A cross psychotherapeutic schools, an individual's response to adversity is often the major focus of psychotherapeutic attention. From this perspective, painful, frightening, frustrating experiences have led to a constricted and self-defeating view of the self and others, and to persistent maladaptive behavior. The therapeutic goal is to assist the patient to achieve mastery and freedom from these recurring reactions, which are of limited relevance to present day circumstances.1 Some authors have thus reconceptualized all therapy as concerned with traumatic experience. Such a perspective can promote an empathie alliance in a therapeutic context, but has little use when the clinician is confronted with the task of differential diagnosis for the purpose of recommending specific treatment.
The clinical treatment of Posttraumatic Stress Disorder (PTSD) requires an integrated perspective on psychopathology, as it is a disorder with both psychological précipitants and biological consequences. A simple causal model that separates psychological and biological paradigms fails to account for the complexity of symptoms and impairment that afflict these individuals. Thus, rational treatment strategies will often combine somatic and psychosocial treatment modalities.2
Individuals often present in search of explanations that will make their plight understandable, with preconceived notions about the relative contributions of environment and biology to their distress. Modern research, however, suggests that most explanatory models of psychiatric disorder are multifactorial and require the employment of complementary clinical perspectives.3
Rigorous research on the specific role that traumatic experiences play in the major mental disorders is only just emerging. For example, various authors have reported high rates of traumatic events in such diverse disorders as major depression, borderline personality disorder, schizophrenia, panic disorder, all anxiety disorders, dissociative disorders, conversion disorders, somatization, and other personality disorders, among both clinical and nonclinical populations.4-13 Across the spectrum of disorders, it is unclear at present whether traumatic experiences represent nonspecific stressors that provoke the emergence of latent vulnerabilities, play a specific causal role, or are irrelevant to the psychopathology in question.
Victims of traumatic experiences are often profoundly demoralized. They may struggle with intense reactions of powerlessness, rage, alienation, and guilt. Within this spectrum of responses to trauma, however, a common constellation of symptoms was described in 1980 (DSM-III) as Posttraumatic Stress Disorder (PTSD), based on several decades of stress response research. As currently defined in the DSM-IV, the trauma must involve a significant threat to oneself or others that evoked emotions of intense fear, helplessness, or horror.
Preliminary research in this area focused primarily on war veterans. It has recently been recognized, however, that between 1% and 3% of Americans have suffered the full syndrome of PTSD.14*17 In vulnerable communities and groups who have suffered severe trauma, the incidence is considerably higher. In one retrospective study of urban adults in Detroit, Michigan, the lifetime prevalence was 9.2%. 18 Rothbaum et al found that 47% of sexual assault victims had PTSD 3 months after the attack.19 In a group of 124 holocaust survivors, 47% still suffered from the full PTSD syndrome several decades afterward, and the incidence increased with exposure to the most extreme atrocities.20 Symptomatology was severe for virtually the entire group and included sleep disturbance (96%), recurrent nightmares (83%), poor concentration (67%), and physiologic reactivity (60%).
Posttraumatic reactions may occur immediately after the event or after a delay of many years. The majority of individuals who suffer severe traumatic events will experience some symptoms, usually some symptoms of increased arousal, intrusive and disturbing thoughts, and imagery of the traumatic scene,21 such persons may meet DSM-IV criteria for Acute Stress Disorder in the immediate aftermath. Once symptoms have persisted for 1 month or more, the diagnosis of PTSD is applicable.
The trauma that provokes PTSD is not necessarily a single event; in fact, evidence suggests that the likelihood of developing PTSD increases with cumulative exposure to traumatic events.22
The symptoms of PTSD have been grouped into three clusters:
1. persistent reexperiencing of the trauma as flashbacks, nightmares, or vivid intrusive memories;
2. behavioral and emotional avoidance of reminders of the trauma, with emotional numbing and detachment; and
3. increased autonomic arousal with prominent physical symptoms of anxiety.
Once an individual begins to avoid circumstances and thoughts that provoke these intensely dysphoric reactions, there may be a downward spiral of withdrawal, increasing symptoms, demoralization, and social and occupational impairment. Warshaw et al found that patients with PTSD had the worst overall functioning in a large Anxiety Disorders cohort (N=688), with significantly higher suicide attempts (30%), psychiatric hospitalization (48%), major depression (76%), alcohol abuse and dependence (38%), and work disability (25%).23
Herman and van der Kolk have proposed the existence of a condition that results from prolonged, severe, recurrent trauma, called Disorder of Extreme Stress (DESNOS), or "complex PTSD."24 The concept refers to a diffuse pattern of comorbid symptoms seen in some severely traumatized individuals in diverse domains such as affective, anxiety, dissociative, impulse control, and substance abuse. It also includes more complex and enduring effects of trauma on the personality, including the capacity to form and maintain intimate relationships, handle ordinary stresses and disappointments, or use normal protective mechanisms in dangerous situations. At present, this hypothesis awaits empirical validation, as does the clinical corollary that addressing and processing the trauma is important to complete recovery. After review of existing data, the DSM-IV work group did not find sufficient grounds at present to propose this as a tentative category.
