The n e w e ng l a n d j o u r na l of m e dic i n e

Review Article

Dan L. Longo, M.D., Editor

Post-Traumatic Stress Disorder

Arieh Shalev, M.D., Israel Liberzon, M.D., and Charles Marmar, M.D.​​

R
eports of violence, injury, and death appear daily on headline From the Steven and Alexandra Cohen
news. More than 70% of adults worldwide experience a traumatic event at Veterans Center for Posttraumatic Stress
and TBI, Department of Psychiatry, New
some time in their lives, and 31% experience four or more events.1 Post- York University School of Medicine, New
traumatic stress disorder (PTSD) is the most prevalent psychopathological conse- York (A.S., C.M.); and the Department of
quence of exposure to traumatic events. The lifetime prevalence of PTSD varies Psychiatry, University of Michigan, and the
Mental Health Service, Veterans Affairs
according to social background and country of residence, ranging from 1.3 to Ann Arbor Health Systems — both in Ann
12.2%, and the 1-year prevalence is 0.2 to 3.8%.2 The core features of PTSD are Arbor (I.L.). Address reprint requests to
the persistence of intense, distressing, and fearfully avoided reactions to reminders Dr. Marmar at New York University School
of Medicine, 1 Park Ave., Rm. 8-214, New
of the triggering event, alteration of mood and cognition, a pervasive sense of im- York, NY 10016, or at c­ harles​.­marmar@​
minent threat, disturbed sleep, and hypervigilance. This report outlines our current ­nyumc​.­org.
understanding of the diagnosis, prevalence, neurobiologic characteristics, and N Engl J Med 2017;376:2459-69.
treatment of PTSD, as well as the clinical implications of this knowledge. DOI: 10.1056/NEJMra1612499
Copyright © 2017 Massachusetts Medical Society.

Defini t ion a nd Di agnosis

The diagnostic criteria for PTSD have been substantially updated in the fifth edition
of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental
Disorders (DSM-5),3 as compared with the fourth edition (DSM-IV-TR)4 (Table 1).
PTSD now belongs to a new category, called “Trauma- and Stressor-Related Dis-
orders”; avoidance has been added as one of the required “diagnostic clusters,”
negative cognitions are highlighted, and traumatic events are not defined by an
initial reaction of fear, horror, or helplessness. In contrast, the World Health Or-
ganization’s forthcoming International Classification of Diseases, 11th Revision (ICD-11),
retains six PTSD-specific symptoms and eliminates those shared by other disor-
ders (Table 1).
The results of these modifications are clinically significant.5 Recent field stud-
ies have shown only a 55% overlap between persons identified as having PTSD
according to the DSM-IV criteria and those meeting DSM-5 criteria, with a meager
30% overlap among the three nosologies (DSM-IV, DSM-5, and ICD-11).6 Moreover,
research in previous decades used DSM-IV diagnostic criteria, and the extent to
which previous findings are still valid with the use of DSM-5 criteria is unclear.
The new diagnostic criteria highlight PTSD-related negative cognitions, self-
denigration, and negative worldviews and encourage clinicians to consider these
features in their assessments and interventions. Discrepancies between diagnostic
templates should alert clinicians to the fundamental difference between diagnostic
criteria, which are meant to index disorders, and the fuller array of symptoms in
patients.7 Until the broader implications of changes in the definition of PTSD
become clear, clinicians should be careful not to disallow treatment or insurance
and disability benefits for persons who cease to meet PTSD diagnostic criteria in
the transition from earlier to later definitions (Table 1).

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 Table 1. Diagnostic Criteria for Post-Traumatic Stress Disorder.*

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DSM-IV-TR Criteria DSM-5 Criteria ICD-11 Criteria
A. The person has been exposed to a traumatic event in A. Exposure to actual or threatened death, serious injury, or sexual violence Exposure to an extremely threatening or horrific
which both of the following were present: in one (or more) of the following ways: event or series of events
1. The person experienced, witnessed, or was con- 1. Directly experiencing the traumatic event(s).
fronted with an event that involved actual or threat- 2. Witnessing, in person, the event(s) as it occurred to others.
ened death or serious injury, or a threat to the physi- 3. Learning that the traumatic event(s) occurred to a close family mem-
cal integrity of self or others. ber or close friend. In cases of actual or threatened death of a family
2. The person’s response involved intense fear, help- member or friend, the event(s) must have been violent or accidental.
lessness, or horror. Note: In children this may be 4. Experiencing repeated or extreme exposure to aversive details of the
expressed, instead, by disorganized or agitated be- traumatic event(s) (e.g., first responders collecting human remains;
havior. police officers repeatedly exposed to details of child abuse).
Note: Criterion A4 does not apply to exposure through electronic media,
television, movies, or pictures, unless this exposure is work related.
B. The traumatic event is persistently re-experienced in B. Presence of one (or more) of the following intrusion symptoms associated Intrusion symptoms:
one (or more) of the following ways: with the traumatic event(s), beginning after the traumatic event(s) Re-experiencing the traumatic event or events
1. Recurrent and intrusive distressing recollections of the occurred: in the present in the form of vivid intrusive
event, including images, thoughts, or perceptions. 1. Recurrent, involuntary, and intrusive distressing memories of the trau- memories, flashbacks, or nightmares.
2. Recurrent distressing dreams of the event. matic event(s). Re-experiencing accompanied by strong and
The

3. Acting or feeling as if the traumatic event were recurring 2. Recurrent distressing dreams in which the content and/or affect of the overwhelming emotions such as fear or
(includes a sense of reliving the experience, illusions, hal- dream are related to the traumatic event(s). horror and strong physical sensations,
lucinations, and dissociative flashback episodes, includ- 3. Dissociative reactions (e.g., flashbacks) in which the individual feels or or feelings of being overwhelmed or im-
ing those that occur on awakening or when intoxicated). acts as if the traumatic event(s) were recurring. (Such reactions may mersed in the same intense emotions
4. Intense psychological distress at exposure to internal occur on a continuum, with the most extreme expression being a that were experienced during the trau-
or external cues that symbolize or resemble an as- complete loss of awareness of present surroundings.) matic event.
pect of the traumatic event. 4. Intense or prolonged psychological distress at exposure to internal or exter-
5. Physiological reactivity on exposure to internal or exter- nal cues that symbolize or resemble an aspect of the traumatic event(s).

