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

www.mghcme.org

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

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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• 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


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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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• Conclusions:

– Genetic and or early environmental influences on brain development in ADHD are fixed, nonprogressive and unrelated to stimulant treatment


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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


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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

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

www.mghcme.org Bush et al. Arch Gen Psychiatry. 2008:65:102-114.

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

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


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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

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


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


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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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


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Protective Effect of Stimulants

2(1) =18.4, p<0.001


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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

www.mghcme.org Humphreys et al. JAMA Psychiatry 2013

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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

www.mghcme.org Clinical and Research Programs in Pediatric Psychopharmacology

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

www.mghcme.org

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

www.mghcme.org Man et al. Pediatrics. 2014 Dec 15.

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

www.mghcme.org

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

www.mghcme.org

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

adhd across the lifecycle: definitions and...

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