5
Issues in PTSD Treatment Research

In its review of the evidence—pharmacotherapy and psychotherapy randomized controlled trials—in Chapters 3 and 4, the committee identified several issues that warrant examination. The first part of this chapter discusses these issues and makes recommendations to address the challenges they present. The second part of the chapter seeks to respond to several issues raised in the Statement of Task, specifically pertaining to posttraumatic stress disorder (PTSD) recovery, early intervention, and length of treatment.

ISSUES IDENTIFIED IN REVIEWING THE EVIDENCE

In its review of the PTSD treatment literature, a number of common themes and important questions emerged. These include: methodological problems, especially attrition and subsequent handling of missing data; funding of pharmacotherapy studies by pharmaceutical companies, raising concern about publication bias and investigator independence; applicability of the PTSD treatment outcome studies in civilian populations to the Department of Veterans Affairs (VA) and veteran populations (including the fact that there is neither evidence to show that PTSD in the two populations is different, nor that it is the same); research gaps in regard to special veteran populations; length of follow-up (discussed in conjunction with length of treatment in the latter part of this chapter); and apparent divergence between the committee’s conclusion and the Food and Drug Administration (FDA)’s regulatory determination on the evidence regarding two selective serotonin reuptake inhibitors (SSRIs).



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5 Issues in PTSD Treatment Research I n its review of the evidence—pharmacotherapy and psychotherapy ran- domized controlled trials—in Chapters 3 and 4, the committee identified several issues that warrant examination. The first part of this chapter discusses these issues and makes recommendations to address the chal- lenges they present. The second part of the chapter seeks to respond to several issues raised in the Statement of Task, specifically pertaining to post- traumatic stress disorder (PTSD) recovery, early intervention, and length of treatment. ISSUES IDENTIFIED IN REVIEWING THE EVIDENCE In its review of the PTSD treatment literature, a number of common themes and important questions emerged. These include: methodological problems, especially attrition and subsequent handling of missing data; funding of pharmacotherapy studies by pharmaceutical companies, raising concern about publication bias and investigator independence; applicability of the PTSD treatment outcome studies in civilian populations to the Depart- ment of Veterans Affairs (VA) and veteran populations (including the fact that there is neither evidence to show that PTSD in the two populations is different, nor that it is the same); research gaps in regard to special veteran populations; length of follow-up (discussed in conjunction with length of treatment in the latter part of this chapter); and apparent divergence be- tween the committee’s conclusion and the Food and Drug Administration (FDA)’s regulatory determination on the evidence regarding two selective serotonin reuptake inhibitors (SSRIs). 

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 TREATMENT OF POSTTRAUMATIC STRESS DISORDER A Challenge to Internal Validity The available evidence on PTSD treatment is limited in that relatively few high-quality randomized controlled (by placebo, wait list, or equivalent) trials, or RCTs, have been performed for most modalities. The committee excluded a large volume of studies that were case reports and case-series, and controlled studies without randomization. The remaining studies varied in their adherence to current standards of design quality, had problems with sample size, assessor blinding or independence, high dropout rates, and had short or no follow-up after treatment concluded. A characteristic of most studies of PTSD reviewed by the committee is a high degree of attrition of participants from assigned treatment, whether pharmacologic or psychotherapeutic. This may be due to the underlying condition and patient characteristics that may make adherence to any form of therapy difficult, or it may be due to improvement or worsening of symptoms. High degrees of dropout are common in studies of a broad range of psychological conditions. In a review of studies by Khan (2001a, b), dropout rates in trials of antidepressants averaged 37 percent, similar between treatment and placebo arms, and were in the 50 to 60 percent range for trials of antipsychotics, somewhat greater in treatment than in placebo, and intermediate among active controls. A particularly difficult challenge is the assessment of efficacy in the face of different rates of dropout for different study treatments. As an illustra- tion of this challenge (Figure 5-1), consider a study of an intervention with identical 50 percent remission rates in the intervention and control arms. Assume that 25 percent of patients who undergo the treatment but who are not improving fail to return for follow-up evaluation (perhaps due to treatment side effects) versus 5 percent among nonimproving control sub- jects. When the analysis focuses only on those with follow-up evaluations, this ineffective intervention will appear effective (67 percent remission rate versus 53 percent for controls). The point of the illustration is not that a study with dropouts is invalid, but rather, that an improper analysis (in this case, among completers only) in the face of differential dropout rates that are related to the clinical course can produce a biased result. If outcome data are not obtained from patients who drop out from treatment, outcome data from those participants will be missing. It is criti- cal to recognize that dropout from treatment does not necessarily mean that outcome data “must” be missing. With aggressive and systematic follow-up procedures, outcome data can still be obtained from many subjects who discontinue treatment. This was demonstrated in studies by Schnurr and colleagues (2003, 2007) where outcomes were successfully measured in a high proportion of participants who discontinued treatment. The commit- tee viewed missing outcome data partly as a result of choices made in study

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 ISSUES IN PTSD TREATMENT RESEARCH Actual Apparent Remission 50 50 50 Control Completer 45 45 100 45 No remission 50 200 Non-Completer 5 x Subjects 5 Remission 50 50 50 Treatment Completer 25 25 100 25 No remission 50 Non-Completer 25 x Remission rates 25 Actual Apparent Control 50/100 (50%) 50/95 (53%) Treat 50/100 (50%) 50/75 (67%) FIGURE 5-1 Potential impact of attrition: illustrating the importance of proper analysis. 2-1 design and not an inevitable result of the condition, treatment, or behavior. Unfortunately, few of the studies examined by the committee obtained outcome information after a patient stopped treatment or during post- treatment follow-up. Because a very high percentage of patients—typically 20 to 50 percent—typically dropped out of these studies, large fractions of outcome data were missing. Over the past three decades, analytic approaches to handling missing data have matured, with multiple imputation and mixed-model repeated measurement (MMRM) and similar approaches being implemented in stan- dard software and commonly used by biostatisticians in many fields (Little and Rubin, 2002; Molenberghs and Kenward, 2007). Unfortunately, the most common way missing data were handled in the literature reviewed was to use the last recorded outcome as the final outcome in a patient who dropped out—also known as the “last observation carried forward”

