PTSD:
Challenges
with Returning
Veterans
Charles R. Marmar, MD
New York University
Langone Medical Center
New York, NY
Charles R. Marmar, MD
Disclosures
● Dr. Marmar has no disclosures to report
1
Learning
Objective
Define the clinical
challenges in the
management of PTSD in
returning veterans
History of Post-traumatic
Stress Disorder (PTSD)
● Homer: Trojan War Veterans
● Civil War: Soldier’s Heart
● 19th Century Europe: Railroad Spine
● WW I: Shell Shock
● Vietnam War: Vietnam Syndrome
● 1980 DSM III: PTSD
Longitudinal Course of
PTSD
% with PTSD Symptoms
Most People Who Develop PTSD Recover
94%
47%
42%
30%
W 3m 9m
Years
Yehuda R, et al. Biol Psychiatry. 1998;44(12):1305-1313. PMID: 9861473.
2
Four-Class Latent Growth
Mixture Model (LGMM) of
General Distress (GSI) N = 234
1 Resilient (76.7%) Distressed Increasing (15.8%) Recovering (2.9%) AnGcipatory Distress (2.9%) 0.8 0.6 0.4 0.2 0 Acadamy Training 12-­‐months post 24-­‐months post 36-­‐months post 48-­‐months post Yehuda R, et al. Biol Psychiatry. 1998;44(12):1305-1313. PMID: 9861473.
Prevalence and Course of
PTSD
●  Trauma exposure occurs in over 50% of adults
●  PTSD occurs in 25% of those exposed
●  10% of women, 5% of men will develop PTSD
●  Most people recover from PTSD; 30% develop
chronic and persistent symptoms
●  Depression is common following traumatic loss
of close person, a home or job
●  In those with chronic PTSD, 50% will develop
secondary depression
Yehuda R, et al. Biol Psychiatry. 1998;44(12):1305-1313. PMID: 9861473.
PTSD Impairs Function
and Quality of Life
Zatzick DF et al. Am J Psychiatry. 1997;154(12):1690-1695. PMID: 9396947.
3
Risk/Vulnerability Factors
●  Demographics: Female; Hispanic ethnicity1
●  Childhood abuse or neglect
●  Family and personal history of anxiety or
mood disorder2
●  Poorer social support before and after event
●  Lower IQ and educational attainment1
1. Pole N, et al. Cultur Divers Ethnic Minor Psychol. 2005;11(2):144-161.
PMID: 15884985.
2. Marmar C, et al. Presented at: Annual Conference on Criminal Justice
Research and Evaluation. July 19-21, 2005 Washington DC. Abstract.
Risk/Vulnerability Factors
● Stressful life events in prior and following
year
● Panic reaction at time of event1,2
● Dissociative reactions at time of event:
slow motion, tunnel vision, like a dream,
movie, play3
1. Brunet A, et al. Am J Psychiatry. 2001;158(9):1480-1485. PMID: 11532735.
2. Marmar C, et al. Presented at: Annual Conference on Criminal Justice Research and
Evaluation. July 19-21, 2005 Washington DC. Abstract.
3. Marmar C, et al. The Peritraumatic Dissociative Experiences Questionnaire. In Wilson, JP
and Keane™, (Eds). Assessing Psychological Trauma and PTSD. 2004.
Two-Year Period Prevalence of Specific Mental
Health Diagnoses in Distinct Cohorts of OEF/OIF
Veterans Entering VA in Successive Calendar
Quarters and Followed for 2 years, April 1, 2002March 31, 2006. (N = 289,328)
20%
Depression
Alcohol Use Disorders
Drug Use Disorders
16%
2-Year Period Prevalence e
2-Year Period Prevalence
PTSD
18%
14%
12%
OIF
Begins
10%
8%
6%
4%
2%
0%
2002,
Q2
2002,
Q3
2002,
Q4
2003,
Q1
2003,
Q2
2003,
Q3
2003,
Q4
2004,
Q1
2004,
Q2
2004,
Q3
2004,
Q4
2005,
Q1
2005,
Q2
2005,
Q3
2005,
Q4
2006,
Q1
Cohort
Cohort
OEF = Operation Enduring Freedom; OIF = Operation Iraqi Freedom
Seal KH, et al. Am J Public Health. 2009;99(9):1651-1658. PMID: 19608954.
