ADHD Across the Lifecycle: an...
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www.mghcme.org ADHD Across the Lifecycle: an Overview Joseph Biederman, MD Professor of Psychiatry Harvard Medical School Chief, Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD Massachusetts General Hospital
Transcript of ADHD Across the Lifecycle: an...
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ADHD Across the Lifecycle: an 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: The Department of Defense, Food & Drug Administration, Ironshore, Lundbeck, Magceutics Inc., Merck, Neurocentria Inc., PamLab, Pfizer, Shire Pharmaceuticals Inc., SPRITES, Sunovion, Vaya Pharma/Enzymotec, and NIH Consultant: I have a financial interest in Avekshan LLC, a company that develops treatments for attention deficit hyperactivity disorder (ADHD). My interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies Departmental Royalties (from a copyrighted rating scale used for ADHD diagnoses): Ingenix, Prophase, Shire, Bracket Global, Sunovion, and Theravance; these royalties were paid to the Department of Psychiatry at MGH
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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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Adherence in ADHD is Dismal
• Only 13% of patients consistently take their
medication one year out Within 2 to 3 months, a majority of patients with ADHD have stopped taking medication consistently
Patients renewed their monthly prescriptions about 2 to 3 times per year1
0%
20%
40%
60%
80%
100%
1 3 5 7 9 11 13 15
Month
Pa
tie
nts
(%
)
OROS MPH
MPH LA
MAS XR
Atomoxetine
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Poor Adherence to Treatment in ADHD
• This is so despite the well documented morbidity of ADHD and the marked efficacy and safety of stimulants
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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
www.mghcme.org Moffitt et al. Am J Psychiatry 2015; 172:967–977.
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Adult Onset ADHD
• It is unclear whether such adults do not recall childhood symptoms, are unable to report on them, or are unable to distinguish onset of symptoms form onset of symptoms-associated impairments that may account for the different ages of onset
Faraone and Biederman JAMA Psychiatry Editorial 2016
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Adult Onset ADHD
• Onset of symptoms and onset of impairment are often separated by many years, particularly among those with strong intellectual abilities and those living in supportive, well-structured childhood environments
Faraone and Biederman JAMA Psychiatry Editorial 2016
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Adult Onset ADHD
• This view of ADHD posits that symptoms and impairment emerge due to the accumulation of environmental and genetic risk factors
• Those with lower levels of risk at birth will take longer to accumulate sufficient risk factors and longer to onset with symptoms and impairment
Faraone and Biederman JAMA Psychiatry Editorial 2016
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Adult Onset ADHD
• Such a scenario may suggest that ADHD may be a disorder with a continuum of ages of onsets, with some subjects starting their symptoms earlier while others later
Faraone and Biederman JAMA Psychiatry Editorial 2016
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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 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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Nakao et al. Am J Psychiatry 2011
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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
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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
Faraone et al. Nature Reviews Disease Primers 2015
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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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New Results from Genomewide Association Studies (GWAS)
0
10
,00
020
,00
030
,00
040
,00
0
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 PGC ADHD/iPSYCH-SSI-Broad Collaboration
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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
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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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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a p<0.05 vs. comparison subjects b p<0.05 vs. comparison subjects plus alcohol dependence c p<0.05 vs. subjects with ADHD a-c
a
Risk For Alcohol Dependence in Relatives
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a p<0.05 vs. comparison subjects b p<0.05 vs. comparison subjects plus drug dependence c p<0.05 vs. subjects with ADHD
a
a
Risk For Drug Dependence in Relatives
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Risk Factors for SUD
SUD
+FH of SUD
Personal or +FH of ADHD
+FH of both ADHD
& SUD
Yule and Biederman 2016
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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Lichtenstein et al. New Eng J Med 2012;367(21):2006-14.
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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
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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
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
Chang et al. JAMA Psychiatry Published online January 29, 2014. doi:10.1001/jamapsychiatry.2013.4174
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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Newly Approved Amphetamine Formulations
• The FDA has approved 2 new amphetamine products for treatment of ADHD in children >6 years old
• Amphetamine extended-release orally distintegrating tablets (Adzenys XR-ODT –
• Neos Therapeutics) do not have to be swallowed or sprinkled on food
• Amphetamine oral liquid (Dyanavel XR – Tris Pharma) is claimed to have an onset of action at 1 hour and a duration of action that persists throughout the day
The Medical Letter 2016
www.mghcme.org
In Brief: ER Extended-Release Chewable MPH Tablets
• The FDA has approved a once-daily, extended-release chewable tablet formulation of methylphenidate (Quillichew ER – Pfizer) for treatment of ADHD
• It is the first chewable formulation of the drug to be marketed for once-daily use
• Short-acting chewable methylphenidate tablets (Methylin, and generics) have been available since 2003 (Med Lett Drugs Ther 2015).
The Medical Letter 2016
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
