The ASAM Principles of Addiction Medicine 5th Edition

91. Posttraumatic Stress Disorder and Substance Use Disorder Comorbidity

Michael E. Saladin, PhD, Sudie E. Back, PhD, Rebecca A. Payne, MD, Jeremiah Schumm, PhD, R. Jeffrey Goldsmith, MD, and Kathleen M. Chard, PhD

CHAPTER OUTLINE

■  EPIDEMIOLOGY

■  ETIOLOGIC RELATIONSHIP BETWEEN PTSD AND SUD

■  NEUROBIOLOGIC FACTORS IN COMORBID PTSD AND SUD

■  ASSESSMENT OF PTSD IN SUD

■  TREATMENT OF PTSD AND PTSD–SUD COMORBIDITY

■  CONCLUDING COMMENTS

For centuries, the diagnostic condition presently known as posttraumatic stress disorder (PTSD) has been recognized in combat survivors and known by various names, including soldier’s heart, irritable heart, shell shock, and combat neurosis, among others (1). The diagnosis was first formulated and expanded beyond combat-related contexts in the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III), resulting in a growing body of research investigating the etiology, neurobiology, comorbidity, and treatment of the disorder (2). Epidemiologic studies of civilian populations and combat veterans have investigated PTSD and its comorbidities over the past two decades. Results from these studies show that depression, other anxiety disorders, and substance use disorders (SUDs) are common among persons with PTSD. Among civilian populations, the prevalence of lifetime SUDs has been estimated to be between 21.6% and 43.0% in people with PTSD, compared to 8.1% to 24.7% among individuals without PTSD. In one study of Vietnam veterans with PTSD, as many as 75% met criteria for an alcohol use disorder (3). The highly comorbid nature of PTSD and SUDs indicates that persons presenting to treatment for either PTSD or SUD should be screened for both disorders to ensure accurate assessment and appropriate treatment.

In both civilian and combat veteran populations, studies have demonstrated a more complicated clinical course and worse outcomes in persons with comorbid PTSD and SUDs. In general, veterans with comorbid PTSD and SUDs have poorer treatment outcomes than those with SUDs alone on various indices of functioning, including more social and legal problems, suicide attempts, and violence (4). They tend to have longer duration of substance use and more symptoms of substance dependence, undergo more episodes of substance abuse treatment, and demonstrate less improvement during treatment than their counterparts with SUDs alone (4). In one study of civilian women (N = 65) with comorbid PTSD and substance dependence, high rates of suicide attempts (21.5%), suicidal ideation, and parasuicidal behaviors were reported (5). Another study examining the health and well-being of civilian men (N = 65) and women (N = 68) with SUDs, with or without comorbid PTSD, found that the presence of comorbid PTSD was associated with significantly more chronic physical, cardiovascular, and neurologic symptoms as well as poorer mental health functional status and well-being (6). In a sample of Operation Iraqi Freedom veterans (N = 2,863), those with both PTSD and problematic drinking reported worse physical health, more somatic complaints, and more sick employment sick days versus those with PTSD or problematic drinking alone (7). These studies are part of a much larger body of literature examining the impact of comorbid PTSD and SUDs on various parameters of functioning and clearly demonstrate the necessity of a thorough understanding and assessment of persons with PTSD–SUD comorbidity. In this chapter, we address the phenomenology, epidemiology, assessment, and treatment of patients with comorbid PTSD and SUDs to assist clinicians in providing informed and effective care.

PHENOMENOLOGY

The current DSM-IV-TR outlines the following criteria necessary to diagnose PTSD: (a) the occurrence of a traumatic event (criterion A); (b) greater than 1 month of symptoms (criterion E) within the three symptom clusters of reexperiencing (criterion B), avoidance (criterion C), and hypervigilance (criterion D); and (c) subsequent impaired functioning or significant distress (criterion F). The definition of a traumatic event has changed since PTSD was first described in the DSM-III. In the current DSM-IV-TR, it is defined as either an experienced or a witnessed event involving “actual or threatened death” or “serious injury or a threat to the physical integrity of self or others” (criterion A1). To qualify for PTSD, the response must include “intense fear, helplessness, or horror” (criterion A2) (8). It has been estimated that between 39% and 90% of the population has been exposed to a traumatic event (9). Of those who experience a traumatic event, only 10% to 20% will develop PTSD (10).

There are many ways in which patients with PTSD reexperience (criterion B) traumatic events. They may report dreams or intrusive memories of the event or behave as if an event were currently happening (i.e., flashbacks). Cues that elicit memories of the trauma(s) may trigger psychological distress or physiologic reactivity, thus leading to avoidance behaviors (criterion C). Patients may avoid thoughts, feelings, conversations, activities, places, or people associated with the trauma and demonstrate anhedonia or lack of participation in important life activities. They may be unable to remember portions of the trauma and describe feelings of detachment or a sense of foreshortened future. Affect range may also be restricted. The symptoms of increased arousal (criterion D) or hypervigilance may involve exaggerated startle response, sleep disturbance, poor concentration, irritability, and/or anger outbursts (8). There are three specifiers that provide information about the duration and onset of symptoms. If symptoms have been present for less than 3 months, the disorder is considered acute; if symptoms have persisted for more than 3 months, the disorder is described as chronic. If the onset of symptoms is 6 months or more after the traumatic event, the disorder is considered to have a delayed onset.

Exposure to a traumatic event can also lead to a condition known as acute stress disorder (ASD). The primary distinction between PTSD and ASD is the duration of symptoms. While PTSD and ASD share many similar symptoms including reexperiencing symptoms, avoidance, increased arousal, and subsequent distress or impairment, ASD can occur for as little as 2 days after exposure to the traumatic event and last up to 1 month afterward. Other symptoms of ASD include dissociative symptoms, such as feelings of derealization, depersonalization, dissociative amnesia, or reduced awareness of the environment.

EPIDEMIOLOGY

The National Comorbidity Survey (NCS), a large-scale epidemiologic survey (N = 5,877) conducted in the early 1990s, examined psychiatric disorders in the US general population. Using the DSM-III—Revised criteria, the NCS found the overall lifetime prevalence rate for PTSD at 7.8%, and those with PTSD were two to four times more likely than their counterparts without PTSD to meet criteria for an SUD (11). The National Comorbidity Survey Replication (NSC-R), which took place approximately one decade after the NCS, found a similar overall lifetime PTSD prevalence rate (6.8%) using DSM-IV criteria (12).

The prevalence of comorbid PTSD and SUDs has been examined in various populations, with war veterans being one of the most extensively investigated groups. As mentioned, Vietnam veterans have demonstrated a high prevalence of comorbid PTSD and SUDs. The Vietnam Experience Study found that in veterans with PTSD, 39% met criteria for current alcohol abuse or dependence. Another study of Vietnam veterans found that 98.9% of those with PTSD also met criteria for other disorders, including major depression (28%), antisocial personality disorder (31%), and, most commonly, SUD (73%) (13). In Persian Gulf War veterans, the presence of PTSD hyperarousal symptoms at 18 to 24 months after return predicted drug use, but not alcohol use, at 6 years after return (14). Finally, the Land Combat Study was a population-based study of US army soldiers (N = 88,235) who were deployed during Operation Iraqi Freedom (15). This study found that during the 3 to 6 months postdeployment, 17% of active duty and 25% of reserve soldiers screened positive for PTSD, and 12% of active duty and 15% of reserve soldiers screened positive for problematic alcohol use.

Studies from the civilian population indicate that PTSD and SUDs frequently co-occur. Cottler et al. (16) investigated PTSD and SUDs in the general population and found that individuals with cocaine and opiate use disorders were three times more likely to experience a traumatic event and, subsequently, PTSD rates were significantly higher in this population than in those without an SUD. Careful examination of the civilian data reveals that men and women differ in the prevalence of comorbid psychiatric illnesses and PTSD. The most common comorbid diagnoses in women with PTSD are (in order) depression, other anxiety disorders, and alcohol use disorders. In men (veteran and civilian), the most common comorbidities in those with PTSD are (in order) alcohol use disorders, depression, other anxiety disorders, conduct disorder, and drug use disorders (3).

Finally, distinct populations, including adolescents, young adults, elderly adults, and minorities, have evidenced similar high prevalence rates of comorbid PTSD and SUD (1720). Collectively, these data indicate a high prevalence of this comorbidity in a variety of clinical populations, suggesting a unique and potent interconnectedness between PTSD and SUDs and raising questions about the chronologic order of onset of these disorders.

ETIOLOGIC RELATIONSHIP BETWEEN PTSD AND SUD

Various theories have been proposed to characterize the development of comorbid PTSD and SUD. One of the most prominent, the self-medication theory (cf. 20–23), postulates that substance use serves to alleviate PTSD symptoms. In one study (24), alcohol dependence was more common in individuals with PTSD and prominent symptoms within the hyperarousal cluster (criterion D). Likewise, cocaine dependence was more commonly associated with those individuals that demonstrated more avoidance (criterion C) and flashback symptoms (criterion B). Therefore, a PTSD and SUD comorbid individual’s preference for either a central nervous system depressant or a stimulant may reflect his or her attempt, conscious or otherwise, to alleviate a particular cluster of symptoms. To further complicate matters, withdrawal from substances may closely mimic some symptoms of PTSD (i.e., sleep disturbance, difficulty concentrating, feelings of detachment, irritability) and contribute to a reinforcing cycle of self-medication that fosters the development of an SUD.

The most common competing theory hypothesizes that SUDs precede the development of PTSD. In this model, the probability of developing PTSD is increased via two potential causal pathways. The lifestyle of a substance abuser, which is typically considered to be high risk with dangerous environments and behaviors associated with obtaining or using alcohol or drugs, may increase the likelihood of experiencing a traumatic event and subsequently developing PTSD. Alternatively, the increased anxiety and arousal that accompanies chronic substance use may increase one’s biologic vulnerability to develop PTSD after trauma exposure (3).

Last, there is some evidence that other factors may play a role in the development of comorbid PTSD and an SUD. Plausible factors that have been investigated include genetics, common neurophysiologic systems, and conduct disorder. Though the direction of the causal relationship between comorbid PTSD and SUD is likely to vary from one individual to another and further research is indicated, the self-medication hypothesis remains the dominant explanatory model (25,26).

