adhd, ptsd, & tbi - amazon s3 · • individuals with adhd should be considered at high risk...
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ADHD, PTSD, & TBI
Joseph Biederman, MDProfessor of Psychiatry Harvard Medical School
Chief, Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD
Director, Bressler Program for Autism Spectrum DisordersMassachusetts General Hospital
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Disclosures 2018-2019
My spouse/partner and I have the following relevant financial relationships with commercial interests to disclose:
– Research support: Genentech, Headspace Inc., Lundbeck, Neurocentria Inc., Pfizer, Roche TCRC Inc., Shire Pharmaceuticals Inc., and Sunovion.
– Consulting fees: Akili, Jazz Pharma, and Shire– Royalties paid to the Department of Psychiatry at MGH, for a
copyrighted ADHD rating scale used for ADHD diagnoses: Bracket Global, Ingenix, Prophase, Shire, Sunovion, and Theravance
– Financial interest: Avekshan LLC, a company that develops treatments for ADHD. My interests were reviewed and are managed by MGH and Partners HealthCare in accordance with their COI policies
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Collaborators
• Andrea Spencer MD
• Marie-France Marin, PhD
• Mohammed R. Milad, PhD
• Thomas J. Spencer, MD
• Maura Fitzgerald, MPH
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Background and Significance
• PTSD is a unique disorder in that it requires a traumatic experience to precede it
• However, only a minority of traumatized individuals develop PTSD
• This suggests that some individuals may have a vulnerability to develop PTSD after a traumatic experience
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Background and Significance
• Thus, research aimed at identifying and targeting risk factors that hasten the conversion of trauma to PTSD could mitigate the risk for PTSD in at risk individuals
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TraumaCommon (>50%)
Posttraumatic Stress Disorder (PTSD)
Intrusions, Avoidance,
Hyperarousal
Lifetime incidence 8%
Majority
do not develop PTSD
following Trauma
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TraumaCommon (>50%)
Posttraumatic Stress Disorder (PTSD)
Intrusions, Avoidance,
Hyperarousal, Mood changes
Lifetime incidence 8%
Majority
do not develop PTSD
following Trauma
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TraumaCommon (>50%)
Posttraumatic Stress Disorder (PTSD)
Intrusions, Avoidance,
Hyperarousal, Mood changes
Lifetime incidence 8%
Majority
do not develop PTSD
following Trauma
Vulnerability(Risk Factors)
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TraumaCommon (>50%)
Posttraumatic Stress Disorder (PTSD)
Intrusions, Avoidance,
Hyperarousal, Mood changes
Lifetime incidence 8%
Majority
do not develop PTSD
following Trauma
ADHD?
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• ADHD is a prevalent neurobiological disorder that onsets in the preschool years, while PTSD more commonly develops in later years
• ADHD is associated with high levels of risk-taking and impulsivity that could lead to traumatic events
• Deficits in attention and prefrontal cortical function resembling those in ADHD have been identified in PTSD
ADHD as a Possible Risk factor for PTSD
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ADHD as a Possible Risk Factor for PTSD
• Preclinical studies document that exposure to nicotine perinatally is associated with both ADHD-like symptoms and behaviors (animal model of ADHD) as well as fear exposure deficits(animal model of PTSD) in rodents suggesting a link between the two disorders
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Is There a Relationship Between ADHD and PTSD?
Step 1: A Systematic Review of the Literature and Meta-Analysis
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Methods
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Literature Review and Meta-Analysis
• We conducted a systematic review of the literature on the relationship between ADHD and PTSD and subjected the data to qualitative and quantitative analysis
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Results
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Risk for PTSD in Individuals with ADHD
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Meta-analysis: Relative Risk for PTSD in ADHD
• 15 samples from 13 studies
• 9 Pediatric, 6 Adult
• RR=2.9, p=0.0005
Spencer AE et al, J Clin Psychiatry. 2016 Jan;77(1):72-83.