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0 TREATMENT OF POSTTRAUMATIC STRESS DISORDER (LOCF) approach. As explained in detail in Appendix D, the LOCF ap- proach has long been recognized as a poor method for handling missing data (in some cases introducing a conservative and other cases an anti- conservative bias, and always overstating precision), requiring that results based on LOCF analyses must be scrutinized very closely. The committee notes that at least one major peer-reviewed journal, the Journal of the American Medical Association, requires that study authors provide flow diagrams of study participation, including loss to follow-up and reasons (JAMA, 2007). Finding 1. The committee found that treatment of PTSD has not received the level of research activity needed to support conclusions about the potential benefits of treatment modalities. Although progress in scientific standards can be observed, and recent studies tend to provide more use- ful information than older studies, important limitations remain. There are very few large-scale, multi-site initiatives of the type that have been successfully applied to other psychiatric disorders. The studies conducted over the nearly three decades since Diagnostic and Statistical Manual of Mental Disorders (DSM) adoption of the PTSD definition do not form a cohesive body of evidence about what works and what does not. As described elsewhere in this report, studies have used a wide variety of outcome measures and lengths of treatment for the same treatment modality. Further, many studies lack basic characteristics of internal validity including suffering from high dropout rates handled with weak missing data analyses, and high differential dropout among treatment arms. Other important characteristics that the committee found lacking included follow-up of all patients admitted to the trials, attention to con- flict of interest, assessor independence, and length of follow-up. Although experts in the field (Foa and Meadows, 1997; Harvey et al., 2003) have called for setting research standards that would strengthen methodologic quality and internal validity, more work is needed. Recommendation 1. The committee recommends that VA and other funders of PTSD research take steps to identify and require investi- gators to use methods that will improve the internal validity of the research, with particular attention to standardization of treatment and outcome measures, follow-up of individuals dropping out of clinical trials, and handling of missing data. Investigator Independence The psychotherapy studies were often conducted by the individuals who developed the techniques, and some did not include blind or independent

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 ISSUES IN PTSD TREATMENT RESEARCH assessment of outcomes. The committee also was concerned about the pos- sibility of publication bias in this domain, especially the effect of industry sponsorship of the majority of the drug studies. Finding 2. The committee found that the majority of drug studies were funded by pharmaceutical manufacturers. This is an issue that has received much attention in recent years from the academic research community, government agencies, patient communities, and the editors of major biomedical journals. The committee also found that many of the psychotherapy studies were conducted by individuals who developed the techniques or their close collaborators. It is important to know whether these treatments would show the same effect if imple- mented in other settings, requiring the confirmation and replication of these research results by other investigators. Recommendation 2. The committee recommends that VA and other funders of PTSD treatment research seek ways to give opportunities to a broad and diverse group of investigators to ensure that studies are conducted by individuals and in settings without potential financial or intellectual conflicts of interest.1 Special Veteran Populations PTSD Comorbid with Traumatic Brain Injury (TBI) A high percentage of returning soldiers with PTSD also have sustained concussive TBI (Seal et al., 2007). Moreover, the diagnosis of either condi- tion may be complicated by the number of symptoms that are identical for PTSD and the chronic postconcussion syndrome. These overlapping symp- toms include noise sensitivity, fatigue, anxiety, insomnia, poor concentra- tion, poor memory, irritability and anger, and depression. PTSD patients with concussive TBI may have more prominent postconcussive symptoms (e.g., problems with concentration, dizziness, fatigue, headaches, and visual disturbances), suggesting that PTSD can exacerbate cognitive and other symptoms in TBI (Lezak et al., 2004). Psychological treatment of patients with TBI and PTSD may be com- plicated by cognitive impairments due to concussive TBI. Such impairments can interfere with a patient’s abilities to focus attention and deflect distrac- tions, grasp spoken statements fully, and communicate easily, all of which 1Some ways to do this include: developing designs with an eye to balancing investigator interests and potential biases, and organizing studies in a way that ensures independent data collection and analysis (e.g., forming a coordinating center for all studies).

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 TREATMENT OF POSTTRAUMATIC STRESS DISORDER are necessary for cognitive behavior therapies to be effective. The committee did not identify any PTSD treatment research that recognizes these potential factors in veterans currently returning from Iraq and Afghanistan. PTSD Comorbid with Major Depression and Substance Abuse The committee noted that major depression, other anxiety disorders, and substance abuse are common among patients with PTSD, and yet some research systematically excludes such patients from the clinical trials. The result is that the literature is almost completely uninformative about how best to treat the substantial proportion of veterans who have an important comorbid condition. PTSD in Special Populations The committee noted that the literature also is almost entirely silent on the efficacy of treatment in discrete ethnic and cultural minorities, and on related issues of potential subgroup differences in their acceptance of treatment modalities and tolerability of distinct types of medications. These concerns are also pertinent to subgroup differences by sex, degree and types of physical impairment, socioeconomic status, education, age, and by vet- eran cohorts with diverse trauma experiences. Finding 3. The committee found that the available research leaves significant gaps in assessing the efficacy of interventions in important subpopulations of veterans with PTSD, especially those with traumatic brain injury, major depression, other anxiety disorders, or substance abuse, as well as ethnic and cultural minorities, women, and older individuals. Recommendation 3. The committee recommends that VA assist clini- cians and researchers in identifying the most important subpopulations of veterans with PTSD and designing specific research studies of inter- ventions tailored to these subpopulations. Applicability to VA and Veteran Populations The committee found a lack of information elucidating how the great heterogeneity in triggering stressors (e.g., combat-related versus civilian, frequent and continuous exposure versus one-time exposure) may affect the effectiveness of different treatments. For example, is PTSD in male vet- erans different from PTSD in civilian female rape survivors?—just to name two of the major trauma types in the literature. The committee examined