n engl j med 376;25

nal cues that symbolize or resemble an aspect of 5. Marked physiological reactions to internal or external cues that sym-
the traumatic event. bolize or resemble an aspect of the traumatic event(s).
C. Persistent avoidance of stimuli associated with the C. Persistent avoidance of stimuli associated with the traumatic event(s), Avoidance:
trauma and numbing of general responsiveness ­beginning after the traumatic event(s) occurred, as evidenced by Avoidance of thoughts and memories of the

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(not present before the trauma), as indicated by one or both of the following: event or events.
n e w e ng l a n d j o u r na l

The New England Journal of Medicine

three (or more) of the following: 1. Avoidance of or efforts to avoid distressing memories, thoughts, or Avoidance of activities, situations, or people
of

1. Efforts to avoid thoughts, feelings, or conversations feelings about or closely associated with the traumatic event(s). reminiscent of the event or events.
­associated with the trauma. 2. Avoidance of or efforts to avoid external reminders (people, places, con-
2. Efforts to avoid activities, places, or people that versations, activities, objects, situations) that arouse distressing

June 22, 2017

arouse recollections of the trauma. memories, thoughts, or feelings about or closely associated with the
3. Inability to recall an important aspect of the trauma. traumatic event(s).

Copyright © 2017 Massachusetts Medical Society. All rights reserved.

4. Markedly diminished interest or participation in sig- D. Negative alterations in cognitions and mood associated with the traumatic
m e dic i n e

nificant activities. event(s), beginning or worsening after the traumatic event(s) occurred,
5. Feeling of detachment or estrangement from others. as evidenced by two (or more) of the following:
6. Restricted range of affect (e.g., unable to have lov- 1. Inability to remember an important aspect of the traumatic event(s)
ing feelings). (typically due to dissociative amnesia and not to other factors such
7. Sense of a foreshortened future (e.g., does not ex- as head injury, alcohol, or drugs).

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pect to have a career, marriage, children, or a nor- 2. Persistent and exaggerated negative beliefs or expectations about oneself, oth-
mal life span). ers, or the world (e.g., “I am bad,” “No one can be trusted,” “The world is
completely dangerous,” “My whole nervous system is permanently ruined”).
3. Persistent, distorted cognitions about the cause or consequences of the trau-
matic event(s) that lead the individual to blame himself/herself or others.
4. Persistent negative emotional state (e.g., fear, horror, anger, guilt, or shame).
5. Markedly diminished interest or participation in significant activities.
6. Feelings of detachment or estrangement from others.
7. Persistent inability to experience positive emotions (e.g., inability to
experience happiness, satisfaction, or loving feelings).
 DSM-IV-TR Criteria DSM-5 Criteria ICD-11 Criteria
D. Persistent symptoms of increased arousal (not present E. Marked alterations in arousal and reactivity associated with the traumatic Persistent perceptions of heightened current
before the trauma), as indicated by two (or more) event(s), beginning or worsening after the traumatic event(s) oc- threat:
of the following: curred, as evidenced by two (or more) of the following: Hypervigilance.
1. Difficulty falling or staying asleep. 1. Irritable behavior and angry outbursts (with little or no provocation) Enhanced startle reaction to stimuli such
2. Irritability or outbursts of anger. ­typically expressed as verbal or physical aggression toward people as u
­ nexpected noises.
3. Difficulty concentrating. or objects.
4. Hypervigilance. 2. Reckless or self-destructive behavior.
5. Exaggerated startle response. 3. Hypervigilance.
4. Exaggerated startle response.
5. Problems with concentration.
6. Sleep disturbance (e.g., difficulty falling or staying asleep or restless
sleep).
E. Duration of the disturbance (symptoms in Criteria B, C, F. Duration of the disturbance (Criteria B, C, D, and E) is more than The symptoms must persist for at least several
and D) is more than 1 month. 1 month. weeks.
F. The disturbance causes clinically significant distress or G. The disturbance causes clinically significant distress or impairment in The symptoms must cause significant impair-
impairment in social, occupational, or other impor- ­social, occupational, or other important areas of functioning. ment in personal, family, social, educa-
tant areas of functioning. tional, occupational or other important
areas of functioning.
H. The disturbance is not attributable to the physiological effects of a sub-

n engl j med 376;25

stance (e.g., medication, alcohol) or another medical condition.
Specify if: Specify whether: With dissociative symptoms: The individual’s symptoms
Acute: if duration of symptoms is less than 3 months. meet the criteria for posttraumatic stress disorder, and in addition,
Chronic: if duration of symptoms is 3 months or more. in response to the stressor, the individual experiences persistent or

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With delayed onset: if onset of symptoms is at least 6 recurrent symptoms of either of the following:
months after the stressor. 1. Depersonalization: Persistent or recurrent experiences of feeling de-
tached from, and as if one were an outside observer of, one’s mental
processes or body (e.g., feeling as though one were in a dream; feel-
ing a sense of unreality of self or body or of time moving slowly).
Post-Tr aumatic Stress Disorder

June 22, 2017

2. Derealization: Persistent or recurrent experiences of unreality of sur-

The New England Journal of Medicine

roundings (e.g., the world around the individual is experienced as un-
real, dreamlike, distant, or distorted).
Note: To use this subtype, the dissociative symptoms must not be attribut-
able to the physiological effects of a substance (e.g., blackouts, be-
havior during alcohol intoxication) or another medical condition

Copyright © 2017 Massachusetts Medical Society. All rights reserved.

(e.g., complex partial seizures).
Specify if: With delayed expression: If the full diagnostic criteria are not met
until at least 6 months after the event (although the onset and ex-
pression of some symptoms may be immediate).

* Diagnostic criteria are reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR),4 and fifth edition (DSM-5),3

Downloaded from nejm.org on June 21, 2017. For personal use only. No other uses without permission.
and adapted with permission from the forthcoming International Classification of Diseases, 11th Revision (ICD-11; http://apps​.­who​.­int/​­classifications/​­icd11/​­browse/​­l-m/​­en#/​
­http%3a%2f%2fid​.­who​.­int%2ficd%2fentity%2f2070699808).

