A N N A L S O F T H E N E W Y O R K A C A D E M Y O F S C I E N C E S Issue:Psychiatric and Neurologic Aspects of War
Evidence-based treatments for PTSD, new directions,
and special challenges
Judith Cukor, Megan Olden, Francis Lee, and JoAnn Difede
Department of Psychiatry, Weill Cornell Medical College of Cornell University, New York, New York
Address for correspondence: Judith Cukor, Ph.D., Weill Cornell Medical College, 525 East 68th Street, Box 200, New York, New York 10065. juc2010@med.cornell.edu
This paper provides a current review of existing evidence-based treatments for posttraumatic stress disorder (PTSD), with a description of psychopharmacologic options, prolonged exposure therapy, cognitive processing therapy, and eye movement desensitization and reprocessing, especially as they pertain to military populations. It further offers a brief summary of promising treatments with a developing evidence base, encompassing both psychotherapy and pharmacotherapy. Finally, challenges to the treatment of PTSD are summarized and future directions suggested. Keywords: posttraumatic stress disorder; evidence-based treatment; PE; novel treatments
Introduction
Posttraumatic stress disorder (PTSD) is estimated to affect 8–9% of individuals in the population at some point in their lives.1,2It is characterized by a pattern of symptoms arising in the aftermath of a trauma that causes significant functional impairment and distress to the individual.3PTSD is associated with high rates of comorbidity and increased risk for sui-cide4and is often chronic in nature, with more than one-third of cases continuing to meet diagnostic criteria after many years.5
In the 30 years since its diagnostic criteria was first outlined in the Diagnostic and Statistical Man-ual of Mental Disorders, Third Edition (DSM-III), a body of research has emerged, identifying rates of PTSD in various populations, isolating risk factors for its development, and developing effective meth-ods for its treatment. These three decades of research have revealed that psychotherapy, and specifically exposure-based therapies have the most compelling evidence base and should be used as the first line treatment for PTSD6,7with limited evidence for the efficacy of any of the U.S. Food and Drug Admin-istration (FDA) approved pharmacologic agents.8 Yet, despite the unparalleled success of these inter-ventions, treatment failures persist. A meta-analysis of 26 studies with 44 treatment conditions found that overall, 56% of those enrolled in treatment
and 67% of those who completed treatment no longer met criteria for PTSD after treatment and 44% of enrollees and 54% of completers had clini-cally meaningful improvement by standards defined by the authors.9At best, then, one-third of patients who complete these evidence-based therapies retain a diagnosis of PTSD at completion of treatment, offering compelling reason to continue to pursue alternative treatments or augmentations to current interventions.
With recent events in the nation and world his-tory, and the high rates of PTSD in returning military from Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF), the urgency of iden-tifying effective treatment options for PTSD is imperative.
Evidence-based treatments for PTSD
Treatment recommendation guidelines indicate that psychotherapy is the most effective treatment for PTSD.7 Among the various modalities of psy-chotherapy, cognitive behavioral therapy (CBT) has the strongest evidence base, as highlighted by a recent meta-analysis encompassing 26 treatment outcome studies.9 Similarly, a report by the Insti-tute of Medicine6concluded that exposure therapy is the only treatment with sufficient evidence to recommend for the treatment of PTSD.
Bissonet al.,10in a meta-analysis of 38 studies, re-ported that CBT for trauma was significantly more effective than waitlist or usual care groups in im-proving symptoms of PTSD. Eye movement desen-sitization and reprocessing (EMDR) was also sig-nificantly effective, though the evidence base for EMDR was not as strong as that for CBT. Stress management/relaxation and group CBTs showed success on some measures but to a lesser degree, while other therapies, including supportive apy/nondirective counseling, psychodynamic ther-apies, and hypnotherapy, did not show clinically significant effects on PTSD symptoms.
