Post-Traumatic Stress Disorder Alcoholism pathophysiology.
Matthew A. Friedman, Ph.D., M.D.
The world can be a dangerous place. From earliest prehistoric times to the current moment, men, women and children have been confronted by overwhelming events. On balance, humans have coped successfully with catastrophic stressors such as sabre-tooth tiger attacks, earthquakes, war, genocide, rape, and torture. The evolutionary process has played a crucial role in this regard by selecting, preserving, and fine-tuning a number of psychobiological adaptive mechanisms that have promoted survival of the human species.
Indeed, humans are well-equipped psychobiologically to respond to the many different kinds of stressors that are encountered in the course of a lifetime. Sometimes, however, the stress is so great that the adaptive capacities of most persons are taxed to the utmost, if not exceeded. In a clinical context, such stressors have been defined as "traumatic," and they sometimes precipitate post-traumatic stress disorder (PTSD). In my opinion, humans exposed to traumatic stressors utilize the same psychobiologic mechanisms that are activated following exposure to a less severe, ordinary stressor. Whereas successful adaptation is followed by a restoration of normal homeostatic balance, unsuccessful coping results in stable psychobiologic abnormalities that may be expressed clinically as PTSD.
We will return to this point later in this chapter when we describe abnormalities in psychobiological coping mechanisms that have been detected in PTSD patients. We will show how conceptualizing these abnormalities from the perspective of coping and adaptation is useful for understanding the etiology, pathophysiology, and clinical phenomenology of this disorder. We will also evaluate current PTSD treatment from this conceptual approach. First, however, we must consider the clinical phenomenology and diagnostic criteria for PTSD.
Robert J worked the night shift at a small convenience store in rural New England. He was a happily married, Caucasian, 42-year-old father of three school-aged children who was in excellent health and who had neither a personal nor a family history of psychiatric illness, alcoholism, or substance abuse. One night in November, 1995, two men wearing ski masks entered his store while he was alone. Each had a gun. The taller man placed the barrel of his gun against Robert's temple and ordered him to hand over all the money in the cash register. When this had been done, he was pushed towards the interior of the store, between two stacks of shelves and pushed face-down onto the floor. He was gagged, his hands and feet were tied, and the first robber again placed his gun against Robert's head and said, "I'm going to blow your brains out!" Robert's terror was overwhelming. He didn't want to die. He had so much to live for. His heart raced, he perspired profusely, and his whole body shook. He took a deep breath, heard the click of the hammer against the empty chamber of the gun, and his whole body slumped with disbelief when he realized that he had literally been the butt of the cruelest kind of joke. He vaguely remembers the gruff laughter of the two robbers before they made their escape. Then he passed out.
At first, Robert could only think about how happy he was to still be alive. He regarded his wife and children with new found love and appreciation. But as grateful as he felt about a second chance in life, he also experienced growing discomfort during his tour of duty at the convenience store. He really didn't want to go to work because he kept replaying the robbery in his mind, visualizing the men in ski masks, feeling the gun against his head, and reexperiencing the panic that had engulfed him during this episode. In response to advice from his family doctor, he took a month's leave of absence to "settle his nerves." When he returned to the store, however, he was worse than before. The familiar sights of the cash register and merchandise displayed on the shelves, all reminded him of how terrified he'd been during the hold-up. Sometimes, he even thought he saw men in ski masks lurking in the shadows behind the shelves, although he knew that his mind was playing tricks on him. He started making serious errors at the cash register, pressing the wrong keys, or giving the wrong change because he couldn't concentrate on the task at hand?so absorbed was he in his repetitive recollections of the robbery. Nightmares occurred at least four times a week that were reenactments of the crime. In the most frequent and vivid nightmare, he saw himself bound and gagged face down on the floor when a man in a ski mask shot him in the head and he woke up screaming. It got so bad that he was afraid to go to sleep at night, so great was his dread of this nightmare. Eventually, he had to quit his job, so terrified had he become at work. Later he found that he couldn't even go near the convenience store, because just seeing the scene of the crime evoked intolerable feelings of terror and recollections of the robbery. He found himself obsessed with fear about personal safety. Whereas he had previously been an open, easy-going, happy-go-lucky individual who was extremely popular, he was now fearful, withdrawn, irritable, jumpy, suspicious, and unable to focus on any task long enough to work at a steady job. He also found any intense (positive or negative) emotional experience intolerable and withdrew from his wife and children as well.
CLINICAL PHENOMENOLOGY AND DIAGNOSTIC CRITERIA
Individuals can only develop PTSD if they have been exposed to a traumatic event. As operationalized in the DSM-IV ( 2 ) and shown in Table 1 (as the "A1" criterion), traumatic events "involve actual or threatened death or serious injury, or a threat to the physical integrity of oneself or others." Certainly the potentially lethal assault with a gun experienced by Robert J meets this definition, as does exposure to war, torture, genocide, nuclear attack, natural disasters or industrial accidents. When PTSD was first introduced as a diagnostic entity in the DSM-III ( 3 ), it was thought that such events were "beyond the range of normal human experience." Unfortunately, we have learned since that time that exposure to trauma is not a rare event. As shown in Table 2 (abstracted from ref. 37 ) more than half of all American men (60.7%) and women (51.2%) have been exposed to at least one traumatic event in the course of their lives.
All adverse events are not traumatic. Indeed, very painful stressors such as divorce, failure, rejection, serious illness, financial reverses and the like do not meet the DSM-IV "A1" criterion. Serious psychological reactions to such vicissitudes of life are characterized as Adjustment Disorders rather than PTSD. This dichotomization between traumatic and other stressors is based on the assumption that although most individuals have the ability to cope with ordinary stress, their adaptive capacities may be overwhelmed by a traumatic stressor.