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Epidemiol o gic Fe at ur e s of P T SD cumulative life stressors, loneliness, or alienation,

all of which are valid targets for intervention.
Prevalence and Conditional Probability
The most frequently reported traumatic events in Natural Course, Prediction, and Risk Factors
the United States are physical and sexual assaults Transient symptoms of PTSD are frequently ob-
(52% lifetime prevalence) and accidents or fires served shortly after traumatic events, and most
(50%). Worldwide, accidents and injuries are re- cases of chronic PTSD follow an early onset of
ported most frequently (36% lifetime prevalence).1 symptoms. A delayed expression of PTSD, most
Higher rates of PTSD have been documented frequently seen among deployed military per-
among socially disadvantaged persons, younger sonnel, accounts for 25% of chronic cases.16 In
persons, women, military personnel, police offi- most trauma-exposed persons (e.g., 78% of those
cers, firefighters, and first responders to disasters exposed to combat17), PTSD does not develop
and mass trauma.2,6 The conditional probability after the exposure. Among those in whom the
that PTSD will develop varies according to sex disorder does develop, the severity of symptoms
and the type of trauma; for example, the respec- fluctuates over time, with periods of greater
tive probabilities for men and women are 65% severity probably reflecting sensitivity to co-
and 46% after rape, 2% and 22% after physical occurring stressors, illness, and life transitions.
assault, and 6% and 9% after an accident.8 The The intensity of the trauma and individual
probability is higher in high-income countries susceptibility interact to influence the likelihood
than in lower-income countries.2 These differ- of PTSD. Factors associated with increased sus-
ences probably reflect the roles of sex and social ceptibility include female sex, childhood trauma,
and situational factors in the development, ex- fewer years of schooling, prior mental disorders,
pression, and persistence of PTSD symptoms. exposure to four or more traumatic events, and
Physical assault, for example, might be perceived a history of exposure to interpersonal violence.18
differently by men and women, and combatants The intensity of the traumatic exposure is also
trained to persevere during action may not read- related to the risk of PTSD, and the risk is in-
ily express fear, helplessness, or horror. creased with exposure to death, injury, torture, or
bodily disfigurement; traumatic brain injury19;
Coexisting Disorders and Mortality and a traumatic experience that is unexpected,
In more than 50% of cases, PTSD co-occurs with inescapable, or uncontrollable. Physiological and
mood, anxiety, or substance-use disorders.9 It is neuroendocrine predictors of PTSD include elevat-
associated with serious disability, medical illness, ed heart and respiration rates and a low plasma
and premature death.10 Data on physical illness cortisol level.20
in patients with PTSD encompass subjectively
reported health status and diagnosed diseases in Biol o gic Fe at ur e s of P T SD
all categories.11 In a nationally representative
sample of Vietnam veterans,10 PTSD was associ- Biologic Correlates
ated with an increase in age-related mortality by Arguably the most important developments in
a factor of 2; the leading causes of death were the biologic understanding of PTSD are efforts
neoplasms affecting the respiratory tract and to organize various findings into functionally
ischemic heart diseases.10,11 integrated mechanistic models. The peripheral
PTSD is also associated with suicidal behav- biologic correlates of PTSD to date (reviewed by
ior,12 but the relationship is neither specific nor Pitman et al.21) encompass genes,22 epigenetic
simple. The relative risk of a suicide attempt regulation,23 neuroendocrine factors,24 inflamma-
among civilians with PTSD (2.0) is similar to the tory markers,25 autonomic risk and resilience,26
relative risk of generalized anxiety disorder (2.3) and sleep disturbances.27 Some biologic features
or alcohol dependence (2.5) and is lower than constitute preexposure vulnerability factors (e.g.,
that of depression (4.8).13 Recent studies of active a polymorphism in the FKBP5 gene28 and heart-
military personnel did not show an association rate variability26), whereas others might reflect
between suicide and war-zone deployment14 or ex- trauma-induced alterations (e.g., immune changes,
posure to combat.15 Thus, elevated suicide rates neuroinflammation,25 and postexposure epigene-
among veterans may reflect protracted PTSD, tic regulation23). The multiplicity and interdepen-

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 Post-Tr aumatic Stress Disorder

dence of biologic correlates, their variable distri- with PTSD. Functional neuroimaging studies
bution among affected persons, their contribution have identified a network of brain regions that
to other disorders in addition to PTSD, and the identify threat and salience in general, including
small effect of each one limit their current use the amygdala, the dorsal anterior cingulate cor-
as biomarkers for PTSD. The pressing need for tex, and the insula or operculum.34 PTSD has
diagnostic, prognostic, and therapeutic biomark- been associated with overreactivity in the insula,35
ers calls for large-scale research initiatives that amygdala, and dorsal anterior cingulate cortex36
use advanced bioinformatics to derive new knowl- and with hyperconnectivity of brain networks
edge about the pathogenesis of PTSD and treat- that detect salient stimuli in the environment.37
ment targets (e.g., the initiative described by
Logue et al.29). Executive Function and Emotion Regulation
Flexibility in emotional responding requires hold-
Neurobiologic Models ing information in mind, resisting distractors,
Functional neural systems thought to have a planning, and switching tasks (i.e., the integrity
prominent role in the pathophysiology of PTSD of working memory, attention, inhibition, and
include fear learning, threat detection, executive task-shifting components of executive function).
function and emotion regulation, and contextual Emotion regulation relies on the integrity of ex-
processing. Abnormalities in these sets of inter- ecutive function; thus, impaired executive func-
connected regions (often referred to as circuits) tion and emotion regulation in PTSD may under-
mediate the acquisition of fear responses in lie memory and concentration deficits, poorly
PTSD, avoidance of trauma reminders, impaired controlled emotional responses, irritability, and
regulation of emotions (manifested as irritability, impulsivity. Impaired connectivity in the fronto-
anger, or reckless behavior), and the persistence parietal regions, within and between executive-
of defensive responses once safety has been re- function networks, has been observed in patients
stored. Abnormalities of declarative memory21 with PTSD, providing evidence of dysfunctional
and dysfunctional reward processing (manifest- executive-function and emotion-regulation cir-
ed as anhedonia and motivational deficits30) are cuits.37
shared by PTSD and other disorders (Fig. 1).
Contextual Processing
Fear Learning Proper processing of contextual information al-
Abnormal fear learning has been a prime candi- lows one to freeze, flee, or enjoy a situation, as
date for explaining the pathophysiology of PTSD. appropriate (e.g., an alligator in one’s backyard
Studies have localized fear-related memory for- is seen as threatening, whereas an alligator in a
mation to the amygdala,31 and its subsequent zoo is seen as exciting). PTSD is characterized by
modulation to a complex interplay between vari- hypervigilance that is inappropriate to the situa-
ous nuclei and cell types in the basolateral com- tion and the misreading of cues as threatening
plex of the amygdala. The persistence of fear despite a safe context (e.g., a response to trauma
responses in patients with PTSD has been attrib- reminders in a movie as if the event were recur-
uted to abnormalities in extinction of fear, in ring). Appropriate contextual processing depends
safety learning,32 and in retaining the fact that on good signaling in the medial prefrontal cor-
extinction of associative learning has occurred tex and the hippocampus.38 Hippocampal chang-
(known as extinction recall).33 The fear-learning es have been reported in patients with PTSD.21,39
model of PTSD has inspired some of the com- Diminished signaling in the medial prefrontal
mon therapies for the disorder, such as expo- cortex in affected patients has been linked to
sure-based cognitive behavioral therapy, which impaired extinction recall,40 abnormal processing
is reviewed below. of contextual information,41 and impaired safety-
signal learning, implicating contextual process-
Threat Detection ing circuitry in the pathophysiology of PTSD.
Dysfunctional threat detection may underlie pref- Such neurobehavioral models can account for
erential attention to threatening stimuli, hyper- many of the peripheral biologic findings in PTSD.
vigilance, heightened threat anticipation, and ex- Neuroendocrine alterations have been linked with
aggerated reactivity to salient stimuli in patients altered activity in the amygdala. Noradrenergic