CBTs for PTSD place varying emphases on the ex-posure or behavioral components versus the cogni-tive elements, and have garnered different amounts of support. Prolonged exposure (PE), a treatment protocol developed by Foa et al.,11 was one of the first techniques to amass an evidence base and is widely accepted as the gold standard for CBT treatment. The theoretical basis for PE re-lies upon the learning model, and views PTSD as a disorder of extinction, whereby the individual’s response to crisis does not diminish sufficiently, and the association between the memory of the event and a message of danger has not been ex-tinguished even when the danger has passed. The main components of PE, imaginal exposure and in vivo exposure, entail the revisiting of trauma memories and triggers to extinguish this response, by facilitating habituation to the memory, decreas-ing avoidance, and eliminatdecreas-ing associations with danger by providing corrective information about safety. During imaginal exposure, patients are in-structed to relate their trauma experience in detail with their eyes closed, while trying to engage emo-tionally in the memory. The patient retells his/her trauma experience repeatedly over the course of a number of sessions, thereby allowing the processing of the trauma experience.In vivo exposure entails approaching activities, people, and/or places the pa-tient may have been avoiding to allow habituation to the environment, and the assimilation of the cor-rective information regarding safety.
Within cognitive behavioral treatments for PTSD, an impressive evidence base supports the use of pro-longed imaginal exposure as a specific therapeutic technique in various populations including sexual assault and motor vehicle accidents.12In one of the few randomized controlled trials of CBT in
mili-tary populations,13female veterans and active duty service personnel receiving 10 sessions of PE were more likely to no longer meet PTSD diagnostic cri-teria and to achieve total PTSD remission than those in the supportive arm.
A recent meta-analysis of PE14 found large ef-fect sizes for PE as compared to control conditions with patients receiving PE treatment improving at a rate of 86% greater than those in the control con-dition. There was no evidence of the superiority of PE over other treatments (i.e., cognitive processing therapy (CPT), cognitive therapy, stress inoculation training, and EMDR) though a very small number of studies were available for comparison, so further research is necessary to provide conclusive answers regarding comparability of treatments. Based on the overall positive findings related to PE, the Veterans’ Administration Office of Mental Health Services has introduced a program to disseminate PE treatment to its providers so it can be delivered as a treatment of choice in Veterans Affairs establishments.15
CPT is another exposure-based protocol with a strong emphasis on increasing the cognitive com-ponents and decreasing the amount of exposure necessary for treatment, which some believe will be more palatable to individuals with PTSD. CPT consists of a 12-session protocol that was originally developed as a treatment for PTSD related to sex-ual assault,16 but has more recently been applied to military trauma and motor vehicle accidents. It comprises two integrated elements. The cogni-tive therapy component focuses on deconstruct-ing assimilated distorted beliefs, such as guilt, and more global beliefs about the world and self, and generating more balanced statements. The expo-sure component entails having the patient write the trauma memory and read it to their therapist and to themselves and then examine the writing for “stuck points.”17
Initial case studies and clinical trials were promis-ing and led to a randomized controlled trial com-paring CPT to PE and a minimal attention waitlist control for the treatment of PTSD in a sample of chronically distressed rape victims.17Results found that both PE and CPT were highly successful in treating PTSD and comorbid depressive symptoma-tology. Applications to a military population with chronic PTSD have been encouraging. In one ran-domized trial of CPT versus waitlist control, 40% of patients receiving CPT no longer met criteria for
PTSD at the study’s end and 50% demonstrated a re-liable drop in PTSD symptoms at posttreatment as-sessment 1 month later, with further significant im-provements in comorbid depression, anxiety, guilt, and social adjustment.18Similarly to PE, dissemina-tion efforts are providing training in CPT for veteran providers nationwide.
EMDR has been at the center of considerable controversy since its inception. EMDR is an eight-stage information processing treatment proposed by Shapiro19that entails focusing on a vivid image of the memory while the therapist leads the pa-tient through a series of eye movements, tones, tap-ping, or other tactile stimulation. The treatment is said to work by enhancing processing of the trauma memory when new connections are made with more positive information and the associations with the memory no longer hold emotional or physiological arousal.20
The evidence base for EMDR seems to support its effectiveness for the treatment of PTSD, with some studies finding it comparable to exposure-based CBT,21 and others finding it less effective.10 The central question at the heart of the debate sur-rounding EMDR is whether the effectiveness of the treatment is due solely to the exposure to the trauma memory during the exercise, thereby rendering the treatment merely a disguised exposure therapy, or whether there is in fact added benefit to the dual stimulation.22Due to the nature of the treatment, it would be difficult to separate the elements to eval-uate their independent contributions.