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Risk for PTSD in Adults with ADHD
RR=3.7*
RR=1.6*
RR=1.7
*p<0.05Spencer AE et al, J Clin Psychiatry. 2016 Jan;77(1):72-83.
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Meta-analysis: Relative Risk for PTSD in ADHD
Significantly increased relative risk for PTSD in ADHD in samples using normal and traumatized
controls (increased risk using psychiatric samples)
Control Type # Samples Relative Risk P value
Normal 9 3.7 0.001*
Traumatized 4 1.6 0.003*
Psychiatric 2 1.7 0.08
Spencer AE et al, J Clin Psychiatry. 2016 Jan;77(1):72-83.
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Risk for ADHD in Individuals with PTSD
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Meta-analysis: Relative Risk for ADHD in PTSD
• 16 samples from 13 studies
• 11 Pediatric, 5 Adult
• RR=1.7, p<0.0005
Spencer AE et al, J Clin Psychiatry. 2016 Jan;77(1):72-83.
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Risk for ADHD in Adults with PTSD
RR=1.8
RR=0.9
RR=2.1*
*p<0.05
Spencer AE et al, J Clin Psychiatry. 2016 Jan;77(1):72-83.
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Relative Risk for ADHD in PTSDBy Control Type
Control Type # Samples Relative Risk P value
Normal 2 1.8 0.32
Traumatized 10 2.1 <0.0005*
Psychiatric 4 0.9 0.16
Significantly increased relative risk for ADHD in PTSD in samples using traumatized controls
(elevated risk in samples using normal controls)Spencer AE et al, J Clin Psychiatry, Jan 2016.
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Additional Findings
• ADHD had an earlier age of onset than PTSD in all studies that examined temporality
• Significant, positive correlation between severity of symptoms when both disorders were present
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Conclusion:ADHD may be a risk factor for PTSD
• Robust, bidirectional association between ADHD and PTSD in both community and clinical samples
• Compared to normal controls, individuals with ADHD had nearly 4x the risk of developing PTSD than those without ADHD
• Findings were not explained by trauma exposure
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Is There a Predisposition for PTSD in Individuals with ADHD?
• If ADHD is an antecedent risk
factor for PTSD, it could be due to
a neurobiological vulnerability for
PTSD in ADHD such as fear
circuitry abnormalities
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Is There a Relationship Between ADHD and PTSD?
Step 2: To Investigate Fear Circuitry Abnormalities in ADHD
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Neurobiology of PTSD
• Preclinical and clinical studies have begun to document a neurobiological basis for PTSD by studying fear extinction learning and extinction recall (i.e., the “metabolization” of fear) in rodents and humans
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Neurobiology of PTSD
• These findings provide an opportunity to investigate fear circuitry in individuals at clinically high risk for acquiring PTSD, such as those with ADHD
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Neurobiology of PTSD
• To this end, the main goal of this study was to examine whether individuals with ADHD have abnormalities in fear circuitry resembling those found in PTSD
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Methods
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Subjects
• ADHD: N= 27 (13 male and 14 female)
non-traumatized, right-handed,
medication-naïve, young adult subjects
age 19-33 (M=23, SEM=1)
• Controls: 20 (10 male and 10 female)
non-traumatized, right-handed healthy
controls (HC) age 21-34 (M= 26, SEM=1)
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Neuroimaging Protocol
• Participants underwent a 2-day fear
conditioning and extinction paradigm in a
3-T fMRI scanner
• The protocol was identical to one
previously developed and validated in
healthy subjects and clinical populations
with PTSD
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Neuroimaging Protocol
• Day 1: Conditioning and
extinction training
• Day 2: Extinction recall
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Fear Conditioning & Extinction
Good extretrieval
Poor extretrieval
Co
nd
itio
ned
res
po
nse
s
Conditioning Acquisition Consolidation Retrieval
ExtinctionNeuropsychopharmacology (2007) 33, 56-72. doi:10.1038/sj.npp.1301555
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Neuroimaging Protocol
• Skin conductance response
(SCR) was obtained as an index
of the conditioned response
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Results
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Demographics and Clinical Scores
Spencer AE et al, Psychiatry Res. 2017 Feb 10;262:55-62.