A number of factors appear to influence the posttraumatic response in a particular individual. The type of trauma often directly relates to the content of reexperienced memories and individual patterns of avoidance (avoiding subways for a crime victim; avoiding automobiles for crash victims; avoiding dating for rape victims). A more severe trauma tends to cause worse symptoms and disability, although this is clearly not the only influential factor in the genesis of PTSD. McFarlane found that the intensity and severity of intrusive symptoms were the best predictor of subsequent PTSD among firefighters involved in a natural disaster.21 Other factors that may increase the likelihood of developing PTSD include younger age; sustaining physical injury; the perception of a serious threat of injury or death; the use of physical force by the abuser; and, for war veterans, participation in aggressive acts.12'16 Struggles over personal responsibility and guilt may accompany and intensify the symptoms, regardless of how realistic such impressions may be.
A prior history of psychological problems or psychiatric disorder has also consistently been shown to increase the likelihood of developing PTSD after a serious traumatic event.15 In one survey of victims of a mass shooting in which 24 persons were killed by a single gunman in a cafeteria, 97% of individuals experienced some symptoms.25 A full 20% of men and 36% of women developed PTSD; the majority had no prior psychiatric disorder. However, more than half of those with preexisting depression or anxiety disorders did develop PTSD. Some clinicians in the field have been concerned that such data may be distorted as placing blame on the victim, although the existence of prior distress or disorder in no way implies moral or personal culpability. In fact, further understanding of the patient's particular vulnerabilities should have useful therapeutic implications.
A family history of psychiatric disorder also represents a vulnerability.21»25 In a large group of Vietnam-era veterans (¿V=8084), inheritance substantially influenced liability for all symptoms of PTSD.26 Genetic factors accounted for 13% to 30% of the variance in the reexperiencing cluster, 30% to 34% in the avoidance cluster, and 28% to 32% in the arousal cluster. Shared environment made no significant contribution to liability. Consistent with prior studies, more severe combat exposure (a measure of severity of trauma) was associated with more intrusive memories as well as behavioral avoidance.
Several authors have found that individuals meeting criteria for Borderline Personality Disorder (BPD) are more likely to report early and severe childhood trauma, in comparison to other clinical populations.27-29 Unlike individuals with PTSD, however, these patients often do not connect these experiences with current difficulties, nor do they necessarily reexperience these early traumatic events directly. Herman et al found that PTSD symptoms did not correlate with severity of trauma, whereas dissociative symptoms did in patients with BPD.27
Clearly, other factors are also influential, as all abused individuals do not develop such symptoms and behaviors, and all patients with Borderline Personality Disorder do not report histories of early severe abuse. Those who do appear to have more comorbid diagnoses such as substance abuse and eating disorders.29 Such data suggest that the relationship between trauma, PTSD, and other psychiatric disorders may be critically important and poorly understood.
Likewise, the much publicized controversy surrounding recovered memories is not relevant to PTSD, as persons with PTSD are unable to suppress already conscious memories and associated emotional responses. Treatment is primarily directed toward alleviating symptoms and desensitizing patients to the associated reactions. An uncovering therapy would theoretically only be indicated when memories are dissociated from consciousness, but creating symptoms.
BIOLOGY OF PTSD
Perceived threat and acute stress provoke a robust, acute systemic response human and animal studies, with increased locus ceruleus activity, sympathetic arousal, and Cortisol and opioid release. Posttraumatic symptoms have been viewed as conditioned emotional responses that originate in an actual experience of perceived threat, and then generalize beyond the original cue.30'31 The conditioned reaction recurs in the presence of meaningfully related stimuli and in thematically congruent nightmares.32 It is likely that the associated physiology of these reactions eventually produces the chronic biological abnormalities observed in PTSD.33
The complex biological phenomena of PTSD may thus be most parsimoniously viewed as the sequelae of centrally driven, chronically elevated fear responses. These can appear in cognitive, behavioral, biological, affective, and interpersonal domains.