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 The n e w e ng l a n d j o u r na l of m e dic i n e

hyperreactivity has been linked to diminished uncontrollable, and unpredictable and that the
frontal-lobe activity, which mediates executive patient is ineffectual, helpless, or guilty) and
function.42 Updates of contextual information challenges them in a Socratic dialogue.
occur during rapid-eye-movement (REM) sleep, Nonexposure therapies include present-centered
require a “turning off” of the locus ceruleus, and therapy, which focuses on dysfunction in current
could be impaired by PTSD-associated hyper- relationships and life challenges; interpersonal
adrenergic states.43 Several innovative therapies therapy, focusing on interpersonal conflicts and
(e.g., transcranial magnetic stimulation44 and role transitions,49 which was shown to be similar
neurocognitive modulation training45) directly to prolonged exposure as a treatment for PTSD
address components of the neural circuitries and slightly better for patients with both PTSD
noted above. and major depressive disorder; and mindfulness,
which refocuses the patient’s attention on bodily
and sensory experiences occurring in the present
T r e atmen t
moment.50 Critical reviews and treatment guide-
Therapies for PTSD include psychological, phar- lines emphasize the relative advantage of cogni-
macologic, and innovative interventions. Treat- tive behavioral therapy over nonexposure thera-
ment goals, techniques, and effects in the early pies.51 However, a recent review suggests that
aftermath of trauma differ from those in cases present-centered therapy might be similarly bene-
of protracted PTSD and are therefore reviewed ficial in war veterans.47 Indeed, a recent com-
separately. Successful implementation of treat- parison of treatment protocols by the investiga-
ment requires careful assessment, as outlined in tors who developed them suggests that “branded”
the subsequent discussion of clinical practice. interventions have many common components
(e.g., psychoeducation and a focus on emotion
Interventions for Steady-State, regulation, cognitive processing, and meaning
Protracted PTSD making52). Psychological therapies that target
Trauma-focused cognitive behavioral therapy is specific PTSD symptoms (e.g., insomnia)53 offer
the best-supported psychological intervention for alternatives to pharmacologic treatment.
PTSD.46,47 Cognitive behavioral therapy revisits Most patients with PTSD (e.g., 74% of affected
distressing elements of the traumatic events and war veterans) receive some form of pharmaco-
consequent avoidance and cognitive distortions. logic treatment,54 including antidepressant agents,
Specific cognitive behavioral therapy protocols anxiolytic or sedative–hypnotic agents, and anti-
can be grossly divided into exposure therapies psychotic agents (prescribed, respectively, for 89%,
(e.g., prolonged exposure) and nonexposure ther- 61%, and 34% of those receiving pharmaco-
apies (e.g., cognitive processing). In exposure therapy). Paroxetine and sertraline are approved
therapies, distressing and fearfully avoided mem- by the Food and Drug Administration for the
ories of traumatic events are engaged in a safe treatment of PTSD.51,55 In addition, venlafaxine
environment. For example, a patient is first and nefazodone have been recommended for
trained in self-regulating techniques, such as PTSD51; mirtazapine, trazodone, and prazosin
deep breathing, and is taught to quantify and have been used for insomnia and nightmares56;
communicate current distress. The patient then and topiramate has been used in patients with
progressively recalls fearfully avoided elements PTSD and alcohol use disorder. However, unpub-
of the traumatic event while keeping distress at lished results of a large, randomized, placebo-
tolerable levels with the use of deep breathing controlled study of prazosin (Prazosin and Com-
and with support from the therapist. The se- bat Trauma PTSD [PACT]; ClinicalTrials.gov
quence is repeated until the memories no longer number, NCT00532493) have failed to show a
trigger intolerable responses and are not avoid- beneficial effect on insomnia, nightmares, PTSD
ed. In eye-movement desensitization and repro- symptoms, or general distress. Effect sizes for
cessing therapy,48 the patient recalls traumatic antidepressants in patients with PTSD are rela-
images while engaging in horizontal eye move- tively small.57 These agents alleviate symptoms
ment. Cognitive processing therapy explores the but rarely induce remission, and there is a sub-
patient’s dysfunctional post-traumatic beliefs and stantial risk of relapse on discontinuation. Main-
cognitions (e.g., that the world is dangerous, taining a full therapeutic dose for 6 to 12 months

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 Post-Tr aumatic Stress Disorder