NEUROBIOLOGIC FACTORS IN COMORBID PTSD AND SUD

The model for the human stress response, in which the hypothalamic–pituitary–adrenal (HPA) axis plays an integral role, is also thought to be a key component in the biologic development and maintenance of PTSD. The majority of research to date focuses on the HPA axis and noradrenergic systems, though other systems including dopamine, serotonin, thyroid, and γ-aminobutyric acid (GABA) have been investigated and likely play a role (27). Stressor exposure elicits a cascade of neurohormones. The hypothalamus releases corticotropin-releasing hormone (CRH), thereby stimulating the release of adrenocorticotropic hormone from the pituitary gland and finally release of cortisol from the adrenal glands (3).

In patients with PTSD, basal cortisol levels are lower, lymphocyte glucocorticoid receptors are up-regulated, and there is increased suppression of cortisol after dexamethasone administration (3). These findings suggest that glucocorticoid feedback is enhanced in PTSD. Individuals with SUDs commonly report stress as a trigger for relapse, and studies have shown that exposure to stress results in increased craving and salivary cortisol, suggesting HPA axis activation similar to activation in PTSD (3). Furthermore, cerebrospinal fluid CRH levels are elevated in PTSD patients and during acute alcohol withdrawal. Debate continues about the meaning and implications of these findings, and the complex interplay is not yet fully understood.

Noradrenergic dysregulation has also been consistently demonstrated in both PTSD and withdrawal states from chronic alcohol and drug use through laboratory testing (3). Elevated levels of 24-hour plasma norepinephrine and fewer platelet alpha-2-adrenergic receptors are some of the findings of both PTSD and withdrawal states of SUDs. This mechanism is the basis for the use of clonidine, an alpha-2-adrenergic receptor agonist, in both PTSD and opiate withdrawal (3).

ASSESSMENT OF PTSD IN SUD

Given the high rates of trauma and PTSD among individuals with SUDs, it is important to screen all SUD patients. Numerous interviewer-rated and self-report assessments of PTSD are available (28,29). A recent review found that brief PTSD measures (i.e., 4 to 30 items) appear to perform as well as longer, more complicated measures (30). Accordingly, it cannot be argued that the assessment of PTSD in persons with SUDs is too burdensome from a clinical resource management perspective (i.e., staff/clinician time). In fact, the gains to be achieved in terms of quality of care far exceed any resource expenditures. In this section, we highlight some of the most commonly used and psychometrically sound interview and self-report instruments for assessing PTSD (31).

As a general rule, PTSD assessment should be conducted after a patient has emerged from acute alcohol or drug intoxication and withdrawal (32). In contrast to other anxiety disorders (e.g., generalized anxiety disorder), less abstinence may be required in order to establish a diagnosis of PTSD among SUD patients because of the unique nature of the diagnostic criteria (i.e., requirement of exposure to a criterion A traumatic event). Intrusive PTSD symptoms (e.g., recurrent thoughts or images related to the trauma) are uniquely characteristic of PTSD and are less likely to be mimicked by substance use or withdrawal. Other PTSD symptoms (e.g., irritability or outbursts of anger, sleep impairment) could be exacerbated by the use of, or withdrawal from, alcohol and drugs and should be carefully assessed. The duration of abstinence required before a valid and clinically meaningful assessment of PTSD can be conducted with a patient will vary depending on whether the substance used is short or long acting. If there is any diagnostic uncertainty, reassessment of PTSD symptoms as the patient becomes abstinent can provide helpful information (e.g., do PTSD symptoms remit over time with continued abstinence?).

Interviewer-Rated Assessment of Posttraumatic Stress Disorder

Clinician-Administered Posttraumatic Stress Disorder Scale

The most widely used interviewer-rated PTSD assessment is the Clinician-Administered PTSD Scale (CAPS) (33,34). This is a 30-item structured interview that was developed at the National Center for PTSD and is designed for use by clinicians and trained paraprofessionals. A checklist of potentially traumatic events is included at the beginning of the interview to assess lifetime trauma exposure. Seventeen items assess the frequency and intensity of diagnostic PTSD symptoms (e.g., reexperiencing, avoidance, hyperarousal). In addition, associated features of PTSD (e.g., survivor guilt, homicidality, hopelessness), social and occupational functioning, and global PTSD severity are also rated. Several versions of the CAPS are available, including versions that assess past week, past month, and lifetime symptoms.

Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders

The structured clinical interview (SCID) (35) is a semistructured interview designed to diagnose most Axis I disorders (e.g., mood, psychotic, anxiety, substance use, and eating disorders). The DSM-III-R SCID (36) was the first comprehensive semistructured interview for the diagnosis of PTSD. The SCID has been revised to reflect modifications for each version of the DSM. The SCID contains a section that briefly reviews lifetime exposure to traumatic events and the age of occurrence, followed by diagnostic questions to assess PTSD symptoms. If multiple traumas exist, the diagnostic questions are asked in relation to the trauma that has most affected the patient.

Potential Stressful Events Interview and the National Women’s Study Posttraumatic Stress Disorder Module

The potential stressful events interview (PSEI) and the National Women’s Study (NWS) PTSD module instruments were developed by the research group at the National Crime Victims’ Research and Treatment Center (Medical University of South Carolina) in Charleston, South Carolina. Though originally developed for use in the NWS, these instruments can be used to assess trauma exposure and PTSD in a variety of populations. The PSEI (37) is a multicomponent instrument for assessing trauma exposure history and PTSD symptomatology (via the NWS PTSD module, which is a component of the PSEI). Using behaviorally specific questions, the PSEI trauma exposure module assesses crime-related (e.g., sexual and physical assault), non–crime-related (e.g., natural disaster, serious accident), and combat-related traumatic events. Age of onset for first and last occurrence of an event is also determined. The NWS PTSD module is a 20-item structured clinical interview that is designed for use by lay interviewers (38). It was derived from the Diagnostic Interview Schedule that was used in the National Vietnam Veterans Readjustment Study. None of the items attempts to link a specific PTSD symptom to a particular traumatic event and so are easily used with individuals with complex trauma histories. Like the CAPS, this instrument has been shown to have strong psychometric properties and can be used to assess PTSD symptomatology in approximately 30 minutes.

PTSD Symptom Scale—Interview

The PTSD Symptom Scale-Interview (PSS-I) (39,40) is a 17-item semistructured interview that assesses PTSD symptom frequency and severity over the past 2 weeks. The PSS-I can be administered by trained paraprofessionals.

Structured Interview for PTSD

The structured interview for PTSD (SIP) (41) contains 17 items that assess the diagnosis of PTSD and symptom severity. Measures of survivor and behavioral guilt are also included.

Mini-International Neuropsychiatric Interview PTSD Module

The Mini-International Neuropsychiatric Interview (MINI) (42) is a brief structured clinical interview that, like the SCID, assesses most major Axis I psychiatric disorders, including PTSD. The MINI PTSD module assesses diagnostic PTSD symptoms during the past month. Relative to the SCID, this instrument has the advantage of shorter administration time.

Composite International Diagnostic Interview

The Composite International Diagnostic Interview (CIDI) (43,44), a standardized interview, assesses most major mental disorders. Unlike the other interviewer-rated measures mentioned in this chapter, the CIDI provides diagnosis according to the International Classification of Diseases, 10th Edition (ICD-10), which is slightly different from the DSM-IV with regard to PTSD diagnostic criteria. The CIDI is suitable for lay interviewers. Versions are available to assess past 12 months’ and lifetime symptoms. In addition, a computerized version of the CIDI is available.

Self-Report Assessment of Posttraumatic Stress Disorder

PTSD Checklist

The PTSD Checklist (PCL) (45) is a self-report rating scale for assessing PTSD. The PCL consists of 17 items that correspond to the DSM-IV symptoms of PTSD. Individuals are asked to indicate how much they have been bothered by each symptom in the past week using a five-point scale, ranging from “Not at all” to “Extremely.” Prior studies on the PCL have found test–retest reliability of 0.96 and internal consistency (alpha coefficient) of 0.97 for all 17 symptoms. Convergent validity was demonstrated by strong correlations between the PCL and the Mississippi Scale (0.93) and the Impact of Event Scale (0.90). Using a cutoff score of 50, the PCL yielded a sensitivity of 0.82, a specificity of 0.83, and a kappa of 0.64. Many prior studies have used the PCL in Veteran and civilian studies of PTSD, and the PCL is used extensively in the Veterans Health Administration to monitor symptom change.

Impact of Events Scale—Revised

The Impact of Events Scale—Revised (IES-R) (46) is a brief and popular 22-item scale for assessing PTSD symptoms in all three of the major categories: reexperiencing, avoidance, and arousal. It is a revision of the IES by Horowitz et al. (47), which does not address the arousal category of PTSD symptoms, and therefore the IES-R is more consistent with the DSM-IV (48) diagnostic criteria. Prospective respondents use Likert scales to rate “how distressed or bothered” they were by each specified symptom over the previous week. This instrument has been translated into several different languages (4952) and has been used with a variety of trauma populations (e.g., earthquake emergency response personnel, earthquake survivors). Though the earlier version of this instrument has been shown to have strong psychometric properties, existing data on the psychometric properties of the IES-R are considered limited, so additional study appears necessary. There are some unpublished data suggesting that the IES-R is a reliable, valid, and clinically sensitive measure of PTSD symptomatology when used with traumatized SUD and SUD–PTSD comorbid patients (53).

Posttraumatic Stress Diagnostic Scale

The Posttraumatic Stress Diagnostic Scale (PDS) (54) is a user-friendly 49-item Likert-type scale that measures DSM-IV PTSD criteria and symptom severity for all three symptom clusters. This is an updated version of the Foa et al. (40) 17-item self-report PTSD Symptom Scale (PSS-SR) that was based on DSM-III-R (55) criteria. The PDS assesses trauma exposure (12 items) and identifies an individual’s most distressing trauma(s). The instrument also assesses trauma features (e.g., physical threat, helplessness) and functional impairment resulting from PTSD symptoms. It has been psychometrically validated on a sample with diverse trauma exposure (54), and it correlates highly with other instruments that measure responses to trauma and has good diagnostic agreement with the SCID. This instrument provides a very efficient means of assessing both type of trauma exposure and PTSD symptomatology. However, like most instruments, it has not been validated on a sample of PTSD and SUD comorbid individuals.

Modified Posttraumatic Stress Disorder Symptom Scale (Self-Report)

Like the PDS earlier, the Modified PTSD Symptom Scale (Self-Report) (MPSS-SR) (56) is based on Foa et al.’s (40) PTSD Symptom Scale (PSS-SR). It was developed to extend the PSS-SR’s symptom frequency assessment to include the assessment of PTSD symptom severity. Not only has this instrument been validated with clinical and nonclinical samples of trauma exposed individuals (57) but it has been shown to have good psychometric properties with respect to the assessment of PTSD symptoms in SUD samples (58,59). Thus, this measure can be used with confidence in screening and assessing PTSD and SUD comorbid individuals.