Investigators have recently linked a number of well-researched animal models of stress to various aspects of the clinical phenomena of PTSD, including inescapable shock, time-dependent sensitization, fear-orientated startle response, experimental neurosis, and long-term potentiation.33 The relevance and limitations of each to the clinical syndrome in humans is controversial. Perhaps the most widely researched of these is inescapable shock, in which the repeated presentation of an inescapable severe stressor results in behavioral and biologic aberrations.34 This constellation of behaviors has been described as "learned helplessness," and refers to marked passivity, diminished responsiveness to environmental stimuli, and inability to recognize and learn subsequent opportunities to escape from aversive stimuli. This model was originally proposed as a paradigm for human depression, but has been reconceptualized as a possible model of some aspects of PTSD.35»36 Inescapable repetitive shock produces significant biological abnormalities in animals in concordance with profound behavioral changes.37 Similarly, biological research in individuals with chronic PTSD has demonstrated associated and probably interrelated abnormalities in serotonergic, noradrenergic, endocrine, endorphin, and sleep systems.38
The primary endocrine abnormality in PTSD appears to be dysregulation of the hypothalamicpituitary-adrenal (HPA) axis.39 In acute stress, Cortisol is rapidly released, and activates systemic processes which promote vigilance, physical exertion, and increased endurance.40 The effects of chronic stress, however, are more relevant to PTSD. Taken together, most studies suggest an overall lowering of Cortisol secretion, simultaneous with an exaggerated responsiveness of the Cortisol system. It is worth noting that abnormalities of Cortisol regulation can have widespread effects on multiple organ systems.
Diminished serotonergic functioning is also associated with severe anxiety symptoms in PTSD patients.41 Serotonergic pathways are involved in regulation of the amygdala, hippocampus, and locus ceruleus. Although little is known at present, it is reasonable to speculate that the SSRIs may exert their diverse clinical effects through these common pathways.
PHARMACOTHERAPY OF PTSD
Clinically, it is useful to distinguish between core symptoms, which are the primary PTSD criteria; and the associated symptoms, such as panic attacks, major depression, aggressive outbursts, or substance abuse, which appear to follow from the trauma. This distinction is critical so as not to confuse improvement in PTSD with improvement in symptoms of depression and anxiety, which are often responsive to treatment. To evaluate outcome, the core symptoms are further subdivided into the three major clusters of reexperiencing, avoidance, and hyperarousal.
We are aware of only seven randomized, controlled pharmacotherapy trials in PTSD.4250 The generalizability of these studies is handicapped by differences on critical variables such as subject population, study design, type of trauma, chronicity of symptoms, length of treatment, dropout rate, and comorbid affective, anxiety, personality, and substance abuse disorders. In particular, several lines of evidence suggest that US war veterans and civilians with PTSD are distinct populations. Often, veterans have already tried other pharmacologic and psychosocial treatments, defining the group as treatment refractory. Comorbid substance abuse may also limit treatment efficacy. For example, in van der Kolk's study of fluoxetine, outcome differed between war veterans and patients in a trauma clinic.
Four categories of antidepressants and an antianxiety agent have been studied in PTSD. Iniipraniine, amitriptyline, and desipramine - all tricyclic antidepressants - have been investigated in war veterans.43-46 Both Imipramine and amitriptyline were moderately effective for core PTSD symptoms in 8-week trials. Desipramine was not effective, but the 4-week trial was too brief to be considered definitive. Associated symptoms of depression and anxiety improved in the amitriptyline study, but not with Imipramine. Most importantly, approximately two thirds of veterans in the amitriptyline study still met criteria for PTSD at the conclusion of the study.
Phenelzine, an antidepressant monoamine oxidase inhibitor (MAOI), has shown mixed results in two studies. In two reports of a continuous study, Kosten and Frank et al found phenelzine superior to placebo and particularly helpful with core symptoms of intrusion, with a trend toward improvement in avoidance.44'45 All patients were also receiving psychotherapy. Phenelzine also appeared superior to Imipramine, although the observed differences were not statistically significant (44% vs 25% on the Impact of Event Scale50). In a related study of a subset of these patients, low alexithymia predicted improvement in avoidance but not in intrusive symptoms in all groups.52
In contrast, phenelzine was not effective in a small, crossover, 5-week study of civilians and veterans with chronic severe PTSD (N=IO).47 Because MAOI therapy necessitates following a tyramine-free diet and avoiding certain medications, and carries the risk of hypertensive crisis if the diet is not followed, it is generally reserved for patients who have not benefited from other medications. However, under proper supervision, it is safe and at times uniquely effective for a range of affective and anxiety disorders.
