Post-Traumatic Stress Disorder

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.

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 1 and TBI, Department of Psychiatry, New some time in their lives, and 31% experience four or more events. Post- York University School of Medicine, New R York (A.S., C.M.); and the Department of traumatic stress disorder (PTSD) is the most prevalent psychopathological conse- 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 charles .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.

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 disorders (Table 1). The results of these modifications are clinically significant.5 Recent field studies 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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ICD-11 Criteria event or events. or event events. or event the of reminiscent in the present in the form of vivid intrusivevivid of form the in present the in nightmares. or flashbacks, memories, orfear as such emotions overwhelming sensations,physical strong and horror im - or overwhelmed being of feelings or emotionsintense same the in mersed trau - the during experienced were that maticevent. event or series of events of series or event Avoidance of thoughts and memories of theof memories and thoughts of Avoidance peopleor situations, activities, of Avoidance Re-experiencing the traumatic event or eventsor event traumatic the Re-experiencing andstrong by accompanied Re-experiencing Avoidance: Exposure to an extremely threatening or horrific or threatening extremely an to Exposure symptoms: Intrusion

DSM-5 Criteria one or both of the following: the of both or one event(s). traumatic the with associated closely or about feelings distressing arouse that situations) objects, activities, versations, memories, thewith associated closely or about feelings or thoughts, event(s). traumatic event(s) occurred,traumatic worsening after the beginning or event(s), following: the of more) (or two by evidenced as such factors other to not and amnesia dissociative to (typically due drugs). or alcohol, injury, head as isworld “The trusted,” be can one “No bad,” am “I (e.g., world the or ers, completely dangerous,” “My whole nervous system is permanently ruined”). others. or himself/herself blame to individual the lead that event(s) matic feelings). loving or satisfaction, happiness, experience beginning after the traumatic event(s) occurred, as evidenced by evidenced as occurred, event(s) traumatic the after beginning in one (or more) of the following ways: following the of more) (or one in family a of death threatened or actual of cases In friend. close or ber accidental. or violent been have must event(s) the friend, or member remains; human collecting responders first (e.g., event(s) traumatic abuse). child of details to exposed repeatedly officers police related. work is exposure this unless pictures, or movies, television, occurred: event(s). matic event(s). traumatic the to related dream are may reactions (Such recurring. were event(s) traumatic the as if acts a being expression extreme most the with continuum, a on occur surroundings.) present of awareness of loss complete event(s). traumatic the of aspect an resemble or symbolize that cues nal event(s). traumatic the of aspect an resemble or bolize with the traumatic event(s), beginning after the traumatic event(s)traumatic the after beginning event(s), traumatic the with 1. Avoidance of or efforts to avoid distressing memories, thoughts, or thoughts, memories, distressing avoid to efforts or of Avoidance 1. con - places, (people, reminders external avoid to efforts or of Avoidance 2. event(s) traumatic the of aspect important an remember to Inability 1. oth - oneself, about expectations or beliefs negative exaggerated and Persistent 2. trau - the of consequences or cause the about cognitions distorted Persistent, 3. shame). or guilt, anger, horror, fear, (e.g., state emotional negative Persistent 4. activities. significant in participation or interest diminished Markedly 5. others. from estrangement or detachment of Feelings 6. to inability (e.g., emotions positive experience to inability Persistent 7. 1. Directly experiencing the traumatic event(s). traumatic the experiencing Directly 1. others. to occurred it as event(s) the person, in Witnessing, 2. mem - family close a to occurred event(s) traumatic the that Learning 3. the of details to aversive exposure extreme or repeated Experiencing 4. trau - the of memories distressing intrusive and involuntary, Recurrent, 1. the of affect and/or content the which in dreams distressing Recurrent 2. or feels individual the which in flashbacks) (e.g., reactions Dissociative 3. exter - or internal to exposure at distress psychological prolonged or Intense 4. sym - that cues external or internal to reactions physiological Marked 5. D. Negative alterations in cognitions and mood associated with the traumaticthe with associated mood and cognitions in alterations Negative D. C. Persistent avoidance of stimuli associated with the traumatic event(s), traumatic the with associated stimuli of avoidance Persistent C. A. Exposure to actual or threatened death, serious injury, or sexual violence sexual or injury, serious death, threatened or actual to Exposure A. media, electronic through exposure to apply not does A4 Note: Criterion B. Presence of one (or more) of the following intrusion symptoms associatedsymptoms intrusion following the of more) (or one of Presence B.