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 ISSUES IN PTSD TREATMENT RESEARCH the question of treatment efficacy in PTSD in general populations, not just PTSD in veterans, but found it striking that so few of the studies were conducted in populations of veterans. The committee understands the posi- tion that effects of PTSD treatment may be similar in all populations, but it is not clear from the available evidence that findings about victims of a natural disaster will apply equally well to veterans. Although the literature includes some suggestion that there may be differences in how the civilian and veteran populations respond to treatment (for example, meta-analyses that have found higher effect sizes in civilians compared to veterans), there is no conclusive evidence that shows that PTSD in the two populations is different, nor that it is the same. The committee also notes that the popu- lations of veterans with PTSD now returning from Iraq and Afghanistan might be different enough from U.S. veterans from previous wars such that studies of the latter populations (mostly dating back to the Vietnam conflict) may be minimally informative about treatment efficacy in veterans of the recent conflicts. Acknowledging the heterogeneity of trauma types associated with cases of PTSD, and the question of applicability of evidence regarding treatments for PTSD across different contexts, the current report considers the range of contexts, highlighting the evidence of applicability to the veteran population where it is possible to do so. The studies reviewed by the committee required that eligibility be based on DSM PTSD criteria. (Most studies since 1980 have used this eligibility criterion.) Many recent studies also required a specified level of severity to exclude mild cases. Strictly speaking, a study’s results are generalizable to the population that the sample “represents.” Theoretical arguments or clini- cal experience might also be relevant to the applicability question. There is no a priori basis for limiting the potential applicability of findings on treatment of PTSD by sample characteristics such as trauma type, gender, or chronicity. If a body of evidence is judged to be inadequate for concluding that a treatment is either efficacious or inefficacious, it is also inadequate for concluding that it is applicable or inapplicable to populations of patients other than the population “represented” by the sample. Conflicting findings across studies that test a class of PTSD treatments are difficult to resolve. Results do not form a consistent pattern that might suggest that efficacy depends on type of trauma, chronicity, or gender. However, there are some suggestions from the literature and the experience of clinicians that respon- siveness to specific treatments varies among PTSD populations possibly as a function of chronicity, sex, and other factors. Generalizability Because the number of well-conducted studies in veterans was small, the committee was concerned about generalizing the evidence to veterans

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 TREATMENT OF POSTTRAUMATIC STRESS DISORDER overall, and to the newest veterans from the conflicts in Iraq and Afghani- stan in particular. The committee understands the argument that treatments proven effective on any group of individuals with PTSD should generalize to all who share the diagnosis, but there is no evidence to support this hypothesis or its converse. The committee noted that type of trauma, re- currence or frequency of trauma (as in current combat situations), gender, ethnicity and cultural differences, comorbidities (especially substance abuse and depression), presence of TBI, and compensation issues are likely to be highly relevant to populations of veterans, and observed that the literature is (to varying degrees) uninformative on many of these considerations. Finding 4. The committee found that research on treatment of PTSD in U.S. veterans is inadequate to answer questions about interventions, settings, and lengths of treatment that are applicable in this specific population. The committee recognizes that the successful conduct of research directly applicable to veterans will require close collaboration among funding agencies (Department of Defense, National Institute of Mental Health, National Institute of Alcohol Abuse and Alcohol- ism, National Institute of Drug Abuse), veterans groups, and clinical service settings. Specifically, veterans’ groups could make considerable contributions to the design and conduct of high-quality research on the treatment of PTSD. Recommendation 4. The committee recommends that Congress require and ensure that resources are available for VA and other relevant federal agencies to fund quality research on the treatment of PTSD in veteran populations and that all stakeholders are included in research plans. Selection of Interventions Appropriate for Study In general the committee believes that studies should provide an evi- dence base for current practice patterns in addition to stimulating novel re- search. The committee observed discrepancies between research and clinical practice. For example, the committee understands that benzodiazepines are commonly used in patients with PTSD (APA, 2004; VA/DOD, 2004), but found virtually no directly applicable evidence on primary PTSD outcomes. Further, the committee understands that clinicians and investigators are divided on whether it would be useful or even ethical to conduct further re- search on benzodiazepines in patients with PTSD. As another example, the committee found that research conducted on some drugs or psychotherapies may not correspond to actual use of the therapies in clinical practice with respect to dosage regimen, length of treatment, or follow-up. There is little current incentive (or funding) for researchers to conduct studies on older