Alprazolam, a high-potency benzodiazepine usually prescribed for panic attacks, showed only modest benefit for anxiety symptoms in a 5week crossover study of a mixed group of veterans and civilians with severe chronic PTSD (iV=10).48 This suggests that pharmacologic treatment of PTSD requires more than symptomatic relief from generalized anxiety. It carries the additional risk of dependence and abuse in patients with histories of addiction, a common comorbidity in PTSD.
A promising study was recently reported by van der Kolk et al with fluoxetine, a selective serotonergic reuptake inhibitor (SSRI), in a 5week study of two groups: 31 war veterans and 33 civilian patients in a trauma clinic.49 The trauma clinic group showed significant improvement in the core PTSD symptoms of reexperiencing and emotional numbing, and the associated symptoms of depressed mood, labile affect, and distorted interpersonal relationships. By contrast, the veterans improved in depressive symptoms but not in core PTSD symptoms. The dropout rate in the medication group was 36% versus 13% in the placebo group, with a trend toward statistical significance. Improvement in the core symptom of hyperarousal was minimal in both groups on fluoxetine. There was no improvement in hostility, dissociative symptoms, somatization, or avoidance, but the study was probably too brief for patients to overcome entrenched patterns of avoiding reminders of the trauma.
Finally, an international, multicenter, 14week trial was recently conducted with brofaramine in PTSD patients who had experienced a full range of civilian and military traumatic events.50 Brofaramine is an experimental drug that produces both serotonin uptake inhibition (similar to the SSRIs) and selective, reversible monoamine-? inhibition (similar to phenelzine but without the need for dietary restrictions). Patients did not have comorbid depression, and the final analysis included only those with symptoms for at least 1 year (iV=45). Brofaromine produced moderate improvement as measured by both dimensional and global clinical ratings. At conclusion, over half (55%) of patients no longer met criteria for PTSD, versus 26% of those on placebo.
A number of other medications have also shown promise in small uncontrolled trials, such as Clonidine (an alpha-2 agonist),53 carbamazepine (an anticonvulsant and mood stabilizer),54 valproic acid (also an anticonvulsant and mood stabilizer),55 propranolol (a beta-blocker),56 and naltrexone for flashbacks (an opiate antagonist).57
The Columbia University Anxiety Disorders Clinic is currently conducting an open trial with the SSRI paroxetine, which may have superior anxiolytic properties.58»59 An open trial with fluoxetine was abandoned after a significant rate of adverse effects, part of which worsened arousal symptoms, was observed. Our hypothesis is that paroxetine or a similar SSRI will be particularly helpful with symptoms of increased arousal such as agitation, anxiety, and insomnia.
COMBINING PSYCHOTHERAPY AND PHARMACOTHERAPY
Several therapies for PTSD have been investigated under relatively well-controlled conditions, including cognitive-behavioral desensitization, supportive-psychodynamic therapy, hypnotherapy, and stress inoculation training.42 A detailed review is beyond the scope of this article but, in general, all therapies provide an explicit framework that can assist patients in overcoming demoralization, residual fears, helplessness, expectations of recurrence of the trauma, and avoidance. When Brom et al. randomly assigned 112 individuals to approximately 3 months of traumatic desensitization, supportive-psychodynamic, hypnotherapy, or a "waiting list" control group, all therapies were significantly more effective than the control.60 This is not particularly surprising, however, because the experience of having treatment postponed 3 months is clearly not a credible treatment, and therefore would not provide a placebo benefit in a chronic disorder such as PTSD. There were no differences between the therapies when directly compared to each other, indicating an overall finding that the similarities in clinical benefit greatly outweighed any differences between treatments. The authors concluded there was also some evidence of specificity for the three forms of treatment, all of which explicitly addressed posttraumatic problems.
Differences did appear between treatments in comparison to the wait-list control. In the acute trial, desensitization and hypnotherapy were most effective with intrusive symptoms, whereas psychodynamic therapy was more helpful with avoidance symptoms. Minor differences between the therapies diminished at follow up, as psychodynamic therapy patients showed further improvement in intrusive symptoms. When the total battery of outcome measures was reviewed, the authors concluded that Horowitz's posttraumatic therapy (which combines psychodynamic and cognitive treatment principles) showed the most robust outcome for PTSD symptoms, general psychiatric symptoms, and maladaptive personality scores. This conclusion awaits replication. Finally, there were unexpected improvements in personality variables such as self-esteem, general social inadequacy, and trait anxiety, which may indicate that personality assessments in PTSD are confounded with symptom states.