Clinical experience with the PTSD diagnosis has shown that most people who are exposed to a catastrophic event do not develop PTSD. Indeed, there are vast individual differences regarding the capacity to cope with a traumatic event, and different people may have different psychological responses to the same catastrophic event. Such observations have prompted a recognition that trauma, like pain, is not an external phenomenon that can be completely objectified. Like pain, the traumatic experience is filtered through a cognitive and emotional process called appraisal ( 44 ). Therefore, the same event may be appraised by some as a severe threat, while others will consider it a challenge with which they can cope. Because appraisal plays such an important role in the psychological processing of a catastrophic event, DSM-IV added the "A2" criterion ( Table 1 ) to the definition of trauma; "the individual's response must involve an intense emotional reaction such as fear, helplessness, or horror." In other words, exposure to a catastrophic event can only be considered traumatic if such exposure precipitates an intense emotional reaction. This is certainly true for Robert J who was appropriately terrified and fearful that he would be shot in the head during his frightening ordeal.
The "B" or re-experiencing criterion includes symptoms that are perhaps the most distinctive and readily identifiable manifestations of this disorder. For individuals with PTSD, the traumatic event remains, sometimes for decades or a lifetime, a dominating psychological experience that retains its power to evoke panic, terror, dread, grief, or despair as daytime intrusive recollections, as traumatic nightmares, and as psychotic re-enactments known as PTSD flashbacks. For Robert J, such reexperienced symptoms were so severe that he could not keep his mind on his work, eventually had to quit his job, and could not sleep at night because of nightmares about the robbery. PTSD symptoms are often triggered by stimuli or situations that are reminiscent of the initial traumatic event. For that reason, researchers can reproduce PTSD symptoms in the laboratory by exposing affected individuals to stimuli that are associated with the original traumatic event ( 50, 61 ). That is why fear conditioning has been proposed as one conceptual model for PTSD ( 40 ). Robert J exhibits this phenomenon in a number of ways. First, he became initially symptomatic when reexposed to the stimuli of the convenience store where he expected to be murdered. Sometimes when he was alone in the store, he became so terrified that he had PTSD flashbacks in which he "saw" his assailants hiding behind the shelves. As time progressed, just the sight of the store, itself, triggered intolerable recollections of the robbery. This shows how trauma-related stimuli (related to the store) changed the behavior of a man who had never exhibited such fears before the robbery. This also illustrates how PTSD patients appraise the world as a dangerous place and become easily alarmed by any stimulus that has become associated with the traumatic experience.
The "C" or avoidant/numbing criterion consists of symptoms reflecting behavioral, cognitive, or emotional strategies by which PTSD patients attempt to reduce the likelihood that they will either expose themselves to trauma-related stimuli, or, if exposed, will minimize the intensity of their psychological response. Behavioral strategies include avoiding any situation in which they perceive a risk of confronting such stimuli. In its most extreme manifestation, avoidant behavior may superficially resemble agoraphobia, because the person with PTSD is afraid to leave the house for fear of confronting reminders of the traumatic event(s). For Robert J avoidant behaviors included quitting his job and later avoiding even the sight of the convenience store where the trauma took place.
Numbing symptoms are psychological, rather than behavioral, strategies by which individuals reduce or obliterate the conscious experience of trauma-based memories and feelings. Such symptoms include amnesia for traumatic events, dissociation, feelings of detachment, and a restricted range of affect. Individuals with PTSD cannot tolerate strong emotions, especially those associated with the traumatic experience. They separate the cognitive from the emotional aspects of psychological experiences and perceive only the former. Such "psychic numbing" is an emotional anesthesia that makes it extremely difficult for people with PTSD to participate in meaningful interpersonal relationships. That is why Robert J withdrew emotionally from his wife and children.
Criterion "D" includes arousal symptoms such as insomnia, irritability, and inability to concentrate (all exhibited by Robert J) that are often found in other anxiety disorders such as panic and generalized anxiety disorder. Hypervigilance and an exaggerated startle response (both also exhibited by Robert J) are more characteristic of PTSD. Hypervigilance is a manifestation of the traumatized person's perpetual surveillance of his environment to detect any signs of danger that might provoke another traumatic episode. The hypervigilance in PTSD may sometimes become so intense as to appear like frank paranoia. The agitation and jumpiness seen in PTSD is a manifestation of the exaggerated startle response, a hard-wired neurological reflex that is abnormally resistant to extinction in patients with this disorder ( 40, 74 ).
PTSD symptoms must persist for at least one month to meet the "E" or duration criterion. As described, Robert J exhibited PTSD symptoms very soon after the robbery. This is not PTSD at this point but rather "acute stress disorder" according to DSM-IV. Most people will recover from acute stress disorder. When symptoms persist for a month or more, as with Robert J, the PTSD "E" criterion has been met.
Finally, Robert J met the "F" criterion because his PTSD caused clinically significant distress and impairment with regard to marital, family, social, and vocational function.
In the National Comorbidity Survey, Kessler and associates ( 37 ) reported that the lifetime prevalence of PTSD among American men and women was 5.0% and 10.4% respectively. As shown in Table 3, lifetime prevalence among men and women who have actually been traumatized is 8.1% and 20.4% respectively. It is important to emphasize in this regard that the majority of people exposed to a traumatic event do not develop PTSD. For women, especially, exposure to interpersonal violence (rape, molestation, physical attack, and physical abuse) is especially predictive for the later development of PTSD. Twice as many women (33.2%) as men (17.8%) have been exposed to interpersonal violence. This difference may help explain the finding that PTSD lifetime prevalence is approximately twice as great among American women as men. Although rape is a relatively rare event for men (0.7%) compared to women (9.2%; Table 2 ), when it does occur, it is much more likely to cause PTSD among men (65.0%) compared to women (45.9%; Table 3 ). These data also demonstrate that exposure to interpersonal violence is more likely to cause PTSD than a traumatic event that lacks a human perpetrator, such as a natural disaster with fire.
