A proof-of-concept randomized crossover clinical trial of a first-in-class vasopressin 1a receptor antagonist for PTSD: Design, methods, and recruitment.

Background: Almost eight million Americans suffer from Posttraumatic Stress Disorder (PTSD). Current PTSD drug therapies rely on repurposed antidepressants and anxiolytics, which produce undesirable side effects and have recognized compliance issues. Vasopressin represents a promising and novel target for pharmacological intervention. Logistical issues implementing a clinical trial for a novel PTSD pharmaceutical are relatively uncharted territory as trials concerning a new agent have not been published in the past several decades. All published trials have repurposed FDA-approved psychoactive medications with known risk profiles. Our recruitment challenges are discussed in this context. Methods: An 18-week proof-of-concept randomized crossover clinical trial of a first-in-class vasopressin 1a receptor antagonist (SRX246) for PTSD was conducted. All participants received SRX246 for 8 weeks, the placebo for 8 weeks, and the drug vs. placebo arms were compared. Participants were assessed every 2 weeks for PTSD symptoms as well as other medication effects. Results were expected to provide an initial demonstration of safety and tolerability in this clinical population and potentially clinical efficacy in SRX246-treated patients measured by Clinician Administered PTSD Scale (CAPS) score changes, clinical impression, and other indices compared to placebo. The primary hypothesis was that SRX246 would result in a clinically meaningful 10-point reduction in mean CAPS score compared to placebo. Discussion: This study is the first to investigate an oral vasopressin 1a receptor antagonist for PTSD. As a wave of PTSD clinical trials with new pharmaceutical compounds are beginning now, lessons learned from our recruitment challenges may be invaluable to these endeavors.

Enhancing exposure therapy for posttraumatic stress disorder (PTSD): a randomized clinical trial of virtual reality and imaginal exposure with a cognitive enhancer.

Posttraumatic stress disorder (PTSD) is a significant public health issue. Yet, there are limited treatment options and no data to suggest which treatment will work for whom. We tested the efficacy of virtual reality exposure (VRE) or prolonged imaginal exposure (PE), augmented with D-cycloserine (DCS) for combat-related PTSD. As an exploratory aim, we examined whether brain-derived neurotrophic factor (BDNF) and fatty acid amide hydrolase (FAAH) moderated treatment response. Military personnel with PTSD (n = 192) were recruited into a multisite double-blind randomized controlled trial to receive nine weeks of VRE or PE, with DCS or placebo. Primary outcome was the improvement in symptom severity. Randomization was stratified by comorbid depression (MDD) and site. Participants in both VRE and PE showed similar meaningful clinical improvement with no difference between the treatment groups. A significant interaction (p = 0.45) suggested VRE was more effective for depressed participants (CAPS difference M = 3.51 [95% CI 1.17-5.86], p = 0.004, ES = 0.14) while PE was more effective for nondepressed participants (M = -8.87 [95% CI -11.33 to -6.40], p < 0.001, ES = -0.44). The main effect of DCS vs. placebo was not significant. Augmentation by MDD interaction (p = 0.073) suggested that depressed participants improved more on placebo (M = -8.43 [95% CI -10.98 to -5.88], p < 0.001, ES = -0.42); DCS and placebo were equally effective for nondepressed participants. There was an apparent moderating effect of BDNF Val66Met polymorphism on DCS augmentation (ES = 0.67). Met66 allele carriers improved more on DCS (ES = -0.25). FAAH 385 A carriers improved more than non-carriers (ES = 0.33), particularly those with MDD (ES = 0.62). This study provides a step toward precision therapeutics for PTSD by demonstrating that comorbid MDD and genetic markers may help guide treatment selection.ClinicalTrials.gov Identifier: NCT01352637.

The relationship between posttraumatic and depressive symptoms during virtual reality exposure therapy with a cognitive enhancer.