The overall finding is largely consistent with Jerome Frank's hypothesis that credible psychotherapies share common mechanisms of change which are largely responsible for benefit. That is, that psychotherapy persuasively counters demoralization by coupling an optimistic viewpoint to a coherent, experientially valid therapeutic framework.61 Preliminary research, however, suggests that a therapy that focuses specifically on the trauma is most effective. All trauma-focused therapies encourage the patient to articulate in detail their traumatic experience. The act of overcoming avoidance by confronting the traumatic memory and experiencing the associated effects within a supportive relationship may be the common mechanism of efficacy across trauma therapies. Because of the intensity of negative affect involved, a nondirective therapy that does not specifically encourage and support the patient to confront the traumatic memory may collude with the patient in emotional and behavioral avoidance.
A substantial proportion of patients completing both medication and psychotherapy studies are improved but not recovered. Thus, current clinical practice must be informed but not entirely determined by research findings. There is no systematic evidence that medication interferes with psychotherapy, contrary to traditional dogma. Our experience, in fact, suggests that in many cases, the combination of an effective medication with psychotherapy is the most rapid and efficient means of providing symptomatic relief and helping patients overcome disability resulting from traumatic experiences. It is also likely that PTSD is a heterogeneous syndrome with a wide range of treatment responsiveness across modalities. There is no firm guideline, but if a patient remains markedly symptomatic after 3 to 4 months of psychotherapeutic work, medication treatment should be considered.
This raises the issue of presenting the option of medication to a patient in psychotherapy. If the treatment is shared by a psychotherapist and psychopharmacologist, an open, collaborative relationship in which both clinicians convey support and respect for both approaches is essential. The patient's symptoms can be framed within a multifactorial model that acknowledges biological factors. Medicine may be presented as facilitating the patient's own efforts to surmount his or her problems. In particular, medication can ease the process of overcoming avoidance of situations and overwhelming feelings associated with trauma.
Ms. A is a 22-year-old single college student, living with her mother and supporting herself parttime as a home health aide. She presented to our research clinic suffering with vivid intrusive images of being sexual abused, accompanied by extreme anxiety and derealization. Her alcoholic father had frequently fondled her genitals and breasts, while threatening her to keep silent about the abuse, from age 5 to age 12. She also witnessed her father frequently assaulting and physically injuring her mother. The abuse stopped when her mother took her two daughters and left him, in spite of threats of retribution.
The patient had always been aware of and disturbed by the abuse, but the full PTSD syndrome appeared to have been precipitated by a recent breakup with her boyfriend, whom she described as emotionally abusive, callous, and unfaithful. These memories and associated severe anxiety reactions occurred in numerous contexts, including infrequent visits to her father, dating, attempting to confide in friends, and witnessing any media event, film, or article related to child abuse or neglect.
Her schoolwork had deteriorated in the previous 6 months, and she was failing classes for the first time. She had become increasingly withdrawn from friends and suspicious of people in general, such that there were few social supports in her present life. She also felt emotionally numb, hopeless about her future, and fearful of sexual relationships with men. She experienced constant generalized anxiety with a heightened startle response, nightmares with chronic insomnia, and lethargy. In the interview, she appeared guarded, despondent, very nervous, and withdrawn. She met criteria for both PTSD and Major Depression at the time of presentation, with the following scores on relevant measures: Davidson PTSD Scale - Intrusion 13, Avoidance 31, Hyperarousal 21,62 and Hamilton Depression Scale 16. 63
Although initially fearful about medication treatment, she began taking paroxetine (10 mg) with gradual dosage increases to 40 mg over 6 weeks. She met weekly with one of the authors (R.M.) in a supportive nondirective treatment to , review symptoms and adverse effects. During the medication trial, no specific exploration of traumatic experiences was encouraged, but did occur in the course of symptom assessment. Within 2 weeks, she noticed improvement in sleep, general anxiety, and fearfulness. Her flashbacks soon remitted and she felt less cautious with others and was willing to pursue friendships and schoolwork. The emotional numbness yielded to a capacity to experience enjoyment, sadness, and anger most easily observed in discussions about her father and previous boyfriend. After 3 months of treatment with paroxetine, her scores were the following: Davidson PTSD Scale - Intrusion 3, Avoidance 0, Hyperarousal 5, and Hamilton Depression Scale 3.
During her psychiatrist's vacation, she discontinued her medication and began to reexperience her previous symptoms, but then decided to continue at the previous dosage. She chose not to confront her father with his abuse, but no longer feared him and felt relatively emancipated from his influence over her. Her attitude toward dating became cautious but positive: she would wait to meet a partner who would treat her respectfully. After 6 months of doing well in trauma-focused psychotherapy while taking paroxetine, she accepted a referral to a women's group for incest survivors to work through remaining interpersonal inhibitions and fears of sexual involvement with a male.