Mississippi Scale for Combat-Related Posttraumatic Stress Disorder

The Mississippi Scale is a widely used 35-item instrument that was developed by Keane et al. (60) to assess combat-related PTSD symptoms. The items for this scale were derived from a sample of 200 items developed by experts. Thirty of the items assess the reexperiencing, avoidance and arousal symptom categories, whereas the remaining five assess guilt and suicidality. Prospective respondents use Likert scales to rate the severity of symptoms since the occurrence of the traumatic event(s). Like the IES-R, the Mississippi Scale has been translated into several languages. Because of its strong psychometric properties (61,62), a civilian version of the instrument has also been developed.

TREATMENT OF PTSD AND PTSD–SUD COMORBIDITY

PTSD has had a relatively brief history as a diagnostic entity, and, during that time, a broad range of traditional and specialized therapies have been promoted for its treatment, several of which have received considerable empirical scrutiny. By contrast, there have been very few studies of therapies specifically designed to address PTSD and SUD concurrently. Whether one considers the treatment of PTSD alone or PTSD–SUD comorbidity, treatments tend to fall into two general classes: psychotherapy and pharmacotherapy or, in rare cases, their combination. This section briefly describes, discusses, and evaluates these two general classes of interventions with respect to the treatment of PTSD and PTSD–SUD comorbidity. Though the focus of the following discussion will be on the treatment of PTSD, it should be noted that there is also some evidence that PTSD–SUD comorbid individuals can benefit from interventions that primarily target SUDs (63).

An exhaustive review of the treatment literature is not possible given space limitations; consequently, we have adopted the following focus. First, three types of cognitive– behavioral therapies (CBTs) of PTSD will be discussed: (a) exposure-based therapy, (b) cognitive-focused therapy, and (c) anxiety/stress management therapy. CBTs for PTSD are emphasized here because they are widely accepted as the most empirically valid treatments for PTSD (e.g., (64)). Additionally, it has been suggested (65) that the treatment of one disorder in dually diagnosed individuals often yields clinical benefits for the untreated comorbidity. This being the case, treatment of PTSD in PTSD–SUD comorbid individuals is important because it can be expected to have positive impact on substance use. Second, we will outline and discuss integrative CBTs for the concurrent treatment of PTSD and SUD. These are relatively recent and comprehensive treatments that make an explicit attempt to concurrently address PTSD and SUD symptomatology. Each treatment will be described in some detail in order to elucidate both unique features and specific commonalities, and important research findings will be briefly outlined. Third, we will examine pharmacotherapies for PTSD, and, fourth, we will describe developments in pharmacotherapy for PTSD–SUD comorbidity. These later two sections will be relatively brief, as this type of treatment has not yielded efficacy findings on par with CBT.

On a final note, some investigators have explored the use of psychotherapeutic techniques to prevent the development of PTSD and have found that such single-session critical incident stress debriefing not only is ineffective in preventing the development of PTSD but may be harmful (66). Thus, this chapter will not cover debriefing to prevent PTSD but will instead focus on CBTs designed to treat established PTSD.

Cognitive–Behavioral Therapy for Posttraumatic Stress Disorder

Exposure-Based Therapy

There are several forms of exposure-based therapy (6770), and, as a group, they represent the longest-standing empirically validated psychotherapies for trauma and PTSD. Exposure therapies are based on conditioning (cf. 71–73) or information-processing (74) theories of fear and anxiety, both of which argue that exposure to fear and anxiety-eliciting situations/stimuli (i.e., physical location where a motor vehicle accident occurred) without traumatic outcome (i.e., motor vehicle accident) results in anxiety abatement. Conditioning models assert that fear/anxiety abatement results from behavioral extinction (75), a type of inhibitory learning (cf. 75–77), whereas information-processing theory argues that it occurs via the modification of pathologic elements of a fear-based memory. Procedurally, individuals are exposed to either in vivo or imaginal fear-eliciting cues. In the former case, exposure is performed via presentation of physical stimuli associated with traumatic experiences, whereas in the latter case, the fear stimuli are imagined. One of the major advantages of imaginal exposure over in vivo exposure methods is that trauma cues that would otherwise be difficult and/or unethical (i.e., physical conditions present in a combat situation, distant locations where an assault occurred) to use in exposure therapy can easily be integrated into an imagery-based procedure. Both in vivo and imaginal procedures aim to reduce/preclude avoidance behavior and promote mastery.

One of the most extensively studied exposure treatments for PTSD is prolonged exposure (PE) therapy. Though this therapy can be practiced in varied forms, its essential features have been detailed in a published manual (78). Briefly, the treatment consists of several primary components, including (a) didactic training about common reactions to traumatic events; (b) relaxation via breathing retraining; (c) prolonged imaginal exposure to the trauma via detailed, therapist-guided recounting of the event(s); and (d) in vivo exposure to trauma-related situations that are being avoided because they elicit fear. Though the duration of this therapy can vary, a typical course can be completed in nine sessions, each session lasting about 60 to 90 minutes. In private practice, one of the authors (MES) has achieved substantial therapeutic gains in as few as three sessions of active PE. The authors of the PE treatment manual also suggest a number of PE treatment plan options, two of which contain elements of cognitive therapy (CT) and anxiety management as described further. Thus, PE is easily integrated with other forms of therapy.

There is another form of exposure therapy that requires brief consideration. Shapiro (7981) forwarded an extension of Wolpe’s (73) systematic desensitization therapy that she initially named eye movement desensitization (EMD) therapy and later added the term reprocessing (hence, EMDR therapy) to denote a conceptual shift toward an information-processing interpretation of the therapy’s mechanism of action. EMDR is presumed to exert its effects by modifying the neuronal interface between thought, emotion, and memory. Applying EMDR involves a therapist eliciting trauma-related imagery while having the patient develop alternative interpretations of the imagined traumatic event(s). This aspect of EMDR is essentially analogous to exposure with CT features. The unique and presumably important feature of EMDR is conducting the imaginal exposure while the patient simultaneously visually tracks the back-and-forth movement of a therapist-manipulated object (e.g., therapist’s finger).

Cognition-Focused Therapy

There are essentially two therapies that comprise this class: cognitive therapy (CT) and cognitive processing therapy (CPT). CT was originally forwarded as a treatment for depression (82,83) and has subsequently been extended to address anxiety (84,85) and SUDs (86). As applied to PTSD, the therapy is built conceptually around the notion that it is the meaning that individuals assign to traumatic events, rather than the traumatic events, which determines duration and intensity of emotion/mood states that ensue. Accordingly, interpretations or meanings that are negatively biased or irrational give rise to negative mood states such as fear and anxiety. The goal of CT, then, is to aid individuals in implementing corrective cognitive procedures to identify and challenge inaccurate, irrational thoughts and beliefs and to replace them with ones that are more evidence based, rational, and beneficial. Some categories of thinking and belief that would be the focus of CT for individuals with PTSD would be safety/danger, trust, and self-concept.

The other therapy in this class, CPT, is an adaptation of CT that includes an information-processing focus. Developed by Resick and Schnicke (87,88) to treat PTSD resulting from sexual assault, it has been extended to victims of other types of trauma including sexual abuse and combat (8991). The therapy has several important elements that are presumed to have therapeutic potency. There is a psychoeducation component in which an information-processing model of PTSD is presented. The optional writing element consists of a writing–reading task wherein individuals develop a detailed narrative of their traumatic experience(s). The goal of this component is for the individual to maximize emotional processing of the trauma(s) and to identify areas of incomplete processing or conflict concerning the trauma(s). The primary feature of this treatment is the CT component that involves identification and challenging of key cognitive distortions. Specific areas of belief that are targeted for challenge relate to themes of safety, trust, power, esteem, and intimacy. The therapy concludes with an analysis of beliefs, including changes to dysfunctional thinking, and discussion of future goals. Completion of CPT can be achieved in approximately twelve 60-minute individual or 90-minute group therapy sessions.

Anxiety Management Therapy

Though there are several therapies that could be considered members of this category (e.g., biofeedback and relaxation training) (92), one of the most widely known and studied is stress inoculation training (SIT) (9395). As applied to PTSD (96,97), the main goal of this therapy is to provide individuals with a sense of mastery over their PTSD symptoms by teaching them a variety of coping skills and then permitting them to practice the skills both inside and outside of treatment sessions. SIT can be used in both individual and group formats and has broad application to a variety of anxiety disorders (e.g., panic disorder). Common elements of SIT are relaxation training, breathing training, thought stopping, self-instruction training, assertiveness training, cognitive restructuring, anger management, and problem-solving training. These skills can be taught and practiced over 8 to 12 sessions, and the therapy can be adapted to briefer psychoeducational formats.

Effectiveness of Cognitive–Behavioral Therapy for Posttraumatic Stress Disorder

As already noted, the treatments described earlier represent the state of the art with respect to CBT for PTSD. A detailed review of the associated efficacy literature is neither possible, given space limitations, nor necessary as several recent and thorough reviews and meta-analyses of CBT for PTSD have been conducted (64,98105). An important caveat to the conclusions stated here is that the outcomes from clinical trials involving these therapies may have limited generalizability to PTSD–SUD comorbidity; one recent review (104) noted that 62% of PTSD therapy studies reviewed excluded individuals with a comorbid SUD. With this caveat in mind, there are some general and a few specific conclusions that can be drawn from this literature.

First and foremost, all CBTs produce clinically significant reductions in PTSD symptomatology relative to wait-list or treatment as usual (TAU) comparisons. The treatments also tended to produce appreciable benefits on collateral symptoms of depression and generalized anxiety. The treatments appear to benefit a range of populations including those with civilian and combat-related PTSD. Treatment dropout rates tend to be similar across studies, at approximately 20% to 25%.

Though differences among the treatments are difficult to discern from this vast and complex literature of clinical trials, the reviews do suggest several qualified generalizations can be forwarded. One such generalization is that a combination of in vivo and imaginal exposure produces substantial and persistent symptom reduction beyond what can be achieved with anxiety management procedures such as SIT or with CT. There is some evidence suggesting that exposure therapy benefits are maximized with the combination of in vivo and imaginal exposure and that the addition of other cognitive and anxiety management therapy elements does not appreciably enhance exposure-based therapy outcomes. It also appears that CPT, a CT with exposure elements, is as effective as PE in the treatment of rape-related PTSD and that CPT might be more beneficial in addressing trauma-related guilt. This latter observation was echoed in a recent study of industrial accident-related PTSD (106) in which the emotional focus of the PTSD was related to guilt and anger rather than fear and anxiety. The therapy in the study, imagery rescripting and reprocessing therapy (IRRT), combined elements of exposure and cognitive restructuring to transform traumatic imagery into adaptive imagery. IRRT was administered to industrial accident victims who did not benefit from PE. The authors reported an 80% “complete” recovery rate that they tentatively attributed to the therapy’s ability to address the predominantly guilt–anger emotional focus of the PTSD. Whether IRRT has benefits beyond those conferred by PE (in general) remains a larger unanswered question, but it appears possible that certain strategic integrations of cognitive and exposure therapy elements may offer benefits that cannot be achieved by exposure alone, at least with some subgroups of PTSD-afflicted individuals.

