The ​new england journal ​of ​medicine

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 ​
news. some ​n engl j med

of violence, injury, and death appear daily on headline ​

376;25 nejm.org June 22, 2017 ​2459 ​ More than 70% of adults
worldwide experience a traumatic event at time in their lives, and 31% experience four or more events.​1 ​Post-
traumatic stress disorder (PTSD) is the most prevalent psychopathological conse- quence of exposure to traumatic
events. The lifetime prevalence of PTSD varies according to social background and country of residence, ranging
from 1.3 to 12.2%, and the 1-year prevalence is 0.2 to 3.8%.​2 ​The core features of PTSD are the persistence of
intense, distressing, and fearfully avoided reactions to reminders of the triggering event, alteration of mood and
cognition, a pervasive sense of im- minent threat, disturbed sleep, and hypervigilance. This report outlines our
current understanding of the diagnosis, prevalence, neurobiologic characteristics, and treatment of PTSD, as well as
the clinical implications of this knowledge.
Definition and Diagnosis
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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From the Steven and Alexandra Cohen Veterans Center for Posttraumatic Stress and TBI, Department of Psychiatry, New York University
School of Medicine, New York (A.S., C.M.); and the Department of Psychiatry, University of Michigan, and the Mental Health Service,
Veterans Affairs Ann Arbor Health Systems — both in Ann Arbor (I.L.). Address reprint requests to Dr. Marmar at New York University
School of Medicine, 1 Park Ave., Rm. 8-214, New York, NY 10016, or at charles . marmar@ nyumc . org.
N Engl J Med 2017;376:2459-69. DOI: 10.1056/NEJMra1612499 ​Copyright © 2017 Massachusetts Medical Society.
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2460
Post-Traumatic Stress Disorder
n engl j med 376;25 nejm.org June 22, 2017 ​2461
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The ​new england journal ​of ​medicine
elevated suicide rates among veterans may reflect protracted
PTSD,
Epidemiologic Features of PTSD 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 the United States are
Natural Course, Prediction, and Risk Factors ​Transient
physical and sexual assaults (52% lifetime prevalence) and
symptoms of PTSD are frequently ob- served shortly after
accidents or fires (50%). Worldwide, accidents and injuries
traumatic events, and most cases of chronic PTSD follow an
are re- ported most frequently (36% lifetime prevalence).​1
early onset of symptoms. A delayed expression of PTSD,
Higher rates of PTSD have been documented among
most frequently seen among deployed military per- sonnel,
socially disadvantaged persons, younger persons, women,
accounts for 25% of chronic cases.​16 ​In most
military personnel, police offi- cers, firefighters, and first
trauma-exposed persons (e.g., 78% of those exposed to
responders to disasters and mass trauma.​2,6 ​The conditional
combat​17​), PTSD does not develop after the exposure.
probability that PTSD will develop varies according to sex
Among those in whom the disorder does develop, the
and the type of trauma; for example, the respec- tive
severity of symptoms fluctuates over time, with periods of
probabilities for men and women are 65% and 46% after
greater severity probably reflecting sensitivity to co-
rape, 2% and 22% after physical assault, and 6% and 9%
occurring stressors, illness, and life transitions. The intensity
after an accident.​8 ​The probability is higher in high-income
of the trauma and individual susceptibility interact to
countries than in lower-income countries.​2 ​These differ-
influence the likelihood of PTSD. Factors associated with
ences probably reflect the roles of sex and social and
increased sus- ceptibility include female sex, childhood
situational factors in the development, ex- pression, and
trauma, fewer years of schooling, prior mental disorders,
persistence of PTSD symptoms. Physical assault, for
exposure to four or more traumatic events, and a history of
example, might be perceived differently by men and
exposure to interpersonal violence.​18 ​The intensity of the
women, and combatants trained to persevere during action
traumatic exposure is also related to the risk of PTSD, and
may not read- ily express fear, helplessness, or horror.
the risk is in- creased with exposure to death, injury, torture,
or bodily disfigurement; traumatic brain injury​19​; and a
Coexisting Disorders and Mortality ​In more than 50% of
traumatic experience that is unexpected, inescapable, or
cases, PTSD co-occurs with mood, anxiety, or
uncontrollable. Physiological and neuroendocrine predictors
substance-use disorders.​9 ​It is associated with serious
of PTSD include elevat- ed heart and respiration rates and a
disability, medical illness, and premature death.​10 ​Data on
low plasma cortisol level.​20
physical illness in patients with PTSD encompass
subjectively reported health status and diagnosed diseases in
all categories.​11 ​In a nationally representative sample of Biologic Features of PTSD
Vietnam veterans,​10 ​PTSD was associ- ated with an increase
Biologic Correlates ​Arguably the most important
in age-related mortality by a factor of 2; the leading causes
developments in the biologic understanding of PTSD are
of death were neoplasms affecting the respiratory tract and
efforts to organize various findings into functionally
ischemic heart diseases.​10,11
integrated mechanistic models. The peripheral biologic
PTSD is also associated with suicidal behav- ior,​12 ​but the
correlates of PTSD to date (reviewed by Pitman et al.​21​)
relationship is neither specific nor simple. The relative risk
encompass genes,​22 ​epigenetic regulation,​23 ​neuroendocrine
of a suicide attempt among civilians with PTSD (2.0) is
factors,​24 ​inflamma- tory markers,​25 ​autonomic risk and
similar to the relative risk of generalized anxiety disorder 26 ​
resilience,​ and sleep disturbances.​27 ​Some biologic features
(2.3) or alcohol dependence (2.5) and is lower than that of
constitute preexposure vulnerability factors (e.g., a
depression (4.8).​13 ​Recent studies of active military
polymorphism in the ​FKBP5 ​gene​28 ​and heart- rate
personnel did not show an association between suicide and 26​
variability​ ), whereas others might reflect trauma-induced
war-zone deployment​14 ​or ex- posure to combat.​15 ​Thus,
 alterations (e.g., immune changes, neuroinflammation,​25 ​and gland Journal of Medicine Downloaded from nejm.org on
ut permission. Copyright © 2017 Massachusetts Medical
postexposure epigene- tic regulation​23​). The multiplicity and
ghts reserved.
interdepen-