A Emotion Regulation and Executive Function B Threat and Salience Detection

BRAIN BRAIN
Anterior
cingulate
Medial cortex
prefrontal
cortex

Dorsolateral
prefrontal cortex
Fornix

Insula
Ventrolateral
prefrontal
cortex
Hippocampus
BRAIN

Amygdala

C Contextual Processing D Fear Learning

Medial
Central
nucleus
Cortical nucleus
nucleus
BRAIN

Intercalated
Medial nuclei
prefrontal
cortex AMYGDALA
Basal
nucleus

Thalamus
Fornix
BRAIN

Lateral
nucleus
Fornix

Locus
ceruleus Hippocampus

Hippocampus
CEREBELLUM Amygdala

PONS Cerebellum

MEDULLA
OBLONGATA

Figure 1. Brain Regions Implicated in the Pathophysiology of Post-Traumatic Stress Disorder (PTSD).
Shown are the known connectivity paths within four dysfunctional circuits that play a part in the psychopathology of PTSD: emotion reg-
ulation and executive function, threat detection, contextual processing, and fear learning.

and gradually tapering the dose over a period of cant response heterogeneity, and clinicians are
several months reduces the risk of relapse. encouraged to evaluate the responses in the indi-
Group-based estimates, however, obscure signifi- vidual patient and manage treatment accordingly.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Interventions in the Early Aftermath patients to regulate PTSD-associated brain dys-

of Traumatic Events function by exposing them to malleable real-
Interventions administered shortly after expo- time displays of brain activity (mostly electro-
sure to trauma encompass stress management encephalographic displays). Preliminary studies67
and psychological and pharmacologic approach- show that changing brain-wave activity or con-
es.58 The first stress management approach was nectivity on functional magnetic resonance im-
psychological debriefing, a one-session interven- aging with the use of neurofeedback alleviates
tion in which survivors’ experiences during a PTSD symptoms. Transcranial magnetic stimu-
traumatic event are reviewed and discussed short- lation44 is a noninvasive brain-stimulation proce-
ly after the event. As a result of studies, reviews, dure that can alter neuronal activity through the
and meta-analyses showing that debriefing does administration of magnetic pulses to dedicated
not prevent PTSD and might have harmful con- brain areas. Preliminary studies suggest that
sequences,59 this technique is not recommended. transcranial magnetic stimulation of the right dor-
In contrast, there is evidence that problem-based, solateral prefrontal cortex has a positive effect.
patient-supportive care reduces the severity of Cycloserine, a partial agonist of the glutama-
PTSD symptoms after traumatic injury and iden- tergic N-methyl-d-aspartate (NMDA) receptor, has
tifies patients for “stepped” referral to cognitive been evaluated for its capacity to enhance extinc-
behavioral therapy.60 tion learning (i.e., a reduction in a learned re-
Early cognitive behavioral therapy is currently sponse) during cognitive behavioral therapy, with
the mainstay of preventive psychological inter- conflicting results.68 There is also considerable
vention.61 It is most effective in patients who interest in endocannabinoid modulators. Prelimi-
meet the diagnostic criteria for PTSD, it is equally nary studies suggest that cannabinoids may de-
effective when administered 1 month or 6 months crease PTSD-related insomnia, nightmares, and
after the traumatic event,62 and the results are hyperarousal. Patients with PTSD frequently use
maintained for years.63 It nonetheless is ineffec- cannabis, and PTSD is an approved condition for
tive in numerous survivors.63 medicinal marijuana in some states. However,
Studies of pharmacologic prevention of PTSD large-scale trials of cannabis use have not been
have been negative64 for propranolol, escitalopram, performed,69 and clinicians must consider the
temazepam, and gabapentin. Preliminary evidence risk of addiction, psychosis, and mood disorders
suggests that hydrocortisone administered shortly and carefully monitor the treatment response.
after exposure to trauma may reduce subsequent Finally, preliminary data suggest that intravenous
PTSD symptoms.65 Observational and retrospec- ketamine, a glutamate NMDA receptor antago-
tive studies suggest that morphine may reduce nist, rapidly reduces the severity of PTSD symp-
the prevalence of PTSD among injured survivors of toms,70 but further evidence is required to sub-
trauma. A small, randomized, placebo-controlled stantiate its clinical use.
trial showed that intranasal oxytocin reduced
anxiety, irritability, and intrusive recollections in Limitations and Prediction of Treatment
trauma survivors. In contrast, controlled studies Outcomes
and a recently completed large study (PTSD Despite decades of intensive research, finding an
Prevention Using Escitalopram, NCT00300313) effective treatment for a patient with PTSD is
showed no preventive effect of selective sero- challenging. Responses to treatment differ sub-
tonin-reuptake inhibitors62 and showed a para- stantially between individual patients, nonresponse
doxical increase in fear-driven behavior and PTSD
rates are high across treatment approaches, and
symptoms with benzodiazepines (diazepam, clon- treatment most often attenuates PTSD symp-
azepam, alprazolam, and temazepam). The latter toms without inducing remission.47 In an effort
agents should be avoided in the early aftermath to improve the prediction of treatment outcomes,
of a traumatic event. emerging studies are evaluating biomarkers of
treatment efficacy. These studies suggest that
Innovative and Experimental Therapies predictors of a poor response to cognitive behav-
A growing number of studies investigate innova- ioral therapy, for example, include memory defi-
tive therapies for PTSD.66 Neurofeedback trains cits, impaired connectivity of the neuronal net-

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 Post-Tr aumatic Stress Disorder

work (Etkin A: personal communication), the dations may then be tailored to the preferences
Val66Met polymorphism in brain-derived neuro- of the patient and clinical resources. Among the
tropic factor,71 the short allele of the serotonin available options, interventions with the stron-
transporter gene,72 and diminished activity in gest supportive evidence should be given priority
neural circuits that regulate emotions.73 These (e.g., cognitive behavioral therapy, sertraline, or
new leads await corroboration and point-of-care venlafaxine51), along with those that target the
assessment tools. patient’s most disturbing symptoms (e.g., insom-
nia and irritability). If exposure-based cognitive
behavioral therapy is being considered for a pa-
Impl ic at ions for Cl inic a l
Pr ac t ice tient with emotion-regulation difficulties (i.e.,
angry outbursts, panic, or dissociation), prelimi-
Assessment nary skills training in emotion regulation may
Two recently validated,74 short questionnaires prevent an adverse response and early discon-
have improved clinical screening for PTSD: the tinuation of treatment.77
4-item Primary Care PTSD Screen (PC-PTSD75)
and the 17-item PTSD Checklist (PCL76). The PCL Addressing Treatment Challenges
also quantifies the severity of symptoms and can Clinicians should acknowledge that approved
be used to monitor the response to treatment. therapies leave many patients unwell, that a pa-
To better target the intervention, the clinician tient may have a preferential response to one of
should assess the interference of symptoms with many interventions, and that many patients with
the patient’s daily life, memory, concentration, PTSD receive off-label medications and might be
sleep, and self-care. The patient should also be as- overmedicated. Stabilizing patients’ lives, reducing
sessed for concurrent depression, suicidal ideation, self-destructive behavior, and addressing perva-
alcohol and drug use, and ongoing environmen- sive loneliness and despair are high-priority goals.
tal pressures.
Dr. Liberzon reports receiving grant support and consulting
fees from ARMGO Pharmaceuticals, grant support and hono-
Optimizing Interventions raria from Cohen Veterans Bioscience, and consulting fees from
As a step toward recommending an intervention, Sunovion Pharmaceuticals. No other potential conflict of inter-
est relevant to this article was reported.
the clinician should clarify the patient’s priori- Disclosure forms provided by the authors are available with
ties and treatment goals. Treatment recommen- the full text of this article at NEJM.org.

