Posttraumatic stress disorder.

Review Article

Posttraumatic Stress Disorder Ricardo E. Jorge, MD ABSTRACT Purpose of Review: The objectives of this article are to update the reader on the current definition and diagnostic assessment of posttraumatic stress disorder (PTSD) and to describe its clinical characteristics, discuss its epidemiology and pathophysiologic aspects, as well as to summarize the current therapeutic options for PTSD. Recent Findings: The new nomenclature of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) includes 20 PTSD symptoms clustered into four symptomatic domains: intrusive symptoms, active avoidance, disturbed emotional states, and alterations of arousal and reactivity. Diagnostic structured interviews and severity scales have been updated in order to address this recent revision. It is also recognized that the neural circuits whose disruption might explain the genesis of PTSD symptoms, although overlapping, may be different between these four domains, a fact that may inform new biologically based phenotypes with prognostic and therapeutic implications. During the past years, there has been active research into the different factors influencing vulnerability and resilience to stress, including the effect of genetic and epigenetic variations. The neural circuits involved in the processing of threatening stimuli have been studied in patients with PTSD through paradigms inspired in animal research. These studies suggest that patients with PTSD have difficulty discriminating danger from safety cues and have problems suppressing fear in the presence of safety cues. Functional MRI (fMRI) studies suggest that the increased amygdala activation observed in these patients results from abnormal modulatory input from the ventromedial prefrontal cortex. Structural brain abnormalities, on the other hand, have been more consistently identified in the hippocampus. Prolonged exposure therapy and cognitive reprocessing are the interventions that have the more extensive validation of their psychotherapeutic efficacy. Medications are modestly more effective than placebo to treat PTSD symptoms, and selective serotonin reuptake inhibitors (SSRIs) are considered a safe initial choice. Use of combined strategies including pharmacologic modulation of fear processing is an area of active research. Summary: PTSD is a frequent psychopathologic condition with a lifetime prevalence that is close to 10%. In the past few years, there have been significant advances in the definition of the disorder, in elucidating the neurobiology of vulnerability and resilience, and in developing new treatment alternatives.

Address correspondence to Dr Ricardo E. Jorge, One Baylor Plaza BCM350, Houston, TX 77030, [email protected]. Relationship Disclosure: Dr Jorge reports no disclosure. Unlabeled Use of Products/Investigational Use Disclosure: Dr Jorge reports no disclosure. * 2015, American Academy of Neurology.

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INTRODUCTION Emotions are characterized by their intentionality, which is understood as the way in which an organism interacts with its world, appraises its salient aspects, and initiates adaptive behaviors to assure its integrity and survival. Therefore, it is Continuum (Minneap Minn) 2015;21(3):789–805

not surprising that emotions are intimately related to how an organism processes stressful events and their accompanying homeostatic responses. Humans possess highly developed cognitive and linguistic abilities that determine the richness of their emotional www.ContinuumJournal.com

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

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Posttraumatic Stress Disorder KEY POINTS

h Posttraumatic stress disorder is related to a specific event involving actual or threatened death, serious injury, or sexual violence. Symptoms should be present for at least 1 month and have a significant functional impact. If symptoms are present less than 1 month, the appropriate diagnosis is acute stress disorder.

h The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition describes four symptom clusters of posttraumatic stress disorder: intrusive symptoms, active avoidance, disturbed emotional states, and alterations of arousal and reactivity.

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repertoire and coping behavior. Consequently, any analysis of human responses to stress should incorporate the complexity of this unique existential experience. This article focuses on the process that leads from exposure to extraordinarily severe stress to the development of psychopathology, particularly posttraumatic stress disorder (PTSD). DEFINITION AND PHENOMENOLOGIC PRESENTATION OF POSTTRAUMATIC STRESS DISORDER The current psychiatric nomenclature defines PTSD along eight distinct criteria and four symptomatic dimensions. The development of the disorder is essentially tied to a particular event or series of events that involve exposure to actual or threatened death, serious injury, or sexual violence. Individuals with PTSD may have experienced the inciting event(s), may have directly witnessed the event(s) happening to others, or may have learned of its occurrence to a close family member or friend. Furthermore, PTSD may result from specific circumstances under which the individuals are exposed repeatedly to intense aversive situations, such as those associated with combat and rescue activities that follow natural disasters. In these cases, PTSD emerges even in professionals who have been trained specifically to face severe stress. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), a PTSD diagnosis requires symptoms of at least 1 month’s duration that have a significant impact on social and occupational functioning and that are not the result of either another medical condition or the toxic effect of drugs or other chemical substances.1 If the symptoms are present in close relation to trauma and persist for at least 3 days, but less than 1 month, the appropriate diagnosis is acute stress dis-

