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

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60

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80

90

100

Per

cent

(%)

More than One Head Injury

SRC + No ADHD SRC + ADHD

p<0.001

0

2

4

6

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10

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14

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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