Lori A. Zoellner - US grants

DESCRIPTION (provided by application): Posttraumatic stress disorder (PTSD) is a chronic and debilitating condition, with lifetime prevalence rates ranging from 8%-14% of the US population. Thus, the development of efficacious and cost-effective treatments for PTSD is imperative. Both prolonged exposure therapy (PE) and sertraline (MED) are of established efficacy for PTSD. Yet, we know very little about the comparable effectiveness of these forms of treatment, nor what factors influence treatment acceptance/refusal and completion/drop-out. In this five-year, two-site study, we will examine these issues. This collaborative R01 grant will be conducted at the University of Washington under the direction of Dr. Zoellner and at Case Western Reserve University under the direction of Dr. Feeny. We will conduct a hybrid efficacy-effectiveness trial in which female and male trauma victims will be randomly assigned to either choice or no choice treatment conditions. In the choice condition, participants will choose between prolonged exposure and sertraline. In the no choice condition, participants will be randomly assigned to either prolonged exposure or sertraline. Outcome, as measured by both psychopathology and broader functioning measures, will be assessed through 24-month follow-up. The results of the proposed research will inform clinicians about the relative short-term and long-term effectiveness of PE and MED, provide information about how these treatments influence broader measures of functional impairment, provide information regarding decision making factors in order to maximize treatment utilization, and provide important information about cost effectiveness of both PE and MED for chronic PTSD.

DESCRIPTION (provided by application): Posttraumatic stress disorder (PTSD) is a chronic and debilitating condition, with lifetime prevalence rates ranging from 8%-14% of the US population. Thus, the development of efficacious and cost-effective treatments for PTSD is imperative. Both prolonged exposure therapy (PE) and sertraline (MED) are of established efficacy for PTSD. Yet, we know very little about the comparable effectiveness of these forms of treatment, nor what factors influence treatment acceptance/refusal and completion/drop-out. In this five-year, two-site study, we will examine these issues. This collaborative R01 grant will be conducted at the University of Washington under the direction of Dr. Zoellner and at Case Western Reserve University under the direction of Dr. Feeny. We will conduct a hybrid efficacy-effectiveness trial in which female and male trauma victims will be randomly assigned to either choice or no choice treatment conditions. In the choice condition, participants will choose between prolonged exposure and sertraline. In the no choice condition, participants will be randomly assigned to either prolonged exposure or sertraline. Outcome, as measured by both psychopathology and broader functioning measures, will be assessed through 24-month follow-up. The results of the proposed research will inform clinicians about the relative short-term and long-term effectiveness of PE and MED, provide information about how these treatments influence broader measures of functional impairment, provide information regarding decision making factors in order to maximize treatment utilization, and provide important information about cost effectiveness of both PE and MED for chronic PTSD.