order (ASD). From a phenomenologic standpoint, ASD is characterized by a prominence of dissociative symptoms, such as depersonalization or altered experience of the environment. Thus, it is conceivable that the condition might be the result of other pathophysiologic processes than the ones underlying PTSD. However, ASD and dissociative symptoms occurring in the aftermath of trauma are considered strong predictors for the development of PTSD,2 and both disorders are part of the same spectrum. In addition, PTSD may have a delayed onset. The current classification scheme sets an arbitrary time point of 6 months after trauma to define the occurrence of delayed-onset PTSD (Case 13-1). CURRENT NOMENCLATURE The DSM-5 classification system identifies four symptom clusters that characterize PTSD (Figure 13-1). The first symptom cluster relates to intrusive symptoms, including distressing memories of the traumatic event, nightmares, and dissociative experiences in which the subject appears to be reexperiencing the event (ie, flashbacks). Patients with PTSD may also have intense physiologic responses to trauma-related reminders that can be categorized as intrusive experiences. The second symptom cluster involves the active avoidance of distressing memories of either the traumatic event itself or environmental cues reminiscent of its circumstances. According to the DSM-5, at least one form of avoidant behavior must be present in order to substantiate a PTSD diagnosis. The third symptom cluster consists of disturbed emotional states. Disturbed emotional states include pervasive negative cognitions and beliefs about the self and the world (eg, feelings of worthlessness, hopelessness, shame, and guilt), a sense of estrangement and detachment in interpersonal relationships (eg, emotional numbing), and the inability

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Case 13-1 A 29-year-old man presented with worsening depressive symptoms, sleep disturbance, and irritability. The patient was a veteran who had deployed twice to Iraq and Afghanistan over the past few years. During his last deployment, his vehicle was hit directly with an improvised explosive device (IED). He experienced blast-related neurotrauma with a brief loss of consciousness. Upon awakening, he was covered in blood and found the severed head of the vehicle’s driver resting on his legs. He was horrified, nauseated, and confused. He recalled vomiting once and managed to get himself and his gear to a secure position, although he did not recall the details. He only had partial memories of being rescued and evacuated to a military hospital in Germany. Upon his return to the United States, he began to experience chronic insomnia and had frequent nightmares in which his convoy was attacked, as well as less frequent but severely distressing flashbacks of his friend’s severed head. In some nightmares, he carried the bloody head with him on missions, and woke up drenched in sweat, unable to forget the empty stare in his friend’s eyes. Previously an outgoing and friendly person, the patient had become withdrawn and practically home-bound in an effort to avoid any situation that would remind him of his military experiences. He was easily startled, hypervigilant, and suspicious. He was unable to cope with crowded, open spaces and always had to seek out the nearest exit when he was in a room. He also increased his alcohol intake and admitted to occasional cannabis use ‘‘to relax.’’ Unable to work, he lost his home to repossession and moved in with a childhood friend. He reported their relationship as positive and supportive. He began speaking to his brother again but thought it was too effortful to find common ground between them. His friends and relatives noticed increased irritability and violent outbursts in response to minor frustrations. He has one child with his estranged wife who could no longer cope with his behavior and moved out, taking the child, who he had not seen in 5 months. Comment. This patient’s clinical presentation is consistent with a diagnosis of posttraumatic stress disorder (PTSD) with prominent intrusive, avoidance, and hypervigilance symptoms. Coexistent substance misuse adds to the complexity of the problem. Overall, the disorder has a chronic course and has a major impact on interpersonal relationships, occupational functioning, and general well-being.

to experience positive emotions and derive gratification from enjoyable activities (ie, anhedonia). In the DSM-IV, these symptoms were included in the avoidance dimension,3 but in the DSM-5, they form part of a distinct domain. Furthermore, at least two of these symptoms

FIGURE 13-1

within the cluster need to be present to substantiate a PTSD diagnosis. Finally, the fourth symptom cluster involves alterations of arousal and reactivity, a complex psychopathologic construct that includes physiologic responses such as an exaggerated startle response,

Posttraumatic stress disorder (PTSD) symptom clusters. Symptoms from each cluster should be present to support a PTSD diagnosis.

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h Significant comorbidity exists between posttraumatic stress disorder, mood disorders, chronic pain, and substance misuse. Complex posttraumatic stress disorder is associated with a history of childhood abuse, maladaptive personality traits, defective impulse control, and self-injurious behaviors.

h The Clinician-Administered Posttraumatic Stress Disorder Scale for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (CAPS-5) is a semistructured interview that is considered the gold standard for posttraumatic stress disorder diagnosis. Severity of symptoms can be also assessed by the Posttraumatic Stress Disorder Checklist for the DSM-5.