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 ISSUES IN PTSD TREATMENT RESEARCH drugs (for example, psychopharmacologic agents available in generic form) or psychotherapies. Researchers and their funding sources tend to be more inspired by novelty, leading to a certain inertia about actual treatments in use that are not investigated empirically (Branscomb et al., 2001: 51). Some studies test head-to-head comparisons of interventions that clinicians find irrelevant to actual practice, especially for veterans. Finally, the population of veterans is heterogeneous, including older veterans with chronic PTSD and younger returning veterans; they also include women and members of various ethnic and racial groups. Little is known from systematic research on the potential response to various treatments or the acceptability of vari- ous treatment modalities across the groups identified. VA is in a unique position to help bring order and direction to the research enterprise regard- ing PTSD. Finding 5. The committee found that studies of PTSD interventions have not systematically and comprehensively addressed the needs of veterans with respect to efficacy of treatment and the comparative effectiveness of treatments in clinical use. Recommendation 5. The committee recommends that VA take an active leadership role in identifying research priorities for addressing the most important gaps in evidence in clinical efficacy and comparative effec- tiveness.2 Potential areas for future research include: • Comparisons of psychotherapy (e.g., CBT) and medication • Evaluation of the comparative effectiveness of individual and group formats for psychotherapy modalities • Evaluations of the efficacy of combined psychotherapy and medication, compared with either alone, and compared with 2The committee has noted with interest research on effectiveness in other areas of mental health. For example, the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study aimed to reproduce some real-life settings in allowing participants choice and offer- ing alternatives when a course of treatment did not work, and used an outcome measure of “remission” meaning becoming symptom free. Another study brought to the committee’s attention is the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) Schizo- phrenia study, which compares newer atypical antipsychotics with each other and with conventional antipsychotics in regard to long-term effectiveness and tolerability, and also in identifying antipsychotics that work for patients who have not had success with that class of drugs. Finally, STEP-BD (Systematic Treatment Enhancement Program for Bipolar Disorder) is a long-term study of manic-depressive illness that studied treatment (both pharmacologic and psychosocial) of affected individuals on two “pathways”—one a naturalistic, best practices pathway that allowed patients and clinicians to choose the best course of treatment, and the other a “randomized care pathway” that involved patients in multi-site randomized controlled trials. Program participation lasted for up to 5 years to facilitate adequate follow-up.

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 TREATMENT OF POSTTRAUMATIC STRESS DISORDER control conditions.3 Combined treatment could be tested within study designs like those that have been applied in large studies for other psychiatric conditions. The Evidence on SSRI Efficacy A final issue identified in the process of assessing the evidence per- tains to what may be perceived as a surprising divergence between the committee’s conclusion in regard to the body of evidence on SSRIs and FDA’s approval of the SSRIs sertraline and paroxetine (in 1999 and 2001, respectively), previously approved for treating depression, for treating PTSD. FDA’s determination was of a regulatory nature, and its focus was risk-benefit analysis. The committee considered the published RCTs avail- able on SSRIs and made its conclusion on the basis of what emerged as a very mixed picture on efficacy. Further, at present, FDA generally does not reconsider its regulatory decisions except in cases where new safety data emerges. Reviews of the empirical evidence such as the one contained in this report take into consideration studies and data emerging over years and even decades. ISSUES DEFINED IN THE STATEMENT OF TASK In addition to assessing the quality and direction of the empirical evi- dence on various PTSD treatment modalities, the committee discussed the following issues, as requested by the sponsor: • What are the goals of PTSD treatment? — What is the definition of “recovery”? — For what proportion of patients is recovery possible? — Besides recovery, what other outcomes would benefit patients? • Does evidence support the value of early intervention? • How long should treatment continue? — What is the impact of a hiatus in treatment? — What is the impact of periodic reexamination for asymptomatic patients? 3The committee found one study that does this in the work of van der Kolk and colleagues, 2007.

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 ISSUES IN PTSD TREATMENT RESEARCH Recovery The committee reviewed the literature on PTSD treatment for defini- tions of the term recovery, finding that the term is used inconsistently and is not clinically meaningful in the same way that it is in other clinical domains (e.g., as in acute illnesses). PTSD can be chronic and can also remit and relapse over a patient’s lifetime (Wilson et al., 2001). No longer meeting PTSD diagnostic criteria is a common way to define recovery when inventory or questionnaire scores fall below an important threshold in the condition’s trajectory. However, the studies that constitute the evidence base on the efficacy of treatment modalities for PTSD use a variety of terms to denote a change for the better in PTSD status: improvement (significant improvement, reliable improvement, improvement in functioning), remis- sion, therapeutic success, loss of PTSD diagnosis, symptom reduction or improvement, trauma recovery, good or high end-state functioning, treat- ment response, clinically meaningful change, and so on, while the term recovery is used in only three studies (Davidson et al., 1990; Gersons et al., 2000; McDonagh et al., 2005). In most cases, these terms simply describe the primary outcomes chosen in the individual study leading to a positive, negative, or neutral conclusion regarding efficacy. See Box 5-1 for three definitions of recovery (two pertain to mental health recovery in general, and one relates to PTSD specifically). The studies the committee reviewed employed a range of specific defi- nitions for “recovery” terms. These definitions may be divided into three categories: (1) absence or loss of PTSD diagnosis, (2) multiple domain measures used to determine good or high end-state functioning, and (3) a clinically meaningful threshold for “symptom improvement.” Not all stud- ies seeking to show symptom improvement also reported PTSD diagnostic status, but almost all studies reporting loss of diagnosis did so by showing changes on PTSD symptom measures such as the Clinician administered PTSD Scale (CAPS), the Structured Interview for PTSD (SI-PTSD), and the Structured Clinical Interview for DSM-IV (SCID). In the first category, studies that had as an outcome absence of or loss of PTSD diagnosis, defined recovery by a decrease in percentage or two standard deviations (SDs) improvement in CAPS score, by decrease or disappearance of a number of symptoms or an entire symptom cluster,4 by change in SI-PTSD scores, or by loss of the diagnosis using DSM criteria. The X percent or 2 SDs decrease are appropriate criteria for loss of diag- nosis in many cases. However, a patient with a high score on a measure (>2 SDs above the mean for the PTSD population on which the measure 4 The DSM-IV definition of PTSD includes three symptom clusters: reexperiencing, avoid- ance, and hyperarousal.