References
1. Benjet C, Bromet E, Karam EG, et al. RK, Weathers FW. The prevalence of post- and trauma-related risk factors among a
The epidemiology of traumatic event ex- traumatic stress disorder (PTSD) in US nationally representative sample of Viet-
posure worldwide: results from the World combat soldiers: a head-to-head compari- nam veterans. Am J Epidemiol 2015;​182:​
Mental Health Survey Consortium. Psychol son of DSM-5 versus DSM-IV-TR symptom 980-90.
Med 2016;​46:​327-43. criteria with the PTSD checklist. Lancet 11. Nazarian D, Kimerling R, Frayne SM.
2. Karam EG, Friedman MJ, Hill ED, Psychiatry 2014;​1:​269-77. Posttraumatic stress disorder, substance
et al. Cumulative traumas and risk thresh- 7. Kendler KS. Phenomenology of schizo- use disorders, and medical comorbidity
olds: 12-month PTSD in the World Mental phrenia and the representativeness of among returning U.S. veterans. J Trauma
Health (WMH) surveys. Depress Anxiety modern diagnostic criteria. JAMA Psychi- Stress 2012;​25:​220-5.
2014;​31:​130-42. atry 2016;​73:​1082-92. 12. Sareen J, Cox BJ, Stein MB, Afifi TO,
3. American Psychiatric Association. Di- 8. Kessler RC, Sonnega A, Bromet E, Fleet C, Asmundson GJ. Physical and men-
agnostic and statistical manual of mental Hughes M, Nelson CB. Posttraumatic tal comorbidity, disability, and suicidal
disorders, 5th ed.: DSM-5. Arlington, VA:​ stress disorder in the National Comorbid- behavior associated with posttraumatic
American Psychiatric Publishing, 2013. ity Survey. Arch Gen Psychiatry 1995;​52:​ stress disorder in a large community sam-
4. American Psychiatric Association. Di- 1048-60. ple. Psychosom Med 2007;​69:​242-8.
agnostic and statistical manual of mental 9. Pietrzak RH, Goldstein RB, South- 13. Bernal M, Haro JM, Bernert S, et al.
disorders, 4th ed., text revision. Washing- wick SM, Grant BF. Prevalence and Axis I Risk factors for suicidality in Europe: re-
ton, DC:​American Psychiatric Associa- comorbidity of full and partial posttrau- sults from the ESEMED study. J Affect
tion, 2000. matic stress disorder in the United States: Disord 2007;​101:​27-34.
5. Hoge CW, Yehuda R, Castro CA, et al. results from Wave 2 of the National Epi- 14. Reger MA, Smolenski DJ, Skopp NA,
Unintended consequences of changing demiologic Survey on Alcohol and Related et al. Risk of suicide among US military
the definition of posttraumatic stress dis- Conditions. J Anxiety Disord 2011;​ 25:​ service members following Operation En-
order in DSM-5: critique and call for ac- 456-65. during Freedom or Operation Iraqi Freedom
tion. JAMA Psychiatry 2016;​73:​750-2. 10. Schlenger WE, Corry NH, Williams deployment and separation from the US
6. Hoge CW, Riviere LA, Wilk JE, Herrell CS, et al. A prospective study of mortality military. JAMA Psychiatry 2015;​72:​561-9.

n engl j med 376;25 nejm.org June 22, 2017 2467

The New England Journal of Medicine
Downloaded from nejm.org on June 21, 2017. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