Given the importance of an environmental insult in the genesis of PTSD symptoms, many clinicians first consider a psychosocial treatment. However, there is accumulating evidence that PTSD is associated with significant biological abnormalities, particularly in its chronic manifestation. A small number of controlled studies, mostly in war veterans, suggest moderate efficacy of antidepressant medications for PTSD. Efficacy may be even greater in civilian populations. Fluoxetine proved effective in civilians in a single controlled study. An SSRI with significant anxiolytic properties such as paroxetine might be as effective, with additional benefit for symptoms of hyperarousal. There are no studies that compare medication to psychotherapy nor assess their combination. Until empirical research establishes clear predictors of efficacy that could guide treatment selection, it is our view that psychotherapists should consider medication treatment when the following are present:
* Serious comorbid conditions that are known to respond to medication. Examples include psychosis, major depression, panic disorder,64 and social phobia.65
* Preexisting conditions that are medication responsive. A careful history may reveal, for example, a prior history of panic disorder that recurred after the traumatic event and that contributes to the patient's current disability. Although a trial of psychotherapy for panic disorder is another option, medically treating the panic attacks allows a more immediate focus on the trauma.
* A history of prior failure of an adequate trial of psychotherapy (approximately 3 months) for PTSD.
* Individuals who are not psychologically minded, who prefer medication treatment, or who otherwise appear unable to enter into a collaborative psychotherapeutic relationship. Patient preference must be considered. The psychotherapies and pharmacotherapies require different kinds of commitments. Pharmacotherapy requires a willingness to take medicine, to work with a clinician in adjusting dosage, and to report adverse effects. This may in turn require preparatory psychoeducation for persons with preconceived notions about what constitutes appropriate treatment. Many individuals perceive the taking of psychiatric medication as shameful and a sign of moral or personal failure. The clinician must be alert to correct such harsh and inaccurate self-judgments.
* The absence of significant improvement after 3 to 4 months of psychotherapy based on empirically validated treatment principles for PTSD. Although data is currently lacking, persisting beyond 2 to 3 months without considering medication treatment seems unwarranted.
* A patient's inability to tolerate the overwhelming effects associated with PTSD psychotherapy. Anecdotal evidence suggests that a medication can sufficiently relieve symptoms such that therapy is able to proceed successfully.
1. Frank JD. Persuasion and Healing. Rev. ed. Baltimore, MD: Johns Hopkins University Press; 1973.
2. Hamilton NG, Sacks LH, Hamilton CA. Object relations theory and pharmacopsychotherapy of anxiety disorders. Am J Psychother. 1994; 48:380-391.
3. McHugh P, Slavney P. The Perspectives of Psychiatry. Baltimore, MD: Johns Hopkins University Press; 1983.
4. Bifiilco A, Brown GW, Adler Z. Early sexual abuse and clinical depression in adult life. Br J Psychol. 1991; 159:115-122.
5. Servant D, Bailly D, Allard C, Parquet PJ. Major depression in panic disorder: role of recent comorbidity. J Affect Disord. 1991; 22:79-82.
6. Servant D, Parquet PJ. Early life events and panic disorder: course of illness and comorbidity. Prog Neuropsychopharmacol Biol Psychiatry. 1994; 18:373-379.
7. Muenzenmaier K, Meyer I, Struening E, Ferber J. Childhood abuse and neglect among women outpatients with chronic mental illness. Hosp Community Psychiatry. 1993; 44:666-670.
8. Fierman EJ, Hunt MF, Pratt LA, et al. Traumatic and posttraumatic stress disorder in subjects with anxiety disorders. Am J Psychiatry. 1993; 150:1872-1874.
9. Bowman ES. Etiology and clinical course of pseudoseizures. Psychosomatics. 1993; 34:333-342.
10. Pollack MH, Otto MW, Rosenbaum JF, Sachs GS. Personality disorders in patients with panic disorder: association with childhood anxiety disorders, early trauma, comorbidity, and chronicity. Compr Psychiatry. 1992; 33:78-83.
11. Faravelli C, Webb T, Ambonetti A, Fonnesu F, Sessarego A. Prevalence of traumatic early life events in 31 agoraphobic patients with panic attacks. Am J Psychiatry. 1985; 142:1493-1494.
12. Brier J, Runtz M. Symptomatology associated with childhood sexual victimization in a nonclinical adult sample. Child Abuse Negl. 1988; 12:51-59.
13. Brown GR, Anderson B. Psychiatric morbidity in adult inpatients with childhood histories of sexual and physical abuse. Am J Psychiatry. 1991; 148:55-61.