2462
Post-Traumatic Stress Disorder

Threat Detection ​Dysfunctional threat detection may

dence of biologic correlates, their variable distri- bution
underlie pref- erential attention to threatening stimuli,
among affected persons, their contribution to other disorders
hyper- vigilance, heightened threat anticipation, and ex-
in addition to PTSD, and the small effect of each one limit
aggerated reactivity to salient stimuli in patients
their current use as biomarkers for PTSD. The pressing need
D. Functional neuroimaging studies have identified
for diagnostic, prognostic, and therapeutic biomark- ers calls
k of brain regions that identify threat and salience
for large-scale research initiatives that use advanced
al, including the amygdala, the dorsal anterior
bioinformatics to derive new knowl- edge about the ​
cor- tex, and the insula or operculum.​34 PTSD has
pathogenesis of PTSD and treat- ment targets (e.g., the
sociated with overreactivity in the insula,​35
initiative described by Logue et al.​29​).
a, and dorsal anterior cingulate cortex​36 ​and with
nectivity of brain networks that detect salient
Neurobiologic Models ​Functional neural systems thought
n the environment.​37
to have a prominent role in the pathophysiology of PTSD
include fear learning, threat detection, executive function
e Function and Emotion Regulation F ​ lexibility in
and emotion regulation, and contextual processing.
l responding requires hold- ing information in
Abnormalities in these sets of inter- connected regions
isting distractors, planning, and switching tasks
(often referred to as circuits) mediate the acquisition of fear
integrity of working memory, attention, inhibition,
responses in PTSD, avoidance of trauma reminders,
shifting components of executive function).
impaired regulation of emotions (manifested as irritability,
regulation relies on the integrity of ex- ecutive
anger, or reckless behavior), and the persistence of
thus, impaired executive func- tion and emotion
defensive responses once safety has been re- stored.
n in PTSD may under- lie memory and
Abnormalities of declarative memory​21 ​and dysfunctional
ation deficits, poorly controlled emotional
reward processing (manifest- ed as anhedonia and
s, irritability, and impulsivity. Impaired
motivational deficits​30​) are shared by PTSD and other
vity in the fronto- parietal regions, within and
disorders (Fig. 1).
executive- function networks, has been observed in
with PTSD, providing evidence of dysfunctional
Fear Learning ​Abnormal fear learning has been a prime
e-function and emotion-regulation cir- cuits.​37
candi- date for explaining the pathophysiology of PTSD.
Studies have localized fear-related memory for- mation to
ual Processing ​Proper processing of contextual
the amygdala,​31 ​and its subsequent modulation to a complex
on al- lows one to freeze, flee, or enjoy a situation,
interplay between vari- ous nuclei and cell types in the
priate (e.g., an alligator in one’s backyard is seen as
basolateral com- plex of the amygdala. The persistence of
ng, whereas an alligator in a zoo is seen as
fear responses in patients with PTSD has been attrib- uted to
PTSD is characterized by hypervigilance that is
abnormalities in extinction of fear, in safety learning,​32 ​and
riate to the situa- tion and the misreading of cues as
in retaining the fact that extinction of associative learning
ng despite a safe context (e.g., a response to trauma
has occurred (known as extinction recall).​33 ​The
s in a movie as if the event were recur- ring).
fear-learning model of PTSD has inspired some of the com-
ate contextual processing depends on good
mon therapies for the disorder, such as expo- sure-based
in the medial prefrontal cor- tex and the
cognitive behavioral therapy, which is reviewed below.
mpus.​38 ​Hippocampal chang- es have been reported
s with PTSD.​21,39 ​Diminished signaling in the
medial prefrontal cortex in affected patients has been linked
to impaired extinction recall,​40 ​abnormal processing of
contextual information,​41 ​and impaired safety- signal
learning, implicating contextual process- ing circuitry in the
pathophysiology of PTSD.
Such neurobehavioral models can account
y of the peripheral biologic findings in PTSD.
docrine alterations have been linked with altered
n the amygdala. Noradrenergic