Psychopharmacology
Only two pharmacologic agents are FDA approved for the treatment of PTSD: sertraline and paroxe-tine. These selective serotonin reuptake inhibitors (SSRIs) primarily act upon the serotonin neuro-transmitter system and have the strongest empirical support in the treatment literature. Indeed, response rates are low and rarely reach above 60% with less than 30% achieving full remission.23 Overall, less than 50% of PTSD patients improve on SSRIs.8In addition, maintenance of effects is only achieved through continued medication treatment,24which one might attribute to the medication addressing symptoms rather than the source of the problem, which is the trauma experience.
Surprisingly little consensus has been reached on second line treatments for PTSD. An
encompass-ing systematic review of open and controlled tri-als found some support for the use of risperidone, which was effective in four of six reviewed trials.23 Short-term trials of antipsychotic medications re-vealed some effects but Berger and colleagues23 sug-gest this may reflect treatment of nonspecific symp-toms, such as insomnia, and not those specifically related to PTSD. In addition, severe side effects with longer trials could be problematic. The authors in-dicate that anticonvulsants seem helpful when used as an augmentation to other therapeutic regimens, but studies using it as a monotherapy were largely insignificant. They also caution against the use of benzodiazepenes because of its potentially addictive nature and the question of whether it may con-tribute to the development of PTSD.23In practice, medication is frequently used to target more iso-lated symptoms (i.e., sleep difficulty), rather than the overall disorder.
Barriers to implementation of evidence-based treatments
Dissemination and acceptance of evidence-based treatments pose a significant obstacle to implemen-tation of best practices. van Minnen et al.25 pre-sented 255 trauma experts with case examples, and found that despite the evidence noted above, expo-sure was underutilized, there was a lack of training in the technique, and providers were more likely to offer medication than exposure when the PTSD pre-sented with a comorbid depression. Beckeret al.26 surveyed 217 psychologists and found only 17% used exposure therapy for the treatment of PTSD, and even among those who had received training in exposure, 38–46% did not implement its use. Rea-sons cited among the trained psychologists included hesitancy to use manualized treatments and the con-cern that patients would decompensate, despite the existence of evidence to the contrary. In training a large cohort of psychologists to use PE therapy in the aftermath of 9/11, Cahillet al.27found that discomfort in using exposure and cognitive restruc-turing techniques, concerns about decompensation, and a disinclination to use manualized treatments served as significant barriers to the implementation of treatment.
Promising directions
A recent proliferation in studies of novel and inno-vative treatments for PTSD suggests an awareness of
the need for alternatives to supplement the current evidence-based treatments. Some emerging treat-ments will be summarized here, selected because of their growing evidence base and persuasive scien-tific rationale, though they represent only a small number of interventions that are currently being proposed. Due to the preliminary nature of these studies, there is insufficient evidence to draw con-clusions about the efficacy of these treatments, but there is reason to be optimistic about the possibility for new treatment options.
While treatment outcome studies seek to identify novel, effective interventions, exciting translational research has directed its attention to identifying neu-rocircuitry involved in fear conditioning that may shed light on propensity to develop PTSD or failure to improve with treatment. In light of the conceptu-alization of PTSD as a disorder of fear extinction or inhibition, findings on genetic and neurobiological factors related to fear inhibition may provide more information that may be used to address risk factors or treatment failures.28
Emerging pharmacotherapies
Prazosin. Prazosin, an alpha-1 adrenergic recep-tor blocker, has recently been investigated as a tool in targeting insomnia and nightmares following a traumatic event. Originally marketed to treat hy-pertension and benign prostate hyperplasia,29 pra-zosin’s role in inhibiting adrenergic activity suggests it may also prove efficacious in treating sleep-related PTSD symptoms. These symptoms are believed to be moderated by increased central nervous system adrenergic activity, resulting in greater release of norepinephrine and increased sensitivity to nore-pinephrine at receptor sites.30 Prazosin’s effective-ness for the treatment of nightmares has been re-ported in case studies, retrospective chart reviews, and open label trials.31Preliminary evidence exists for its effectiveness in military populations32,33with reports of 50% decrease in nightmares after 8 weeks of treatment.34 Prazosin demonstrates a promis-ing adjunct to target insomnia and trauma-related nightmares in patients with PTSD. Further studies are needed to determine optimal dosing regimens as well as the applicability of this treatment across a wide variety of traumas.