4
Prevalence of CVD Risk
Factors by Mental Health
Status in Iraq and Afghanistan
Veterans
No Mental
Health
Diagnosis
N = 182,151
PTSD
N = 34,126
Depression
N = 20,909
PTSD +
Depression
N = 38,441
Tobacco Use
10%
25%
27%
34%
Hypertension
8%
13%
16%
18%
Dyslipidemia
10%
17%
20%
23%
Obesity
6%
11%
14%
15%
Diabetes
1.0%
1.4%
2.5%
2.5%
p < .0001 for all comparisons
Seal KH, et al. Am J Public Health. 2009;99(9):1651-1658. PMID: 19608954.
Aging Veterans with PTSD
Have an Increased Risk for
Developing Dementia
● Kristine Yaffe, MD
● Kenneth E. Covinsky, MD, MPH
● Karla Lindquist, MS
● Eric Vittinghoff, PhD
● Thomas Neylan, MD
● Deborah Barnes, PhD
● Charles R. Marmar, MD
Yaffe K, et al. Arch Gen Psychiatry. 2010;67(6): 608–613. PMID: 20530010.
Risk of Dementia by PTSD
Diagnosis After
Excluding At-Risk Groups
PTSD N = 53, 155; Control N = 127, 938
Yaffe K, et al. Arch Gen Psychiatry. 2010;67(6): 608–613. PMID: 20530010.
5
PTSD: An Adrenaline-Driven
Disorder of Unmanageable
Anxious Arousal
●  Genetic factors and affect-management training
influence peritraumatic terror responses
●  Peritraumatic panic and terror result in prolonged
activation of the sympathetic nervous system
●  Lower cortisol levels or other stress hormones such
as neuropeptide Y or inhibitory cognitive controls
are not able to contain the sympathetic nervous
system response
●  Prolonged elevations in adrenaline levels increase
fear conditioning and memory consolidation
Yaffe K, et al. Arch Gen Psychiatry. 2010;67(6): 608–613. PMID: 20530010.
Fear Conditioning
Fear Extinction
Norrholm SD, et al. Front Behav Neurosci. 2011;5:77. PMID: 22125516.
6
Animal Model of PTSD:
Associational and NonAssociational Fear
Conditioning and Extinction
●  Pairing of light and shock leads to fear
responses to light alone (associational fear
conditioning)—this is mediated by the
amygdala
●  After shock, light not paired with shock leads
to fear response (non-associational fear
conditioning)
●  Prolonged exposure to light without shock
decreases associational fear conditioning
(extinction to fear)
Siegmund A, et al. J Psychiatr Res. 2007;41(10):848-860. PMID: 17027033.
Animal Model of PTSD:
Associational and NonAssociational Fear
Conditioning and Extinction
● SSRIs reduce non-associational fear
conditioning
● Reexposure to light-shock at later time
point results in rapid return of fear
responding
● Prefrontal cortical inhibition of amygdala
represents neural mechanism of
extinction to fear responding
SSRI = selective serotonin reuptake inhibitor
Siegmund A, et al. J Psychiatr Res. 2007;41(10):848-860. PMID: 17027033.
Biomarkers for
PTSD
7
Heart Rate Upon ER
Admission
No PTSD
PTSD
24
Cases (N)
20
16
12
8
4
0
2
6
<6 66-7
72
2
4
0
6
-78 78-8 84-9 90-9 6-10 -108 -114 114
>
8
2
9
10
10
Beats Per Minute (BPM)
Shalev AY, et al. Am J Psychiatry. 1996 Feb;153(2):219-25. PMID: 8561202.
Cortisol Levels in the
Aftermath of Trauma
Plasma Cortisol nmol/l
1600
1400
Cortisol levels were
found to be lower
in the immediate
aftermath of trauma
in MVA victims who
developed PTSD
compared to those
who did not
1200
1000
800
600
400
200
0
No Disorder PTSD Depression
Who are these people?