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 TREATMENT OF POSTTRAUMATIC STRESS DISORDER BOX 5-1 Some Definitions of Recovery In its final report, the President’s New Freedom Commission on Mental Health (PNFCMH) defined recovery (not specific to PTSD, but referring to mental health in general) as the process in which people are able to live, work, learn, and participate fully in their communities. For some individuals, recovery is the ability to live a fulfilling and productive life despite a disability. For others, recov- ery implies the reduction or complete remission of symptoms. Science has shown that having hope plays an integral role in an individual’s recovery. (PNFCMH, 2003, 5) From the National Consensus Conference on Mental Health Recovery and Mental Health Systems Transformation (December 2004): Mental health recovery is a journey of healing and transformation en- abling a person with a mental health problem to live a meaningful life in a community of his or her choice while striving to achieve his or her full potential. This definition is noteworthy because it includes an elaboration of 10 funda- mental components of recovery that illustrate the meaning of recovery for the individual. These components or dimensions include: self direction, individualized and person-centered, empowerment, holistic, nonlinear, strengths-based, peer support, respect, responsibility, and hope (Department of Health and Human Services [DHHS], Substance Abuse and Mental Health Services Administration, and Center for Mental Health Services, 2004). The recent Institute of Medicine (IOM) report, PTSD Compensation and Military Service stated the following: Recovery can be defined in various ways. In the context of this report, the committee considered recovery to be a reduction in the frequency and intensity of symptoms accompanied by an increase in social and occupational function. The research reviewed and cited in this sec- tion often used return to work as the specific measure of recovery. (IOM, 2007) was normed, or ≥86th percentile) may report significant improvement in a post-treatment score drop of 2 SDs or 50 percent (to the 36th percentile, for example) while still troubled by PTSD symptoms, albeit in a milder form. Should many patients in a study have a severe form of the condition, these criteria would mask their continuing dysfunction and invalidate a positive conclusion based on these criteria, meaning, in these cases, the statistical

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 ISSUES IN PTSD TREATMENT RESEARCH BOX 5-2 Examples of Domain Measures PTSD specific: • CAPS (total score lower than 19 points) • SI-PTSD (at least 50% decrease) • PTSD Symptom Scale (PSS), both interviewer and self-report • Modified PSS-I (less than 20) • Posttraumatic Diagnostic Scale (PDS) • Distressing Events Questionnaire (score of 25 or less) • Davidson Trauma Scale (score less than 18) criteria do not provide accurate documentation of absence or loss of PTSD diagnosis. Studies in the second category, those with the outcome of good or high end-state functioning, defined recovery by specific levels on multiple domain measures, including one or more PTSD specific measures (such as CAPS; other examples from the literature reviewed by the committee are provided below) in combination with specific levels on other types of measures of depression (Hamilton Rating Scale for Depression and Beck Depression Inventory), anxiety scales (Hamilton Rating Scale for Anxiety, Beck Anxiety Inventory, and State-Trait Anxiety Inventory), and multidimensional mea- sures (Clinical Global Impressions [CGI] Scale and Symptom Checklist-90). See Box 5-2 for examples of domain measures. The third category of studies, those that sought to identify a clinically meaningful threshold for symptom improvement, defined recovery as a change in CAPS (≥10 point decrease, ≥30 percent decrease, or two stan- dard deviations below pretreatment level); a change in Impact of Events Scale (IES), Short PTSD Rating Interview (SPRINT), or SI-PTSD scores; change in Clinical Global Impressions rating (to 1, very much improved, or 2, much improved); change in Davidson Trauma Scale score (≤17); or significant improvement in the Mississippi Scale for Combat-Related PTSD (M-PTSD) score. Finding 6. The committee found no generally accepted and used defi- nition for recovery in PTSD. Also, many studies used measures of questionable validity and reliability instead of validated, high-quality

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0 TREATMENT OF POSTTRAUMATIC STRESS DISORDER measures such as CAPS (Foa and Meadows, 1997). The committee places the lack of agreement about recovery in context of a more general concern about identifying appropriate outcomes for PTSD research. Recommendation 6. The committee recommends that clinicians and researchers work toward common outcome measures in three general domains that relate to recovery: loss of PTSD (DSM) diagnosis, PTSD symptom improvement, and end state functioning. The committee further recommends the following three principles be considered in the selection of outcome measures: • validity in research; • convergence on a core of common outcomes for the purpose of comparability; and • usefulness to clinicians to assess patients over time as symp- toms and function change. The committee recommends that VA assume a leadership and conven- ing role and work with other relevant federal agencies in developing these common approaches. Early Intervention The statement of task asks “Does evidence support the value of early intervention?” (Statement of Task IV-B, see Summary, Box S-1). Early intervention may refer either to a time before the onset of PTSD or early in the course of PTSD. The committee assumes the latter represents VA’s intent in this question, because intervention before the diagnosis of PTSD is outside the committee’s understanding of its charge. In this context, the goal of early intervention is reducing the chronicity of PTSD through early treatment. In its review of the literature, including clinical guidelines and recent publications, the committee found that all or most mentions of “early intervention” refer to antecedent events on the disorder continuum, before a PTSD diagnosis can be made, and generally these refer to treatment modalities such as crisis intervention and psychological debriefing (Harvey et al., 2003; Hembree and Foa, 2003). The committee focused on secondary prevention—reducing the prevalence of PTSD by shortening the duration of the disorder and reducing chronicity, and tertiary prevention—reducing the symptom burden and disability associated with the disorder. The data abstracted from the literature reviewed by the committee are informative about one data element relating to the timing of interven- tion, namely, time since exposure to the trauma. In most studies the length of time a participant had been diagnosed with PTSD before entering the

