impairments
Results of A Survey of 1000 Subjects with and without ADHD
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Educational Impairment in High School
*
*
*
*
* p ≤.001
Percentage of Those Who Attended High School
52%
27%
37%
13%
37%
10%
30%
8%
"C" average or lower
Had a tutor
Had special classes
Had to repeat a grade
ADHD (N=464)
Non-ADHD (N=487)
Biederman et al. J Clin Psychiatry. 2006 Apr; 67(4):524-40
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Current Employment Status
*
*
*
*
* p ≤.001
Percentage of Each Group
52%
72%
34%
57%
48% 27%
14%
5%
Currently employed
Employed full time
Not currently employed
Looking for work
ADHD (N=500)
Non-ADHD (N=501)
Biederman et al. J Clin Psychiatry. 2006 Apr; 67(4):524-40
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Average Household Income by Education Level Attained
$23,859
$46,471
$66,683
$91,316
$29,577
$38,733
$63,086
$52,404
$0
$10,000
$20,000
$30,000
$40,000
$50,000
$60,000
$70,000
$80,000
$90,000
$100,000
Less than HighSchool
High School/SomeCollege
College/Some Post-Grad
Post-graduateDegree
Control ADHD
Education (Highest Degree Obtained) Biederman and Faraone. Medscape General Medicine 2006; 8:12.
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Accidents and Near Misses
0%
10%
20%
30%
40%
50%
60%
70%
80%
Accident Accident and Near Misses
Pro
bab
ilit
y o
f A
ccid
en
t
P<0.05*
P<0.05*
*Indicates P<0.05 after controlling for gender, age, time of day and the age*ADHD interaction
(Reimer et al., submitted)
ADHD ADHD
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Percent of Subjects Involved in Collisions During Surprise Events
LDX = lisdexamfetamine dimesylate
Biederman et al. 2011 submitted
*
During the five surprise events, drivers in the medication group were 67% less likely to have a collision than drivers in the placebo group
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Mean Number of Impaired Health Risk Indicators
Spencer et al. 2013 submitted
Impaired Health Risk indicators: cutoffs defined by values outside the normal range
P=0.003
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Dalsgaard, S., Østergaard, S. D., Leckman, J. F., Mortensen, P. B., & Pedersen, M. G. The Lancet. 2015; http://dx.doi.org/10.1016/S0140-6736(14)61684-6
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Summary
• ADHD is a neurobehavioral disorder with a: – Complex etiology
– Neurobiologic basis
– Strong genetic component
• ADHD – Affects millions of people of both genders
– Persists through adolescence and adulthood in a high percentage of cases
– Can have negative impact on multiple areas of functioning