14. Davidson JRT, Hughes DL, Blazer DG, George LK. Posttraumatic stress disorder in the community: an epidemiological study. Psychol Med. 1991; 21:713-721.
15. Heizer JE, Robin LN, McEvoy L. Post-traumatic stress disorder in the general population: findings from the Epidemiological Catchment Area Survey. N Engl J Med. 1987;317:1630-1634.
16. Davidson J, Smith R. Traumatic experiences in psychiatric outpatients. J Trauma Stress. 1990; 3:459-475.
17. Shore JH, Vollmer WM, Tatum EL. Community patterns of post traumatic stress disorders. J Nerv Ment Dis. 1989; 177:681-685.
18. Breslau N, Davis GC, Andreski P, Peterson E. Traumatic events and post-traumatic stress disorder in an urban population of young adults. Arch Gen Psychiatry. 1991; 48:216-220.
19. Rothbaum BO, Foa EB, Riggs DS, Murdock T, Walsh W. A prospective examination of post-traumatic stress disorder in rape victims. J Trauma Stress. 1992; 5:455-475.
20. Kuch K, Cox BJ. Symptoms of PTSD in 124 survivors of the Holocaust. Am J Psychiatry. 1992; 149:337-340.
21. McFarlane AC. Avoidance and intrusion in posttraumatic stress disorder. J Nerv Ment Dis. 1992; 180:439-445.
22. Breslau N, Davis GC. Posttraumatic stress disorder: the etiologic specificity of wartime stressors. Am J Psychiatry. 1987; 144:578-583.
23. Warshaw MG, Fierman E, Pratt L, et al. Quality of life and dissociation in anxiety disorder patients with histories of trauma or PTSD. Am J Psychiatry. 1993; 150:1512-1516.
24. Herman JL. Complex PTSD: a syndrome in survivors of prolonged and repeated trauma. J Trauma Stress. 1992; 5:377-391.
25. North CS, Smith EM, Spitznagel EL. Posttraumatic stress disorder in survivors of a mass shooting. Am J Psychiatry. 1994; 151:82-88.
26. True WR, Rice J, Eisen SA, et al. A twin study of genetic and environmental contributions to liability for posttraumatic stress symptoms. Arch Gen Psychiatry. 1993; 50:257-264.
27. Herman JL, Perry C, van der Kolk BA. Childhood trauma in Borderline Personality Disorder. Am J Psychiatry. 1989; 146:490-495.
28. Zanarini MC, Gunderson JG, Marino MF, et al. Childhood experiences of borderline patients. Compr Psychiatry. 1989; 30:18-25.
29. Shearer SL, Peters CP, Quaytman MS, Ogden RL. Frequency and correlates of childhood sexual and physical abuse histories in adult female borderline inpatients. Am J Psychiatry. 1990; 147:214-216.
30. Kolb LC. A neuropsychological hypothesis explaining posttraumatic stress disorders. Am J Psychiatry. 1987; 144:989-995.
31. Kolb LC. A critical survey of hypotheses regarding posttraumatic stress disorders in light of recent research findings. Journal of Traumatic Stress. 1988; 1:291-304.
32. Pitman RK, Orr SP, Forgue DF, deJong JB, Claiborn JM. Psychophysiologic assessment of post-traumatic stress disorder imagery in Vietnam combat veterans. Arch Gen Psychiatry. 1987; 44:970-975.
33. Yehuda R, Antelman SM. Criteria for rationally evaluating animal models of posttraumatic stress disorder. Biol Psychiatry. 1993; 33:479-486.
34. Petty F, Kramer G, Wilson L. Prevention of learned helplessness: in vivo correlation with cortical serotonin. Pharmacol Biochem Behau. 1992; 43:361-367.
35. Van der Kolk BA, Greenberg M, Boyd H, Krystal J. Inescapable shock, neurotransmitters, and addiction to trauma: toward a psychobiology of post traumatic stress disorder. Biol Psychiatry. 1985; 20:314-325.
36. Foa EB, Zinbarg R, Rothbaum BO. Uncontrollability and unpredictability in post-traumatic stress disorder: an animal model. Psychol Bull. 1992; 112:218-238.
37. Southwick SM, Brenner D, Krystasl JH, Charney DS. Psychobiologic research in post-traumatic stress disorder. Psychiatr Clin North Am. 1994; 17:251-264.
38. Davidson J. Drug therapy of post-traumatic stress disorder. Br J Psychiatry. 1992; 160:309-314.
39. Friedman MJ. Biological approaches to the diagnosis and treatment of post-traumatic stress disorder. J Trauma Stress. 1991; 4:67-91.