Last, EMDR has been the focus of much controversy (107111) and research, primarily because of the unusual assumption that the rapid saccadic eye movement during imaginal exposure is essential to its efficacy and because EMDR was touted as an especially effective treatment for a variety of disorders, including PTSD. Contrary to these claims, more than a decade of research has shown that the eye movement feature does not appear relevant to treatment outcome (112118) and that EMDR is no more effective than any other more theoretically grounded exposure therapy (115,117121). Thus, EMDR is an efficacious treatment for PTSD, but its efficacy is likely attributable to its exposure and CT elements.

In sum, the bulk of clinical studies point to exposure therapy (in vivo and imaginal combined) as the dominant therapeutic approach for resolving PTSD. Though this assertion may be questionable under some conditions and/ or with some subgroups of persons with PTSD, it is consistent with the fact that the Substance Abuse and Mental Health Services Administration has selected PE as its model program for nationwide dissemination.

Integrated Cognitive–Behavioral Therapy for Posttraumatic Stress Disorder–Substance Use Disorder Comorbidity

In general, psychotherapy is an important part of treatment for PTSD and SUDs. However, the majority of patients with PTSD and comorbid SUDs receive treatment for the SUD only (4,122). Subsequent to the successful completion of SUD treatment, patients are often, but not always, referred to PTSD treatment. It is unknown how many referred patients actually seek out and complete PTSD treatment. Proponents of this treatment model, known as “sequential” treatment, in which the SUD is first treated and then the PTSD is treated, posit that continued substance use during therapy impedes therapeutic efforts to address PTSD and that addressing the trauma increases the risk of relapse (123,124). Importantly, there are little empirical data to support these concerns and this general approach to therapy.

“Integrated” treatment models, in which both the SUD and PTSD are simultaneously addressed in therapy, have been developed over the past decade. The findings from studies of integrated treatments show that alcohol and drug use typically decrease significantly and do not increase with the addition of trauma-focused interventions (125128). Proponents of integrated treatments assert that PTSD symptoms may, at least in part, drive substance use and that untreated PTSD symptoms place SUD patients at risk of relapse. In so far as substance abuse represents self-medication of PTSD symptoms (21), addressing the trauma early in treatment may improve the chances of long-term recovery from addiction (129,130). Furthermore, a substantial proportion of PTSD– SUD comorbid patients express a preference for integrated treatment (122,131,132).

Seeking Safety (SS) is the most widely known and empirically studied integrated CBT (133,134). SS is a 25- session, present-focused, manualized treatment that provides psychoeducation, teaches coping skills, and helps clients gain more control over their lives. SS was first developed for adult women in a group modality but has since been expanded to men, adolescents, and individual therapy. In a randomized controlled trial, Hien et al. (135) compared SS to the “gold standard” substance abuse treatment, relapse prevention (RP), and to TAU among 107 women. At the end of treatment, clients who received TAU failed to demonstrate significant improvement or, in the case of PTSD symptoms, worsened over time. In contrast, patients who received either SS or RP demonstrated significant decrease in substance use, PTSD, and psychiatric symptom severity. SS and RP, however, did not differ from one another on treatment outcomes. In a more recent multisite trial (136), women (N = 353) were randomized to 12 sessions of either SS or a women’s health education group. They received these interventions in addition to TAU. Women in both conditions showed large reductions in PTSD symptoms. However, SS was not superior to the education group in reducing PTSD, and neither condition showed improvements in substance use outcomes. In summary, results from controlled trials suggest that the addition of SS to TAU provides benefits, particularly with regard to reductions in PTSD, and is equivalent to RP or psychoeducation group in improving outcomes (see www.seekingsafety.org for more detailed information on SS).

Other integrated CBTs that use exposure-based techniques, a frontline psychosocial treatment for PTSD, have also been developed. To date, two small studies have systematically examined an intervention that integrates exposure-based techniques for PTSD with empirically validated treatments for SUDs. Triffleman et al. (128,137) pioneered the effort by developing substance dependence posttraumatic stress disorder therapy (SDPT). SDPT is a 20-week manualized outpatient treatment that utilizes RP, coping skills, psychoeducation, and in vivo exposure for individuals with PTSD. In a small controlled pilot trial (N = 19) using methadone-maintained primary cocaine-abusing subjects, SDPT was compared to 12-step facilitation therapy. Patients in both groups showed improvements in PTSD and drug use, but no statistically significant differences between treatment conditions were observed. This may have been owing to the small sample size and the short follow-up period of 1 month.

In a larger trial, Brady et al. (125,138) developed a manualized treatment consisting of imaginal and in vivo exposure therapy for PTSD combined with cognitive–behavioral RP for individuals with PTSD and cocaine dependence. The treatment protocol, called concurrent treatment of PTSD and cocaine dependence (CTPCD), includes 16 individual sessions. Results from an uncontrolled study (N = 39) showed that patients demonstrated significant pre- to post-treatment reductions in PTSD symptoms and in cocaine use. Approximately 10% of urine drug screen tests were positive each week, and this rate did not increase during the course of treatment, as PTSD was more directly addressed with exposure techniques. Symptoms of depression and psychiatric distress showed significant improvement, as well.

More recently, Mills et al. (139) conducted a randomized clinical trial to test the efficacy of a modified version of CTPCD, called concurrent treatment of PTSD and substance use disorders using prolonged exposure (COPE). Individuals (N = 103) were randomized either COPE plus TAU for substance dependence or TAU only. COPE consisted of 13, 90-minute, individual psychotherapy sessions that included motivational and CBT strategies for reducing substance use and exposure-based techniques and CT for reducing PTSD. Those who received COPE had greater improvements in PTSD during the 9 months following the baseline assessment. However, COPE did not produce better improvements in substance use, depression, or anxiety, when compared to TAU.

The findings from these and other investigations (140142) suggest that PTSD-focused treatment can be used safely added to TAU for SUDs. Thus, research shows that addressing PTSD via present- or past-oriented treatments does not worsen patients’ symptoms but rather significantly decreases PTSD. That said, well-controlled studies demonstrate limitations to the efficacy of existing integrated treatments for PTSD and SUDs. Randomized controlled trials show that SS (143,144) is equal but not superior to equally intensive addiction-focused treatment or psychoeducational group. As described by Najavits (145), the COPE randomized trial (139) was plagued by high dropout and patients completing an average of only 5 of 13 COPE sessions over 9 months. In addition, the lack of difference between COPE and TAU on substance use, depression, and anxiety outcomes suggest that this treatment may produce isolated improvements in PTSD but not in other domains. Given the limitations in the findings for these well-researched interventions, additional work is clearly needed to improve integrated treatments for PTSD and SUDs.

Pharmacotherapy of Posttraumatic Stress Disorder

The primary goals of the pharmacologic treatment of PTSD include decreasing PTSD symptoms, improving overall functioning, improving resilience to future stressors, decreasing symptoms of comorbid psychiatric conditions (e.g., depression, SUDs), and reducing risk of PTSD relapse (146). Long-term pharmacologic treatment (e.g., 1 year) is recommended based on evidence that PTSD is likely to return after discontinuation of shorter treatment (66).

Two medications, both selective serotonin reuptake inhibitors (SSRIs), are currently FDA approved for the treatment of PTSD: sertraline (Zoloft) and paroxetine (Paxil). These are considered the first-line pharmacotherapeutic treatment options for PTSD based on their demonstrated efficacy in treating PTSD and other comorbid conditions and their relative safety in overdose (66,146151). SSRIs have been shown to diminish all three symptom clusters of PTSD and improve the overall quality of life, particularly among civilian PTSD patients (150).

Though other pharmacologic agents have been investigated for the treatment of PTSD and some have shown promise, none are FDA approved. As recently reviewed in 2007 by Zhang and Davidson (146), placebo-controlled investigations of dual action serotonergic and noradrenergic medications, such as venlafaxine and mirtazapine, suggest their ability to decrease PTSD symptoms and alleviate sleep disturbances. Though some tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) have been shown to be effective in improving PTSD and associated symptoms, they are no longer commonly used owing to cardiovascular and anticholinergic side effects, risk of seizures with TCAs, and strict dietary restrictions and risk of hypertensive crisis with MAOIs (152). Findings from other studies examining the use of mood stabilizers and anticonvulsants fail to show clear benefit in the treatment of PTSD (146). Encouraging evidence exists that antipsychotic medications, in particular, risperidone, may be beneficial as an augmentation medication to partial responders of SSRIs (146,152). The risk of side effects with the use of antipsychotics, however, needs to be considered when choosing a medication (150). Benzodiazepines, which help alleviate anxiety and sleep impairment, are contraindicated as a monotherapy or preventive strategy based on preliminarily findings that their use was associated with increased risk of PTSD relative to placebo (66,150). Finally, medications that reduce central nervous system activity (e.g., clonidine, prazosin) may be helpful in decreasing nightmares and hyperarousal symptoms, which do not respond particularly well to SSRIs (152). More randomized controlled trials are needed to better assess their spectrum of efficacy.

Research on the pharmacologic prevention of PTSD is limited and methodologically problematic. Consequently, there are no medications that effectively prevent/curtail the development of PTSD (146). However, recent translational research has led to findings that would support cautious optimism. Numerous preclinical studies have implicated the noradrenergic system, likely via action in the basolateral amygdala, in both the formation and maintenance of fear-related memories (153158). A number of studies using fear-conditioning paradigms in animals have suggested a role for the β-adrenoreceptor in memory recall that is prompted by the presentation of cues associated with aversive outcomes (154,159,160). These promising animal studies led to research with human participants suggesting that β-adrenergic antagonists (e.g., propranolol) may selectively interfere with emotional memory (161163). In one of these studies (163), participants with PTSD and non-PTSD controls treated with propranolol (a β-blocking agent) versus placebo evidenced reduced recall of the emotionally arousing content of a story told to them 1 week earlier. There also are some single-case data and a few preliminary intervention studies of individuals with PTSD suggesting that treatment with propranolol after a traumatic experience can decrease PTSD symptoms (164166). In addition, there are preliminary data indicating that propranolol administration immediately after trauma cue exposure in individuals with PTSD dampens emotional reactivity during subsequent trauma cue exposure (167). Collectively, these findings suggest that the strategic use of β-blocking agents (e.g., propranolol) may prevent PTSD development or be used in conjunction with exposure-based therapy to dampen PTSD symptoms.