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irritability, angry outbursts, aggressive behavior directed at the self or others, hypervigilance, and sleep disturbance. Furthermore, recent studies of large numbers of deployed veterans suggest that this symptom cluster may actually consist of two interrelated components with different biological substrates: dysphoric arousal (ie, irritability, anger, aggression, and sleep disturbance) and physiologic arousal (ie, increased startle and hypervigilance) (Figure 13-1).4 Intrusive and hyperarousal symptoms tend to predominate in the initial phases of PTSD, while avoidance and negative emotional states are more prominent in the chronic phases of the disease. In fact, some evidence suggests that alterations in arousal and reactivity are strong predictors of the severity of symptoms corresponding to other domains. PTSD is a heterogeneous disorder with subtypes possessing distinct pathophysiologic mechanisms requiring specific therapeutic approaches. For instance, complex PTSD has been associated with a history of early traumatic experiences and an altered developmental process resulting in maladaptive personality traits with significant alterations in emotional regulation. Complex PTSD is characterized by a poorly integrated self-image, disturbed interpersonal relationships, frequent dissociative experiences, somatization, defective impulse control, and self-destructive behaviors. Dialectic behavioral therapy can be an efficacious treatment for this group of patients with PTSD.5 PTSD rarely presents as an isolated condition. An extensive degree of comorbidity exists with mood disorders, other anxiety disorders, chronic pain, and substance misuse. For instance, the vast majority (98%) of Vietnam veterans have at least one concurrent psychiatric diagnosis. Comorbid with PTSD, chronic pain and addictive disorders are observed frequently among Operation Iraqi Free-

dom, Operation Enduring Freedom, and Operation New Dawn veterans.6 DIAGNOSIS PTSD is diagnosed on the basis of the subjective reports of the affected subjects and occasionally through relevant collateral information of the patient’s intimates using the DSM-5 criteria. Thus, a clinical evaluation by a knowledgeable clinician remains the cornerstone of a reliable assessment. Several structured interviews have been developed to facilitate an accurate diagnosis in both clinical and research settings, with the gold standard being the Clinician-Administered PTSD Scale for the DSM-5 (CAPS-5), developed at the National Center for PTSD.7 The CAPS-5 is a structured interview assessing the frequency and intensity of each PTSD symptom using behaviorally anchored rating scales and providing continuous and dichotomous scores for current and lifetime PTSD symptoms. The scale assesses the 20 PTSD symptoms listed in the DSM-5 and obtains information regarding symptom onset, duration, and functional impact. The full interview takes approximately 50 minutes. The severity of PTSD symptoms can also be assessed using the PTSD Checklist for the DSM-5, which is a 20-item self-report questionnaire that measures the severity of a particular DSM-5-defined PTSD symptom on a 4-point ordinal scale ranging from 0 (not at all) to 4 (extremely).8 Although structured interviews were designed to be administered by clinicians with ample expertise in psychopathology, they can also be administered by appropriately trained research personnel. A summary of the instruments used for the diagnosis of PTSD is presented in Table 13-1.8Y10 EPIDEMIOLOGY Prevalence Traumatic events qualifying as PTSD antecedents (ie, that meet the DSM-5



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KEY POINT

h The lifetime prevalence

Instruments for the Assessment of Posttraumatic Stress Disorder

TABLE 13-1 Instrument

Characteristics

Diagnostic Interview Schedule

Structured interview, dichotomous measure (presence or absence) of 17 posttraumatic stress disorder (PTSD) symptoms

Structured Clinical Interview for DSM-IV

Structured interview, dichotomous measure (presence or absence) of PTSD symptoms as described in the DSM-IV nomenclature

Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)

CAPS-5 is a 30-item questionnaire corresponding to the DSM-5 diagnosis for PTSD

of traumatic events that qualify as antecedents of posttraumatic stress disorder varies between 55.7% and 89.6%. On the other hand, the lifetime prevalence of posttraumatic stress disorder varies between 7.4% and 12.3%.