n engl j med 376;25 nejm.org June 22, 2017 ​2463

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​ edicine
keeping distress at tolerable levels with the use of deep
breathing and with support from the therapist. The se-
hyperreactivity has been linked to diminished frontal-lobe
quence is repeated until the memories no longer trigger
activity, which mediates executive function.​42 ​Updates of
intolerable responses and are not avoid- ed. In
contextual information occur during rapid-eye-movement
eye-movement desensitization and repro- cessing therapy,​48
(REM) sleep, require a “turning off” of the locus ceruleus,
the patient recalls traumatic images while engaging in
and could be impaired by PTSD-associated hyper-
horizontal eye move- ment. Cognitive processing therapy
adrenergic states.​43 ​Several innovative therapies (e.g.,
explores the patient’s dysfunctional post-traumatic beliefs
transcranial magnetic stimulation​44 ​and neurocognitive
and cognitions (e.g., that the world is dangerous,
modulation training​45​) directly address components of the
uncontrollable, and unpredictable and that the patient is
neural circuitries noted above.
ineffectual, helpless, or guilty) and challenges them in a
Socratic dialogue.
Treatment Nonexposure therapies include present-centered
therapy, which focuses on dysfunction in current
Therapies for PTSD include psychological, phar-
relationships and life challenges; interpersonal therapy,
macologic, and innovative interventions. Treat- ment goals,
focusing on interpersonal conflicts and role transitions,​49
techniques, and effects in the early aftermath of trauma
which was shown to be similar to prolonged exposure as a
differ from those in cases of protracted PTSD and are
treatment for PTSD and slightly better for patients with both
therefore reviewed separately. Successful implementation of
PTSD and major depressive disorder; and mindfulness,
treat- ment requires careful assessment, as outlined in the
which refocuses the patient’s attention on bodily and
subsequent discussion of clinical practice.
sensory experiences occurring in the present moment.​50
Critical reviews and treatment guide- lines emphasize the
Interventions for Steady-State, Protracted PTSD
relative advantage of cogni- tive behavioral therapy over
Trauma-focused cognitive behavioral therapy is the
nonexposure thera- pies.​51 ​However, a recent review
best-supported psychological intervention for PTSD.​46,47
suggests that present-centered therapy might be similarly
Cognitive behavioral therapy revisits distressing elements of
bene- ficial in war veterans.​47 ​Indeed, a recent com- parison
the traumatic events and consequent avoidance and
of treatment protocols by the investiga- tors who developed
cognitive distortions. Specific cognitive behavioral therapy
them suggests that “branded” interventions have many
protocols can be grossly divided into exposure therapies
common components (e.g., psychoeducation and a focus on
(e.g., prolonged exposure) and nonexposure ther- apies (e.g.,
emotion regulation, cognitive processing, and meaning
cognitive processing). In exposure therapies, distressing and52​
making​ ). Psychological therapies that target specific PTSD
fearfully avoided mem- ories of traumatic events are
symptoms (e.g., insomnia)​53 ​offer alternatives to
engaged in a safe environment. For example, a patient is
pharmacologic treatment.
first trained in self-regulating techniques, such as deep
Most patients with PTSD (e.g., 74% of affected war
breathing, and is taught to quantify and communicate
veterans)
current distress. The patient then progressively recalls receive some form of pharmaco- logic treatment,​54
fearfully avoided elements of the traumatic event whileincluding antidepressant agents, anxiolytic or
sedative–hypnotic agents, and anti- psychotic agents
(prescribed, respectively, for 89%, 61%, and 34% of those
receiving pharmaco- therapy). Paroxetine and sertraline are
approved by the Food and Drug Administration for the
treatment of PTSD.​51,55 ​In addition, venlafaxine and
nefazodone have been recommended for PTSD​51​;
mirtazapine, trazodone, and prazosin have been used for
insomnia and nightmares​56​; and topiramate has been used in
patients with PTSD and alcohol use disorder. However,
unpub- lished results of a large, randomized, placebo-
controlled study of prazosin (Prazosin and Com- bat Trauma
PTSD [PACT]; ClinicalTrials.gov number, NCT00532493)
have failed to show a beneficial effect on insomnia,
Post-Traumatic Stress Disorder
nightmares, PTSD symptoms, or general distress. Effect
sizes for antidepressants in patients with PTSD are rela-
tively small.​57 ​These agents alleviate symptoms but rarely
induce remission, and there is a sub- stantial risk of relapse
on discontinuation. Main- taining a full therapeutic dose for
6 to 12 months
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 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.
however, obscure signifi-
onse heterogeneity, and clinicians are encouraged
ate the responses in the indi- vidual patient and
and gradually tapering the dose over a period of severalreatment accordingly.
months reduces the risk of relapse. Group-based estimates,
 n engl j med 376;25 nejm.org June 22, 2017 ​2465
A ​Emotion Regulation and Executive Function
B ​Threat and Salience Detection