With respect to Robert J's trauma, threat with a weapon is not uncommon among American men (19.0%) although very few (1.9%) attribute their PTSD to this kind of traumatic event. It may have been that in Robert's case, the severity of this threat was unusually great since the barrel of the gun had been pressed against his head, the robber had threatened to shoot him, and he was completely convinced that he was going to be killed. It is also possible that Robert himself was particularly vulnerable to develop PTSD. As will be shown subsequently, there are number of risk factors that predict the later development of PTSD, including trauma severity, experiential and familial factors, and the post-traumatic recovery environment.
In general, epidemiologic research on PTSD has focused on a limited number of selected populations at risk such as: military veterans, sexual assault survivors, and natural disaster survivors (see comprehensive review, ref. 17, for references), although a few investigators have studied the prevalence of PTSD among victims of crime ( 38, 59 ). Even the literature on the Nazi holocaust has been inconsistent in relating its results to PTSD (see ref. 42 ). In general, much less attention has been paid to cohorts exposed to domestic violence, urban violence, physical abuse, child abuse, or other traumas. Indeed, from a PTSD perspective, it is frustrating to contemplate the large literature in the abuse and violence fields because it usually doesn't go far enough. It is not enough to know whether an individual has been exposed to sexual/physical abuse or domestic/urban violence, since the majority of traumatized people do not develop PTSD. It is equally important to know whether or not such traumatic exposure resulted in PTSD. In epidemiologic research on infectious diseases, both vector (infectious agent) and host (susceptibility to infection) are considered important factors. We must do the same in PTSD research and address both vector (traumatic exposure) and host (vulnerability to PTSD) factors.
In order to understand why some traumatized people develop PTSD while most do not, it is useful to consider three different domains in which individual differences may affect vulnerability: appraisal tendencies; constitutional/genetic variables; and specific risk factors. First, as noted earlier, the appraisal or subjective response to a traumatic event may differ from one individual to another. Some people may be more likely to perceive situations as frightening or threatening than others. That is why the DSM-IV definition of trauma has been expanded to stipulate that exposed individuals must experience "intense fear, helplessness, or horror" (the "A2" criterion) for that exposure to be considered "traumatic."
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Second, Yehuda and McFarlane ( 89 ) have hypothesized that there is a constitutional vulnerability that distinguishes traumatized people who develop PTSD from the majority of traumatized people who never exhibit the disorder. It's interesting in this regard to consider the early work of Cohen, White and associates ( 12 ) on World War II veterans with "neurocirculatory asthenia" (NCA). Many, if not most, of these veterans appear to have had what would now be called PTSD. After characterizing the medical and psychiatric symptoms of these individuals, Cohen, White and associates went on to conduct family studies, since they had concluded that there was a genetically mediated vulnerability for NCA ( 11 ). In that regard, it might be said that Cohen and White anticipated Yehuda and McFarlane's hypothesis regarding a constitutional vulnerability to PTSD almost 50 years ago. Evidence for a genetic risk for developing PTSD has also been obtained from a study of male monozygotic twins who served in Vietnam who were compared with their identical siblings who also served in the military but not in Vietnam ( 28 ).
The third domain in which individuals differ with respect to vulnerability to develop PTSD concerns specific risk factors. When considering risk factors for PTSD, it is useful to divide them into pre-traumatic, traumatic, and post-traumatic factors. Pre-traumatic risk factors that have been identified in a number of studies (see review by Fairbank et al., 17) include: 1) familial psychiatric illness; 2) parental poverty; 3) childhood trauma (e.g., sexual assault, separated or divorced parents before age 10); 4) childhood behavior disorder; 5) neuroticism; 6) introversion; 7) prior psychiatric disorder; 8) adverse life events before and after the trauma; 9) being female and between the ages of 36 and 50; 10) being concerned about finances; and 11) having prior physical health problems. In the National Comorbidity Survey ( 2 ), PTSD was most prevalent among women, the previously married, and persons of lower socioeconomic status.
Such pre-traumatic risk factors play a small but significant role in predicting PTSD prevalence. Much more important predictors are aspects of the traumatic event itself: severity of exposure; whether a person was injured during the episode; for Vietnam veterans, whether the individual witnessed or participated in atrocities ( 21 ); and for rape victims whether the victim had prior acquaintance with the perpetrator or whether her life was threatened at the time of the rape ( 33 ). Indeed, a robust finding in almost all PTSD research has been a linear dose-response curve between severity of the trauma and the later development of PTSD ( 43, 77, 86 ; see ref. 17 for other references).
Characteristics of the post-traumatic environment have also been shown to be related to the later development of PTSD. Among Vietnam veterans, low levels of post-military social support and dysfunctional patterns of social interaction have been shown to increase the risk for PTSD ( 21, 35 ). Similar findings regarding the deleterious impact of low post-traumatic social support have been shown for rape victims ( 5, 8 ). Finally, there has been considerable speculation regarding the importance of rapid post-traumatic clinical interventions such as critical incident stress debriefing (CISD). Mitchell ( 57 ) has maintained that when CISD is provided as soon after the trauma as possible, it will prevent the later development of PTSD. This is currently a matter of controversy, however, as will be discussed subsequently.