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No Differences in Skin Conductance Response Between ADHD and HC During Conditioning
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
CS+ CS-
SC
R (
sqrt
µS
)
Healthy
ADHD
Spencer AE et al, Psychiatry Res. 2017 Feb 10;262:55-62.
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Skin Conductance Response in PTSD
• Previous studies documented differences in skin conductance response between subjects with PTSD compared with traumatized subjects during conditioning suggesting that differences in skin conductance responses could be a correlate of PTSD and not of the risk for developing PTSD
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fMRI Early Extinction
In early extinction, there was significantly
greater insular cortex activation in ADHD
vs. HC and significantly greater dACC
activation in HC vs. ADHD
Insular Cortex
ADHD > HC
dACC
ADHD < HC
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vmPFC
ADHD < HC
dACC
ADHD < HC
In late extinction, there was
significantly higher activation in
vmPFC and dACC in HC vs. ADHD
fMRI Late extinction
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Hippocampus
ADHD < HC
vmPFC
ADHD < HC
In extinction recall, fMRI contrast
revealed significantly more vmPFC and
hippocampus activation in HC vs. ADHD
fMRI Extinction Recall
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Summary of Neuroimaging Findings: ADHD Vs. Controls
• Greater insular cortex activation during early extinction,
• Lesser dorsal anterior cingulate cortex (dACC) activation during
late extinction
• Lesser activation in ventromedial prefrontal cortex (vmPFC)
during late extinction learning and extinction recall
• Lesser activation in hippocampus during extinction recall
Hippocampal and vmPFC deficits were similar to those
documented in PTSD subjects compared to traumatized
controls without PTSD
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Similar deficits as in PTSD
• These findings suggest that ADHD is associated with fear circuitry abnormalities which may predispose ADHD individuals to develop PTSD after trauma which may explain the strong statistical associations between ADHD and PTSD
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Clinical Implications
• Individuals with ADHD should be considered at high risk for PTSD
• It may be important to screen for ADHD in Individuals at high risk for trauma exposure such as military personnel and first responders (i.e, police, paramedics, firefighters)
• Although ADHD is a treatable disorder that responds well to stimulant medications, it is unknown whether treatment for ADHD will mitigate the risk for PTSD
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ADHD & mTBI
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Context
• Mild traumatic brain injury (mTBI) or cerebral concussion is a leading cause of morbidity in the United States
• It is also the largest category of brain injury, representing 70-90% of traumatic brain injury complications
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Context
• According to the CDC, mTBI is estimated to result in 1.6- 3.8 million cases each year and is described in a 2003 report to the U.S. Congress as a silent epidemic
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Context
• Given its high and increasing prevalence, pervasive deleterious sequelae, efforts to help identify factors that may put individuals at greater risk to develop an mTBI or complicate its course are of great clinical, scientific, and public health significance
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Why to Consider ADHD as a risk for mTBI?
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Context
• ADHD is associated with impulsivity and risk taking behavior that could place individuals at greater risk accidents and injuries, including mTBI
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Context
• Thus, it is reasonable to hypothesize that ADHD would increase the risk for mTBI
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Importance
• Considering that ADHD is a treatable disorder, clarifying the relationship between mTBI and ADHD would promote a better standard of care for patients with mTBI
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Examining the Relationship Between ADHD and mTBI
A Review the literature and Meta Analysis
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Study Selection
• Original studies that specifically evaluated the relationship between ADHD and mTBI were included
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Results
• N= 5 studies fitted our a prioriinclusion and exclusion criteria
• These studies comprised 3023 mTBI patients and 9716 controls
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Forest Plot of Studies Examining the ORs of ADHD after mTBI
Psychopharmacology Course 2017
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Results
• Results indicated a significant association between ADHD and mTBI corresponding to a relative risk of 2.0 (z=6.5, p<.0005)
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Discussion
• Sub-analyses attempting to clarify the sequence of ADHD and mTBI were frustrated by the fact that most studies did not specify which came first
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Conclusions
• Our meta-analysis provides strong evidence for an association between ADHD and mTBI but the directionality of this association remains unclear
www.mghcme.orgAdeyemo et al. J Atten Disord 2014 ePub ahead of print.