Two studies suggest that reductions in posttraumatic symptoms (Aderka et al., 2013) and cognitions (Zalta et al., 2014) precede reductions in depressive symptoms during prolonged exposure (PE) therapy for posttraumatic stress disorder (PTSD) in female assault survivors. The present study explored the temporal relationship between posttraumatic and depressive symptoms in a randomized trial of D-Cycloserine (DCS) versus placebo augmented virtual reality exposure (VRE) therapy for chronic World Trade Center-related PTSD following the September 11, 2001 terrorist attacks. Twenty-five male and female participants were randomly assigned to receive either 100 mg DCS (N = 13) or placebo (N = 12) 90 min before 12 weekly VRE sessions. Participants contributed a total of 280 weekly PTSD Checklist (PCL; Weathers et al., 1993) and Beck Depression Inventory-second edition (BDI-II; Beck et al., 1996) symptom scores. Two sets of mediation analyses for longitudinal mixed models assessed the effects of 1) lagged PCL on BDI-II (Model 1), and 2) lagged BDI-II on PCL (Model 2) in the VRE-DCS and VRE-Placebo treatment groups, respectively. Results revealed reciprocal relations between posttraumatic and depressive symptoms during VRE treatment, although reductions in posttraumatic symptoms led to subsequent reductions in depressive symptoms to a greater extent than the converse. These effects were stronger in the DCS-enhanced group. Findings suggest that VRE primarily decreases posttraumatic symptoms, which in turn leads to decreased depressive symptoms, and that DCS may strengthen these effects.

Posttraumatic Stress Disorder, Functional Impairment, and Subjective Distress in World Trade Center Disaster Workers.

Posttraumatic stress disorder (PTSD) is associated with functional deficits, poor physical health, and diminished quality of life. Limited research has examined PTSD symptom clusters and their associations with functioning and distress among disaster recovery workers, a population at high risk for PTSD due to potential for repeated trauma. The purpose of this study was to investigate associations between overall PTSD severity, as well as PTSD symptom clusters, and social and occupational functioning and subjective distress in World Trade Center (WTC) disaster workers after the terrorist attacks on September 11, 2001 (9/11). Disaster workers deployed to the site of the attacks completed assessments at three time points over approximately 5 years post-9/11. Our sample consisted of participants who met criteria for PTSD or subthreshold PTSD at baseline (n = 514), 1-year (n = 289), and 2-year follow-up (n = 179). Adjusted linear regression indicated that Clinician Administered PTSD Scale (CAPS)-rated PTSD severity was positively associated with subjective distress, and deficits in social and occupational functioning, over time, CAPS Criterion F items; ßs = .20 to .62, ps < .001. The reexperiencing and avoidance/numbing symptom clusters were associated with increased subjective distress, the avoidance/numbing and hyperarousal clusters were associated with deficits in social functioning, and the reexperiencing and hyperarousal clusters were associated with worse occupational functioning. These associations were consistent across the study period. Findings point to the importance of targeting PTSD symptom clusters associated with specific areas of functional impairment, with the goal of improving global outcomes.

Pilot Study of a Telehealth-Delivered Medication-Augmented Exposure Therapy Protocol for PTSD.

Posttraumatic stress disorder (PTSD) is a serious condition, with certain occupations at increased risk due to greater trauma exposure. These same individuals face multiple barriers to care. This study aimed to investigate the feasibility of conducting a research trial with exposure therapy delivered via videoconferencing. Eleven adults working in occupations at risk with PTSD enrolled and seven completed 12 to 15 sessions. Individuals were randomized to receive the cognitive enhancer D-cycloserine or placebo, and participants provided saliva samples for genetic analysis. Treatment completers demonstrated decreases in PTSD and depressive symptomatology (measured by CAPS [p < 0.001, d = 2.79] and BDI-II [p = 0.004, d = 0.92]). Participants reported high therapeutic alliance, treatment satisfaction, and telehealth satisfaction. There were no significant technical, medication, or safety issues, and no clinical emergencies. The results suggest that it may be feasible to conduct clinical research using telehealth for PTSD and to use telehealth to increase access to care.

Does desire for hastened death change in terminally ill cancer patients?

Understanding why some terminally ill patients may seek a hastened death (a construct referred to as "desire for hastened death" or DHD) is critical to understanding how to optimize quality of life during an individual's final weeks, months or even years of life. Although a number of predictor variables have emerged in past DHD research, there is a dearth of longitudinal research on how DHD changes over time and what factors might explain such changes. This study examined DHD over time in a sample of terminally ill cancer patients admitted to a palliative care hospital. A random sample of 128 patients completed the Schedule of Attitudes toward Hastened Death (SAHD) at two time points approximately 2-4 weeks apart participated. Patients were categorized into one of four trajectories based on their SAHD scores at both time points: low (low DHD at T1 and T2), rising (low DHD at T1 and high DHD at T2), falling (high DHD at T1 and low DHD at T2) and high (high DHD at T1 and T2). Among patients who were low at T1, several variables distinguished between those who developed DHD and those who did not: physical symptom distress, depression symptom severity, hopelessness, spiritual well-being, baseline DHD, and a history of mental health treatment. However, these same medical and clinical variables did not distinguish between the falling and high trajectories. Overall, there appears to be a relatively high frequency of change in DHD, even in the last weeks of life. Interventions designed to target patients who are exhibiting subthreshold DHD and feelings of hopelessness may reduce the occurrence of DHD emerging in this population.