If an individual meets diagnostic criteria for PTSD, it is likely that he or she will exhibit at least one other DSM-IV disorder ( 13, 43 ). In the National Comorbidity Survey, a lifetime history of at least one other psychiatric disorder was found in approximately 80% of all men and women with lifetime PTSD. Among men and women with PTSD, lifetime prevalence of comorbid disorders was approximately 48% for major depressive disorders, 22% for dysthymia, 16% for generalized anxiety disorder, 30% for simple phobia, and 28% for social phobia. Women exhibited greater lifetime prevalence of panic disorder (12.6% to 7.3%) and agoraphobia (22.4% to 16.1%) while men exhibited greater lifetime prevalence of alcohol abuse/dependence (51.9% to 27.9%), drug abuse/dependence (34.5% to 26.9%), and conduct disorder (43.3% to 15.4%) [ 37 ].
We have argued elsewhere ( 26 ) that high rates of comorbid disorders associated with PTSD may actually reflect shortcomings of a nosology (e.g., DSM-IV) that is predicated entirely on phenomenological observations. For example, there is strong neurobiological evidence suggesting that the major depressive disorder (MDD) usually associated with PTSD is different from true melancholia with respect to adrenocortical function. MDD patients without PTSD are often dexamethasone nonsuppressors, while those with PTSD are often dexamethasone supersuppressors ( 87 ). In other words, PTSD plus MDD may not reflect two comorbid disorders (as dictated by current DSM-IV diagnostic decision rules) but rather a depressive subtype of PTSD that is neurobiologically distinct from classic melancholia, MDD. These considerations may also apply to certain anxiety disorders when they are comorbid with PTSD. Clearly, there is an important and exciting focus for future research.
LONGITUDINAL COURSE AND CHRONICITY
Studies on World War II military veterans and Dutch anti-Nazi resistance fighters have shown that PTSD can persist for decades (see review, ref. 70 ). Furthermore, symptoms may actually worsen rather than improve over time. Data from the National Comorbidity Survey suggest that approximately 40% of patients with lifetime PTSD are unlikely to recover whether or not they have ever received treatment. For others, the longitudinal course, as with other chronic medical and psychiatric disorders, is a series of remissions and relapses. When a patient with lifetime PTSD who has been clinically asymptomatic suddenly begins to exhibit the full PTSD pattern of clinical symptoms, the immediate precipitant is usually a situation that resembles the original trauma in a significant way. For example, we might expect that a fully recovered Robert J who had been asymptomatic for many years, might experience a relapse were he again exposed to armed robbery or threat with a dangerous weapon or even if he learned that his wife or child had been similarly traumatized.
As with other medical and psychiatric disorders, PTSD may differ in severity from one person to the next. Some people with this disorder are able to lead productive and fulfilling lives. Others, however, may develop a persistent incapacitating mental illness marked by severe and intolerable symptoms, marital, social, and vocational disability, and extensive use of psychiatric and community services. Such people can often be found on the fringes of society, in homeless shelters, or enrolled in public-sector programs designed for patients with persistent mental illnesses such as schizophrenia from whom they are superficially indistinguishable ( 24 ).
CROSS-NATIONAL AND CROSS-CULTURAL CONSIDERATIONS
The epidemiologic and comorbidity data presented previously are derived from studies of American men and women. Surveys of PTSD in other nations have yet to be done. Extrapolating from current research findings, however, it seems likely that PTSD prevalence will be much higher in nations where the probability of exposure to interpersonal violence and war is great. Indeed, nations such as Rwanda, Bosnia, and Cambodia in which unspeakable genocidal violence has been perpetrated, can be expected to exhibit PTSD prevalence that greatly exceeds that found in the U.S.A.
A number of criticisms have been leveled at the PTSD diagnosis from a cross-cultural perspective. These include: a) conceptualizing PTSD as a culture-bound syndrome; b) rejecting PTSD for failing to incorporate unique psychohistorical dimensions that define the meaning of trauma; and c) rejecting PTSD as a construct because it pathologizes a normal and healthy rehabilitative process that is more suitably characterized as cultural bereavement. We disagree with these criticisms and have argued elsewhere that the PTSD construct has both culture-bound and universal dimensions ( 23 ). That is not to say, however, that there may not be other culture-specific idioms of distress, such as "calor" or "atiques de nervios," that may fall outside strict DSM-IV diagnostic criteria, but which are significant indicators of clinically significant,post-traumatic distress in their own right ( 53 ). In this regard, PTSD may be only one of a spectrum of post-traumatic syndromes that need further explication in future research and clinical practice.
As stated earlier, several key psychobiologic mechanisms that enable humans to cope successfully with stressful situations function abnormally in PTSD patients.
Sympathetic nervous system (SNS) activation, also known as the "fight or flight response" ( 9 ), is a complex reaction in which autonomic and muscular systems are mobilized to cope with a significant threat. PTSD patients exhibit abnormal increases in SNS reactivity as well as adrenergic dysregulation. They exhibit a) autonomic hyperresponsiveness to both neutral and trauma-related stimuli; b) elevated urinary catecholamine levels; c) downregulation of beta- and alpha-2 adrenergic receptors; and d) increased reactivity to the alpha-2 antagonist, yohimbine, which can provoke panic attacks and trauma-related flashbacks in PTSD, but not in non-PTSD, patients (see ref. 78 for references).
Hypothalamic-Pituitary-Adrenocortical (HPA) mobilization, as part of the "general adaptation syndrome" ( 72 ) is another fundamental response that promotes successful coping with stress. The HPA system is also dysregulated in PTSD. Patients exhibit abnormalities such as: a) lower urinary cortisol levels; b) elevated lymphocyte glucocorticoid receptor levels; and c) dexamethasone supersuppression (see ref. 88 for references). We have suggested elsewhere ( 26 ) that the dexamethasone suppression test may have clinical utility as a psychobiologic diagnostic tool in distinguishing patients with PTSD (supersuppressors) from major depressive disorder (MDD; non-suppressors) from non-PTSD/non-MDD (simple suppressors).