MVA = motor vehicle accident
McFarlane AC, et al. Ann N Y Acad Sci. 1997;821:437-441. PMID: 9238224.
Plasma Cortisol (ug/dl)
Cortisol Circadian Rhythm
20
PTSD
Normal
Depressed
15
10
5
0
10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10
Time of Day
Yehuda R, et al. Biol Psychiatry. 1996;40(2):79-88. PMID: 8793040.
8
Plasma Norepinephrine pg/ml
PTSD Associated With
Increased Norepinephrine
Time of Day
Yehuda R, et al. Biol Psychiatry. 1998;44(1):56-63. PMID: 9646884.
Physiological Responses
to Mental Imagery in PTSD
and Controls
Control
BPM
PTSD
24
µS 2.5
µV 10
21
18
2.0
8
15
12
1.5
6
9
6
3
1.0
4
0.5
2
0
0
Heart Rate
0
Skin
Conductance
EMG-Frnt.
BPM = beats per minute; EMG = Electromyography; Fmt = frontalis muscle tension
Shalev AY, et al. Am J Psychiatry. 1996;153(2):219-225. PMID: 8561202
Auditory Startle Response
in PTSD (SC Habituation)
PTSD (n = 14)
Trauma control (n = 15)
Sq. root, µS
1.0
Anxious (n = 14)
No-trauma control (n = 19)
0.8
0.6
0.4
0.2
0
1
SC = skin conductance
3
5
7
Trials
9
11
13
15
Shalev AY, et al. Am J Psychiatry. 1996;153(2):219-225. PMID: 8561202.
9
Neuroimaging Findings in
PTSD
●  MRI: Smaller hippocampal volume, some
studies
●  MRSI: Altered hippocampal neuronal
metabolism
●  PET: Increased amygdala reactivity to fear
●  PET: Decreased anterior cingulate and
orbitofrontal reactivity to trauma-related stimuli
●  Hippocampal injury interferes with the ability to
unlearn conditioned fear
Hull AM. Br J Psychiatry. 2002;181:102-110. PMID: 12151279.
Processing Methods
Manual Hippocampal
Subfield Marking
CA1-2 transition
● Performed on 70
CA3&DG
CA1
subjects
● Uses high
resolution T2
hippocampal
sequence
SUB
ERC
Wang Z, et al. Arch Gen Psychiatry. 2010;67(3):296-303. PMID: 20194830.
Manual Subfield Analysis
Results
PTSD+ Mean (SD)
PTSD- Mean (SD)
ERC
206.2 (42.7)
209.6 (33.5)
SUB
173.7 (30.3)
162.9 (26.4)
CA1
381.9 (42.4)*
398.6 (37.9)
CA1-2
CA3 & DG
19.1 (33.4)
258.6 (28.4)
22.3 (29.5
254.7 (38.9)
*p < 0.05, also has significant effect for Hispanic demographic, with Hispanics
having a larger CA1 volumes. No significant effects for MD_C, LOC, or ETI total.
Differences in head sizes have been corrected by the subject’s intracranial volume.
ERC = entorhinal cortex; SUB = subiculum; CA = cornu ammonis sectors; DG = dentate gyrus;
LOC = loss of consciousness
Wang Z, et al. Arch Gen Psychiatry. 2010;67(3):296-303. PMID: 20194830.
10
Processing Methods
FreeSurfer v5.1
Whole Brain Parcellation
●  Performed on 114
subjects
●  Skull-stripped and bias
corrected 3D T1 input
●  72 cortical regions
●  54 sub-cortical regions
●  Cortical thickness,
volume, and surface
area measures
FreeSurfer = medical imaging software
Ahmed F, et al. Neuropsychobiology. 2012;66:174-184. PMID: 22948482.