15. Schoenbaum M, Kessler RC, Gilman 29. Logue MW, Amstadter AB, Baker DG, ture and function. Nat Rev Neurosci 2009;​
SE, et al. Predictors of suicide and acci- et al. The Psychiatric Genomics Consor- 10:​410-22.
dent death in the Army Study to Assess tium Posttraumatic Stress Disorder Work- 43. Marshall AJ, Acheson DT, Risbrough
Risk and Resilience in Servicemembers group: posttraumatic stress disorder enters VB, Straus LD, Drummond SP. Fear condi-
(Army STARRS): results from the Army the age of large-scale genomic collabora- tioning, safety learning, and sleep in hu-
Study to Assess Risk and Resilience in tion. Neuropsychopharmacology 2015;​40:​ mans. J Neurosci 2014;​34:​11754-60.
Servicemembers (Army STARRS). JAMA 2287-97. 44. Clark C, Cole J, Winter C, Williams K,
Psychiatry 2014;​71:​493-503. 30. Admon R, Lubin G, Rosenblatt JD, et al. Grammer G. A review of transcranial
16. Andrews B, Brewin CR, Philpott R, Imbalanced neural responsivity to risk magnetic stimulation as a treatment for
Stewart L. Delayed-onset posttraumatic and reward indicates stress vulnerability post-traumatic stress disorder. Curr Psy-
stress disorder: a systematic review of the in humans. Cereb Cortex 2013;​23:​28-35. chiatry Rep 2015;​17:​83.
evidence. Am J Psychiatry 2007;​164:​1319- 31. Fanselow MS, LeDoux JE. Why we 45. Hakamata Y, Lissek S, Bar-Haim Y, et
26. think plasticity underlying Pavlovian fear al. Attention bias modification treatment:
17. Marmar CR, Schlenger W, Henn- conditioning occurs in the basolateral a meta-analysis toward the establishment
Haase C, et al. Course of posttraumatic amygdala. Neuron 1999;​23:​229-32. of novel treatment for anxiety. Biol Psy-
stress disorder 40 years after the Vietnam 32. Jovanovic T, Kazama A, Bachevalier J, chiatry 2010;​68:​982-90.
War: findings from the National Vietnam Davis M. Impaired safety signal learning 46. Roberts NP, Roberts PA, Jones N, Bis-
Veterans Longitudinal Study. JAMA Psy- may be a biomarker of PTSD. Neurophar- son JI. Psychological interventions for post-
chiatry 2015;​72:​875-81. macology 2012;​62:​695-704. traumatic stress disorder and comorbid
18. Ozer EJ, Best SR, Lipsey TL, Weiss DS. 33. Milad MR, Pitman RK, Ellis CB, et al. substance use disorder: a systematic re-
Predictors of posttraumatic stress disor- Neurobiological basis of failure to recall view and meta-analysis. Clin Psychol Rev
der and symptoms in adults: a meta-analy- extinction memory in posttraumatic stress 2015;​38:​25-38.
sis. Psychol Bull 2003;​129:​52-73. disorder. Biol Psychiatry 2009;​66:​1075- 47. Steenkamp MM, Litz BT, Hoge CW,
19. Yurgil KA, Barkauskas DA, Vasterling 82. Marmar CR. Psychotherapy for military-
JJ, et al. Association between traumatic 34. Seeley WW, Menon V, Schatzberg AF, related PTSD: a review of randomized
brain injury and risk of posttraumatic et al. Dissociable intrinsic connectivity net- clinical trials. JAMA 2015;​314:​489-500.
stress disorder in active-duty Marines. works for salience processing and execu- 48. van den Berg DP, de Bont PA, van der
JAMA Psychiatry 2014;​71:​149-57. tive control. J Neurosci 2007;​27:​2349-56. Vleugel BM, et al. Prolonged exposure vs
20. Delahanty DL, Nugent NR, Christo- 35. Lanius RA, Frewen PA, Girotti M, eye movement desensitization and repro-
pher NC, Walsh M. Initial urinary epi- Neufeld RWJ, Stevens TK, Densmore M. cessing vs waiting list for posttraumatic
nephrine and cortisol levels predict acute Neural correlates of trauma script-imag- stress disorder in patients with a psychot-
PTSD symptoms in child trauma victims. ery in posttraumatic stress disorder with ic disorder: a randomized clinical trial.
Psychoneuroendocrinology 2005;​30:​121-8. and without comorbid major depression: JAMA Psychiatry 2015;​72:​259-67.
21. Pitman RK, Rasmusson AM, Koenen a functional MRI investigation. Psychiatry 49. Markowitz JC, Petkova E, Neria Y, et al.
KC, et al. Biological studies of post-trau- Res 2007;​155:​45-56. Is exposure necessary? A randomized clin-
matic stress disorder. Nat Rev Neurosci 36. Milad MR, Quirk GJ, Pitman RK, Orr ical trial of interpersonal psychotherapy
2012;​13:​769-87. SP, Fischl B, Rauch SL. A role for the hu- for PTSD. Am J Psychiatry 2015;​172:​430-40.
22. Smoller JW. The genetics of stress-­ man dorsal anterior cingulate cortex in 50. Polusny MA, Erbes CR, Thuras P, et al.
related disorders: PTSD, depression, and fear expression. Biol Psychiatry 2007;​62:​ Mindfulness-based stress reduction for
anxiety disorders. Neuropsychopharma- 1191-4. posttraumatic stress disorder among vet-
cology 2016;​41:​297-319. 37. Sripada RK, King AP, Welsh RC, et al. erans: a randomized clinical trial. JAMA
23. Mehta D, Klengel T, Conneely KN, et al. Neural dysregulation in posttraumatic 2015;​314:​456-65.
Childhood maltreatment is associated with stress disorder: evidence for disrupted 51. Lee DJ, Schnitzlein CW, Wolf JP,
distinct genomic and epigenetic profiles equilibrium between salience and de- Vythilingam M, Rasmusson AM, Hoge
in posttraumatic stress disorder. Proc Natl fault mode brain networks. Psychosom CW. Psychotherapy versus pharmacother-
Acad Sci U S A 2013;​110:​8302-7. Med 2012;​74:​904-11. apy for posttraumatic stress disorder: sys-
24. Yehuda R. Post-traumatic stress disor- 38. Lang S, Kroll A, Lipinski SJ, et al. temic review and meta-analyses to deter-
der. N Engl J Med 2002;​346:​108-14. Context conditioning and extinction in mine first-line treatments. Depress Anxiety
25. Eraly SA, Nievergelt CM, Maihofer AX, humans: differential contribution of the 2016;​33:​792-806.
et al. Assessment of plasma C-reactive hippocampus, amygdala and prefrontal 52. Schnyder U, Ehlers A, Elbert T, et al.
protein as a biomarker of posttraumatic cortex. Eur J Neurosci 2009;​29:​823-32. Psychotherapies for PTSD: what do they
stress disorder risk. JAMA Psychiatry 39. Shin LM, Liberzon I. The neurocir- have in common? Eur J Psychotraumatol
2014;​71:​423-31. cuitry of fear, stress, and anxiety disor- 2015;​6:​28186.
26. Minassian A, Maihofer AX, Baker DG, ders. Neuropsychopharmacology 2010;​35:​ 53. Nadorff MR, Lambdin KK, Germain A.
Nievergelt CM, Geyer MA, Risbrough VB. 169-91. Pharmacological and non-pharmacologi-
Association of predeployment heart rate 40. Milad MR, Wright CI, Orr SP, Pitman cal treatments for nightmare disorder. Int
variability with risk of postdeployment RK, Quirk GJ, Rauch SL. Recall of fear Rev Psychiatry 2014;​26:​225-36.
posttraumatic stress disorder in active- extinction in humans activates the ventro- 54. Mohamed S, Rosenheck RA. Pharma-
duty Marines. JAMA Psychiatry 2015;​72:​ medial prefrontal cortex and hippocam- cotherapy of PTSD in the U.S. Depart-
979-86. pus in concert. Biol Psychiatry 2007;​62:​ ment of Veterans Affairs: diagnostic- and
27. Germain A. Sleep disturbances as the 446-54. symptom-guided drug selection. J Clin
hallmark of PTSD: where are we now? Am 41. Rougemont-Bücking A, Linnman C, Psychiatry 2008;​69:​959-65.
J Psychiatry 2013;​170:​372-82. Zeffiro TA, et al. Altered processing of 55. Jonas DE, Cusack K, Forneris CA, et al.
28. Binder EB, Bradley RG, Liu W, et al. contextual information during fear extinc- Psychological and pharmacological treat-
Association of FKBP5 polymorphisms and tion in PTSD: an fMRI study. CNS Neuro- ments for adults with posttraumatic
childhood abuse with risk of posttrau- sci Ther 2011;​17:​227-36. stress disorder (PTSD). Rockville, MD:​
matic stress disorder symptoms in adults. 42. Arnsten AFT. Stress signalling path- Agency for Healthcare Research and
JAMA 2008;​299:​1291-305. ways that impair prefrontal cortex struc- Quality, 2013.