trauma and numbing of general responsiveness general of numbing and trauma by indicated as trauma), the before present (not following: the of more) (or three trauma. the with associated trauma. the of recollections arouse activities. nificant feelings). ing nor - a or children, marriage, career, a have to pect span). life mal which both of the following were present: were following the of both which fronted threat - or actual involved that event an with physi - the to threat a or injury, serious or death ened others. or self of integrity cal be may this children In Note: horror. or lessness, expressed,be - agitated or disorganized by instead, havior. one (or more) of the following ways: following the of more) (or one perceptions. or thoughts, images, including event, hal - illusions, experience, the reliving of sense a (includes includ - episodes, flashback dissociative and lucinations, intoxicated). when or awakening on occur that those ing as - an resemble or symbolize that cues external or event. traumatic the of pect of aspect an resemble or symbolize that cues nal event. traumatic the 1. Efforts to avoid thoughts, feelings, or conversations or feelings, thoughts, avoid to Efforts 1. that people or places, activities, avoid to Efforts 2. trauma. the of aspect important an recall to Inability 3. sig - in participation or interest diminished Markedly 4. others.from estrangement or detachment of Feeling 5. lov - have to (e.g., unable affect of range Restricted 6. ex - not does (e.g., future foreshortened a of Sense 7. 1. The person experienced, witnessed, or was con - was or witnessed, experienced, person The 1. help - fear, intense involved response person’s The 2. 1. Recurrent and intrusive distressing recollections of theof recollections distressing intrusive and Recurrent 1. event. the of dreams distressing Recurrent 2. recurringwere event traumatic the if as feeling or Acting 3. internalto exposure at distress psychological Intense 4. exter - or internal to exposure on reactivity Physiological 5. Diagnostic Criteria for Post-Traumatic Stress Disorder.* Stress Post-Traumatic for Criteria Diagnostic 1. Table C. Persistent avoidance of stimuli associated with the with associated stimuli of avoidance Persistent C. A. The person has been exposed to a traumatic event in event traumatic a to exposed been has person The A. DSM-IV-TR Criteria in re-experienced persistently is event traumatic The B.

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3 and fifth edition (DSM-5), 4 ICD-11 Criteria unexpected noises. unexpected threat: as weeks. educa - social, family, in personal, ment important other or occupational tional, functioning. of areas Hypervigilance. such stimuli to reaction startle Enhanced Persistent perceptions of heightened current heightened of perceptions Persistent several least at for persist must symptoms The impair - significant cause must symptoms The

DSM-5 Criteria event(s), beginning or worsening after the traumatic event(s) oc - event(s) traumatic the after worsening or beginning event(s), following: the of more) (or two by evidenced as curred, peopletoward aggression physical or verbal as expressed typically objects. or sleep). or persistent experiences individual the stressor, the to response in following: the of either of symptoms recurrent mental one’s of, observer outside an were one if as and tached from, feel - dream; a in were one though as feeling (e.g., body or processes slowly). moving time of or body or self of unreality of sense a ing un - as experienced is individual the around world the (e.g., roundings distorted). or distant, dreamlike, real, be - blackouts, (e.g., substance a of effects physiological the to able condition medical another or intoxication) alcohol during havior seizures). partial complex (e.g., ex - and onset the (although event the after months 6 least at until immediate). be may symptoms some pression of social, occupational, or other important areas of functioning. areas important other occupational, or social, condition. medical another or alcohol) medication, (e.g., stance addition, in and disorder, stress posttraumatic for criteria the meet 1 month. 1 1. Irritable behavior and angry outbursts (with little or no provocation)no or little (with outbursts angry and behavior Irritable 1. behavior. self-destructive or Reckless 2. Hypervigilance. 3. response. startle Exaggerated 4. concentration. with Problems 5. restlessor asleep staying or falling difficulty (e.g., disturbance Sleep 6. de - feeling of experiences recurrent or Persistent Depersonalization: 1. sur - of unreality of experiences recurrent or Persistent Derealization: 2. E. Marked alterations in arousal and reactivity associated with the traumatic the with associated reactivity and arousal in alterations Marked E. attribut - be not must dissociative symptoms the subtype, this use Note: To met not are criteria diagnostic full the If delayed expression: With if: Specify F. Duration of the disturbance (Criteria B, C, D, and E) is more than more is E) and D, C, B, (Criteria disturbance the of Duration F. in impairment or distress significant clinically causes disturbance The G. sub - a of effects physiological the to attributable not is disturbance The H. symptoms individual’s The symptoms: dissociative With whether: Specify before the trauma), as indicated by two (or more) (or two by indicated as trauma), the before following: the of months after the stressor. the after months and D) is more than 1 month. 1 than more is D) and impor - other or occupational, social, in impairment functioning. of areas tant 1. Difficulty falling or staying asleep. staying or falling Difficulty 1. anger. of outbursts or Irritability 2. concentrating. Difficulty 3. Hypervigilance. 4. response. startle Exaggerated 5. D. Persistent symptoms of increased arousal (not present(not arousal increased of symptoms Persistent D. Specify if: Specify months. 3 than less is symptoms of duration if Acute: more. or months 3 is symptoms of duration if Chronic: 6 least at is symptoms of onset if onset: delayed With DSM-IV-TR Criteria C,B, Criteria in (symptoms disturbance the of Duration E. or distress significant clinically causes disturbance The F. Diagnostic criteria are reprinted with permission from the and Statistical Manual of Mental Disorders , fourth edition, text revision (DSM-IV-TR), 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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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 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 Biologic Features of PTSD 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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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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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 Treatment and sensory experiences occurring in the present 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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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

Contextual Processing Fear Learning C D Medial Central nucleus Cortical nucleus nucleus BRAIN

Intercalated Medial nuclei prefrontal AMYGDALA cortex 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 regulation 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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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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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., insomnia and irritability). If exposure-based cognitive Implications for Clinical behavioral therapy is being considered for a pa- Practice 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 interest 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.

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