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 ISSUES IN PTSD TREATMENT RESEARCH study is not provided. Sometimes a study specifically used duration of diagnosis as part of the inclusion/exclusion criteria (e.g., including chronic PTSD patients only). In those cases, only the minimum or maximum dura- tion required for study inclusion is provided, but not the average duration. Often, the time since exposure to the trauma is provided and/or the number of different traumas they have been exposed to. It cannot be assumed that PTSD developed soon following the trauma, so time since trauma is not informative regarding how long patients have been diagnosed with PTSD. Three of the psychotherapy studies reported durations of illness with a range from 7.8 to 11.6 years (Devilly and Spence, 1999; Paunovic and Ost, 2001; Taylor et al., 2003) and four pharmacotherapy studies with a range of 11 to 30 years (Brady et al., 2000; Davis et al., 2004; Friedman et al., 2007; Rapaport et al., 2002). Time since exposure varied greatly by study, ranging from 4 months to 21.7 years in the psychotherapy studies,5 and 6 months to 25 years in the pharmacotherapy studies. Finding 7. The committee was unable to reach a conclusion on the value of intervention early in the course of PTSD based on the treat- ment literature it reviewed. Recommendation 7. The committee recommends that VA and other government agencies promote and support specific research on early intervention (i.e., reducing chronicity) in PTSD. The committee further recommends that future research specify both time since trauma expo- sure and duration of PTSD diagnosis, and that interventions be tested for efficacy at specific clinically meaningful intervals, as interventions might be expected to vary in effectiveness related to time since exposure and duration of diagnosis. Length of Treatment The committee divided the question of length of treatment into three phases: (1) for a given treatment does treatment of any length have effi- cacy; (2) if so, how does length of the treatment affect outcome (requiring comparative trials); and (3) what are the long-term (greater than 1 year) effects of treatment at follow-up? The literature reviewed by the committee was limited in the information it provided about optimal length of PTSD treatment. Obviously, there would be differences between medication and psychotherapy, but none of the reviewed studies considered length of treat- ment as a dependent variable in their research design. Efficacy associated 5Only includes numbers actually reported in the studies. If exposure type was given (e.g., Vietnam) but the actual months or years were not provided, it is not included here.

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 TREATMENT OF POSTTRAUMATIC STRESS DISORDER with a drug cannot be expected to be maintained after treatment stops, as in other chronic psychiatric and physical conditions. In major depression, the bulk of which is recurrent, there is evidence supporting long maintenance of pharmacotherapy to prevent recurrence. The committee reviewed four maintenance studies (four SSRIs and one anticonvulsant), but they had methodological problems (results discussed in Chapter 3). These studies offer the only data the committee identified as potentially relevant to the question of hiatus in treatment. The impact of periodic reexamination for asymptomatic patients is also difficult to ascertain from the literature reviewed by the committee. Although a number of pharmacotherapy and psychotherapy studies con- ducted follow-up after the completion of treatment, most of the studies did not assess patients’ symptom status specifically, but rather, identified scores on various measures, such as measures of PTSD, depression, and anxiety. Of the ones that assessed symptom status, they generally measured improvement in symptoms on the Impact of Events Scale (much improved, very much improved, etc.), but none found patients to be completely symp- tom free. Therefore, the committee is unable to draw a conclusion about the impact of reexamining patients who no longer show symptoms of PTSD. Length of treatment in the pharmacotherapy studies reviewed by the committee ranged in length from 5 to 6 weeks (5 studies) to 5 to 7 months (4 studies). The majority of the studies provided treatment for between 8 to 16 weeks (28 studies). Length of treatment in the psychotherapy studies varied even more, from a single treatment session to multiple sessions conducted over a period of many months (5–7), and in one case, for up to 1 year. Some studies reported a mean number of sessions when the “dose” was flexible (therapy was concluded when the patient and therapist agreed the patient had improved); others described fixed numbers of sessions administered. Approximately 15 studies provided treatment for less than 8 weeks, about 22 studies (the majority) treated subjects for 8–16 weeks, and another 8 studies provided treatment for longer than 16 weeks (includ- ing two that reported a 16–20 week range). Several studies were unclear about the length of treatment and reported only the number of sessions administered. Compounding the difficulty in assessing the effect of length of treat- ment, there was also great heterogeneity of the studies in terms of the modalities used, dosage regimens for drugs, and standardization of psycho- therapies (despite manualization in some cases). Generally short length of follow-up (in no studies was follow-up longer than 1 year, many did not report follow-up) also made it difficult for the committee to assess the effect of length of treatment on PTSD, which is known for its variable course, with or without treatment. The committee was unable to find a correla- tion between length of treatment and outcome across the studies meeting