DESCRIPTION (provided by applicant): This clinical trial examines the use of the memory-enhancingdrug methylene blue (MB) to facilitate prolonged exposure therapy (PE) in the treatment of chronic posttraumatic stress disorder (PTSD). The efficacy of variants of exposure therapy and, in particular, prolonged exposure, has been replicated across studies with men and women who have experienced a wide range of traumatic events (e.g., Institute of Medicine, 2007). Although PE is highly efficacious, approximately 20-30% of treatment completers continue to have a PTSD diagnosis, slightly more (30-40%) fail to achieve a stringent criterion for good end-state functioning (Foa et al., 1999;Rothbaum et al., 2005), and some fail to complete treatment (20.3%, Hembree et al., 2003). Thus, there is room to further improve PTSD treatment outcomes. The memory-enhancing drug methylene blue administered acutely after extinction training improves fear extinction learning in rats (Gonzalez-Lima &Bruchey, 2004;Wrubel et al., 2007). MB is a metabolic enhancer that is thought to stimulate mitochondrial oxidative metabolism (Sakata et al., 2005;Callaway et al., 2004) and is an FDA-grandfathered drug that, when administered orally in low doses, has been used safely and without significant side effects in humans for years (Meissner et al., 2005;Naylor et al., 1986;1987;1988;Peter et al., 2000). Strong animal research, in combination with established safety and pilot data showing MB-enhanced extinction in humans, provides a firm foundation to extend this work to extinction-based therapies for PTSD such as PE. We seek to pursue the next phase of translation, moving fear-based extinction augmentation using methylene blue in rats to clinical practice in humans by conducting a small feasibility trial. Specifically, this clinical trial will examine the initial safety and relative efficacy of methylene blue in comparison to placebo (PBO) in facilitating extinction learning following imaginal exposure for the treatment of chronic PTSD. We will conduct a double-blind randomized feasibility trial. Males and females with chronic PTSD will be randomly assigned to one of three conditions: imaginal exposure plus MB, imaginal exposure plus matched placebo, or waitlist. 260mg MB or PBO will be administered following five daily imaginal exposure sessions. Physiological and subjective arousal and medication side effects will be monitored. Pre-, post-, and brief follow-up changes in PTSD and other trauma-related symptoms will be assessed, including generalization of extinction learning. PUBLIC HEALTH RELEVANCE: This project proposes to use the memory-enhancing drug, methylene blue (MB), to facilitate prolonged exposure therapy for chronic posttraumatic stress disorder (PTSD). MB, if shown to be a useful adjunct to exposure treatments, will render exposure therapy a more cost-efficient treatment by decreasing the number of treatment sessions, promoting a quicker treatment response, reducing treatment dropout, and making treatment gains more durable over time.

DESCRIPTION (provided by applicant): Although it is well established that both pharmacological and psychological therapies are relatively effective in treating chronic posttraumatic stress disorder (PTSD), the recent Institute of Medicine (IOM, 2007) report highlights vast gaps in our current knowledge noting a lack of knowledge regarding factors influencing treatment acceptance and completion, the combined effectiveness of these pharmacological and psychological treatment, and their efficacy in common subpopulations (e.g., those with diagnostic co-occurrence). To address these gaps, we propose the first large-scale trial to directly focus on individualizing PTSD care across several key parameters: choice of treatment, the effects of combined psychotherapy and pharmacological PTSD treatment, and the presence of co-occurring major depression. Building on our previous psychotherapy and pharmacotherapy trial on PTSD treatment, we will conduct a doubly randomized preference trial in which female and male trauma survivors with chronic PTSD will be randomly assigned to either choice or no choice treatment conditions. In the choice condition, patients will choose between prolonged exposure (PE) and prolonged exposure plus sertraline (PE + SER). In the no choice condition, patients will be randomly assigned to either prolonged exposure alone (PE) or prolonged exposure plus sertraline (PE + SER). In addition, we will specifically recruit and examine patients with co-occurring major depressive disorder (MDD). Outcome, as measured by both psychopathology and broader functioning measures, will be assessed at post-treatment and through 24-month follow-up. We will also examine biopsychosocial markers of response, psychotherapy change processes, and cost-effectiveness of these treatments. The Specific Aims are: 1) To compare the short-term and long-term effectiveness of PE to that of PE + SER;2) To systematically compare patients who have chosen their treatment to those who have not in terms of treatment adherence, treatment completion, and effectiveness;and 3) To compare individuals with PTSD alone to those with PTSD and co-occurring major depression. In line with the NIMH's strategic plan, this proposal focuses on more personalized medicine, focusing on patients'choices and better understanding individual trajectories of outcome.