Comprehensive scale embedded within a structured interview that allows making current and lifetime diagnosis of PTSD as well as the severity of PTSD symptoms during the past week Assesses frequency and intensity of symptoms as well as their repercussion on social and occupational functioning CAPS-5 is considered the gold standard for PTSD diagnosis PTSD Checklist for DSM-5 (PCL-5)

The PCL-5 is a 20-item self-report measure corresponding to the DSM-5 symptom criteria for PTSD The rating scale is 0 to 4 for each symptom corresponding to the following descriptors: ‘‘not at all,’’ ‘‘a little bit,’’ ‘‘moderately,’’ ‘‘quite a bit,’’ and ‘‘extremely’’

DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.

criterion) are frequent in community samples (Figure 13-211). For instance, 69% of US women reported trauma exposure.12 The National Comorbidity Survey (the first large survey of mental health conditions in the United States) reported that 55.7% of 5877 study subjects reported experiencing a qualifying traumatic event during their lifetime.13 The Detroit Area Survey of Trauma found that 89.6% of 2991 study subjects reported a traumatic history.14 These figures are comparable to similar community studies conducted in the Netherlands that found a lifetime prevalence of traumatic events of 80.7%.15 Only a fraction of people exposed to trauma develop PTSD. The prevalence of PTSD in the aforementioned study of Continuum (Minneap Minn) 2015;21(3):789–805

US women was 12.3%.12 Among the individuals enrolled in the National Comorbidity Survey, 7.8% met diagnostic criteria for lifetime PTSD, and approximately one-third had a chronic course.13 The Detroit Area Survey of Trauma reported a PTSD prevalence of 9.2%, while the aforementioned Dutch study reported a 7.4% prevalence.15 Although the unexpected death of a loved one was the most frequent type of trauma reported in these community studies, assaultive violence conveys the highest risk for developing PTSD. Combatrelated violence is the preeminent factor among males, and sexual violence is the strongest predictor among women. When controlling for the type and severity of trauma, women and younger people www.ContinuumJournal.com


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Posttraumatic Stress Disorder

FIGURE 13-2

Life Events Checklist from the National PTSD Center. 11

Reprinted from Weathers FW, et al. National Center for PTSD. www.ptsd.va.gov/professional/assessment/te-measures/life_events_checklist.asp.

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appear to be more vulnerable to PTSD. However, PTSD is increasingly recognized among the elderly. For instance, Spitzer and colleagues16 reported that the prevalence of PTSD was 3.1% in a sample of 851 subjects aged 65 years and older. Risk Factors Most people are resilient in that they do not experience the dangerous psychological and physical consequences of exposure to severe stress seen in patients with PTSD. Although the neurobiology of resilience and vulnerability are intricately connected, specific factors promote either one or the other. Resilience is tied to the deeply rooted circumstances of an individual’s history, particularly his or her childhood experiences. However, the neurobiological substrate of this process has only recently been studied systematically. For instance, animal studies in rodents and ethologic studies in primates indicate that the relationship between the intensity of stress exposure and the expression of an adaptive response has an inverted U-shape, suggesting that both limited and excessive levels of stress experienced during critical developmental periods are associated with long-term maladaptive responses to stress.17,18 Thus, childhood abuse will produce long-lasting changes in stress reactivity as measured by hypothalamic-pituitary-adrenal (HPA) axis response and autonomic nervous system activation.19 Furthermore, a history of childhood abuse is an established risk factor for developing PTSD after adulthood trauma. Women may be at higher risk for PTSD because of variations in hormonal levels. Testosterone and dehydroepiandrosterone (DHEA) levels are correlated positively with resilient behavior,20Y22 while fluctuating levels of ovarian hormones are correlated positively with anxious responses to stress.23 However, Continuum (Minneap Minn) 2015;21(3):789–805

increased oxytocin levels may decrease the risk of stress-related psychopathology.24 Other factors also influence the risk of developing PTSD after trauma exposure. For example, subjects who had lower performance on neuropsychological tasks assessing fluid intelligence (the ability to solve novel problems independently of previously acquired knowledge) were more vulnerable to developing PTSD following trauma.25,26 This finding is consistent with a modulating role of the prefrontal cortex over the limbic structures, where emotions and stress responses are integrated. In the case of military populations, factors inherent to the subjects’ deployment experience, such as the cohesiveness of combat units and command style, also modify the risk of developing PTSD. Moreover, the quality of social support available after deployment influences the onset of stressrelated psychopathology during the process of veterans’ reintegration back into civilian life.27

KEY POINTS

h Sexual-related violence is the preeminent etiology for posttraumatic stress disorder among women, and combat-related violence is the more frequent antecedent among men. Women and younger people appear to be more vulnerable to developing posttraumatic stress disorder after trauma.

h Both limited and excessive levels of stress during developmental years have been associated with abnormal responses to stress. Hormonal variations might be an important factor explaining the increased vulnerability of women developing posttraumatic stress disorder.