The acoustic startle-response is a sequence of muscular and autonomic responses that alert organisms to an impending threat ( 15 ). An exaggerated startle response is one of the diagnostic symptoms of PTSD ( Table 1 ). PTSD patients exhibit: a) shorter latency and increased amplitude of the acoustic-startle-eyeblink reflex ( 74 ); b) significant loss of the normal inhibitory modulation of the startle reflex ( 60 ); and c) resistance to habituation of the startle response ( 75 ).
Fear conditioning is a mechanism by which neutral cues associated with a traumatic (or otherwise aversive) event subsequently acquire the capacity to evoke a conditioned emotional (fearful) response in the absence of the aversive stimulus. First described by Pavlov and associates, this psychological mechanism preserves information about exposure to previous threats in order to promote future survival ( 14 ). In our clinical vignette, the fearful response of Robert J to the previously neutral (or even positive) stimuli of the convenience store illustrates a typical progression of fear conditioning in a PTSD patient.
Appraisal ( 44 ) is a psychological process by which humans evaluate whether a specific situation is potentially dangerous. Coping, adaptation, and survival depend on the capacity of individuals to assess different situations accurately as pleasant, benign, challenging or threatening. PTSD patients have lost this capacity and are much more likely to appraise neutral situations as threatening. This pronounced tendency to perceive the world as dangerous is maladaptive and has serious cognitive, emotional, behavioral, and clinical consequences.
A comprehensive review of the psychobiologic abnormalities present among PTSD patients is beyond the scope of this chapter but can be found elsewhere ( 22 ). It should be stated in passing, however, that other abnormalities detected among PTSD patients in other major psychobiologic systems include: abnormalities in the diurnal sleep cycle, elevated thyroid function, and dysregulation of the opioid system. Less well-established empirically, but strongly supported by pertinent animal research is the likelihood that PTSD is associated with suppressed immunologic function, kindling/behavioral sensitization in limbic nuclei, altered glutamatergic processes with respect to information processing, altered memory function, and abnormal serotonergic activity ( 10, 22, 63, 82 ).
ABNORMALITIES IN BRAIN STRUCTURE AND FUNCTION
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Abnormalities in brain structure and function have been demonstrated in PTSD patients. In three independent laboratories, magnetic resonance imaging (MRI) has shown reduced hippocampal volume among male and female PTSD patients who had been exposed to combat trauma, sexual assault or motor vehicle accidents ( 7, 29, 80 ). One intriguing hypothesis, invoked to explain this finding, is an extrapolation from animal studies showing that sustained stress produces hippocampal degeneration and atrophy of apical dendrites of CA3 hippocampal pyramidal neurons ( 58, 81, 83 ), presumably through release of neurotoxic excitatory amino acids by high levels of glucocorticoids ( 68 ). Thus, it has been proposed that HPA dysregulation associated with PTSD ( 88 ) may also produce hippocampal damage.
Functional brain abnormalities associated with PTSD are suggested by two investigations utilizing positron emission tomography (PET). PTSD subjects exposed to trauma-related stimuli exhibited increased regional cerebral blood flow (rCBF) to limbic and paralimbic areas, especially to the ventral anterior cingulate gyrus and right amygdala ( 65, 76 ). Since both of these brain structures appear to be involved in the recognition and expression of emotions and in the processing of stimuli with affective significance, it is likely that they play important roles in fear conditioning and appraisal. Both PET studies also detected decreased rCBF among PTSD subjects in Broca's area in the left temporal lobe ( 65, 76 ), suggesting that PTSD may also be associated with impaired language function and linguistic processing.
Finally, PTSD patients with substance abuse histories received three consecutive PET scans to measure rCBF while performing the auditory continuous performance task ( 73 ). In comparison with normal subjects, PTSD patients showed decreased rCBF to parietal cortex while simultaneously exhibiting an information-processing deficit related to attentional task performance.
These studies all indicate that PTSD patients exhibit important abnormalities in hippocampal volume and brain function that may be related to impaired cognitive capabilities. As noted by Gurvitz et al. ( 29 ), since these are all cross-sectional studies, they cannot tell us whether these abnormalities were caused by PTSD or whether they represent a pretraumatic abnormality that made these subjects more vulnerable to developing PTSD in the first place.
PSYCHOBIOLOGIC APPROACHES TO DIAGNOSIS
Given the great amount of symptom overlap between PTSD, major depressive disorder, panic disorder, generalized anxiety disorder, and other DSM-IV diagnoses, it is important to identify assessment strategies that might distinguish PTSD from these other psychiatric disorders. We recently reviewed psychobiologic laboratory strategies that have detected abnormalities among PTSD patients and evaluated their potential applicability as clinical tools for distinguishing PTSD from other disorders ( 26 ). At this time, it appears that six psychobiologic approaches may have clinical utility for diagnostic assessment in the foreseeable future:
1. Psychophysiological reactivity,in which PTSD patients exhibit excessive arousal to trauma-related (auditory or visual) stimuli or to autobiographical scripts of their traumatic experiences ( 50, 61 ).
2. Dexamethasone suppression test, in which PTSD patients exhibit supersensitivity to the glucocorticoid dexamethasone, which suppresses HPA function. Therefore, PTSD patients differ significantly from normal subjects, who display normal HPA suppression and from depressed patients, who exhibit nonsuppression ( 88 ).
3. Acoustic startle response, in which PTSD patients show a shorter latency, increased amplitude and resistance to extinction ( 74, 75 ).