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 ISSUES IN PTSD TREATMENT RESEARCH inclusion criteria. The committee also notes that there may be a need for the development and evaluation of efficient adaptations of standard psycho- therapies for PTSD, such as prolonged exposure. A course of treatment, delivered in a shorter period of time (less than the typical 10–12 weeks), in more frequent and fewer sessions, might have the added benefit of increas- ing the rate of treatment completion. Finding 8. The evidence base contained studies that varied greatly on length of treatment and other variables, therefore, the committee was unable to draw conclusions regarding optimal length of treatment with psychopharmacology or psychotherapy. Recommendation 8. The committee recommends that VA and other funders call for research on the optimal duration of various treatments. Trials of comparative effectiveness of different treatment lengths for those treatments found efficacious should follow. Finally, studies with adequate long-term (i.e., greater than 1 year) follow-up should be con- ducted on treatments of any length found to be efficacious. Length of Follow-Up Ideally, improvements during treatment endure long after treatment is complete. Evaluation of treatment effectiveness should include follow-up over a sufficient period to determine whether improvement is maintained, continued, or declines. Treatments for which improvements are not main- tained provide short-term relief but may have long-term consequences as symptoms recur. Patients may be reluctant to try again, or may remain dependent on the treatment, which may be impractical or costly. When improvement is maintained or continues after treatment concludes, one can infer that these patients have acquired permanent positive changes that enable them to function more effectively or comfortably independent of treatment. The literature examined by the committee was limited in providing long-term follow-up. The committee understands that follow-up beyond treatment is uncommon in drug studies aimed at addressing efficacy, regard- less of clinical condition, but nonetheless observed that only 11 of 36 drug studies followed patients beyond treatment cessation, and none longer than 6 months. Thus, in general, the committee could not address what occurs when medications are discontinued. The evidence on longer-term follow- up is somewhat more extensive for psychotherapy. Of 52 psychotherapy studies, 43 reported follow-up data: 14 for 3 months or less, 18 for 6 to 9 months, 6 for 12 months, and 5 for 15 or more months. The evidence becomes scant, however, for effectiveness beyond 15 months, with the

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 TREATMENT OF POSTTRAUMATIC STRESS DISORDER longest follow-up 2 years post-treatment in studies examined by the com- mittee. Many of these studies reassessed their subjects two or three times after treatment concluded. CONCLUDING OBSERVATIONS In this report the committee sought to describe the evidence regarding the efficacy of available treatment modalities for PTSD, identify some of the major issues in the field, and make recommendations to help guide further research in PTD treatment. The committee’s findings, conclusions, and recommendations about the evidence for the treatment modalities reviewed in this report are not clinical practice guidelines. The committee does not intend to imply that, for example, exposure therapy is the only treatment that should be used in treating individuals with PTSD. The committee recognizes that the transparent presentation and assessment of evidence is just one part of the larger picture of PTSD treatment that includes many other factors. Further, assessing the scientific evidence may reveal areas of uncertainty. The next step in the process toward clinical decisionmaking is developing recommendations for clinical practice—a step the committee was not asked to, and did not, take. Such recommendations must propose strategies in the face of scientific uncertainty that are informed by clinician and patient preferences, access, safety, cost, alternatives, local practice pat- terns, medicolegal issues, ethical concerns, and other factors. The committee applied contemporary standards to evaluate research, including research dating back to 1980 when PTSD was first defined. The principal finding of the committee is that the scientific evidence on treat- ment modalities for PTSD does not reach the level of certainty that would be desired for such a common and serious condition among veterans. For some modalities, for example, novel antipsychotic drugs and SSRIs, the committee debated whether to characterize the body of evidence as “sugges- tive” or “inadequate.” It is important to emphasize that in the larger picture of PTSD treatment, had the debate ended with “suggestive” conclusions (rather than the “inadequate” conclusions the committee finally reached), the core message that better-quality research is needed would not have been rendered less urgent in consequence. The committee reached a strong con- sensus that additional high-quality research is essential for every treatment modality. This extends equally to the one treatment modality—exposure therapies—for which the committee found the evidence to be the strongest. As outlined in the recommendations above, better understanding of the most important and active components of exposure therapy, determining optimal administration and length of treatment, attention to principal subpopulations, and determining whether group therapies can be made as

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 ISSUES IN PTSD TREATMENT RESEARCH effective present a challenging and urgent agenda for researchers and clini- cians in the field. The committee views its more general findings and recommendations regarding further research to be as important as its conclusions regarding the evidence supporting treatment modalities. The committee became aware of the formidable challenges that researchers face in conducting high-quality studies of efficacy and comparative effectiveness. The committee was able to identify studies that met the highest internationally accepted standards for randomized controlled trials (in assembling populations, administering treatment, measuring outcomes, and following up enrolled subjects), show- ing that such studies are possible even for such a difficult clinical condition as PTSD. As outlined in the committee’s recommendations in this chapter, setting a high standard for research on PTSD and delivering on it will require close collaboration between VA and other government agencies, researchers, clinicians, and patient groups. Thus, the committee’s recom- mendations are its suggestions for setting a framework for the future that can more successfully address the critical needs of veterans who return to civilian life with the diagnosis of PTSD. REFERENCES APA (American Psychiatric Association). 2004. Practice guideline for the treatment of patients with acute stress disorder and posttraumatic stress disorder. Arlington, VA: APA. Brady, K., T. Pearlstein, G. M. Asnis, D. Baker, B. Rothbaum, C. R. Sikes, and G. M. Farfel. 2000. Efficacy and safety of sertraline treatment of posttraumatic stress dis- order: A randomized controlled trial. Journal of the American Medical Association 283(14):1837-1844. Branscomb L., G. Holton, and G. Sonnert. 2001. Science for society: Cutting-edge basic research in the service of public objectives. In Nelson, Teich and AAAS S&T Yearbook. Washington, DC: AAAS. Davidson, J., H. Kudler, R. Smith, S. L. Mahorney, S. Lipper, E. Hammett, W. B. Saunders, and J. O. Cavenar, Jr. 1990. Treatment of posttraumatic stress disorder with amitriptyline and placebo. Archives of General Psychiatry 47(3):259-266. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, and Center for Mental Health Services. National consensus statement on mental health recovery. http://download.ncadi.samhsa.gov/ken/pdf/SMA05-4129/trifold. pdf (accessed September 2007). Devilly, G. J., and S. H. Spence. 1999. The relative efficacy and treatment distress of EMDR and a cognitive-behavior trauma treatment protocol in the amelioration of posttraumatic stress disorder. Journal of Anxiety Disorders 13(1-2):131-157. Foa, E. B., and E. A. Meadows. 1997. Psychosocial treatments for posttraumatic stress dis- order: A critical review. Annual Review of Psychology 48:449-480. Friedman, M. J., C. R. Marmar, D. G. Baker, C. R. Sikes, and G. M. Farfel. 2007. Randomized, double-blind comparison of sertraline and placebo for posttraumatic stress disorder in a department of veterans affairs setting. Journal of Clinical Psychiatry 68(5):711-720.