PROJECT SUMMARY/ABSTRACT Rates of PTSD, a chronic and debilitating mental disorder, are considerably higher in war-torn regions like Somalia, known for sexual violence and other human rights violations (e.g., 50.1%; Johnson et al., 2010). In the aftermath of substantial war- and refugee-related trauma, there is a clear need for effectiveness research addressing the significant, under-addressed mental health needs of Somalis and the broader Muslim community. While efficacious treatments exist for PTSD and related difficulties, such treatments typically require extensive training of providers prior to treatment delivery. Furthermore, there are significant barriers to dissemination of such treatments, particularly to the Somali community, due to Islamic beliefs that run contradictory to mental health interventions, language differences, and limited access to care (e.g., Bentley et al., 2011; Aloud & Rathur, 2009). For a population that is almost exclusively Muslim, a treatment that incorporates Islamic principles is essential. No existing trauma-focused treatments have an Islamic focus, despite the fact that almost a quarter of the world's population practices this religion. We have developed a brief, group-based, lay-led intervention, Islamic Trauma Healing, which specifically targets healing the mental wounds of trauma within mosques. The six-session intervention combines empirically-supported exposure- based and cognitive restructuring techniques with Islamic principles central to spiritual, social, family, and work life. Core intervention components include cognitive restructuring through Prophet stories, and exposure to trauma memories through talking to Allah. Tea, incense, and supplications are included as part of each group session to promote a sense of community and spirituality. We will examine the intervention in a small RCT and examine intervention mechanisms, specifically the effects of shifts in negative cognitions about self, world, and others and changes in connectedness with others and Allah. We also will demonstrate the initial feasibility of implementing the program outside of the U.S. to an Islamic country by conducting a small pre- to post-study design. Taken together, this work will serve as the foundation for a larger scale RCT within the U.S. Islamic refugee community and/or in the larger Islamic community outside of the U.S. The Islamic Trauma Healing program has the potential to provide a low-cost, self-sustaining model of faith-based intervention that can address the psychological wounds of trauma.

PROJECT SUMMARY Evidence-based psychotherapies for posttraumatic stress disorder (PTSD) and depression consistently produce strong, clinically meaningful effects for many individuals. However, these interventions also have significant dropout rates, a large minority of individuals continue to have debilitating symptoms, and even those who respond may be vulnerable to relapse upon future stressors. More efficient and mechanistically precise interventions are needed. Consistent with the cross-cutting theme of studying the role of the environment in the NIMH Strategic Plan, the etiologic role of exposure to destabilizing, stressful life events is common to both PTSD and depression. Not only do they share common distress-related triggers, symptoms, and maintaining processes, but they also commonly co-occur (upwards of 60%). Current PTSD and depression treatments typically focus on their respective disorders rather than on common processes that maintain psychopathology; and, importantly, they do not explicitly target positive adaptive processes associated with resilience. Decades of experimental studies, prospective studies, and psychotherapy trials have identified interconnected maladaptive and adaptive processes associated with persistent psychopathology after stressful, destabilizing events. These maladaptive processes include: 1) unproductive event processing; 2) avoidance; and 3) reward sensitivity and processing deficits. These processes prolong negative mood, interfere with adaptive coping and processing of emotional material, and increase sensitivity to future stressful life events. PATH (Positive Processes and Transition to Health) directly targets these maladaptive processes while also teaching parallel adaptive skills (constructive processing, approach, and positive emotion processing and reward seeking). Six, 90-min sessions target individuals who have experienced a destabilizing life event and have persistent stressor-related symptoms. PATH utilizes life event processing (revisiting, meaning making), focusing repeatedly on an identified destabilizing life event, positive life events, and future events as a framework to identify maladaptive processes and teach constructive processing skills. In a small open trial (R61, N = 45), we will examine whether PATH engages the key targets of unproductive processing, avoidance, and reward deficits. Next, we will conduct a randomized trial of PATH (R33, N = 135), comparing PATH to a Progressive Muscle Relaxation, seeking to replicate changes in the targets in a larger sample and examine PATH's impact on stressor-related psychopathology (PTSD, depression). PATH, a brief and focused treatment that targets key psychological processes common to PTSD and MDD, has the potential to reduce dropout, improve treatment engagement and outcomes, identify potential treatment mechanisms, and ultimately reduce the costly human and economic burden of stressor-related psychopathology.