4. Hyperresponsiveness to yohimbine (the alpha-2 adrenergic antagonist), which elicits panic attacks in most PTSD patients and trauma-related flashbacks in many ( 78 ).
5. Elevated thyroid function tests, which, for some PTSD patients, may be so high that they are at or near the thyrotoxic range ( 55 ).
6. A unique, 24-hour, urinary neurohormone profile, marked by elevated catecholamines and reduced urinary free cortisol ( 54 ).
This list will undoubtedly grow as new clinically applicable laboratory paradigms are developed for detecting psychobiologic abnormalities among PTSD patients.
Three major treatment approaches are currently available for PTSD patients: cognitive-behavioral therapy, pharmacotherapy, and more traditional individual and group dynamic psychotherapy. Relatively few randomized clinical trials have been published to date, and serious methodological questions can be raised about some of the studies that have been completed. In short, treatment outcome research on PTSD is at an early stage.
Cognitive-behavioral therapy (CBT) is currently regarded as the most successful treatment for PTSD. Foa, Rothbaum, and associates have consistently achieved excellent results providing this treatment to adult female rape victims with PTSD ( 18, 19, 67 ). This technique is currently being tested with other traumatized groups (military veterans, survivors of child abuse, traffic accident survivors), but such data have yet to be published. A CBT approach consists of two components: exposure therapy and anxiety management strategies.
Exposure therapy is a process designed to extinguish the powerful influence of fear conditioning among PTSD patients. Through sustained exposure (usually through a vivid imaginal focus on the traumatic event), the patient's fear-response to trauma-related stimuli becomes markedly reduced. In addition to extinction of the fear response, the patient's SNS/adrenergic hyperreactivity to trauma-related stimuli is also reduced.
Anxiety management training strategies include acquisition of skills for reducing anxiety such as relaxation training, stress inoculation training, biofeedback training, social skills training, distraction techniques, and cognitive restructuring. Cognitive restructuring is probably the most important of these techniques ( 20 ). It is a technique for correcting the distorted appraisal process exhibited by PTSD patients, in which they have a great tendency to perceive danger, even in neutral and innocuous situations.
Although CBT was provided as individual therapy for the rape victims treated by Foa, Rothbaum, and associates, it can also be provided in a group therapy context. Indeed, Resick and associates ( 66 ) have reported on a group psychotherapy technique which consists of psychoeducation, exposure, and cognitive processing therapy. Our research group is currently testing a similar approach in a group therapy context for Vietnam veterans with PTSD.
From the psychobiologic perspective presented earlier, it appears that CBT directly addresses a number of the key abnormalities in PTSD patients. There is great reason to hope that it will prove equally effective with patients whose PTSD is due to a wide variety of traumatic events.
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Given our expanding knowledge of the many neurobiological abnormalities associated with PTSD ( 22 ), pharmacotherapy appears to have a place in PTSD treatment. From a practical perspective, there is no question that drugs can provide some symptomatic relief of anxiety, depression, and insomnia, whether or not they ameliorate core PTSD intrusive and avoidant/numbing symptoms. At this time, no particular drug has emerged as a definitive treatment for PTSD, although medication is clearly useful for symptom relief, thereby making it possible for patients to participate in group, psychodynamic, cognitive-behavioral, or other forms of psychotherapy. Almost all randomized drug trials have been carried out with antidepressants (imipramine, amitriptyline, phenelzine, and fluoxetine) and not with other classes of drugs. Results have been mixed and generally quite modest in magnitude. Patients with severe and chronic PTSD appear to be refractory to pharmacotherapy. A number of promising trials with selective serotonin reuptake inhibitors have raised hopes, recently, that these drugs may prove to be effective drugs for PTSD treatment. There have also been promising results in uncontrolled trials with antiadrenergic agents such as clonidine and propranolol and with anticonvulsant/antikindling agents such as carbamazepine and valproate ( 25 ), indicating that further testing is warranted with these drugs.
When considered from the psychobiologic perspective proposed throughout this chapter, one might conclude that results have been unimpressive thus far because the wrong drugs have been tested. Even though PTSD is biologically distinct from MDD (based on elegant research on the HPA system in both disorders [ 88 ]), most drug trials with PTSD patients have involved antidepressants. There have been no randomized clinical trials with antiadrenergic agents and no trials with drugs that have a primary action on the HPA system. I have suggested elsewhere ( 27 ) that the most effective pharmacotherapeutic approach to PTSD should be with drugs that address the unique pathophysiology of this disorder. In this regard, I believe that one potential focus for future research might be on corticotropin releasing factor (CRF), because CRF activates both the HPA and SNS/adrenergic systems in response to stress. Therefore, CRF antagonists currently being developed by several pharmaceutical companies for human trials may prove to be a very promising family of drugs for treating PTSD patients in the future.
Herman ( 33 ) has shown that therapists working with patients who have survived different kinds of traumatic events (war, natural disasters, etc.) generally agree that therapy can be divided into three phases: a) establishing trust, safety, and "earning the right to gain access" to carefully guarded traumatic material ( 46 ; p. 806); b) trauma-focused therapy: exploring traumatic material in depth, titrating intrusive recollections with avoidant/numbing symptoms ( 34 ); and c) helping the patient disconnect from the trauma and reconnect with family, friends, and society. It should be noted that patients who reach the third phase have achieved some resolution of trauma-specific concerns and are ready to concentrate, almost exclusively, on here-and-now issues concerning marriage, family, work, and other current issues ( 33, 46, 71 ).