For more information regarding pharmacotherapy algorithms that provide helpful guidance in treating PTSD patients, see the International Psychopharmacology Algorithm Project (http://www.ipap.org).

Pharmacotherapy of Posttraumatic Stress Disorder–Substance Use Disorder Comorbidity

There is a notable paucity of research on pharmacotherapy for PTSD and comorbid SUDs (168,169). Most studies, however, show promise and suggest that patients with PTSD and comorbid SUDs respond as well to standard PTSD pharmacotherapies as compared to patients without comorbid SUDs.

Several studies have examined the use of SSRIs, the pharmacologic treatment of choice for PTSD, among patients with comorbid SUDs. All of these studies have evaluated sertraline. The first was a small (N = 9) open-label trial among outpatients with alcohol dependence and PTSD (170). Decreases in alcohol use severity (e.g., number of drinking days, number of drinks per day) were shown, and approximately half (4 of 9) were abstinent during the 12-week follow-up period. In addition, significant reductions in all three PTSD symptom clusters were reported.

A second investigation extended the 1995 Brady et al. study (171) and examined the efficacy of 12 weeks of sertraline versus placebo among 94 outpatients with alcohol dependence and PTSD. Both groups showed reduction in alcohol use severity, but no significant between-group differences were revealed. Statistical trends for the sertraline group to demonstrate greater improvement in PTSD symptoms, particularly in intrusion and hyperarousal symptoms, were observed. Follow-up cluster analyses identified that the medication-responsive group tended to have less severe alcohol use and primary PTSD, in which the development of PTSD preceded the onset of alcohol dependence.

A secondary analysis of the Brady et al. (171) data examined the influence of comorbid depression or other anxiety disorders among patients with alcohol dependence and PTSD who were treated with sertraline or placebo (172). The results indicated that having comorbid depression or a second anxiety disorder did not detract from treatment response to sertraline.

Finally, Zatzick et al. (173) combined case management, motivational enhancement for alcohol use disorders, and pharmacologic treatment for the prevention of PTSD. This intervention, termed collaborative care, was compared to TAU among injured surgical inpatients. The preliminary results were encouraging. Though patients in the TAU group evidenced a worsening of PTSD symptoms, patients who received pharmacotherapy did not. Unfortunately, the specific medications used were not reported, so a full understanding of the data is limited. The results for alcohol use severity were also promising but may be attributable to the psychosocial intervention rather than pharmacologic intervention. More research is clearly needed to help advance the pharmacologic treatment of comorbid PTSD and SUDs.

Last, there is developing research indicating a potential for D-cycloserine (DCS) to enhance exposure-based treatment outcomes with anxiety-disordered individuals (e.g., PTSD) and may also have potential as an innovative treatment for PTSD–SUD comorbidity. The medication, DCS, is a partial N-methyl-D-aspartate agonist and an FDA-approved antibiotic treatment for tuberculosis. As already noted, exposure-based therapy is founded on the principles of conditioned fear extinction and has demonstrated efficacy in the treatment of several anxiety disorders, including PTSD. Building upon the animal studies demonstrating DCS-facilitated extinction of conditioned fear responses (174179), a number of recent clinical trials have examined the potential facilitative effects of DCS on extinction of fear-based responses and symptoms associated with anxiety disorders. To date, three published clinical trials have shown that DCS can facilitate extinction of anxiety/fear symptomatology in acrophobia (180), social anxiety disorder (181), and obsessive-compulsive disorder (182). Despite negative findings from one recent study of DCS-augmented exposure therapy for subclinical fear of spiders (183), the existing clinical data strongly suggest that DCS might enhance exposure-based treatment outcome for severe anxiety disorders. Accordingly, it seems timely that the effects of DCS-augmented exposure therapy should be studied in PTSD-afflicted individuals.

In addition to its potential for advancing exposure therapy for PTSD, the ability of DCS to facilitate extinction might be fruitfully explored with respect to exposure-based treatment of SUDs (cf. 184,185), known as cue exposure therapy (CE). Briefly, CE involves exposing addicted individuals to stimuli that have acquired the ability, via Pavlovian conditioning, to elicit craving and other reactions (e.g., heart rate increases) as a consequence of a long history of contiguous pairings with drug or alcohol administration. These craving and other cue-elicited reactions are assumed to have an important role in the maintenance of, and relapse to, substance use (186189). The goal of CE is to attenuate or eliminate craving and reactivity via extinction, thereby reducing the risk of further substance use (i.e., maintaining abstinence). To date, CE therapy has been associated with modest efficacy (190), but medication developments such as DCS hold promise for bolstering the effects of CE. Furthermore, future clinical studies involving PTSD–SUD comorbid individuals could investigate the possibility of DCS-enhanced outcomes of an integrated exposure-based therapy consisting of PE and CE.

CONCLUDING COMMENTS

As a clinical entity, PTSD is an evolving disorder, and a portion of its evolution relates specifically to our growing understanding of the interface between it and SUDs. It is now well established that SUDs frequently co-occur with PTSD and that this comorbidity is profoundly detrimental to physical and psychological well-being.

Theory and research about the nature of the causal relationship between the two disorders suggest that even though no single model has received unequivocal empirical support, it appears that PTSD most often precedes SUD onset, thereby lending support to the notion that an SUD may serve to diminish PTSD symptoms (i.e., self-medication hypothesis). Though the contribution of neurobiologic factors to the etiology and maintenance of PTSD–SUD comorbidity is not completely understood, there is considerable evidence of shared causal processes. Chief among these processes is dysregulation of both the HPA axis and noradrenergic systems.

The effective management of PTSD–SUD comorbidity begins with a thorough assessment. Fortunately, thorough does not mean burdensome. There are numerous interview and self-report methods that can be used to efficiently determine the PTSD status of adult civilians and veterans with a comorbid SUD. As always, ensuring that a sufficient period of abstinence has occurred prior to conducting an assessment will enhance the integrity of assessment findings.

Some of the best treatments for PTSD–SUD comorbid individuals are those that concurrently address both disorders. It is unfortunate that such treatments are often unavailable. Nonetheless, there are several highly efficacious CBTs for PTSD that can be readily employed with comorbid individuals and that often yield collateral benefits for the untreated SUD. Trauma-focused CBTs such as PE or CPT are considered the gold standard in treatment of PTSD. Pharmacotherapy has also been used (with or without CBT) to address PTSD alone or PTSD–SUD comorbidity. Specifically, sertraline and paroxetine are FDA approved for the treatment of PTSD. Other innovative pharmacotherapies that have the potential to augment exposure-based therapy (i.e., DCS) or disrupt emotional memories (i.e., propranolol) are under investigation. Since treatment of any form can often prove challenging to the recipient, clinicians should employ strategies to enhance retention, such as telephone contact between sessions, and continue outpatient care for at least 3 months after treatment completion (191,192).

REFERENCES

1.Sadock B, Sadock VA. Kaplan & Sadock’s synopsis of psychiatry, behavioral sciences/clinical psychiatry. Philadelphia, PA: Lippincott Williams & Wilkins, 2003.

2.American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 3rd ed. Washington, DC: American Psychiatric Press, Inc., 1980.

3.Jacobsen LK, Southwick SM, Kosten TR. Substance use disorders in patients with posttraumatic stress disorder: a review of the literature. Am J Psychiatry 2001;158(8):1184–1190.

4.Young HE, Rosen CS, Finney JW. A survey of PTSD screening and referral practices in VA addiction treatment programs. J Subst Abuse Treat 2005;28(4):313–319.

5.Harned MS, Najavits LM, Weiss RD. Self-harm and suicidal behavior in women with comorbid PTSD and substance dependence. Am J Addict 2006;15(5):392–395.

6.Ouimette P, Goodwin E, Brown PJ. Health and well being of substance use disorder patients with and without posttraumatic stress disorder. Addict Behav 2006;31(8):1415–1423.

7.Hoge CW, Terhakopian A, Castro CA, et al. Association of posttraumatic stress disorder with somatic symptoms, health care visits, and absenteeism among Iraq war veterans. Am J Psychiatry2007;164:150–153.

8.American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. [Text revision]. Washington, DC: American Psychiatric Press, Inc., 2000.

9.Hidalgo RB, Davidson JR. Posttraumatic stress disorder: epidemiology and health-related considerations. J Clin Psychiatry 2000;61(Suppl 7):5–13.

10.Brunello N, Davidson JR, Deahl M, et al. Posttraumatic stress disorder: diagnosis and epidemiology, comorbidity and social consequences, biology and treatment. Neuropsychobiology2001;43(3):150–162.

11.Kessler RC, Sonnega A, Bromet E, et al. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry 1995;52(12):1048–1060.

12.Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry2005;62(6):593–602.

13.Brady KT, Killeen TK, Brewerton T, et al. Comorbidity of psychiatric disorders and posttraumatic stress disorder. J Clin Psychiatry 2000;61(Suppl 7):22–32.

14.Shipherd JC, Stafford J, Tanner LR. Predicting alcohol and drug abuse in Persian Gulf War veterans: what role do PTSD symptoms play? Addict Behav 2005;30(3):595–599.

15.Milliken CS, Auchterlonie JL, Hoge CW. Longitudinal assessment of mental health problems among active and reserve component soldiers returning from the Iraq war. JAMA2007;298(18):2141–2148.

16.Cottler LB, Compton WM, Mager D, et al. Posttraumatic stress disorder among substance users from the general population. Am J Psychiatry 1992;149(5):664–670.

17.Acierno R, Lawyer SR, Rheingold A, et al. Current psychopathology in previously assaulted older adults. J Interpers Violence 2007;22(2):250–258.

18.Kilpatrick DG, Acierno R, Saunders BE, et al. Risk factors for adolescent substance abuse and dependence: data from a national sample. J Consult Clin Psychol 2000;68(1):19–30.

19.Johnson SD, Striley C, Cottler LB. The association of substance use disorders with trauma exposure and PTSD among African American drug users. Addict Behav 2006;31(11):2063–2073.

20.Reed PL, Anthony JC, Breslau N. Incidence of drug problems in young adults exposed to trauma and posttraumatic stress disorder: do early life experiences and predispositions matter? Arch Gen Psychiatry 2007;64(12):1435–1442.