FreeSurfer a Priori Region
of Interest Analysis
Results
Amygdala
PTSD+ n = 37
Mean (SD)
PTSD- n = 51
Mean (SD)
3.55 (3.64)
3.51 (3.25)
8.62 (7.00)
16.2 (10.4)
5.57 (0.42)*
4.99 (0.39)**
4.73 (0.17)
5.14 (0.23)
4.82 (0.27)
6.08 (0.33)*
8.62 (6.97
16.4 (11.2)
5.72 (0.30)
5.11 (0.41)
4.72 (0.20)
5.19 (0.23)
4.86 (0.22)
6.19 (0.24)
cm3
Hippocampus cm3
Thalamus cm3
RA Cingulate mm
CA Cingulate mm
RM Frontal mm
CM Frontal mm
Med Orbitofrontal mm
Insula mm
*p < .05, age was negatively correlated with all volumes/thickness. No effects of Hispanic +/-,
LOC or ETI. **p < .05 for PTSD and with MD_C in model. Differences in head sizes have
been corrected by the subject’s intracranial volume.
Ahmed F, et al. Neuropsychobiology. 2012;66:174-184. PMID: 22948482.
FK506 Binding Protein =
FKBP5
A chaperone protein critically involved in
Glucocorticoid Receptor (GR) feedback sensitivity
P23
GR GR
HSP90
FKBP5
cortisol
dynein
FKBP5
FKBP4
GR GR
HSP90
FKBP4
AAAAA
Ultrashort
negative feedback
on GR sensitivity
Binder EB, et al. JAMA. 2008;299(11):1291-1305. PMID: 18349090.
11
FKBP5 and PTSD
●  FKBP5 chaperone protein is critically involved in
the feedback regulation of GR sensitivity
●  Cortisol induces FKBP5 expression reducing
GR binding affinity in healthy controls; may
increase GR binding affinity in PTSD
●  FKBP5 polymorphisms associated with
peritraumatic dissociation in medically injured
children1 with relevance for DSM-V
1. Koenen, et al. Mol Psychiatry. 2005;10:1058-1059.
Binder EB, et al. JAMA. 2008;19;299(11):1291-1305.
FKBP5 and PTSD
●  FKBP5 polymorphisms x severity of
childhood abuse predicts adult PTSD
symptom severity1
●  FKBP5 polymorphisms explain enhanced
negative feedback sensitivity to
dexamethasone
●  Increased FKBP5 mRNA expression levels
immediately after exposure predict PTSD at
4 months2
1.  Binder EB, et al. JAMA. 2008;299(11):1291-1305. PMID: 18349090.
2.  Begman, et al. Mol Psych. 2005:10:500-513.
Additional Candidate
Genes
● GR receptor polymorphisms
● COMT gene polymorphisms
● Serotonin transmitter polymorphisms
● PACAP & PAC1 receptor polymorphisms
● FKBP5 polymorphisms
● BDNF polymorphisms
Binder EB, et al. JAMA. 2008;299(11):1291-1305. PMID: 18349090.
12
Neurogenetics Core
Gene
Total SNPs
p-Value
APOE
15
.29
BDNF
25
.002
COMT
42
.14
FKBP5
19
.92
4 tests, threshold p = .013, 100K permutations, 2 covariates, logistic regression;
set-based analysis with all SNPs, p = 1, r2 = 1.
Binder EB, et al. JAMA. 2008;299(11):1291-1305. PMID: 18349090.
Neurogenetics Core
Gene
SNP
MAF PTSD
MAF Control
OR
p
COMT
rs165824
0.30
0.10
4.03
.0004
BDNF
rs11030119
0.16
0.36
0.35
.003
BDNF
rs11030108
0.15
0.34
0.35
.004
BDNF
rs962369
0.13
0.30
0.34
.005
COMT
rs165728
0.20
0.07
3.46
.007
BDNF
rs925946
0.18
0.35
0.40
.01
BDNF
rs10767658
0.18
0.35
0.40
.01
101 tests, threshold p = .0005, 2 covariates, logistic regression
MAF = minor allele frequency
Binder EB, et al. JAMA. 2008;299(11):1291-1305. PMID: 18349090.
Urinary cortisol (ug/24hr)
Norepinephrine (ug/24hr)
PTSD/MDD Comorbidity
Associated with
Higher Urinary Norepinephrine
and Possibly Lower Cortisol
Oneway ANOVA F (2,88) = 2.88, p = .062
Oneway ANOVA F (2,91) = 1.19, ns
Young EA, et al. Arch Gen Psychiatry. 2004;61(4):394-401. PMID: 15066898.