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The MGH Study of ADHD in Student Atlethes with mTBI
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TBI + No ADHD
N=32†TBI + ADHD
N=47†Test
Statistic
P-
Value
Mean ± SD Mean ± SD
Age 19.6 ± 3.4 19.4 ± 3.3 t77=0.32 0.75
Socioeconomic Status 1.5 ± 0.7 1.5 ± 0.6 χ2=0.003 0.96
Full IQ 116.7 ± 13.4 110.7 ± 11.8 t47=-1.62 0.11
Time since Oldest Injury (years) 4.3 ± 3.5 3.0 ± 2.0 t115=-2.46 0.02
Time since Most Recent Injury
(years)
4.2 ± 4.0 2.7 ± 2.8 t115=-2.33 0.02
N (%) N (%)
Gender (% Male) 7 (22) 24 (51) χ2=6.80 0.009
Intact (% Intact) 25 (89) 33 (75) χ2=2.23 0.14
Race (% Caucasian) 30 (94) 40 (85) Exact 0.30
Demographics & Clinical Characteristics
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0
10
20
30
40
50
60
70
80
90
100
Children & Adolescents
(≤17 Years of Age)
Adults
(>17 Years of Age)
Per
cent
wit
h A
DH
D (
%)
U.S. Population SRC Subjects
Subthreshold ADHDFull ADHD
Rates of ADHD in SRC Subjects vs. U.S. Population Rates
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p=0.02
0
10
20
30
40
50
60
70
80
90
100
Per
cent
(%)
More than One Head Injury
SRC + No ADHD SRC + ADHD
p<0.001
0
2
4
6
8
10
12
14
16
18
20
SRC + ADHD
Mea
n A
ge
Age at Onset of ADHD Age at Time of SRC
Subthreshold ADHDFull ADHD
A. Age at Onset of ADHD and SRC B. More than One Head Injury
Age at Onset of ADHD and SRC in Student Athletes with SRC+ADHD and % with >1
Head Injury
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p<0.001p=0.02
p<0.001
p<0.001
p<0.001
p<0.001 p<0.001p<0.001
p<0.001
p<0.001
30
35
40
45
50
55
60
65
Inhibit Shift Emotional Self
Monitoring
Initiate Working
Memory
Plan/
Organize
Organize
Materials
MI BRI GEC
Sca
led S
core
SRC + No ADHD SRC + ADHD
BRIEF Scores in Student Athletes with and without ADHD
a SMD (95% CI) for each significant subscale: Inhibit: -1.17 (-1.55, -0.78); Shift: -0.43 (-0.79, -0.07); Self Monitoring: -0.77 (-1.14, -0.40); Initiate: -0.77
(-1.14, -0.04); Working Memory: -1.18 (-1.57, -0.80); Plan/Organize: -0.94 (-1.32, -0.57); Organize Materials: -0.88 (-1.25, -0.50); MI: -1.05 (-1.43, -
0.67); BRI: -0.78 (-1.15, -0.41); GEC: -1.07 (-1.45, -0.69)
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ADHD and Concussion
• ADHD associated with prolonged recovery. (Miller et
al., 2015)
• ADHD associated with greater concussion history. (Alosco 2014) S
ym
pto
m S
everity
Time Since Injury
Adapted from Collins et al. (2006)
www.mghcme.orgMikolajczyk et al. JAMA Pediatr. 2015; doi: 10.1001/jamapediatrics.2014.3275
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Clinical Implications
• ADHD is a treatable disorder that responds well to stimulant medications
• Thus, if patients with mTBI meet diagnostic criteria for ADHD, interventions for ADHD could be considered