21.Khantzian EJ. The self-medication hypothesis of addictive disorders: focus on heroin and cocaine dependence. Am J Psychiatry 1985;142(11):1259–1264.

22.Khantzian EJ. Self-regulation and self-medication factors in alcoholism and the addictions. Similarities and differences. Recent Dev Alcohol 1990;8:255–271.

23.Khantzian EJ. The self-medication hypothesis of substance use disorders: a reconsideration and recent applications (see comment). Harv Rev Psychiatry 1997;4(5):231–244.

24.Saladin ME, Brady KT, Dansky BS, et al. Understanding comorbidity between PTSD and substance use disorder: two preliminary investigations. Addict Behav 1995;20(5):643–655.

25.Chilcoat HD, Breslau N. Investigations of causal pathways between PTSD and drug use disorders. Addict Behav 1998;23(6):827–840.

26.Stewart SH, Conrod PJ. Psychosocial models of functional associations between posttraumatic stress disorder and substance use disorder. In: Ouimette P, Brown PJ, eds. Trauma and substance abuse: causes, consequences, and treatment of comorbid disorders. Washington, DC: American Psychological Association, 2003:29–55.

27.Friedman MJ. What might the psychobiology of posttraumatic stress disorder teach us about future approaches to pharmacotherapy? J Clin Psychiatry 2000;61(Suppl 7):44–51.

28.Antony MM, Orsillo SM, Roemer L, eds. Practitioner’s guide to empirically based measures of anxiety. New York, NY: Kluwer Academic/Plenum Publishers, 2001.

29.Wilson J, Keane TM, eds. Assessing psychological trauma and PTSD. New York, NY: Guildford Press, 1997.

30.Brewin CR. Systematic review of screening instruments for adults at risk of PTSD. J Trauma Stress 2005;18(1):53–62.

31.Elhai JD, Gray MJ, Kashdan TB, et al. Which instruments are most commonly used to assess traumatic event exposure and posttraumatic effects?: a survey of traumatic stress professionals. J Trauma Stress 2005;18(5):541–545.

32.Read JP, Bollinger AR, Sharkansky EJ. Assessment of comorbid substance use disorder and posttraumatic stress disorder. In: Ouimette P, Brown PJ, eds. Trauma and substance abuse: causes, consequences, and treatment of comorbid disorders. Washington, DC: American Psychological Association, 2003:111–125.

33.Blake DD, Weathers FW, Nagy LM, et al. The development of a clinician-administered PTSD scale. J Trauma Stress 1995;8:75–90.

34.Weathers FW, Keane TM, Davidson JRT. Clinician-administered PTSD Scale: a review of the first ten years of research. Depress Anxiety 2001;13(3):132–156.

35.First MB, Spitzer RL, Gibbon M, et al. Structured clinical interview for DSM-IV-TR Axis I disorders, research version, patient edition (SCID-I/P). New York, NY: Biometrics Research, New York State Psychiatric Institute, 2002.

36.Spitzer RL, Williams JBW, Gibbon M, et al. The structured clinical interview for DSM-III-R: I. History, rationale and description. Arch Gen Psychiatry 1992;49:624–629.

37.Kilpatrick D, Resnick H, Freedy J. The potential stressful events interview. Charleston, SC: Medical University of South Carolina, 1991.

38.Kilpatrick D, Resnick H, Saunders B, et al. The National Women’s Study PTSD module. Charleston, SC: Medical University of South Carolina, 1989.

39.Foa EB, Tolin DF. Comparison of the PTSD Symptom Scale-Interview Version and the clinician-administered PTSD scale. J Trauma Stress 2000;13(2):181–191.

40.Foa E, Riggs DS, Dancu CV, et al. Reliability and validity of a brief instrument for assessing posttraumatic stress disorder. J Trauma Stress 1993;6:459–473.

41.Davidson JR, Malik MA, Travers J. Structured interview for PTSD (SIP): psychometric validation for DSM-IV criteria. Depress Anxiety 1997;5(3):127–129.

42.Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998;59(Suppl 20):22–33.

43.Wittchen HU. Reliability and validity studies of the WHO— Composite International Diagnostic Interview (CIDI): a critical review. J Psychiatr Res 1994;28(1):57–84.

44.World Health Organization. Composite International Diagnostic Interview (CIDI). Geneva, Switzerland: Author, 1993.

45.Weathers F, Litz B, Herman D, et al. The PTSD Checklist (PCL): reliability, validity, and diagnostic utility. Paper presented at the annual meeting of the International Society for Trauma Stress Studies, 1993. San Antonio, TX.

46.Weiss S, Marmar CR. The impact of event scale—revised. In: Wilson J, Keane TM, eds. Assessing psychological trauma and PTSD. New York, NY: Guilford Press, 1997:399–411.

47.Horowitz MJ, Wilner N, Alvarez W. Impact of Event Scale: a measure of subjective stress. Psychosom Med 1979;41(3):209–218.

48.American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Press, Inc., 1994.

49.Kazlauskas E, Gailiene D, Domanskaite-Gota V, et al. Psychometric properties of the Lithuanian version of the Impact of Event Scale-Revised (IES-R). Psichologija 2006;33:22–30.

50.Asukai N, Kato H, Kawamura N, et al. Reliability and validity of the Japanese-language version of the Impact of Event Scale-revised (IES-R-J): four studies of different traumatic events. J Nerv Ment Dis2002;190(3):175–182.

51.Baguena MJ, Villarroya E, Belena A, et al. Psychometric properties of the Spanish version of the Impact of Event Scale-Revised (IES-R). Anal Modif Conduct 2001;27(114):581–604.

52.Maercker A, Schutzwohl M. Assessment of post-traumatic stress reactions: the Impact of Event Scale-Revised (IES-R). Diagnostica 1998;44(3):130–141.

53.Rash CJ, Coffey SF, Bashnagel JS, et al. Psychometric properties of the IES-R in traumatized substance dependent individuals with and without PTSD. Addict Behav 2008;33(8):1039–1047.

54.Foa EB, Cashman L, Jaycox L, et al. The validation of a self-report measure of posttraumatic stress disorder: the posttraumatic diagnostic scale. Psychol Assess 1997;9(4):445–451.

55.American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 3rd ed. [Revised edition]. Washington, DC: American Psychiatric Press, Inc., 1987.

56.Falsetti SA, Resnick HS, Resick PA, et al. The Modified PTSD Symptom Scale: a brief self-report measure of posttraumatic stress disorder. Behav Ther 1993;16:161–162.

57.Falsetti SA, Resick PA, Resnick HS, et al. Posttraumatic stress disorder: the assessment of frequency and severity of symptoms in clinical and non-clinical samples. Boston, MA: Association for the Advancement of Behavior Therapy, 1992.

58.Coffey SF, Dansky BS, Falsetti SA, et al. Screening for PTSD in a substance abuse sample: psychometric properties of a modified version of the PTSD Symptom Scale Self-Report. Posttraumatic stress disorder. J Trauma Stress 1998;11(2):393–399.

59.Dansky BS, Saladin ME, Coffey SF, et al. Use of self-report measures of crime-related posttraumatic stress disorder with substance use disordered patients. J Subst Abuse Treat1997;14(5):431–437.

60.Keane TM, Caddell JM, Taylor KL. Mississippi Scale for Combat-Related Posttraumatic Stress Disorder: three studies in reliability and validity. J Consult Clin Psychol 1988;56(1):85–90.

61.McFall ME, Smith DE, Mackay PW, et al. Reliability and validity of Mississippi Scale for Combat-Related Posttraumatic Stress Disorder. Psychol Assess 1990;2(2):114–121.

62.McFall ME, Smith DE, Roszell DK, et al. Convergent validity of measures of PTSD in Vietnam combat veterans. Am J Psychiatry 1990;147(5):645–648.

63.Ouimette P, Humphreys K, Moos RH, et al. Self-help group participation among substance use disorder patients with posttraumatic stress disorder. J Subst Abuse Treat 2001;20(1):25–32.

64.Nemeroff CB, Bremmer JD, Foa EB, et al. Posttraumatic stress disorder: a state-of-the-science review. J Psychiatr Res 2006;40(1):1–21.

65.Tiet QQ, Mausbach, B. Treatments for patients with dual diagnosis: a review. Alcohol Clin Exp Res 2007;31(4):513–536.

66.Ballenger JC, Davidson JR, Lecrubier Y, et al. Consensus statement update on posttraumatic stress disorder from the international consensus group on depression and anxiety. J Clin Psychiatry2004;65(Suppl 1):55–62.

67.Brom D, Kleber RJ, Defares PB. Brief psychotherapy for posttraumatic stress disorders. J Consult Clin Psychol 1989;57(5):607–612.

68.Foa EB, Danru CV, Hembree EA, et al. A comparison of exposure therapy, stress inoculation training, and their combination for reducing posttraumatic stress disorder in female assault victims. J Consult Clin Psychol 1999;67(2):194–200.

69.Hyer L, Woods MG, Bruno R, et al. Treatment outcomes of Vietnam veterans with PTSD and the consistency of the MCMI. J Clin Psychol 1989;45(4):547–552.

70.Tarrier N, Pilgrim H, Sommerfield C, et al. A randomized trial of cognitive therapy and imaginal exposure in the treatment of chronic posttraumatic stress disorder. J Consult Clin Psychol1999;67(1):13–18.

71.Mowrer OA. Learning theory and behavior. New York, NY: Wiley, 1960.

72.Stampfl TG, Levis DJ. Essentials of implosive therapy: a learning-theory-based psychodynamic behavioral therapy. J Abnorm Psychol 1967;72(6):496–503.

73.Wolpe J. Psychotherapy by reciprocal inhibition. Stanford, CL: Stanford University Press, 1958.

74.Foa EB, Kozak MJ. Emotional processing of fear: exposure to corrective information. Psychol Bull 1986;99(1):20–35.

75.Pavlov IP. Conditioned reflexes. New York, NY: Dover Publications, 1927.

76.Konorski J. Conditioned reflexes and neuronal organization. London, UK: Cambridge University Press, 1948.

77.Rescorla RA. Spontaneous recovery. Learn Mem 2004;11(5): 501–509.

78.Foa E, Rothbaum BO. Treating the trauma of rape. New York, NY: The Guilford Press, 1998.

79.Shapiro F, Maxfield L. Eye Movement Desensitization and Reprocessing (EMDR): information processing in the treatment of trauma. J Clin Psychol 2002;58(8):933–946. behavioral procedures and counseling. J Consult Clin Psychol 1991;59(5):715–723.