13
Between-Group Differences in
Anthropometric, Metabolic, Endocrine,
Oxidative, Neurotrophic and Cell Aging
Variables: (Raw) Non-Ln-Transformed
Values
Variable
PTSD(-)
PTSD(+)
Unadjusted* t / p
Glucose
HgA1c
Cholesterol
80.7 + 12.2
5.4 = 0.4
167.8 + 25.8
93.3 + 26.1
5.5 + 1.0
172.1 + 35.9
3.58 / .001
.42 / ns
.77 / ns
Triglycerides
BMI
Pulse
F2-isoprostanes
101.9 + 98.1
27.7 + 4.7
64.9 + 10.5
0.500 + 0.211
116.8 + 67.7
30.1 + 5.6
72.0 + 7.9
0.427 + 0.129
.92 / ns
2.39 / .02
2.84 / .006
1.54 / .12
DHEA-S
171.0 + 90.0
187.2 + 101.2
.93 / ns
Telomere Length
Telomerase
CRP
BDNF
1.225 + 0.206
8.583 + 1.806
1.159 + 2.20
25.7 + 9.1
1.184 + 0.189
8.114 + 2.334
2.95 + 5.85
30.4 + 7.4
1.00 / ns
.33 / ns
1.79 / .08
3.08 / .003
*Values are means + SD. These are raw data (not Ln-transformed), and no covariates
have been applied in the 2-sample t-tests.
Young EA, et al. Arch Gen Psychiatry. 2004;61(4):394-401. PMID: 15066898.
Higher SCL90 Positive Symptom
Totals are Associated with Shorter
Telomeres in PTSD-Positive
Subjects
●  Comparison corrected for
age
●  Mean difference in
telomere length represents
approx. 5 years of
“accelerated cell aging” in
the high symptom group
compared to the low
symptom group
SCL90 = symptom shecklist-90; N = 18 (PTSD); N = 47 (Control)
Donovan A, et al. Biol Psychiatry. 2011;70(5):465-471. PMID: 21489410.
Effects of Psychological
Debriefing (PD) on MVA Victims
with High and Low Initial Impact of
Event Scale (IES)
IES
Randomized Controlled Trial
Mayou RA, et al. Br J Psychiatry. 2000;176:589-593. PMID: 10974967.
14
CBT Prevention Program
for Acute PTSD
●
●
●
●
Four to five weekly sessions
Typically within 2-5 weeks post-trauma
Delivered in individual setting
Intervention Includes:
●  Discussions of normal reactions to assault
●  Breathing retraining
●  Deep muscle relaxation
●  Recounting the assault
●  Cognitive restructuring
●  Exposure in vivo assignments
Shalev AY, et al. Arch Gen Psychiatry. 2012;69(2):166-176. PMID: 21969418.
CBT for Acute Stress
Disorder
Impact of Event Scale
Motor Vehicle Accident/Assault Victims with Acute Stress Disorder
Bryant RA, et al. Am J Psychiatry. 1999;156(11):1780-1786. PMID: 10553743.
Efficacy of CBT for ASD/
Acute PTSD
●  Foa EB, et al. Clin Psychol. 1995;63(6):948-955. PMID:
8543717.
●  Bryant RA, et al. J Consult Clin Psychol. 1998;66(5):
862-866. PMID: 9803707.
●  Bryant RA, et al. Am J Psychiatry. 1999;156(11):
1780-1786. PMID: 10553743.
●  Bryant RA, et al. J Consult Clin Psychol. 2003;71(4):
706-712. PMID: 12924676.
●  Foa EB, et al. J Consult Clin Psychol. 2004;72(5):
879-884. PMID: 15482045.
●  Bryant RA, et al. Trauma Dissociation. 2005;6(2):5-15.
PMID: 16150665.
ASD = acute stress disorder
15
Efficacy of CBT for ASD/
Acute PTSD
●  Bisson J, et al. Clin Evid. 2005;(13):1318-1337.