Evidence-based treatment of post-traumatic stress disorder.

The term translational research is typically used to refer both to "bench to bedside" research, in which preclinical research findings inform the development of novel therapeutics, and to the dissemination of new treatments to the community to encourage the use of the new health practices and treatments. Both definitions are germane to understanding the evidence base for treatment of post-traumatic stress disorder (PTSD) today. This article offers (a) an overview of evidence-based treatments for PTSD, (b) a description of a translational model of PTSD, and (c) a discussion of common barriers to dissemination and implementation of the empirically validated treatments. Recent studies in the field are discussed with a focus on pharmacotherapies, psychotherapies, and combined treatments.

D-cycloserine augmentation of exposure therapy for post-traumatic stress disorder: a pilot randomized clinical trial.

Viewing post-traumatic stress disorder (PTSD) as a disorder of emotional learning, this study used a cognitive enhancer synergistically with virtual reality exposure (VRE) therapy for the treatment of PTSD. The main objective was to determine if a novel pharmacotherapy, D-cycloserine (DCS), enhanced the efficacy of the psychotherapy. Pre-clinical studies suggest that when fear extinction occurs during DCS administration, neuroplasticity may be enhanced. VRE therapy is a particularly promising format to test the hypothesis that DCS enhances extinction learning, as sensory fear cues are standardized across patients. In a pilot randomized, double-blind, placebo-controlled trial, 100 mg of DCS or placebo was administered 90 min before each weekly VRE session, to ensure peak plasma concentrations during the sessions in 25 patients with chronic PTSD. The primary outcome measure was the Clinician Administered PTSD Scale (CAPS). Secondary outcome measures included the Beck Depression Inventory-II and the State-Trait Anger Expression Inventory-2. Assessments occurred at pre-treatment, following sessions 3, 6, 10, post-treatment, and at 6 months. The difference in CAPS between the VRE-DCS (n=13) and VRE-placebo (n=12) groups increased over time beginning at 6 weeks, with medium to large between-group effect sizes immediately post-treatment and 6 months later (d=0.68 and d=1.13, respectively). A similar pattern was observed for depression, anger expression, and sleep. PTSD remission rates were significantly greater for the VRE-DCS group (46% vs 8% at post-treatment; 69% vs 17% at 6 months). Patients in the VRE-DCS group showed earlier and greater improvement in PTSD symptoms compared with the VRE-placebo group. These results suggest a promising new treatment for PTSD.

Conceptualizing prognostic awareness in advanced cancer: a systematic review.

This systematic review synthesizes the complex literature on prognostic awareness in cancer. A total of 37 studies examining cancer patients' understanding of their prognosis were included. Prognostic awareness definitions and assessment methods were inconsistent across studies. A surprisingly high percentage of patients (up to 75%) were unaware of their poor prognosis, and in several studies, even their cancer diagnosis (up to 96%), particularly in studies conducted outside of North America. This review highlights surprisingly low rates of prognostic awareness in patients with advanced cancer as well as discrepancies in prognostic awareness assessment, suggesting the need for empirically validated measures of prognostic awareness.

Pilot randomized controlled trial of individual meaning-centered psychotherapy for patients with advanced cancer.