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 TREATMENT OF POSTTRAUMATIC STRESS DISORDER Gersons, B. P., I. V. Carlier, R. D. Lamberts, and B. A. van der Kolk. 2000. Randomized clinical trial of brief eclectic psychotherapy for police officers with posttraumatic stress disorder. Journal of Traumatic Stress 13(2):333-347. Harvey, A. G., R. A. Bryant, and N. Tarrier. 2003. Cognitive behaviour therapy for post- traumatic stress disorder. Clinical Psychology Review 23(3):501-522. Hembree, E. A., and E. B. Foa. 2003. Interventions for trauma-related emotional disturbances in adult victims of crime. Journal of Traumatic Stress 16(2):187-199. IOM (Institute of Medicine). 2007. PTSD compensation and military service. Washington, DC: The National Academies Press. JAMA (Journal of the American Medical Association). 2007. JAMA instructions for authors. http://jama.ama-assn.org/misc/ifora.dtl#ClinicalTrial (accessed September 2007). Khan, A., S. R. Khan, R. M. Leventhal, and W. A. Brown. 2001a. Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials: A replica- tion analysis of the Food and Drug Administration database. International Journal of Neuropsychopharmacology 4:113-118. Khan, A., S. R. Khan, R. M. Leventhal, and W. A. Brown. 2001b. Symptom reduction and suicide risk among patients treated with placebo in antipsychotic clinical trials: An analysis of the Food and Drug Administration database. American Journal of Psychiatry 158:1449-1454. Little, R. J. A., and D. Rubin. 2002. Statistical analysis with incomplete data. New York: Wiley. McDonagh, A., M. Friedman, G. McHugo, J. Ford, A. Sengupta, K. Mueser, C. C. Demment, D. Fournier, P. P. Schnurr, and M. Descamps. 2005. Randomized trial of cognitive- behavioral therapy for chronic posttraumatic stress disorder in adult female survivors of childhood sexual abuse. Journal of Consulting and Clinical Psychology 73(3):515-524. Molenberghs, G., and M. G. Kenward. 2007. Missing data in clinical studies. Chichester, England: John Wiley & Sons. Paunovic, N., and L. G. Ost. 2001. Cognitive-behavior therapy vs exposure therapy in the treatment of PTSD in refugees. Behaviour Research and Therapy 39(10):1183-1197. Rapaport, M. H., J. Endicott, and C. M. Clary. 2002. Posttraumatic stress disorder and quality of life: Results across 64 weeks of sertraline treatment. Journal of Clinical Psychiatry 63(1):59-65. Schnurr, P., M. Friedman, D. Foy, M. Shea, F. Hsieh, P. Lavori, S. Glynn, M. Wattenberg, and N. Bernardy. 2003. Randomized trial of trauma-focused group therapy for posttraumatic stress disorder: Results from a department of veterans affairs cooperative study. Archives of General Psychiatry 60(5):481-489. Schnurr, P. P., M. J. Friedman, C. C. Engel, E. B. Foa, M. T. Shea, B. K. Chow, P. A. Resick, V. Thurston, S. M. Orsillo, R. Haug, C. Turner, and N. Bernardy. 2007. Cognitive behavioral therapy for posttraumatic stress disorder in women: A randomized controlled trial. Journal of the American Medical Association 297(8):820-830. Seal, K. H., D. Bertenthal, C. R. Miner, S. Sen, and C. Marmar. 2007. Bringing the war back home: Mental health disorders among 103,788 US veterans returning from Iraq and Afghanistan seen at Department of Veterans Affairs facilities. Archives of Internal Medicine 167(5):476-482. Taylor, S., D. S. Thordarson, L. Maxfield, I. C. Fedoroff, K. Lovell, and J. Ogrodniczuk. 2003. Comparative efficacy, speed, and adverse effects of three PTSD treatments: Exposure therapy, EMDR, and relaxation training. Journal of Consulting and Clinical Psychology 71(2):330-338.

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 ISSUES IN PTSD TREATMENT RESEARCH VA (Veterans Affairs), DoD (Department of Defense), Management of Post-Traumatic Stress Working Group. 2004. VA/DoD clinical practice guideline for the management of post- traumatic stress, version .0. Washington, DC: Department of Veterans Affairs and Department of Defense. van der Kolk, B. A., J. Spinazzola, M. E. Blaustein, J. W. Hopper, E. K. Hopper, D. L. Korn, and W. B. Simpson. 2007. A randomized clinical trial of eye movement desensitization and reprocessing (EMDR), fluoxetine, and pill placebo in the treatment of posttraumatic stress disorder: Treatment effects and long-term maintenance. Journal of Clinical Psy- chiatry 68(1):37-46. Wilson, J. P., M. Friedman, and J. Lindy, eds. 2001. Treating psychological trauma and PTSD. New York: The Guilford Press.

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