PMID: 15652063.
●  Sijbrandij M, et al. Am J Psychiatry. 2007;164
(1):82-90.PMID: 17202548.
●  Van Emmerik AA, et al. Psychother Psychosom.
2008;77(2):93-100. PMID: 18230942.
●  Bryant RA, et al. J Clin Psychiatry. 2008;69(6):
923-929. PMID: 18422396.
ASD = acute stress disorder
Mean Severity Score
CBT for Chronic PTSD
Prolonged Exposure (n = 23)
Stress Inoculation Training(n = 19)
Wait-List Control (n = 15)
35
30
25
20
15
10
5
Pre
Post
12 Mo.
PSS-I = PTSD Symptom Scale—Interview Version
Foa E et al. J Consult Clin Psychol. 1999;67(2):194-200. PMID: 1022472.
Adrenergic-Inhibiting
Agents: Alpha2Adrenergic Agonists
●  Guanfacine 0.5-3.0 mg at bedtime*
●  Alpha2-adrenoceptor agonist, inhibitory transmitter,
acts at autoreceptor slowing locus coeruleus firing
●  Decreases central catecholamine release
●  Less sedation and hypotension than clonidine
●  Children: reduced nightmares1
●  Controlled trial with adults: no benefit2
●  Adverse reactions: dry mouth, drowsiness, dizziness
*This indication has not been approved by the FDA and is an off label use
1. Horrigan JP, et al. J Clin Psychiatry. 1996;57(8):371. PMID: 8752021.
2. Neyan TC, et al. Am J Psychiatry. 2006;163(12):2186-2188. PMID: 17151174.
16
Anti-Anxiety Agents:
Benzodiazepines
●  Alprazolam 0.25-6.0 mg/day
●  GABA agonist
●  Acute stress disorder: alprazolam vs. placebo1
●  Did not prevent development of PTSD
●  Chronic PTSD: alprazolam vs. placebo2
●  Improves anxiety, no effect for core symptoms of
PTSD
●  May interfere with exposure-based desensitization
●  Adverse reactions: drowsiness, light-headed,
dependency
1. Shalev AY, et al. International Handbook of Human Response to Trauma. 1999.
2. Braun P, et al. J Clin Psychiatry. 1990;51:236-238. PMID: 2189869.
Paroxetine Fixed-Dose
PTSD Study (N = 368)
Adjusted Mean Change in CAPS-2
Total Score
Mean Change in CAPS-2 Total Score
0
Paroxetine 40 mg
Paroxetine 20 mg
Placebo
-5
-10
-15
-20
-25
-30
*
-35
*
-40
-45
4
Week
*
*
*
8
12
*
LOCF dataset; *p < .001 vs. placebo; CAPS-2 = clinician-administered PTSD scale
Marshall RD, et al. Am J Psychiatry. 2001;158(12):1982-1988. PMID: 11729013.
Sertraline PTSD Study
(N = 187)
90
80
70
CAPS
60
50
Placebo
40
Sertraline
30
20
10
0
0
2
4
6
8
10
12 Week
CAPS-2 = clinician-administered PTSD scale
Brady K, et al. JAMA. 2000;283(14):1837-1844.
17
80
70
60
50
40
30
20
10
0
CAPS-2 score
IES score
Baseline Week 12 Week 20 Week 28 Week 36 Endpoint
(LOCF)
Acute Phase Study
35
30
25
20
15
10
5
0
Impact of Event Total Score
CAPS-2 Total Severity Score
The Effect of Continuation
Treatment with Sertraline on
Core Symptoms of PTSD
(N = 128)
Open-Label Continuation Study
CAPS-2 = clinician-administered PTSD scale; IES = impact of events
Londborg PD, et al. J Clin Psychiatry. 2001;62(5):325-331. PMID: 11411812.
Sertraline in PTSD Relapse
Prevention (N = 96)
Kaplan-Meier
survival
probability
Log-rank
test
p < .001
12 Weeks
24 Weeks
Acute
Phase
Open-Label
Continuation
Weeks of Double-Blind Treatment
Relapse-Prevention
Davidson J, et al. Am J Psychiatry. 2001;158:1974-1981.