40. McEwen BS, De Kloet ER, Rostene W. Adrenal steroid receptors and actions in the nervous system. Physiol Rev. 1986;66:1121-1188.
41. Arora RC, Fichtner CG, O'Connor F, Crayton JW. Paroxetine binding in the blood platelets of post-traumatic stress disorder patients. Life Sci. 1993; 53:919-928.
42. Solomon SD, Gerrity ET, Muff AML. Efficacy of treatments for posttraumatic stress disorder. JAMA. 1992; 268:633-638.
43. Davidson J, Kudler H, Smith R, et al. Treatment of posttraumatic stress disorder with amitriptyline and placebo. Arch Gen Psychiatry. 1990; 47:259-266.
44. Frank JB, Kosten TR, Giller EL, Dan E. A randomized clinical trial of phenelzine and Imipramine for post traumatic stress disorder. Am J Psychiatry. 1988; 1145:1289-1291.
45. Kosten TR, Frank JB, Dan E, McDougle CJ, Giller EL. Pharmacotherapy for posttraumatic stress disorder using phenelzine or Imipramine. J Nerv Ment Dis. 1991; 179:366-370.
46. Reist C, Kauñman CD, Haier RJ. A controlled trial of desipramine in 18 men with post-traumatic stress disorder. Am J Psychiatry. 1976; 146:513-516.
47. Shestatsky M, Greenberg D, Lerer B. A controlled trial of phenelzine in posttraumatic stress disorder. Psychiatry Res. 1984;24:149-155.
48. Braun P, Greenberg D, Dasberg H, Lerer B. Core symptoms of posttraumatic stress disorder unimproved by alprazolam treatment. J Clin Psychiatry. 1990; 51:236-238.
49. van der Kolk BA, Dreyfuss D, Michaels M, et al. Fluoxetine in posttraumatic stress disorder. J Clin Psychiatry. 1994;55:517-522.
50. Katz RJ, Lott MH, Arbus P, et al. Pharmacotherapy of posttraumatic stress disorder with a novel psychotropic. Anxiety. In press.
51. Horowitz M, Wilner N, Alvarez W. Impact of event scale: a measure of subjective stress. Psychosom Med. 1979; 41:209-218.
52. Kosten TR, Krystal JH, Giller EL, Frank J, Dan E. Alexithymia as a predictor of treatment response in posttraumatic stress disorder. J Trauma Stress. 1992; 5:563-573.
53. Kinzie JD, Leung P. Clonidine in Cambodian patients with posttraumatic stress disorder. J Nerv Ment Dis. 1989; 177:546-550.
54. Lipper S, Davidson JRT, Grady TA, et al. Preliminary study of carbamazepine in post-traumatic stress disorder. Psychosomatics. 1986; 27:849-859.
55. Fesler FA. Valproate in combat-related posttraumatic stress disorder. J Clin Psychiatry. 1991; 52:361-364.
56. Kolb LC, Burns BC, Griffiths S. Propranolol and Clonidine in the treatment of post-traumatic stress disorders of war. In: van der Kolk BA, ed. Post-traumatic Stress Disorder: Psychological and Biological Sequelae. Washington, DC: American Psychiatric Press; 1984:98-105.
57. Bills LJ, Kreisler K. Treatment of flashbacks with naltrexone. Am J Psychiatry. 1993; 150:1430.
58. De Wilde J, Spiers R, Mertens C, Bartholome F, Schotte G, Leyman S. A double-blind, comparative, multicentre study comparing paroxetine with fluoxetine in depressed patients. Acta Psychiatr Scand. 1993; 87:141-145.
59. Marshall RD, Printz D, Cardenas D, Abbate L, Liebowitz MR. Adverse events in patients with PTSD and panic attacks on fluoxetine. Am J Psychiatry. 1995; 152:1238. Letter.
60. Brom D, Kleber RJ, Defares PB. Brief psychotherapy for posttraumatic stress disorders. J Consult Clin Psychol. 1989; 57:607-612.
61. Frank JD.Therapeutic components shared by all psychotherapies. In: Harvey JH, Parks MM, eds. Psychotherapy Research and Behavior Change. Washington, DC: American Psychological Association; 1982:5-38.
62. Book S, Tupler L, Roth S, et al. The Davidson Traumatic Stress Scale: validity and reliability. Poster presented at Anxiety Disorders of America Association; 1995.
63. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960; 23:56-62.
64. Klein DF. Treatment of panic disorder, agoraphobia, and social phobia. Clin Neuropsychopharmacol. In press.
65. Marshall RD, Schneier FR, Feerick J, Fallon BA, Liebowitz MR. Medication therapy for social phobia. J Clin Psychiatry. 1994; 55:33-37.