Genetic Risk Factors During the past few years, there has been progress in understanding genetic factors associated with PTSD. Conflicting reports have emerged on the effect of different variants of the gene that encodes the serotonin transporter receptor (SLC6A4). Overall, the short allele (s) has been proposed as a vulnerability factor for developing stress-related psychopathology, while the long allele (l) may have a protective effect.28 Different single nucleotide polymorphisms of the gene encoding a chaperone protein that modulates the transcriptional effects of the glucocorticoid receptor (FKBP5) have been associated with an increased risk of developing PTSD among children exposed to physical and sexual abuse.29 In addition, a relatively common single nucleotide polymorphism in the BDNF gene has been shown to influence the process of fear www.ContinuumJournal.com


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h Genetic factors increasing the vulnerability for posttraumatic stress disorder include the presence of polymorphisms in the SLC6A4, FKBP5, and BDNF genes. On the other hand, polymorphisms in the CRHR1 and NPY genes have been associated with decreased risk. Epigenetic modification of the glucocorticoid receptors may also influence stress response.

h Stress-related changes in steroid levels are difficult to interpret because of the effect of coexistent mood disorders in many patients with PTSD. However, evidence indicates an increased hypothalamic-pituitaryadrenal axis feedback suppression. Chronic elevation of adrenergic tone is associated with increased cardiovascular risk, sleep disturbance, and metabolic syndrome.

extinction, a physiologic mechanism relevant to PTSD pathophysiology.30 Different single nucleotide polymorphisms in the gene encoding the corticotropinreleasing hormone receptor 1 (CRHR1) appear to decrease the risk of developing stress-related disorders among women with a history of childhood abuse.31 Similarly, the long-form variant of the neuropeptide Y (NPY) gene has been associated with a decreased risk of developing PTSD.32 Chronic stress may induce epigenetic mechanisms that induce chromatin modifications and changes in gene expression.33 These changes may be associated with either the onset and chronicity of PTSD symptoms or with resilience. Decreased methylation of the glucocorticoid receptor (GR) gene, and the resulting increased levels of glucocorticoid receptors, may be associated with an adaptive response of the HPA axis.34 In addition, epigenetic modifications of the glutamate receptor, ionotropic, AMPA 2 (GRIA2) gene and of different genes within the wingless-type MMTV integration site family, member 1 (WNT1) signaling cascade in the ventral tegmental area and the nucleus accumbens have been observed in rodents resilient to chronic social defeat stress.35,36 PATHOPHYSIOLOGY Hypothalamic-Pituitary-Adrenal Axis Changes Both the HPA axis and the autonomic nervous system play a critical role in coordinating stress responses. Environmental and endogenous stressors activate corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus. This activation results in increased pituitary gland secretion of adrenocorticotropic hormone (ACTH) and, consequently, increased adrenal secretion of corticosteroids and catecholamines. In addition, CRH pathways increase the firing of locus ceruleus

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neurons, resulting in increased adrenergic neurotransmission in both central and peripheral pathways. Both positive and negative feedback loops finely regulate this system that elicits, sustains, and terminates stress responses to reestablish homeostasis.37 Although lower basal cortisol levels were once considered a biomarker of PTSD,38 recent experimental findings using more complex hormonal stimulation and suppression paradigms have challenged this notion. These studies suggest that increased HPA axis feedback suppression occurs in individuals with PTSD. However, the fact that a significant proportion of PTSD subjects have coexistent major depressive disorder, a condition that may cause elevated, nonsuppressed cortisol secretion, makes changes in steroid levels difficult to interpret and might explain conflicting findings.39 Autonomic Changes PTSD has been associated consistently with increased autonomic responses (eg, increased heart rate and blood pressure) to stimuli that are related to the traumatic event. Furthermore, overly sensitized sympathetic responses are associated significantly with the severity of general and dysphoric arousal symptoms.40 Chronic elevation of adrenergic tone has a significant impact on multiple physiologic systems, including dysregulation of cardiovascular responses, circadian rhythms, and the intermediate metabolism of lipids, proteins, and carbohydrates. These autonomic changes result in an increased risk of cardiovascular illness, promote significant sleep disturbance, and produce biological changes akin to the metabolic syndrome. Alterations in Fear Processing Patients with PTSD show impaired fear inhibition. They have difficulty discriminating danger from safety cues and have