Venlafaxine ER vs. Placebo
(N = 329)
CAPS-SX17 Change from Baseline (LOCF)
0
Placebo (N = 168)
Mean Change
from Baseline
-10
Venlafaxine ER (N = 161)
-20
-30
*
-40
*
-50
*
‡
†
†
-60
-70
0
2
4
6
8
12
Weeks on Therapy
18
24
Observed
Cases
* p < .05; † p < .01; ‡ p < .001
Davidson J, et al., Arch Gen Psychiatry. 2006;63(10):1158-1165. PMID: 17015818.
18
Antidepressants:
Trazodone*
● 5-HT2 antagonist
● Hertzberg, 1996
● Multiple baseline design, 200-400 mg/day
● Helped sleep disturbances in all patients
● Reduced intrusions and avoidance in 2/3
patients
● No improvement in depression
● Adverse reactions: daytime somnolence
*This indication has not been approved by the FDA and is an off label use
Hertzberg MA, et al. J Clin Psychopharmacol. 1996;16(4):294-298. PMID: 8835704.
Open and Controlled Trials
for Nightmares1
●  Trazodone*: 50-200 mg at bedtime
●  Cyproheptadine*: 4-28 mg at bedtime
●  Nefazodone*: reduced dream recall
●  Clonidine*: reduced nightmares in Cambodian refugees
●  Prazosin*:2 5 mg to 15 mg qhs
●  Alpha1-adrenergic postsynaptic receptor antagonist
●  Shortens stages 1 & 2 and normalizes REM
●  Raskind, 2001: combat vets, N = 10 placebo dbl x
over
●  normalizes dreams, reduces int, avoid and arousal
*This indication has not been approved by the FDA and is an off label use
1. Escamilla M, et al. Curr Psychiatry Rep. 2012;14(5):529-535. PMID: 22865154.
2. Raskind MA, et al. J Clin Psychiatry. 2002;63(7):565-568. PMID: 12143911.
Prazosin* in PTSD
●  Dosing
● 7 to 15 mg QHS
● Gradual titration, limited by lightheadedness
●  Double-blind RCT1
● 40 veterans, 13.3 +/- 3 mg/day
● Robust improvement in sleep quality and
distressing dreams
● Medium to large effect size in each PTSD
symptom cluster
*This indication has not been approved by the FDA and is an off label use
Raskind M, et al. Biol Psychiatry 2007;61(8): 928-934. PMID: 17069768.
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Atypical Antipsychotics*
in PTSD
●  Risperidone: positive RCTs
●  Chronic PTSD in combat vets (n = 65)1
●  Irritable aggression in PTSD combat vets (n = 8) 2
●  Augmentation of incomplete response to sertraline (n = 20)3
●  Multi-site VA trial currently underway
●  Olanzapine: 2 small RCTs with inconsistent results4,5
●  Quetiapine: 4 positive open trials
●  Combat (n = 20), combat (n = 20), combat and civilian (n = 17)
●  Juveniles (n = 6)
