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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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

www.mghcme.org 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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Age-Dependent Decline and Persistence of ADHD Throughout the Lifetime

Faraone et al. Nature Reviews Disease Primers 2015

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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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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 MPHPlacebo

• 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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www.mghcme.org Nakao et al. Am J Psychiatry 2011

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www.mghcme.org Faraone et al. Nature Reviews Disease Primers 2015

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Brain Mechanisms in ADHD Faraone et al. Nature Reviews Disease Primers 2015

The executive control and cortico-cerebellar networks coordinate EFs

The DLPC is linked to WM, the VMPFC to complex decision making and strategic planning, and the parietal cortex to attention

The VMPFC, OFC & ventral striatum are the brain network associated with anticipation and reward

The frontal and parietal cortices and the thalamus support attentional functioning

Negative correlations between the DMN and the frontoparietal control network are weaker in patients with ADHD

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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

Mattfeld et al. Brain: A Journal of Neurology 2014, epub: June 10, 2014

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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)

Mattfeld et al. Brain: A Journal of Neurology 2014, epub: June 10, 2014

www.mghcme.org Mattfeld et al. Brain: A Journal of Neurology 2014, epub: June 10, 2014

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ADHD Imaging Studies Summary

• Neuroimaging studies confirm that brain abnormalities in fronto-subcortical networks are associated with ADHD

• Neuroimaging techniques are not valid tools for ADHD diagnosis; imaging measures are not sensitive or specific enough to be used for diagnostic purposes

• Treatment attenuate neural deficits

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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Genetics of ADHD


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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

Bind

ing p <0.008

N=21 N=26

15 %

Spencer et al Biol Psychiatry 2007

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New Results from Genomewide Association Studies (GWAS)

010

,000

20,0

0030

,000

40,0

00

Y2012 Y2014 Q4_2015 Q1_2019

Number of ADHD GWAS Samples

Faraone et al, 2015

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Preliminary ADHD meta-analysis 18,284 cases 33,836 controls

Preliminary analyses suggest eight genome-wide significant loci Faraone et al, 2015

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FOXP2 association

Faraone et al, 2015

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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

Hist

ory

of M

ater

nal

Smok

ing

(%)

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 µm

3 )

(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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00.10.20.30.40.50.60.70.80.9

1

Cum

ulat

ive

Mor

bidi

ty 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


Holli

ngsh

ead

Mea

n Sc

ore

(Hig

her S

core

= H

ighe

r SES

Overall SES at the 16-Year Follow-Up

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6.1 6.6

5.1 5.2

0.01.02.03.04.05.06.07.08.09.0

Educational Level (1 to 7) Occupational Level (1 to 9)

Controls ADHD

Holli

ngsh

ead

Mea

n Sc

ore

(Hig

her S

core

= H

ighe

r 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

χ2(1) =19.7, p<0.001 χ2

(1) =17.8, p<0.001

χ2(1) =3.5, p=0.063

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Protective Effect of Stimulants on Comorbidity

χ2(1) =21.4, p<0.001

χ2(1) =19.9, p<0.001

χ2(1) =1.3, p=0.258


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Protective Effect of Stimulants

χ2(1) =18.4, p<0.001


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67

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

Risk

for S

UD

(%)

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)

Perc

ent o

f 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 P

rob

abil

ity

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

8.6 7.1 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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Lichtenstein et al. New Eng J Med 2012;367(21):2006-14.

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Novel Comorbidities

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Emotional Dysregulation

www.mghcme.org (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

χ2(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

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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

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

Prob

abili

ty o

f Acc

iden

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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Assessment Guides Management


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Management Decision Tree

Faraone et al. Nature Reviews Disease Primers

2015

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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

adhd across the lifecycle: definitions and...

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