d-cycloserine. The cognitive enhancer d
-cycloserine (DCS; trade name Seromycin) shows promise among pharmacologic agents for PTSD for
its potential to facilitate extinction learning. Origi-nally developed as an antituberculosis antibiotic, DCS is a partial agonist for the N-methyl-d
-aspartate (NMDA) glutamate receptor, which has a crucial role in learning and memory functions. DCS has been shown to facilitate extinction learning in animal models of conditioned fear and in some human trials of other types of learning.35–41
In the first double-blind randomized controlled trial,42 patients with acrophobia in the DCS con-dition reported significantly lower anxiety and demonstrated reduced galvanic skin response when in the virtual environment than those receiving a placebo, and reported increased real-life exposure to heights at 3 months. Positive results were also demonstrated in a double-blind randomized con-trolled trial of 27 patients with social phobia (N= 27)43and a randomized controlled trial of 56 pa-tients with social anxiety.44
Existing research highlights the potential role of DCS in facilitating fear extinction and reducing posttreatment relapse.36 Studies are under way to investigate the use of DCS in PTSD patients to aug-ment PE and virtual reality therapy, with the hope that its use may improve or accelerate treatment ef-fects through enhancement of extinction learning on a biological level.
Emerging psychotherapies
Couples and family therapy. PTSD frequently neg-atively impacts marital and family relationships, sometimes resulting in isolating behaviors and in-creased anger and irritability.45In fact, upwards of 75% of OIF/OEF veterans report relationship dif-ficulties.46Family interventions for PTSD sufferers may focus treatment on reducing stress to the fam-ily system, or they may target the individual with PTSD, building support for this person within the family.47
Several couples-based treatments have been de-veloped, including cognitive behavioral conjoint therapy (CBCT) for PTSD.45 This 15-session pro-tocol treats couples with behavioral and communi-cation techniques, and cognitive interventions ad-dressing maladaptive thoughts about the trauma and their impact on the relationship and symptoms of PTSD. CBCT has obtained preliminary support, with one pilot study of married Vietnam veterans and their spouses (N=7)48finding significant im-provement in PTSD scores by clinician and spouse
ratings. Adaptations are under way to apply this therapy to OIF/OEF veterans and assess its efficacy.45 Despite a lack of systematic investigations, the use of family- and couples-based treatments for PTSD has a strong theoretical base, particularly for use with military service members struggling to com-municate wartime experiences to family members.
Interpersonal psychotherapy. As individuals with PTSD frequently experience disrupted relationships with family, friends, and colleagues, interpersonal psychotherapy (IPT), with its focus on social func-tioning, has been a focus of empirical inquiry. One pilot study of a 14-week IPT treatment for patients suffering from a variety of traumas,49 found that 69% of patients demonstrated a 50% reduction in PTSD symptoms. Group applications of IPT have been more mixed, with one study reporting greater reductions in PTSD and depression symptoms for a group IPT intervention than a waitlist control group50and another finding that IPT was only mod-erately effective in reducing PTSD symptoms.51
Future work will be needed to determine whether an interpersonal focus is effective in reducing the full range of PTSD symptoms, or whether IPT is best used as a supplementary treatment tool to address relational deficits in patients following a traumatic experience.
Virtual reality. Virtual reality exposure therapy (VRET) uses technological advances to augment traditional imaginal exposure treatment. In inal exposure, the patient relies upon his/her imag-inal capacities to retell the trauma experience in a manner that evokes emotional engagement. Virtual reality enhanced exposure facilitates this emotional engagement by adding visual, auditory, olfactory, and even haptic computer-generated sim-ulation experiences as the patient relates the trauma memory, thereby increasing presence in the mem-ory. Evidence for the efficacy of VRET has been shown for Vietnam veterans,52,53 survivors of the World Trade Center attacks,54and OIF/OEF veter-ans.55
VRET has garnered interest especially in the mil-itary population for the treatment of returning OIF/OEF veterans. It is hypothesized that virtual reality technology may increase engagement in the exposure exercises, an advantage to a subset of indi-viduals who are trained to keep emotions at bay to think clearly in life-threatening situations.56It is
fur-ther hypothesized that virtual reality may represent a palatable alternative treatment for a generation of active duty personnel who are concerned about stigma of mental health treatment, and have grown up with gaming technology.57 Current efforts are targeting dissemination of VRET to military bases nationwide. Ongoing randomized controlled trials will shed light on the potential independent con-tribution of this treatment above that of imaginal exposure. Virtual reality is discussed in detail else-where in this volume.