Marmar and associates ( 51 ) have suggested that there are five identifiable post-traumatic syndromes, each requiring a different treatment approach: normal stress response; acute catastrophic stress reaction; uncomplicated PTSD; PTSD co-morbid with other disorders; and post-traumatic personality. The normal stress response occurs when healthy adults who have been exposed to a single discrete traumatic event in adulthood experience intense, intrusive recollections, numbing, denial, feelings of unreality, and arousal. It has become generally (but not universally? see below) accepted that most individuals will achieve complete recovery following rapid post-traumatic individual or group interventions, such as critical incident stress debriefing (CISD) [ 4, 57, 64 ]. Often, a single, two-hour group debriefing experience is all that is needed. Such sessions begin by describing the traumatic event. They then progress to an exploration of survivors' emotional responses to the event. Next, there is an open discussion of symptoms which have been precipitated by the trauma. Finally, there is a resolution, in which survivors' responses are normalized and adaptive coping strategies are identified. Recent studies, however, have challenged the effectiveness of CISD. Kenardy and associates ( 36 ) reported that Australian emergency workers did not benefit from debriefing following an earthquake, while Bisson ( 6 ) reported that British burn trauma victims randomly assigned to CISD had worse outcomes than those who did not receive debriefing. In view of the general world-wide belief in the efficacy of CISD, and the lack of randomized clinical trials to support this belief, this is a very important area for current and future research.
Acute catastrophic stress reactions are characterized by panic reactions, cognitive disorganization, disorientation, dissociation, severe insomnia, tics and other movement disorders, paranoid reactions, and incapacity to manage even basic self care, work, and interpersonal functions ( 52 ). Treatment includes immediate support, removal from the scene of the trauma, use of anxiolytic medication for immediate relief of anxiety and insomnia, and brief, supportive, aggressive, dynamic psychotherapy provided in the context of crisis intervention ( 51 ).
Uncomplicated PTSD may respond to group, psychodynamic, cognitive behavioral, pharmacological, or combination approaches. During the past ten years, we have come to appreciate the powerful therapeutic potential of positive peer group treatment as practiced in Vet Centers for military veterans and in rape crisis centers for sexual assault and domestic violence victims. Peer groups provide an excellent therapeutic setting for trauma survivors, because their post-traumatic emotions, memories, and behaviors are validated, normalized, understood, and de-stigmatized. They are able to risk sharing traumatic material in an atmosphere of safety, cohesion and empathy of fellow trauma survivors. It is often much easier to accept confrontation from a fellow sufferer who has impeccable credentials as a trauma survivor than from a professional therapist who never went through those experiences first-hand. When group members achieve greater understanding and resolution of traumatic themes, they must next integrate such themes with their current lives and focus on the present rather than the past ( 33, 71 ).
In brief psychodynamic psychotherapy, trauma survivors focus on the traumatic event itself. Through the retelling of the traumatic event to a calm, empathetic, compassionate and non-judgmental therapist, the patient achieves a greater sense of self-cohesion, develops more adaptive defenses and coping strategies, and more successfully modulates intense emotions that emerge during therapy ( 51 ). The therapist needs to constantly address the linkage between post-traumatic and current life stress by helping the patient identify current life situations that set off traumatic memories and exacerbate PTSD symptoms.
PTSD comorbid with other DSM-IV Axis I disorders is actually much more common than uncomplicated PTSD. As noted earlier, PTSD is usually associated with at least one other major psychiatric disorder such as depression, alcohol/substance abuse, panic disorder, and other anxiety disorders ( 37 ). Sometimes the co-morbid disorder is the presenting complaint that requires immediate attention. At other times, the PTSD appears to be the major problem. In general, the best results are achieved when both PTSD and the co-morbid disorder(s) are treated concurrently rather than one after the other. This is especially true for PTSD and alcohol/substance abuse ( 1, 39 ). Treatment previously described for uncomplicated PTSD should also be used for these patients.
Post-traumatic personality disorder is found among individuals who have been exposed to prolonged traumatic circumstances, especially during childhood, such as childhood sexual abuse. These individuals often meet DSM-IV criteria for diagnoses such as borderline personality disorder, somatoform disorder, and dissociative identity disorder (multiple personality disorder). Such patients exhibit behavioral difficulties (such as impulsivity, aggression, sexual acting out, eating disorders, alcohol/drug abuse, and self-destructive actions), emotional difficulties (such as affect lability, rage, depression, panic), and cognitive difficulties (such as fragmented thoughts, dissociation, and amnesia). Treatment generally focuses on behavioral and affect management in a here-and-now context, with emphasis on family function, vocational rehabilitation, social skills training, and alcohol/drug rehabilitation. Long-term individual and group treatments have been described for such patients (see 33, 41, 71 ). Dialectical behavior therapy, a cognitive behavioral group approach developed by Linehan and her associates for chronically suicidal borderline patients ( 47 ), may also have a role in the treatment of post-traumatic personality disorder. Trauma-focused treatment should only be initiated after long therapeutic preparation. Inpatient treatment may be needed to provide adequate safety and safeguards before undertaking therapeutic exploration of traumatic themes. The three phases of treatment, described earlier, apply to these patients as well as those with uncomplicated PTSD, but treatment may take much longer, may progress at a much slower rate, and may be fraught with much more complexity than with other traumatized patients.
PTSD is a relatively new diagnosis, having been born when the DSM III was first published in 1980 ( 3 ). During the past 18 years, it has proven its legitimacy to many skeptics within the scientific and clinical communities. PTSD researchers have developed elegant assessment techniques (see 79, 85 ) and an empirical foundation that incorporates classic psychological, stress and neurobiological research (see ref. 22 ). With the maturing of this field have come many thoughtful controversies which have both theoretical and clinical implications. At this time, I believe that the most important controversies concern: a) the efficacy of rapid intervention strategies such as CISD; b) the question of whether the memory of a traumatic event can be forgotten and later recovered; and c) the possibility that an additional diagnosis, besides PTSD, is needed to do justice to the wide variety of post-traumatic psychiatric problems.