AMYGDALA

C ​Contextual Processing ​D ​Fear Learning

Medial nucleus
Central nucleus

Anterior cingulate
cortex

Locus ceruleus

PONS
Medial prefrontal
cortex
Medial prefrontal
cortex

Basal nucleus
Basal nucleus
 Intercalated nuclei

Cerebellum

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other uses without permission. Copyright © 2017 Massachusetts Medical Society. All rights reserved.
BRAIN BRAIN
MEDULLA OBLONGATA
CEREBELLUM
Ventrolateral prefrontal cortex ​BRAIN

BRAIN
Dorsolateral prefrontal
cortex
 Fornix
BRAIN
Cortical nucleus

Central nucleus

Lateral nucleus

Amygdala
Hippocampus
Hippocampus

Thalamus
Amygdala
Fornix
The ​new england journal ​of m
​ edicine
interven- tion in which survivors’ experiences during a
traumatic event are reviewed and discussed short- ly after
Interventions in the Early Aftermath of Traumatic Events
the event. As a result of studies, reviews, and meta-analyses
Interventions administered shortly after expo- sure to trauma
showing that debriefing does not prevent PTSD and might
encompass stress management and psychological and
have harmful con- sequences,​59 ​this technique is not
pharmacologic approach- es.​58 ​The first stress management
recommended. In contrast, there is evidence that
approach was psychological debriefing, a one-session
problem-based, patient-supportive care reduces the severity
 of PTSD symptoms after traumatic injury and iden- pulses
tifies to dedicated brain areas. Preliminary studies suggest
patients for “stepped” referral to cognitive behavioral
that transcranial magnetic stimulation of the right dor-
therapy.​60 solateral prefrontal cortex has a positive effect.
Early cognitive behavioral therapy is currently the mainstay of Cycloserine, a partial agonist of the glutama- tergic
61 ​
preventive psychological inter- vention.​ It is most N ​-methyl-​d​-aspartate (NMDA) receptor, has been evaluated
effective
in patients who meet the diagnostic criteria for PTSD, for itsit iscapacity to enhance extinc- tion learning (i.e., a
equally effective when administered 1 month or 6reduction months in a learned re- sponse) during cognitive
after the traumatic event,​62 ​and the results are maintained for therapy, with conflicting results.​68 ​There is also
behavioral
years.​63 ​It nonetheless is ineffec- tive in numerous considerable interest in endocannabinoid modulators.
survivors.​63 Prelimi- nary studies suggest that cannabinoids may de-
Studies of pharmacologic prevention of PTSD have creasebeen PTSD-related insomnia, nightmares, and
64 ​
negative​ for propranolol, escitalopram, temazepam, hyperarousal.
and Patients with PTSD frequently use cannabis,
gabapentin. Preliminary evidence and
suggests PTSD
that is an approved condition for medicinal marijuana
hydrocortisone administered shortly after exposure to in some states. However, large-scale trials of cannabis use
69 ​
trauma may reduce subsequent PTSD symptoms.​ have not been performed,​ and clinicians must consider the
65