2468 n engl j med 376;25 nejm.org June 22, 2017

The New England Journal of Medicine

Downloaded from nejm.org on June 21, 2017. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
 Post-Tr aumatic Stress Disorder

56. Khachatryan D, Groll D, Booij L, Long-term outcome of early interventions Schofield PR, Quirk GJ, Bryant RA. The
Sepehry AA, Schütz CG. Prazosin for to prevent posttraumatic stress disorder. brain-derived neurotrophic factor Val66Met
treating sleep disturbances in adults with J Clin Psychiatry 2016;​77(5):​e580-e587. polymorphism predicts response to expo-
posttraumatic stress disorder: a system- 64. Amos T, Stein DJ, Ipser JC. Pharmaco- sure therapy in posttraumatic stress dis-
atic review and meta-analysis of random- logical interventions for preventing post- order. Biol Psychiatry 2013;​73:​1059-63.
ized controlled trials. Gen Hosp Psychia- traumatic stress disorder (PTSD). Cochrane 72. Bryant RA, Felmingham KL, Falconer
try 2016;​39:​46-52. Database Syst Rev 2014;​7:​CD006239. EM, et al. Preliminary evidence of the
57. Hoskins M, Pearce J, Bethell A, et al. 65. Zohar J, Yahalom H, Kozlovsky N, et al. short allele of the serotonin transporter
Pharmacotherapy for post-traumatic stress High dose hydrocortisone immediately gene predicting poor response to cogni-
disorder: systematic review and meta- after trauma may alter the trajectory of tive behavior therapy in posttraumatic
analysis. Br J Psychiatry 2015;​206:​93-100. PTSD: interplay between clinical and ani- stress disorder. Biol Psychiatry 2010;​67:​
58. Gartlehner G, Forneris CA, Brownley mal studies. Eur Neuropsychopharmacol 1217-9.
KA, et al. Interventions for the prevention 2011;​21:​796-809. 73. Falconer E, Allen A, Felmingham KL,
of posttraumatic stress disorder (PTSD) 66. Metcalf O, Varker T, Forbes D, et al. Williams LM, Bryant RA. Inhibitory neu-
in adults after exposure to psychological Efficacy of fifteen emerging interventions ral activity predicts response to cognitive-
trauma. Rockville, MD:​Agency for Health- for the treatment of posttraumatic stress behavioral therapy for posttraumatic stress
care Research and Quality, 2013. disorder: a systematic review. J Trauma disorder. J Clin Psychiatry 2013;​74:​895-901.
59. Rose S, Bisson J, Churchill R, Wessely Stress 2016;​29:​88-92. 74. Spoont MR, Williams JW Jr, Kehle-
S. Psychological debriefing for preventing 67. Reiter K, Andersen SB, Carlsson J. Forbes S, Nieuwsma JA, Mann-Wrobel
post traumatic stress disorder (PTSD). Neurofeedback treatment and posttrau- MC, Gross R. Does this patient have post-
Cochrane Database Syst Rev 2002;​ 2:​ matic stress disorder: effectiveness of traumatic stress disorder? Rational clini-
CD000560. neurofeedback on posttraumatic stress cal examination systematic review. JAMA
60. Zatzick D, Roy-Byrne P, Russo J, et al. disorder and the optimal choice of proto- 2015;​314:​501-10.
A randomized effectiveness trial of stepped col. J Nerv Ment Dis 2016;​204:​69-77. 75. Prins A, Ouimette P, Kimerling R, et al.
collaborative care for acutely injured trau- 68. Ori R, Amos T, Bergman H, Soares- The primary care PTSD screen (PC-PTSD):
ma survivors. Arch Gen Psychiatry 2004;​ Weiser K, Ipser JC, Stein DJ. Augmenta- development and operating characteris-
61:​498-506. tion of cognitive and behavioural thera- tics. Prim Care Psychiatry 2003;​9:​9-14.
61. Roberts NP, Kitchiner NJ, Kenardy J, pies (CBT) with d-cycloserine for anxiety 76. Bovin MJ, Marx BP, Weathers FW, et al.
Bisson JI. Early psychological interven- and related disorders. Cochrane Database Psychometric properties of the PTSD
tions to treat acute traumatic stress symp- Syst Rev 2015;​5:​CD007803. Checklist for Diagnostic and Statistical
toms. Cochrane Database Syst Rev 2010;​ 69. Yarnell S. The use of medicinal mari- Manual of Mental Disorders-Fifth Edition
3:​CD007944. juana for posttraumatic stress disorder: (PCL-5) in veterans. Psychol Assess 2016;​
62. Shalev AY, Ankri Y, Israeli-Shalev Y, a review of the current literature. Prim Care 28:​1379-91.
Peleg T, Adessky R, Freedman S. Preven- Companion CNS Disord 2015;​17. 77. Cloitre M, Koenen KC, Cohen LR,
tion of posttraumatic stress disorder by 70. Feder A, Parides MK, Murrough JW, Han H. Skills training in affective and
early treatment: results from the Jerusa- et al. Efficacy of intravenous ketamine for interpersonal regulation followed by ex-
lem Trauma Outreach And Prevention treatment of chronic posttraumatic stress posure: a phase-based treatment for PTSD
study. Arch Gen Psychiatry 2012;​69:​166- disorder: a randomized clinical trial. related to childhood abuse. J Consult Clin
76. JAMA Psychiatry 2014;​71:​681-8. Psychol 2002;​70:​1067-74.
63. Shalev AY, Ankri Y, Gilad M, et al. 71. Felmingham KL, Dobson-Stone C, Copyright © 2017 Massachusetts Medical Society.

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