Critical Incident Stress Debriefing
During the past year, empirical evidence has emerged ( 6, 36 ) that challenges the general belief that clinical interventions such as critical incident stress debriefing (CISD) should be made available as soon as possible after acute traumatization. It is surprising, perhaps, that CISD has become so universally accepted despite the fact that there is no data from randomized clinical trials demonstrating its efficacy as a clinical intervention. Indeed, as noted earlier, two recent studies suggest that CISD is either ineffective ( 36 ) or actually worsens PTSD symptoms ( 6 ) instead of preventing the later development of PTSD, as is generally believed. Obviously, much more research is needed. As we ask ourselves, however, how CISD could have attracted so many strong adherents in the absence of convincing data, the answer may lie in the low prevalence of PTSD among individuals exposed to natural disasters ( Table 3 ). If most people exposed to natural disasters will never develop PTSD, then most people exposed to natural disasters who receive CISD will never develop PTSD. The pertinent question, therefore, is whether individuals most at risk to develop PTSD following acute traumatization will have more favorable outcomes if they receive CISD. Clearly we must move beyond clinical impressions and descriptive studies to rigorous randomized trials if we hope to learn whether CISD can actually prevent the later development of PTSD among acutely traumatized individuals.
The "Recovered" Memories Controversy
A trauma-related controversy that has been fueled by forensic rather than clinical activity concerns the question of "recovered" memories. Adults who were sexually assaulted as children sometimes have no memories of these childhood assaults ( 84 ). Sometimes, such missing traumatic memories later become accessible so that patients regain access to discrete recollections of childhood events such as father-daughter incest ( 31 ). In some cases, there is irrefutable evidence that such childhood trauma actually occurred. In many other cases, there is no proof regarding the veracity of the alleged sexual contact ( 69 ). Although there is little rigorous research on this question, it was recently reported that approximately one-third of such "recovered memories" have emerged during the course of psychotherapy, whereas most such memories had been triggered spontaneously by life events that included significant aspects of the initial trauma ( 30 ). Such a scenario is entirely consistent with a fear conditioning model of PTSD in which pertinent stimuli can evoke trauma-related feelings, or behavior. Some patients who claim to have regained traumatic memories of this nature have confronted parents whom they now regard as perpetrators of childhood sexual trauma. In some cases, they have taken parents to court for these alleged abuses. Sometimes the accused parents vehemently deny that such events ever occurred and maintain that these "traumatic memories" are really emblematic of a "false memory syndrome" that has been manufactured in the course of therapy. Loftus ( 49 ) has written extensively about the problem of authenticating such rediscovered, previously repressed, memories. Williams ( 84 ), on the other hand, has shown that women who were sexually assaulted during childhood (documented by recorded visits to hospital emergency rooms), are sometimes unable to recall that traumatic event. Schacter ( 69 ) has reported that there is adequate proof of a few cases in which traumatic memories were forgotten and later "recovered," but it is not known whether this is an extremely rare or not uncommon event. Although a comprehensive review of this issue is beyond the scope of this chapter, there is general agreement that: a) memory, especially childhood memory, is fallible but not necessarily incorrect; b) documented traumatic events are sometimes forgotten; and c) forgotten memories of documented traumatic events are sometimes "recovered" ( 16, 45, 48, 56, 62 ). When we move from generalities to specifics, especially in a courtroom, it is often difficult to meet legal standards of proof regarding the veracity of a specific traumatic memory. This is especially so when the alleged perpetrator denies participating in such an event, and when there is neither additional evidence nor another witness to support the plaintiff's case. This hotly debated issue has theoretical, clinical, and forensic implications which will need to be sorted out in the future. On a more positive note, this controversy has generated a great deal of exciting new research on basic memory processes and whether such processes utilize different mechanisms for traumatic than for non-traumatic memories.
Finally, clinicians who work with victims of prolonged trauma, such as incest and torture, argue that such patients suffer from a clinical syndrome that is not adequately characterized by the PTSD construct. Although most patients in this category meet PTSD diagnostic criteria, it is argued that their primary problem is not PTSD. Instead, Herman ( 32 ) has proposed a new syndrome which she has named "complex PTSD," characterized by problems with impulsivity, affect regulation, dissociative symptoms, self-destructive behavior, abnormalities in sexual expression, and somatic symptoms. Identification and treatment of these patients has been described previously (post-traumatic personality). The controversy is whether complex PTSD is distinct from PTSD and whether it should have its own diagnostic identity. After much discussion, it was decided not to include complex PTSD in the DSM-IV. The controversy has stimulated a number of research initiatives. It is expected that this issue will be revisited during development of the next revision of the DSM-IV, the DSM-V.
PTSD can be distinguished from other DSM-IV Axis I disorders by the centrality of the event?the trauma?within the diagnostic criteria. A more fundamental difference, in my opinion, is how the pathophysiology of PTSD can be conceptualized as the consequence of a failure to cope with overwhelming stress. Abnormalities exhibited by PTSD patients appear, in part, to represent abnormalities in crucial psychobiologic mechanisms that evolved for coping, adaptation, and survival of the human species. Such a conceptual approach opens the field of psychotraumatology to a rich experimental literature in psychology and neurobiology that is relevant to research on coping and adaptation to stress. This approach also provides a useful frame of reference for understanding both laboratory abnormalities and clinical symptoms exhibited by PTSD patients. A psychobiologic perspective also helps us understand why certain treatments, such as cognitive-behavioral therapy, have been so successful. Finally, and most importantly, this approach may help us design more effective treatments for PTSD patients in the future.