●  Aripiprazole: Small positive open trial (n = 22)6
*This indication has not been approved by the FDA and is an off label use
1.  Bartzokis G, et al. Biol Psychiatry. 2005;57(5):474-479. PMID: 15737661.
2.  Monnelly EP, et al. J Clin Psychopharmacol. 2003;23(2):193-196. PMID: 12640221.
3.  Rothbaum BO, et al. J Clin Psychiatry. 2008; 69(4):520-525. PMID: 18278987.
4.  Butterfield MI, et al. Int Clin Psychopharmacol. 2001;16(4):197-203. PMID: 11459333.
5.  Stein MB, et al. Am J Psychiatry. 2002;159(10):1777-1779. PMID: 12359687.
6.  Ahern EP, et al. Int Clin Psychopharmacol. 2011;26(4):193-200. PMID: 21597381.
7.  Villarreal G, et al. Psychopharmacol Bull. 2007;40(2):6-18. PMID: 17514183.
PTSD and Psychosis
●  Psychotic symptoms in people with PTSD are
more common than generally realized
●  Inpatient study screening for psychotic
symptoms in combat veterans with PTSD1
● 40% with psychotic symptoms the preceding
6 months
●  PTSD patients with psychosis have more
severe PTSD symptoms and co-occurring
MDD2
1. David D, et al. J Clin Psychiatry. 1999;60(1):29-32. PMID: 10074874.
2. Hamner MB, et al. Biol Psychiatry. 1999;45(7):846-852. PMID: 10202572.
PTSD and Psychosis
●  Content of psychotic symptoms is most often
related to the traumatic event and is usually not
bizarre
●  Auditory hallucinations are common but visual,
olfactory and tactile hallucinations can also
occur
●  Paranoid ideation is common and delusions
have also been observed
●  A formal thought disorder is usually not present
David D, et al. J Clin Psychiatry. 1999;60(1):29-32. PMID: 10074874.
Hamner MB, et al. Biol Psychiatry. 1999;45(7):846-852. PMID: 10202572.
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Sudden Escalation to
Anger & Impulsive
Aggression
●  Decreases in 5HT activity associated with
aggression
●  SSRIs reduce irritability and aggressive behavior1
●  Mood stabilizers reduce affective lability and
aggressive behavior
●  Adrenergic inhibiting agents
●  Reduce irritability and aggressive behavior2
●  Antipsychotic* medication for reducing
aggression
*This indication has not been approved by the FDA and is an off label use
1. Cherek DR, et al. Psychopharmacology. 2002;159(3):226-274. PMID: 11862359.
2. Mattes JA, et al. Psychopharmacology Bulletin. 1984;20(1):98-100. PMID: 6718656.
PTSD and Substance Use
Disorders
●  Avoid benzodiazepines
●  Buspirone for symptoms of generalized anxiety
●  Trazodone for sleep disturbances
●  Adrenergic agents for arousal and nightmares*
●  Disulfiram and naltrexone effective for alcohol abuse in
PTSD1
●  Sertraline RCT: drinking significantly reduced in less
severe alcohol dependence and later onset PTSD2
*This indication has not been approved by the FDA and is an off label use
1. Petrakis IL, et al. Biol Psychiatry. 2006;60(7):777-783. PMID: 17008146.
2. Brady KT, et al. Alcohol Clin Exp Res. 2005;29(3):395-401. PMID: 15770115.
Recommendations for the
Management of Chronic
PTSD
●  Establish a trusting relationship
●  Education and support
●  Treat alcohol and drug addiction, first or concurrently?
●  12-20 sessions of CBT; BDP for Traumatic Grief
●  Low dose trazadone for sleep
●  Full-dose SSRI maintained for 12-18 months
●  Add adrenergic agent if arousal persists
●  Add mood stabilizing agent if anger persists
●  Booster doses of CBT for periods of high stress
BDP = brief dynamic psychotherapy
Cahill SP, et al. Treatment for Chronic PTSD In: Effective Treatments for PTSD, Second
Edition: Practice Guidelines from the International Society for Traumatic Stress Studies. 2009.
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New Directions:
Facilitating Fear Extinction
●  NMDA receptor partial agonists facilitate
extinction
●  Accelerate extinction of conditioned fear in rats
●  DCS plus exposure therapy for fear of heights
●  Virtual exposure to glass elevator
●  Clinical improvement in two sessions
●  Combining DCS with Exposure Therapy for
PTSD
●  16% of Iraq Veterans estimated to have PTSD
Ressler R, et al. Arch Gen Psychiatry. 2004;61(11):1136-1144. PMID: 1552036.
Clinical Connections
● PTSD occurs in 25% of those exposed to
a traumatic event.
● Most people recover from PTSD; 30%
develop chronic and persistent symptoms
● Depression is common following
traumatic loss
Clinical Connections
● Biomarkers for PTSD can demonstrate
changes in:
● heart rate
● cortisol levels
● cortisol circadian rhythm
● norepinephrine
● startle response
● Neuroimaging
● Cognitive behavior therapy can be an
effective tool in the treatment of PTSD
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