Observational and retrospec- tive studies suggest risk that

of addiction, psychosis, and mood disorders and
morphine may reduce the prevalence of PTSDcarefully among monitor the treatment response. Finally,
injured survivors of trauma. A small, randomized, preliminary data suggest that intravenous ketamine, a
placebo-controlled trial showed that intranasal glutamate
oxytocin NMDA receptor antago- nist, rapidly reduces the
severityin of PTSD symp- toms,​70 ​but further evidence is
reduced anxiety, irritability, and intrusive recollections
trauma survivors. In contrast, controlled studiesrequired and a to sub- stantiate its clinical use.
recently completed large study (PTSD Prevention Using
Escitalopram, NCT00300313) showed no preventive Limitations
effect and Prediction of Treatment Outcomes
62 ​ Despite
of selective sero- tonin-reuptake inhibitors​ and showed a decades of intensive research, finding an effective
treatment
para- doxical increase in fear-driven behavior and PTSD for a patient with PTSD is challenging. Responses
symptoms with benzodiazepines (diazepam, clon- to treatment differ sub- stantially between individual
azepam,
alprazolam, and temazepam). The latter agents should benonresponse rates are high across treatment
patients,
avoided in the early aftermath of a traumatic event. approaches, and treatment most often attenuates PTSD
symp- toms without inducing remission.​47 ​In an effort to
Innovative and Experimental Therapies ​A growing improve the prediction of treatment outcomes, emerging
number of studies investigate innova- tive therapies studies
for are evaluating biomarkers of treatment efficacy.
66 ​
PTSD.​ Neurofeedback trains These studies suggest that predictors of a poor response to
patients to regulate PTSD-associated brain dys- function by cognitive behav- ioral therapy, for example, include
exposing them to malleable real- time displays of brain memory defi- cits, impaired connectivity of the neuronal
activity (mostly electro- encephalographic displays). net-
Preliminary studies​67 ​show that changing brain-wave activity
or con- nectivity on functional magnetic resonance im-
aging with the use of neurofeedback alleviates PTSD
symptoms. Transcranial magnetic stimu- lation​44 ​is a gland Journal of Medicine Downloaded from nejm.org on
noninvasive brain-stimulation proce- dure that can alter ut permission. Copyright © 2017 Massachusetts Medical
neuronal activity through the administration of magnetic ghts reserved.
Post-Traumatic Stress Disorder
emotions.​73 ​These new leads await corroboration and
point-of-care assessment tools.
work (Etkin A: personal communication), the Val66Met
polymorphism in brain-derived neuro- tropic factor,​71 ​the
short allele of the serotonin transporter gene,​72 ​and Implications ​Practice for
​ Clinical ​Assessment
diminished activity in neural circuits that regulate
 Two recently validated,​74 ​short questionnaires have
improved clinical screening for PTSD: the 4-item Primary
Care PTSD Screen (PC-PTSD​75​) and the 17-item PTSD
Checklist (PCL​76​). The PCL also quantifies the severity of
symptoms and can be used to monitor the response to
treatment. To better target the intervention, the clinician
should assess the interference of symptoms with the
patient’s daily life, memory, concentration, sleep, and
self-care. The patient should also be as- sessed for
concurrent depression, suicidal ideation, alcohol and drug
use, and ongoing environmen- tal pressures.
Optimizing Interventions ​As a step toward recommending
an intervention, the clinician should clarify the patient’s
priori- ties and treatment goals. Treatment recommen-
dations may then be tailored to the preferences of the patient
and clinical resources. Among the available options,
interventions with the stron- gest supportive evidence
should be given priority (e.g., cognitive behavioral therapy,
sertraline, or venlafaxine​51​), along with those that target the
patient’s most disturbing symptoms (e.g., insom- nia and
irritability). If exposure-based cognitive behavioral therapy
is being considered for a pa- tient with emotion-regulation
difficulties (i.e., angry outbursts, panic, or dissociation),
prelimi- nary skills training in emotion regulation may
prevent an adverse response and early discon- tinuation of
treatment.​77
Addressing Treatment Challenges ​Clinicians should
acknowledge that approved therapies leave many patients
unwell, that a pa- tient may have a preferential response to
one of many interventions, and that many patients with
PTSD receive off-label medications and might be
overmedicated. Stabilizing patients’ lives, reducing
self-destructive behavior, and addressing perva- sive
loneliness and despair are high-priority goals.
Dr. Liberzon reports receiving grant support and
consulting fees from ARMGO Pharmaceuticals, grant support and hono- raria
from Cohen Veterans Bioscience, and consulting fees from Sunovion
Pharmaceuticals. No other potential conflict of inter- est relevant to this article
was reported.
Disclosure forms provided by the authors are available
with the full text of this article at NEJM.org.
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The ​new england journal ​of m
​ edicine
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