ADHD Across the Life Cycle: An Overview
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ADHD Across the Life Cycle:
An Overview
Joseph Biederman, MD
Professor of Psychiatry
Harvard Medical School
Chief, Clinical and Research Programs in
Pediatric Psychopharmacology and Adult ADHD
Director, Bressler Program for Autism Spectrum Disorders
Trustees Endowed Chair in Pediatric Psychopharmacology
Massachusetts General Hospital
www.mghcme.org
Disclosures 2020-2021
My spouse/partner and I have the following relevant financial relationships
with commercial interests to disclose:
– Research support: Genentech, Headspace Inc., Pfizer Pharmaceuticals, Roche
TCRC Inc., Sunovion Pharmaceuticals Inc., Takeda/Shire Pharmaceuticals Inc.,
and Tris.
– Consulting fees: Akili, Avekshan LLC, Jazz Pharma, and Shire/Takeda
– Honorarium for scientific presentation: Tris
– Royalties paid to the Department of Psychiatry at MGH, for a copyrighted
ADHD rating scale used for ADHD diagnoses: Biomarin, Bracket Global,
Cogstate, Ingenix, Medavent Prophase, Shire, Sunovion, and Theravance
– Through Partners Healthcare Innovation, I have a partnership with MEMOTEXT
to commercialize a digital health intervention to improve adherence in ADHD.
www.mghcme.org
Worldwide Prevalence of ADHD in Children
USA Ex USA
Spain
N.Y., Mich., Wis. New Zealand
North Carolina Canada
Ireland
Virginia United Kingdom
Missouri Israel
Switzerland
Oregon Netherlands/Belgium
Minnesota Germany
Tennessee Ukraine
Brazil
Iowa Japan
Pittsburgh New Zealand
New York City Netherlands
China
Puerto Rico India
0 5 10 15 20 0 5 10 15 20
Prevalence of ADHD (%) Prevalence of ADHD (%)
Faraone SV et al. (2003), World Psychiatry 2(2):104-113
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Akinbami et al. NCHS Data Brief No. 70, August 2011
www.mghcme.org
Cenat et al. JAMA Psychiatry. 2021;78(1):21-28.
doi:10.1001/jamapsychiatry.2020.2788
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Zuvekas al. Am J Psychiatry 2012; 169:160-166
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Percent of Children with ADHD who Renewed their First Stimulant Rx: A
Partners Healthcare EMR Review
# of patients # of patients who refilled % of patients who refilled
a prescription for ≥1 medication
2,206 1,023 46%
100
90
80
70
Percent (%)
60
50
40
30
20
10
0
Patients who refilled a
prescription for ≥1 medication
Biederman et al. Psychiatric Services 2019;70:874-880
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Poor Adherence to Treatment in
ADHD
• Poor adherence occurs despite
the well documented morbidity
of ADHD, the marked efficacy
and safety of stimulants as well
as the fact that ADHD symptoms
return rapidly when the
medication is not taken
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Long Delays in the Initiation of
Treatment (n=1498)
9
8
7.8
7
6
p < 0.001
5
4 3.3
3
2
1
0
Age of Onset of Diagnosis Age of Onset of Treatment
MGH Pediatric Psychopharmacology Clinic
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Diagnosis of ADHD
• Diagnosis is based on clinical
assessment of symptoms,
associated impairment and age
of onset
• No test is available
• Symptoms are subjective, as well
as developmentally and context
sensitive
www.mghcme.orgADHD: Core Symptom Areas
Inattention
Impulsivity/Hyperactivity
www.mghcme.orgADHD: Course of the Disorder
Hyperactivity
Impulsivity
Inattention
Time
www.mghcme.orgAge-Dependent Decline and Persistence of
ADHD Throughout the Lifetime
Faraone et al. Nature Reviews Disease Primers 2015
www.mghcme.orgPersistent Controversy BMJ | 3 april 2010 | Vol 340
www.mghcme.orgChanges in DSM-5 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
www.mghcme.orgADHD as a Brain Disorder:
Neuroimaging Findings
www.mghcme.orgFaraone et al. Nature Reviews Disease Primers 2015
www.mghcme.orgBrain Mechanisms in ADHD
The DLPC is linked to
WM, the VMPFC to
complex decision
making and strategic
planning, and the The executive control and
parietal cortex to cortico-cerebellar networks
attention
coordinate EFs
The VMPFC, OFC & ventral striatum are The frontal and parietal
the brain network associated with cortices and the thalamus Negative correlations between the DMN and the
anticipation and reward support attentional frontoparietal control network are weaker in patients
functioning with ADHD
Faraone et al. Nature Reviews Disease Primers 2015
www.mghcme.orgADHD 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
Spencer etneural deficits
al. J Clin Psychiatry 2013 Sep;74(9):902-17.
www.mghcme.orgADHD as a Neurobiological Disorder:
Catecholamine Dysregulation
www.mghcme.orgFrontosubcortical 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.