80.Shapiro F. Eye movement desensitization and reprocessing: basic principles, protocols, and procedures, 2nd ed. New York, NY: Guilford Press, 2001:xxiv, 472.

81.Shapiro F. Efficacy of the Eye Movement Desensitization procedure in the treatment of traumatic memories. J Trauma Stress 1989;2(2):199–223.

82.Beck AT. Cognitive therapy and the emotional disorders. New York, NY: International Universities Press, 1976:356.

83.Beck AT. Cognitive therapy of depression. New York, NY: Guilford Press, 1979:425.

84.Beck AT, Emery G, Greenberg RL. Anxiety disorders and phobias: a cognitive perspective [15th anniversary edition]. Cambridge, MA: Basic Books, 2005:xxxvi, 343.

85.Clark DM. A cognitive approach to panic. Behav Res Ther 1986;24(4):461–470.

86.Beck AT, Wright FD, Newman CF, et al. Cognitive therapy of substance abuse. New York, NY: Guilford Press, 1993:xiii, 354.

87.Resick PA, Schnicke MK. Cognitive processing therapy for sexual assault victims. J Consult Clin Psychol 1992;60(5):748–756.

88.Resick PA, Schnicke MK. Cognitive processing therapy for rape victims: a treatment manual. Interpersonal violence: the practice series, Vol. 4. Newbury Park, CA: Sage, 1993.

89.Monson CM, Schnorr PP, Resick PA, et al. Cognitive processing therapy for veterans with military-related posttraumatic stress disorder. J Consult Clin Psychol 2006;74(5):898–907.

90.Ahrens J, Rexford L. Cognitive processing therapy for incarcerated adolescents with PTSD. J Aggress Maltreat Trauma 2002;6(1):201–216.

91.Chard KM. An evaluation of cognitive processing therapy for the treatment of posttraumatic stress disorder related to childhood sexual abuse. J Consult Clin Psychol 2005;73:965–971.

92.Silver SM, Brooks A, Obenchain J. Treatment of Vietnam War veterans with PTSD: a comparison of eye movement desensitization and reprocessing, biofeedback, and relaxation training. J Trauma Stress1995;8(2):337–342.

93.Meichenbaum D. Stress inoculation training. Psychology practitioner guidebooks. New York, NY: Pergamon Press, 1985:xi, 115.

94.Meichenbaum D. Clinical handbook/therapist manual for assessing and treating adults with PTSD. Waterloo, ON: Institute Press, 1994:600.

95.Meichenbaum D. Self-instructional training. In: Kanfer FH, Goldstein A, eds. Helping people change. New York, NY: Pergamon Press, 1975:357–391.

96.Veronen LJ, Kilpatrick DG. Stress management for rape victims. In: Meichenbaum D, Jaremko ME, eds. Stress reduction and prevention. New York, NY: Plenum Press, 1983:341–374.

97.Foa EB, Rothbaum BO, Riggs DS, et al. Treatment of posttraumatic stress disorder in rape victims: a comparison between cognitive-

98.Yadin E, Foa E. Cognitive behavioral treatments for posttraumatic stress disorder. In: Kirmayer LJ, Lemelson R, Barad M, eds. Understanding trauma: integrating biological, clinical, and cultural perspectives. Cambridge, MA: Cambridge University Press, 2007:178–193.

99.Foa EB, Cahill S. Psychological treatments for PTSD: an overview. In: Neria Y, et al., eds. 9/11: public health in the wake of terrorist attacks. Cambridge, MA: Cambridge University Press, 2006:457–474.

100.Foa EB. Psychosocial therapy for posttraumatic stress disorder. J Clin Psychiatry 2006;67(Suppl 2):40–45.

101.Bisson JI, Ehlers A, Matthews R, et al. Psychological treatments for chronic post-traumatic stress disorder. Systematic review and meta-analysis. Br J Psychiatry 2007;190:97–104.

102.Keane TM, Marshall AD, Taft CT. Posttraumatic stress disorder: etiology, epidemiology, and treatment outcome. Annu Rev Clin Psychol 2006;2:161–197.

103.Bisson J, Andrew M. Psychological treatment of post-traumatic stress disorder (PTSD). Cochrane Database Syst Rev 2007;(3):1–20.

104.Bradley R, Greene J, Russ E, et al. A multidimensional meta-analysis of psychotherapy for PTSD. Am J Psychiatry 2005;162(2):214–227.

105.Foa E, Rothbaum BO, Furr JM. Augmenting exposure therapy with other BT procedures. Psychiatr Ann 2003;33(1):47–53.

106.Grunert BK, Weis JM, Smucker MR, et al. Imagery rescripting and reprocessing therapy after failed prolonged exposure for posttraumatic stress disorder following industrial injury. J Behav Ther Exp Psychiatry 2007;38(4):317–328.

107.Acierno R, Hersen M, van Hasselt VB, et al. Review of the validation and dissemination of eye-movement desensitization and reprocessing: a scientific and ethical dilemma. Clin Psychol Rev1994;14(4):287–299.

108.McNally RJ. EMDR and Mesmerism: a comparative historical analysis. J Anxiety Disord 1999;13(1–2):225–236.

109.Herbert JD, Lilienfield SO, Lohr JM, et al. Science and pseudoscience in the development of eye movement desensitization and reprocessing: implications for clinical psychology. Clin Psychol Rev2000;20(8):945–971.

110.Rosen GM, McNally R, Lohr JM, et al. A realistic appraisal of EMDR. Calif Psychol 1998;31:25–27.

111.McNally R. Research on eye movement desensitization and reprocessing (EMDR) as a treatment for PTSD. In: Friedman MJ, ed. PTSD research quarterly. White River Junction, VT: VA Medical and Regional Office Center, 1999:1–8.

112.Lohr JM, Lilienfield SO, Tolin DF, et al. Eye movement desensitization and reprocessing: an analysis of specific versus nonspecific treatment factors. J Anxiety Disord 1999;13(1–2):185–207.

113.Lohr JM, Kleinknecht RA, Tolin, DF, et al. The empirical status of the clinical application of eye movement desensitization and reprocessing. J Behav Ther Exp Psychiatry 1995;26(4): 285–302.

114.Lohr JM, Kleinknecht RA, Conley AT, et al. A methodological critique of the current status of eye movement desensitization (EMD). J Behav Ther Exp Psychiatry 1992;23(3):159–167.

115.Pitman RK, Orr SP, Altman B, et al. Emotional processing during eye movement desensitization and reprocessing therapy of Vietnam veterans with chronic posttraumatic stress disorder. Compr Psychiatry1996;37(6):419–429.

116.Lohr JM, Tolin DF, Lilienfeld SO. Efficacy of eye movement desensitization and reprocessing: implications for behavior therapy. Behav Ther 1998;29(1):123–156.

117.Cahill SP, Carrigan MH, Frueh BC. Does EMDR work? And if so, why?: a critical review of controlled outcome and dismantling research. J Anxiety Disord 1999;13(1–2):5–33.

118.Davidson PR, Parker KC. Eye movement desensitization and reprocessing (EMDR): a meta-analysis. J Consult Clin Psychol 2001;69(2):305–316.

119.Rothbaum BO, Astin MC, Marsteller F. Prolonged exposure versus eye movement desensitization and reprocessing (EMDR) for PTSD rape victims. J Trauma Stress 2005;18(6):607–616.

120.Macklin ML, Metzger LJ, Lasko NB, et al. Five-year follow-up study of eye movement desensitization and reprocessing therapy for combat-related posttraumatic stress disorder. Compr Psychiatry2000;41(1):24–27.

121.Renfrey G, Spates CR. Eye movement desensitization: a partial dismantling study. J Behav Ther Exp Psychiatry 1994;25(3):231–239.

122.Najavits LM, Sullivan TP, Schmitz M, et al. Treatment utilization by women with PTSD and substance dependence. Am J Addict 2004;13(3):215–224.

123.Nace EP. Posttraumatic stress disorder and substance abuse. Clinical issues. Recent Dev Alcohol 1988;6:9–26.

124.Pitman RK, Altman B, Greenwald E, et al. Psychiatric complications during flooding therapy for posttraumatic stress disorder. J Clin Psychiatry 1991;52(1):17–20.

125.Brady KT, Dansky BS, Back SE, et al. Exposure therapy in the treatment of PTSD among cocaine-dependent individuals: preliminary findings. J Subst Abuse Treat 2001;21(1):47–54.

126.Foa E, Chrestman K, Riggs DS. Integrating prolonged exposure therapy and substance abuse treatment. Hollywood, CA: International Society for Traumatic Stress Studies, 2006.

127.Najavits LM, Schmitz M, Gotthardt S, et al. Seeking safety plus exposure therapy: an outcome study on dual diagnosis men. J Psychoactive Drugs 2005;37(4):425–435.

128.Triffleman E. Gender differences in a controlled pilot study of psychosocial treatments in substance dependent patients with post-traumatic stress disorder: design considerations and outcomes. Alcohol Treat Q 2000;18(3):113–126.

129.Back SE, Brady KT, Sonne SC, et al. Symptom improvement in co-occurring PTSD and alcohol dependence. J Nerv Ment Dis 2006;194(9):690–696.

130.Ouimette P, Ahrens C, Moos R, et al. Posttraumatic stress disorder in substance abuse patients: relationships to 1 year posttreatment outcomes. Psychol Addict Behav 1997;1:34–47.

131.Back SE, Brady KT, Jaaimägi U, et al. Cocaine dependence and PTSD: a pilot study of symptom interplay and treatment preferences. Addict Behav 2006;31(2):351–354.

132.Brown PJ, Stout RL, Gannon-Rowley J. Substance use disorder-PTSD comorbidity: patients’ perceptions of symptom interplay and treatment issues. J Subst Abuse Treat1998;15(5):445–448.

133.Najavits LM. Seeking safety: a treatment manual for PTSD and substance abuse. In: Blane HT, Kosten TR, eds. Guilford Substance Abuse Series. New York, NY: Guilford Press, 2002.

134.Najavits LM, Weiss RD, Shaw SR, et al. Seeking safety: outcome of a new cognitive-behavioral psychotherapy for women with posttraumatic stress disorder and substance dependence. J Trauma Stress1998;11(3):437–456.

135.Hien DA, Cohen LR, Miele GM, et al. Promising treatments for women with comorbid PTSD and substance use disorders. Am J Psychiatry 2004;161(8):1426–1432.

136.Hien DA, Wells EA, Jiang H, et al. Multisite randomized trial of behavioral interventions for women with co-occurring PTSD and substance use disorders. J Consult Clin Psychol2009;77(4):607–619.