Special considerations
Specific issues related to special populations may necessitate further research on the applicability of current treatments. The challenge of treating PTSD is further amplified by the presence of comorbid disorders, which frequently occur with a diagnosis of PTSD. Rates of lifetime Major Depression are cited by the National Comorbidity Survey5as 48% in men and 49% in women with PTSD, making it the most common comorbidity. More than 51% of men and 27% of women with PTSD met criteria for alcohol abuse or dependence and over 34% of men and 26% of women met criteria for drug abuse or dependence.
Despite the high rates of comorbid PTSD and depression, there is little to no examination of the use of therapies in populations with this comorbid-ity.58With little exception,59most studies focus on a PTSD population and examine depressive symp-tomatology as a secondary outcome. A recent meta-analysis of PTSD outcome studies suggests that these treatments may also improve symptoms of depres-sion,10but this is far from a certainty.
Debate has centered over the best method of ad-dressing comorbid PTSD and substance use. Gen-eral practice has been to use sequential treatment, requiring the patient to first complete substance-use treatment, and then refer them to a PTSD treatment program. Yet, clinical wisdom and recent evidence60 suggest that gains made in substance-use treatment are at great risk for relapse at cues related to the trauma memory that may serve as triggers for sub-stance use and self-medication.61A recent study of a trauma-focused treatment found that as PTSD symptoms improved, substance use showed signifi-cant improvement; however, the reciprocal relation-ship was not found.62
Evidence suggests that treating the problems con-currently is the best strategy. Integrated treatment trials of PTSD and substance use have been largely positive, but are still in preliminary stages. Positive effects on both PTSD and substance use have been reported using the Seeking Safety treatment,61,62 PE,63–65and a CBT protocol66and further trials are under way using COPE (concurrent treatment with PE),60behavioral couples therapy,67and PE.68
Physical impairment in the aftermath of a trauma with physical injuries may also complicate the course of mental health treatment as the patient copes with scarring or disfigurement, pain, and functional impairment that prohibits functioning in premorbid roles.69Research has indicated that the physical injury itself impacts treatment for PTSD as more severely injured patients, while more likely to develop PTSD, are also less likely to benefit from traditional CBT treatment.70Yet, despite the effect physical injury may have upon PTSD, there exists no guide for treatment of PTSD in the context of a physical injury.
With the recent increase in its occurrence due to military related injuries, more attention is be-ing given to the comorbid presentation of PTSD and traumatic brain injury (TBI). To date, little work has focused on effective treatment strategies for both, and due to the common exclusion of indi-viduals with TBI from PTSD treatment studies, little is known of the efficacy of PTSD treatment in this population.71Future research must address whether treatments are effective in their current form, or must be modified to some extent or changed com-pletely to be effective for individuals with mild TBI with or without lasting cognitive deficits.72
Conclusions
The evidence base for the treatment of PTSD offers effective options in the form of exposure therapies. Novel treatments, including couples and interper-sonal therapies, virtual reality therapy, and the use of prazosin and DCS, are being developed and eval-uated through outcome trials. Yet, the task before us remains great. Chronic PTSD exists in large num-bers throughout the world and especially among those sent to battle to protect our national interests. Our responsibility lies in the further development of alternative treatments and the dissemination of cur-rent evidence-based practices. Failure of providers to use established treatments is a barrier to effective
care that as a community must be addressed. Con-trolled trials of new therapies need to be conducted before they can be added to the list of tools at the disposal of a clinician. Close examination of appli-cations of current protocols to special populations may yield the development of modified treatments that can increase efficacy. While translational re-search stands to provide exciting contributions to our knowledge base, it must then be applied clini-cally to the implementation of differential therapeu-tics. In conclusion, exposure therapy is a powerful tool in the treatment of PTSD, and novel treatments are filling in the gap left by treatment failures. It remains incumbent upon the scientific community to put evidence-based treatments in the hands of the clinicians and to develop and evaluate broader treatment options.
Conflicts of interest
The authors declare no conflicts of interest.
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