www.mghcme.orgBrain Stem
to diencephalon and cerebrum
Substantia nigra MESENCEPHALON
tegmentum
(dopamine) to cerebellum
Locus ceruleus
(norepinephrine) PONS
Raphe nuclei MEDULLA
(serotonin)
to cord
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ADHD as a Neurobiological
Disorder: Genetic Findings
www.mghcme.orgTwin Studies of ADHD
(Faraone & Larsson, Molecular Psychiatry, 2018)
Rydell 2017
Chen 2016
Chang 2013
Langner 2013
Polderman 2011
Greven 2011
Lichtenstein 2010
Ilott 2010
Bornovalova 2010 Symptom Counts
Cole 2009
Tuvblad 2009
Spatola 2007
Diagnoses
Polderman 2007
Derks 2007
Hudziak 2005 Mean heritability
Dick 2005
Laarson 2004
Rietveld 2003
across 37 studies = 74%
Martin 2002
Kuntsi 2001
Coolidge 2000
Thapar 2000
Willcutt 2000
Hudziak 2000
Nadder 1998
Levy 1997
Sherman 1997
Silberg 1996
Gjone 1996
Thapar 1995
Schmitz 1995
Stevenson 1992
Edelbrock 1992
Gillis 1992
Goodman 1989
Willerman 1973
Matheny 1971
0 0.2 0.4 0.6 0.8 1 1.2
Heritability
www.mghcme.orgMaternal Smoking During Pregnancy:
Results in Children
25% P=0.002
* P=0.04, controlling for SES,
20% parental ADHD, and parental IQ
History of Maternal
15%
Smoking (%)
10% 22%
5%
8%
0%
ADHD Controls
N=140 N=120
Milberger et al. Am J Psychiatry 1996;153:1138.
www.mghcme.orgADHD Diagnostic
Considerations
Inattention
Impulsivity/Hyperactivit
y
www.mghcme.orgCumulative Morbidity Risks for Psychiatric
Disorders in ADHD and Control Probands
1
0.9
Cumulative Morbidity Risk
0.8 Control ADHD
0.7 P ≤ .009 for all categories
0.6
0.5
0.4
0.3
0.2
0.1
0
Biederman et al. Psychological Medicine, 2006, 36, 167–179.
www.mghcme.orgBiederman et al.
AJP. April 2010
www.mghcme.orgPharmacotherapy of ADHD
• ADHD remains the most treatable disorder in
Psychiatry
• Stimulants (amphetamines and
methylphenidate compounds) remain the
mainstay of treatment for ADHD due to their
robust (High Effect Size) efficacy and safety
• FDA-approved Non Stimulants (Atomoxetine and
Alpha-2 Agonist (guanfacine and clonidine
extended release) are generally less effective
than the stimulants (moderate effect sizes of 0.4-
0.6)
www.mghcme.orgBiederman et al.
Pediatrics 2009
Jul;124(1):71-8.
www.mghcme.orgProtective Effect of Stimulants on Comorbidity
χ2(1) =19.7, pProtective Effect of Stimulants on Comorbidity
χ2(1) =1.3, p=0.258 χ2(1) =21.4, pProtective Effect of Stimulants
χ2(1) =18.4, pADHD and SUDs
Risk for Substance Use Disorder (SUD)
Onset in Adults With Untreated ADHD
100
ADHD
90
Control
80
Risk for SUD (%)
70
60
50 P ≤0.05, ADHD vs
40 control at end point
Earlier onset
30
20
10 Higher risk
0
0 10 20 30 40 50 60
Age at onset (years)
Wilens et al. J Nerv Ment Dis. 1997;185(8): 475-482.
www.mghcme.orgSUD in ADHD Youth Growing Up:
Overall Rate of Substance Use Disorder
35
30
Percent of Group
25 p < 0.001
20
15
10
5
0
Control Medicated Unmedicated
(n=344) (n=117) (n = 45)
Biederman, Wilens, Mick et al., Pediatric 1999
www.mghcme.orgOnset of Nicotine Use in Children and
Adolescents with ADHD
0.6 ADHD
Control
Survival Probability
0.5
0.4
0.
3
0.2 PProspective Study of OROS MPH vs. non-ADHD and ADHD
Omnibus test, chi-squared(1)=8.44, p=0.04
p=0.02
25
p=0.007 20.8
20
% current
smoking 15
according to
Fagerstrom 10 8.6 8.3
7.1
Tolerance
Questionnaire 5
0
Non-ADHD OROS MPH ADHD Current ADHD Not
(n=177) (n=154) Meds (n=36) Current Meds
(n=49)
Not significant (all p>0.60)
Hammerness and Biederman, Jounal of Pediatrics 2012
www.mghcme.orgAccidents and Near Misses
80% PPercent of Subjects Involved in Collisions During
Surprise Events
*
During the five
surprise events,
drivers in the
medication group
were 67% less likely
to have a collision
than drivers in the
placebo group
LDX = lisdexamfetamine dimesylate
Biederman et al. 2012
www.mghcme.orgLiterature Review of Registries and
Large Databases Examining the
Effects of Stimulants on Functional
Outcome
www.mghcme.orgSummary of Results
• The majority of the N=40 articles identified
document a robust protective effect of ADHD
medications on mood disorders, suicidality,
criminality, substance use disorders, accidents
and injuries, traumatic brain injuries, motor
vehicle crashes, and educational outcomes
• Similarly, the meta-analyses demonstrated an
overall protective effect of medication treatment
on these functional outcomes
www.mghcme.orgGoode et al. Pediatrics. 2018 Jun;141(6).
www.mghcme.orgSummary
• 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 is a highly treatable disorder
– Adherence to treatment remains very poor
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