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problems suppressing fear in the presence of safety cues.41 Increased amygdala activation resulting from faulty modulatory input from the left ventromedial prefrontal cortex and, to a lesser extent, the hippocampus, underlies fear responses in PTSD.42,43 The amygdala encodes the salience of aversive cues and integrates a reflex response mediated by effector nuclei in the diencephalon and the brainstem. Different regions within the ventromedial prefrontal cortex modulate amygdala function, with the infralimbic cortex inhibiting amygdala output and the prelimbic area facilitating output.44 fMRI studies suggest that the ventromedial prefrontal cortex, particularly the rostral anterior cingulate cortex, is less active during response inhibition tasks in patients with PTSD compared to healthy controls.45Y48 Similar findings have been observed in both female sexual trauma victims with PTSD44 and combat veterans with PTSD.49 The hippocampus also modulates amygdala function through its role in contextual fear conditioning and consolidation of extinction memory.46,50 Repeated exposure to conditioned stimuli (eg, a tone) without coupling them with an aversive event (eg, an electrical shock) leads to a progressive decrease of the behavioral response (eg, freezing) elicited by the conditioned stimuli. This active extinction process requires new associative learning. These extinction memories are consolidated and recalled upon reexposure to the original cues. Although patients with PTSD show normal extinction of conditioned cues, they exhibit altered retention of the extinction memories,47 and their extinction recall is associated with decreased ventromedial prefrontal cortex activation.48 Deficits in fear processing are significantly related to the severity of intrusive and hyperarousal symptoms in PTSD.51 However, other PTSD symptom dimenContinuum (Minneap Minn) 2015;21(3):789–805

sions likely have different neurobiological mechanisms. For instance, rather than originating from decreased prefrontal inhibition of the amygdala, dissociative symptoms might result from enhanced inhibition of this structure. Recent neuroimaging findings suggest that, when compared with patients with PTSD with low levels of dissociation, patients with PTSD who experience severe dissociative symptoms have increased ventromedial prefrontal cortex activation during the processing of aversive symptoms.52 Structural Brain Changes PTSD has been associated with structural changes in the brain, particularly in the prefrontal cortex and the hippocampus. It is unclear whether these changes precede trauma, making the subject more vulnerable to developing psychopathologic conditions, or whether they occur as a consequence of the pathophysiologic changes that result from the disorder. Reduced hippocampal volumes have been consistently reported among subjects with PTSD of different etiologies.53Y55 The volumetric changes are most significant in the subfields of the hippocampus with the greatest concentration of glucocorticoid receptors (ie, CA3/dentate gyrus). Corticosteroids may impair neurogenesis, decrease dendritic branching, and potentiate the excitotoxic effect of glutamate neurotransmission.56 More importantly, these hippocampal changes are associated with memory deficits, which are the most frequent cognitive alterations observed among patients with PTSD.57 Chronic stress also has a deleterious effect on the prefrontal cortex, and atrophic changes can also be observed in patients with chronic PTSD.58 Structural MRI studies demonstrate that the thickness of the ventromedial prefrontal cortex cortical strip is correlated with extinction retention.59,60 Moreover, past research has demonstrated that greater rostral

KEY POINTS

h Patients with posttraumatic stress disorder have difficulty discriminating danger from safety cues and have problems suppressing fear in the presence of safety cues. Functional MRI studies show increased amygdala activation resulting from abnormal modulatory activity of the ventromedial prefrontal cortex.

h Reduced hippocampal volumes have been consistently reported among patients with posttraumatic stress disorder.



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anterior cingulate cortex volume predicted positive outcomes to cognitivebehavior therapy.61 TREATMENT OF POSTTRAUMATIC STRESS DISORDER Psychotherapy Psychotherapy appears to be effective in reducing the severity of PTSD symptoms.62 Although variation occurs in the type of psychotherapeutic techniques and in their clinical implementation, both controlled exposure to aversive memories and cognitive processing constitute the TABLE 13-2

Psychotherapy for the Treatment of Posttraumatic Stress Disorder

Therapy Exposure-Based Systematic desensitization

Content Education, relaxation techniques, in crescendo exposure to aversive memories

Eye movement desensitization and reprocessing (EMDR)

Combines traumatic image exposure with simultaneous performance of eye saccadic movements

Stress inoculation

Education, relaxation training, exposure to aversive memories, role playing, guided self-dialogue

Prolonged exposure

Education, exposure to traumatic memories, confrontation, cognitive restructuring

Virtual reality exposure

Exposure to computerized, vividly recreated environments

Cognitive-Based Trauma-focused psychodynamic therapy

Education, free association, dream interpretation, cognitive restructuring

Cognitive processing therapy

Education, limited exposure to traumatic memories, Socratic questioning, identification of maladaptive cognition and automatic thoughts, cognitive restructuring

Acceptance and commitment therapy (ACT)

Acceptance, defusion, contact with the present moment, self as context, values, committed action

Other Biofeedback

Mindfulness-based cognitive therapy

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cornerstone of successful approaches. The most important alternatives are summarized in Table 13-2.63Y69 A meta-analysis of therapeutic trials comparing cognitive processing and exposure-based therapies with either being on a waiting list or engaging in supportive control interventions revealed that, at least in the short term, active therapies produced significant reductions in PTSD symptoms. The mean effect sizes were moderate to large, with smaller effects observed in the case of combat-related PTSD,70 and some studies