137.Triffleman E, Carroll K, Kellogg S. Substance dependence posttraumatic stress disorder therapy. An integrated cognitive-behavioral approach. J Subst Abuse Treat 1999;17(1–2):3–14.

138.Back SE, Dansky BS, Carroll KM, et al. Exposure therapy in the treatment of PTSD among cocaine-dependent individuals: description of procedures. J Subst Abuse Treat2001;21(1):35–45.

139.Mills KL, Teesson M, Back SE, et al. Integrated exposure-based therapy for co-occurring posttraumatic stress disorder and substance dependence: a randomized controlled trial. JAMA2012;308(7):690–699.

140.Donovan B, Padin-Rivera E, Kowaliw S. Transcend: initial outcomes from a posttraumatic stress disorder/substance abuse treatment program. J Trauma Stress 2001;14(4):757–772.

141.Harris M. Trauma recovery and empowerment: a clinician’s guide for working with women in groups. New York, NY: Free Press, 1998.

142.Toussaint D, van DeMark N, Bornemann A, et al. Modifications to the Trauma Recovery and Empowerment Model (TREM) for substance-abusing women with histories of violence: outcomes and lessons learned at a Colorado substance abuse treatment center. J Commun Psychol 2007;35(7):879–894.

143.Najavits LM, Ryngala D, Back SE, et al. Treatment for PTSD and comorbid disorders: a review of the literature. In: Foa E, Keane TM, Friedman MJ, eds, Effective treatments for PTSD. New York, NY: Guilford Press, 2008.

144.Zlotnick C, Najavits LM, Rohsenow DJ, et al. A cognitive-behavioral treatment for incarcerated women with substance abuse disorder and posttraumatic stress disorder: findings from a pilot study. J Subst Abuse Treat 2003;25(2):99–105.

145.Najavits LM. Expanding the Boundaries of PTSD Treatment. JAMA 2012;308(7):714–716.

146.Zhang W, Davidson JR. Post-traumatic stress disorder: an evaluation of existing pharmacotherapies and new strategies. Expert Opin Pharmacother 2007;8(12):1861–1870.

147.Brady K, Pearlstein T, Asnis GM, et al. Efficacy and safety of sertraline treatment of posttraumatic stress disorder: a randomized controlled trial. JAMA 2000;283(14):1837–1844.

148.Davidson J, Pearlson T, Londborg P, et al. Efficacy of sertraline in preventing relapse of posttraumatic stress disorder: results of a 28-week double-blind, placebo-controlled study. Am J Psychiatry2001;158(12):1974–1981.

149.Ipser J, Seedat S, Stein DJ. Pharmacotherapy for post-traumatic stress disorder—a systematic review and meta-analysis. S Afr Med J 2006;96(10):1088–1096.

150.Davidson JR. Pharmacologic treatment of acute and chronic stress following trauma: 2006. J Clin Psychiatry 2006;67(Suppl 2):34–39.

151.Marshall RD, Beebe KL, Oldham M, et al. Efficacy and safety of paroxetine treatment for chronic PTSD: a fixed-dose, placebo-controlled study. Am J Psychiatry 2001;158(12):1982–1988.

152.Schoenfeld FB, Marmar CR, Neylan TC. Current concepts in pharmacotherapy for posttraumatic stress disorder. Psychiatr Serv 2004;55(5):519–531.

153.Berlau DJ, McGaugh JL. Enhancement of extinction memory consolidation: the role of the noradrenergic and GABAergic systems within the basolateral amygdala. Neurobiol Learn Mem 2006;86(2):123–132.

154.Debiec J, Ledoux JE. Disruption of reconsolidation but not consolidation of auditory fear conditioning by noradrenergic blockade in the amygdala. Neuroscience 2004;129(2):267–272.

155.Lee JL, DiCiano P, Thomas KL, et al. Disrupting reconsolidation of drug memories reduces cocaine-seeking behavior. Neuron 2005;47(6):795–801.

156.McGaugh JL. Memory—a century of consolidation. Science 2000;287(5451):248–251.

157.Nader K. Memory traces unbound. Trends Neurosci 2003;26(2):65–72.

158.Sara SJ. Retrieval and reconsolidation: toward a neurobiology of remembering. Learn Mem 2000;7(2):73–84.

159.Cahill L, Pham CA, Setlow B. Impaired memory consolidation in rats produced with beta-adrenergic blockade. Neurobiol Learn Mem 2000;74(3):259–266.

160.Morris RW, Westbrook RF, Killcross AS. Reinstatement of extinguished fear by beta-adrenergic arousal elicited by a conditioned context. Behav Neurosci 2005;119(6):1662–1671.

161.Cahill L, Prins B, Weber M, et al. Beta-adrenergic activation and memory for emotional events. Nature 1994;371(6499):702–704.

162.O’Carroll RE, Drysdale E, Cahill L, et al. Stimulation of the noradrenergic system enhances and blockade reduces memory for emotional material in man. Psychol Med1999;29(5):1083–1088.

163.Reist C, Duffy JG, Fujimoto K, et al. Beta-adrenergic blockade and emotional memory in PTSD. Int J Neuropsychopharmacol 2001;4(4):377–383.

164.Pitman RK, Sanders KM, Zusman RM, et al. Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Biol Psychiatry 2002;51(2):189–192.

165.Vaiva G, Ducrocq F, Jezequel K, et al. Immediate treatment with propranolol decreases posttraumatic stress disorder two months after trauma. Biol Psychiatry 2003;54(9):947–949.

166.Taylor F, Cahill L. Propranolol for reemergent posttraumatic stress disorder following an event of retraumatization: a case study. J Trauma Stress 2002;15(5):433–437.

167.Pitman RK, Brunet A, Orr SP, et al. A novel treatment for post-traumatic stress disorder by reconsolidation blockade with propranolol. Neuropsychopharmacology 2006;31(1):S8–S9.

168.Brady KT, Verduin ML. Pharmacotherapy of comorbid mood, anxiety, and substance use disorders. Subst Use Misuse 2005;40 (13–14):2021–2041, 2043–2048.

169.Lingford-Hughes AR, Welch S, Nutt DJ. Evidence-based guidelines for the pharmacological management of substance misuse, addiction, and comorbidity: recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2004;18(3):293–335.

170.Brady KT, Sonne SC, Roberts JM. Sertraline treatment of comorbid posttraumatic stress disorder and alcohol dependence. J Clin Psychiatry 1995;56(11):502–505.

171.Brady KT, Sonne S, Anton RF, et al. Sertraline in the treatment of co-occurring alcohol dependence and posttraumatic stress disorder. Alcohol Clin Exp Res 2005;29(3):395–401.

172.Labbate LA, Sonne SC, Randal CL, et al. Does comorbid anxiety or depression affect clinical outcomes in patients with post-traumatic stress disorder and alcohol use disorders? Compr Psychiatry2004;45(4):304–310.

173.Zatzick D, Roy-Byrne P, Russo J, et al. A randomized effectiveness trial of stepped collaborative care for acutely injured trauma survivors. Arch Gen Psychiatry 2004;61:498–506.

174.Norberg MM, Krystal JH, Tolin DF. A meta-analysis of D-cycloserine and the facilitation of fear extinction and exposure therapy. Biol Psychiatry 2008;63(22):1118–1126.

175.Ledgerwood L, Richardson R, Cranney J. Effects of D-cycloserine on extinction of conditioned freezing. Behav Neurosci 2003;117(2):341–349.

176.Ledgerwood L, Richardson R, Cranney J. D-Cycloserine and the facilitation of extinction of conditioned fear: consequences for reinstatement. Behav Neurosci 2004;118(3):505–513.

177.Ledgerwood L, Richardson R, Cranney J. D-Cycloserine facilitates extinction of learned fear: effects on reacquisition and generalized extinction. Biol Psychiatry 2005;57(8):841–847.

178.Walker DL, Ressler KJ, Lu KT, et al. Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of D-cycloserine as assessed with fear-potentiated startle in rats. J Neurosci 2002;22(6):2343–2351.

179.Yang YL, Lu KT. Facilitation of conditioned fear extinction by D-cycloserine is mediated by mitogen-activated protein kinase and phosphatidylinositol 3-kinase cascades and requires de novo protein synthesis in basolateral nucleus of amygdala. Neuroscience 2005;134(1):247–260.

180.Ressler KJ, Rothbaum BU, Tannebaum L, et al. Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry2004;61(11):1136–1144.

181.Hofmann SG, Meuret AE, Smits JA, et al. Augmentation of exposure therapy with D-cycloserine for social anxiety disorder. Arch Gen Psychiatry 2006;63(3):298–304.

182.Kushner MG, Kim SW, Donahue C, et al. D-cycloserine augmented exposure therapy for obsessive-compulsive disorder. Biol Psychiatry 2007;62(8):835–838.

183.Guastella AJ, Dadds MR; Lovibond PF, et al. A randomized controlled trial of the effect of D-cycloserine on exposure therapy for spider fear. J Psychiatr Res 2007;41(6):466–471.

184.Drummond DC, Tiffany ST, Glautier S, et al. Addictive Sons, Ltd., 1995.

185.Drobes DJ, Saladin ME, Tiffany ST. Classical conditioning mechanisms in alcohol dependence. In: Heather N, Peters TJ, Stockwell T, eds. International handbook of alcohol dependence and problems. Chichester, England: John Wiley & Sons, Ltd., 2001:281–297.

186.Childress AR, Ehrman RN, McLellan AT, et al. Conditioned craving and arousal in cocaine addiction: a preliminary report. NIDA Res Monogr 1988;81:74–80.

187.O’Brien CP, Childress AR, Ehrman R, et al. Conditioning factors in drug abuse: can they explain compulsion? J Psychopharmacol 1998;12(1):15–22.

188.Sinha R, Fuse T, Aubin LR, et al. Psychological stress, drug-related cues and cocaine craving. Psychopharmacology (Berl) 2000;152(2):140–148.

189.Wise RA. The neurobiology of craving: implications for the understanding and treatment of addiction. J Abnorm Psychol 1988;97:118–132.

190.Conklin CA, Tiffany ST. Applying extinction research and theory to cue-exposure addiction treatments. Addiction 2002;97:155–167.

191.Ouimette P, Brown PJ, eds. Trauma and substance abuse: causes, consequences, and treatment of comorbid disorders. Washington, DC: American Psychological Association, 2003.

192.Riggs DS, Rukstalis M, Volpicelli JR, et al. Demographic and social adjustment characteristics of patients with comorbid posttraumatic stress disorder and alcohol dependence: potential pitfalls to PTSD treatment. Addict Behav 2003;28(9):1717–1730.