Voluntary regulation of physiologic responses (eg, muscle activity, heart rate variability, online functional MRI [fMRI] bold signal) Meditation techniques, awareness, breath-focused imagery, silent repetition of words, and letting go of intrusive thoughts



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have yielded negative results. For example, a large US Department of Veterans Affairs cooperative study of 360 Vietnam veterans with PTSD revealed that traumafocused group therapy (a standardized protocol incorporating elements of both exposure and cognitive-retraining therapies) was not superior to a supportive control intervention.71 Conversely, the same researchers reported that, in a group of 60 Vietnam veterans with chronic military-related PTSD, 12 sessions of cognitive-processing therapy were associated with a significant reduction in PTSD symptoms.72 Acceptance and commitment therapy (ACT) and mindfulnessbased cognitive therapy are ‘‘third wave’’ cognitive and behavioral approaches that have recently been studied as alternatives for PTSD treatment. They have not proven to be more efficacious than other established treatments.67 Of note, meta-analytic studies of randomized clinical trials suggest that a significant proportion of patients with PTSD will either drop out or fail to respond to psychotherapeutic treatment.73 Pharmacotherapy Pharmacologic treatment of PTSD can be targeted either to prevent the onset of PTSD after trauma exposure or to reduce the severity of PTSD symptoms once the condition is established. A recent meta-analysis of preventive interventions concluded that there was some evidence that hydrocortisone, given acutely after trauma, might prevent the onset of PTSD. In contrast, there was no evidence that propranolol, benzodiazepines, or selective serotonin reuptake inhibitors (SSRIs) had a preventive effect. However, the clinical trials included in the analysis were small and had multiple methodologic flaws.74 A recent meta-analysis of pharmacologic interventions to reduce the severity of PTSD symptoms suggests that active pharmacologic agents are more effecContinuum (Minneap Minn) 2015;21(3):789–805

tive than placebo.75 However, the size effects observed in the more rigorous controlled trials were modest and usually smaller than those observed in controlled trials of psychotherapeutic options. In addition, no effectiveness studies comparing medications with psychotherapy exist, and little evidence exists that the combination of medications with psychotherapeutic treatment has a synergistic effect. Because PTSD symptoms are heterogeneous and have different pathophysiologic mechanisms, it is unlikely that one particular medication will be equally efficacious in treating all PTSD symptomatic clusters (eg, intrusive symptoms, avoidance, dysphoric experiences). Furthermore, the longitudinal course of PTSD may influence efficacy, as a pharmacologic agent might be more effective in the early stages of the disorder than in the more refractory, chronic period. A summary of the medications that have shown some efficacy in treating PTSD is presented in Table 13-3. Given their safety profile, SSRIs are the agents of choice when initiating pharmacotherapy. Previous studies have shown that sertraline,76 paroxetine,77 and fluoxetine78 are significantly more efficacious than placebo in reducing the severity of PTSD symptoms. This effect is modest and subject to differences in gender, type of traumatic event, refractoriness of PTSD, and symptom clusters. For example, PTSD in military populations appears to be less responsive to treatment with SSRIs. Findings from a randomized double-blind trial performed in 10 US Department of Veteran Affairs medical centers indicate that sertraline is not more effective than placebo to treat combat-related PTSD.79 Serotonin norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine might be more effective in treating PTSD. A recent international multicenter study of 329 patients with PTSD randomized

KEY POINT

h Both controlled exposure to aversive memories and cognitive reprocessing are efficacious psychotherapies for treatment of posttraumatic stress disorder, but they tend to be less effective in combat-related posttraumatic stress disorder.



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TABLE 13-3

Summary of the Medications That Have Shown Some Efficacy in Treating Posttraumatic Stress Disorder

Class/Group

Drug

Total Daily Dosage

Antidepressants Selective serotonin reuptake inhibitors

Fluoxetine

20Y60 mg/d

Sertraline

50Y200 mg/d

Paroxetine

20Y60 mg/d

Citalopram

20Y40 mg/d

Venlafaxine

75Y300 mg/d

Venlafaxine extended release

75Y225 mg/d

Duloxetine

40Y60 mg/d

Amitriptyline

50Y300 mg/d

Imipramine

50Y300 mg/d

Monoamine oxidase inhibitors

Phenelzine

15Y90 mg/d

Other

Mirtazapine

7.5Y45 mg/d

Propranolol

40Y160 mg/d

Clonidine

0.2Y0.6 mg/d

Guanfacine

0.5Y3 mg/d

Prazosin

2Y10 mg/d

Divalproex sodium or valproic acid

500Y2000 mg/d

Serotonin norepinephrine reuptake inhibitors

Tricyclic antidepressants

Sympatholytic Beta-blockers !2 Receptor agonists !1 Receptor antagonists Mood Stabilizers

Lithium

600Y1500 mg/d

Carbamazepine

400Y1000 mg/d

Topiramate

50Y200 mg/d

Risperidone

0.5Y6 mg/d

Antipsychotics

Anxiolytics Benzodiazepines 5-HT1A receptor agonists Other N-methyl-D-aspartate (NMDA) antagonists

Olanzapine

5Y20 mg/d

Quetiapine

25Y300 mg/d

Aripiprazole

5Y15 mg/d

Alprazolam

0.25Y4 mg/d

Clonazepam

0.5Y4 mg/d

Buspirone

15Y60 mg/d

D-Cycloserine Ketamine

8Y12 mg/d 0.5 mg/kg/d IV

IV = intravenous.

to receive either extended-release venlafaxine or placebo for 24 weeks showed significantly greater reduction of

800

Clinician-Administered PTSD Scale for the Diagnostic and Statistical Manual of Mental Disorders (CAPS) total scores in



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the venlafaxine-treated group. Venlafaxine extended release was well tolerated, and dropouts from side effects were similar in the active and placebo groups.80 Antiadrenergic agents may have an effect on certain PTSD-symptom dimensions. For instance, the !1 receptor antagonist prazosin is efficacious in reducing the frequency and severity of intrusive symptoms (eg, nightmares).81 Conversely, the !2 receptor agonist guanfacine was no more effective than placebo in reducing the severity of combat PTSD symptoms.82 Mood stabilizers such as lithium, valproate, and carbamazepine have been largely ineffective in treating PTSD, but might be useful for those patients with coexistent bipolar disorder. In the same way, topiramate might reduce impulsivity and decrease substance misuse in patients with PTSD with these comorbidities. The use of benzodiazepines to treat PTSD is discouraged given their addictive potential and the possibility of aggravating avoidance and depressive symptoms. Finally, although the use of antipsychotics is discouraged in this group of patients, the atypical neuroleptics might constitute a last-resort solution to control disturbing psychotic symptoms. New pharmacologic agents are currently under study in patients with PTSD. These include corticotropin-releasing factor type 1 (CRF1) receptor antagonists83 and modulators of glutamate neurotransmission. For instance, a recent study showed significant beneficial effects of the N-methyl-D-aspartate (NMDA) antagonist ketamine when given intravenously.84 Combined Strategies Exposure therapy works by consolidating new, more adaptive memories of traumatic events. Glutamate transmission and NMDA receptors partly mediate this reconsolidation process. D-Cycloserine, a modulator of the glycine site of NMDA receptors, was studied with exposure Continuum (Minneap Minn) 2015;21(3):789–805

therapy to optimize treatment outcomes. Although initial studies were encouraging, a larger trial had negative results.85 However, pharmacologic modulation of extinction learning is an active area of research, and other combined approaches are expected in the near future. Overall, although different pharmacologic agents have proven to be more efficacious than placebo to reduce the severity of PTSD symptoms, a significant proportion of patients with PTSD display a limited response to these medications. There is a need to develop new alternatives and integrate them into a comprehensive program that should include established psychotherapeutic options, such as prolonged exposure or cognitive-behavioral therapy. CONCLUSION Stress-related psychopathology, including mood disorders and PTSD, is the most frequent psychiatric condition affecting approximately one-fourth of the world’s population sometime during their lifetime. Stress responses are influenced by genetic variables, early environmental factors, and the effect of stressful life situations experienced along the human development cycle. PTSD is related to a particular set of stressors associated with severe trauma. Although the latter is ubiquitously experienced, the number of individuals who develop PTSD is relatively small. Recent advances in the conceptualization of the disorder along with progress in translational neuroscience, neuroimaging, and neurophysiologic techniques have invigorated this field of research and started to elucidate the mechanisms behind an individual’s vulnerability or resilience to develop this disabling disorder. Although efficacious therapies are currently available, an important group of patients with PTSD show only modest therapeutic benefits and are at risk of deleterious medical and psychosocial outcomes. There is a

KEY POINTS

h Medications are modestly more effective than placebo to treat posttraumatic stress disorder symptoms. Selective serotonin reuptake inhibitors are considered a safe initial choice. Antiadrenergic agents like prazosin were shown to reduce the frequency and severity of nightmares and may contribute to decreased hyperarousal.

h Pharmacologic modulation of fear conditioning and extinction is an area of active research for the treatment of posttraumatic stress disorder.



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