PURPOSE: Spiritual well-being and sense of meaning are important concerns for clinicians who care for patients with cancer. We developed Individual Meaning-Centered Psychotherapy (IMCP) to address the need for brief interventions targeting spiritual well-being and meaning for patients with advanced cancer. PATIENTS AND METHODS: Patients with stage III or IV cancer (N = 120) were randomly assigned to seven sessions of either IMCP or therapeutic massage (TM). Patients were assessed before and after completing the intervention and 2 months postintervention. Primary outcome measures assessed spiritual well-being and quality of life; secondary outcomes included anxiety, depression, hopelessness, symptom burden, and symptom-related distress. RESULTS: Of the 120 participants randomly assigned, 78 (65%) completed the post-treatment assessment and 67 (56%) completed the 2-month follow-up. At the post-treatment assessment, IMCP participants demonstrated significantly greater improvement than the control condition for the primary outcomes of spiritual well-being (b = 0.39; P <.001, including both components of spiritual well-being (sense of meaning: b = 0.34; P = .003 and faith: b = 0.42; P = .03), and quality of life (b = 0.76; P = .013). Significantly greater improvements for IMCP patients were also observed for the secondary outcomes of symptom burden (b = -6.56; P < .001) and symptom-related distress (b = -0.47; P < .001) but not for anxiety, depression, or hopelessness. At the 2-month follow-up assessment, the improvements observed for the IMCP group were no longer significantly greater than those observed for the TM group. CONCLUSION: IMCP has clear short-term benefits for spiritual suffering and quality of life in patients with advanced cancer. Clinicians working with patients who have advanced cancer should consider IMCP as an approach to enhance quality of life and spiritual well-being.

The longitudinal course of PTSD among disaster workers deployed to the World Trade Center following the attacks of September 11th.

This study examined the long-term mental health outcomes of 2,960 nonrescue disaster workers deployed to the World Trade Center site in New York City following the September 11, 2001 (9/11) terrorist attacks. Semistructured interviews and standardized self-report measures were used to assess the prevalence of posttraumatic stress disorder (PTSD) and other psychopathology 4 and 6 years after the attacks. Clinician-measured rates of PTSD and partial PTSD 4-years posttrauma were 8.4% and 8.9%, respectively, in a subsample of 727 individuals. Rates decreased to 5.8% and 7.7% for full and partial PTSD 6 years posttrauma. For the larger sample, self-report scores revealed probable PTSD and partial PTSD prevalence to be 4.8% and 3.6% at 4 years, and 2.4% and 1.8% at 6 years. Approximately 70% of workers never met criteria for PTSD. Although PTSD rates decreased significantly over time, many workers remained symptomatic, with others showing delayed-onset PTSD. The strongest predictors of ongoing PTSD 6 years following 9/11 were trauma history (odds ratio (OR) = 2.27, 95% confidence interval (CI) [1.06, 4.85]); the presence of major depressive disorder 1-2 years following the trauma (OR = 2.80, 95% CI [1.17, 6.71]); and extent of occupational exposure (OR = 1.31, 95% CI [1.13, 1.51]). The implications of the findings for both screening and treatment of disaster workers are discussed.

Assessing hopelessness in terminally ill cancer patients: development of the Hopelessness Assessment in Illness Questionnaire.

Hopelessness has become an increasingly important construct in palliative care research, yet concerns exist regarding the utility of existing measures when applied to patients with a terminal illness. This article describes a series of studies focused on the exploration, development, and analysis of a measure of hopelessness specifically intended for use with terminally ill cancer patients. The 1st stage of measure development involved interviews with 13 palliative care experts and 30 terminally ill patients. Qualitative analysis of the patient interviews culminated in the development of a set of potential questionnaire items. In the 2nd study phase, we evaluated these preliminary items with a sample of 314 participants, using item response theory and classical test theory to identify optimal items and response format. These analyses generated an 8-item measure that we tested in a final study phase, using a 3rd sample (n = 228) to assess reliability and concurrent validity. These analyses demonstrated strong support for the Hopelessness Assessment in Illness Questionnaire providing greater explanatory power than existing measures of hopelessness and found little evidence that this assessment was confounded by illness-related variables (e.g., prognosis). In summary, these 3 studies suggest that this brief measure of hopelessness is particularly useful for palliative care settings. Further research is needed to assess the applicability of the measure to other populations and contexts.

Evidence-based treatments for PTSD, new directions, and special challenges.

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.

House calls revisited: leveraging technology to overcome obstacles to veteran psychiatric care and improve treatment outcomes.

Despite an increasing number of military service members in need of mental health treatment following deployment to Iraq and Afghanistan, numerous psychological and practical barriers limit access to care. Perceived stigma about admitting psychological difficulties as well as frequent long distances to treatment facilities reduce many veterans' willingness and ability to receive care. Telemedicine and virtual human technologies offer a unique potential to expand services to those in greatest need. Telemedicine-based treatment has been used to address multiple psychiatric disorders, including posttraumatic stress disorder, depression, and substance use, as well as to provide suicide risk assessment and intervention. Clinician education and training has also been enhanced and expanded through the use of distance technologies, with trainees practicing clinical skills with virtual patients and supervisors connecting with clinicians via videoconferencing. The use of these innovative and creative vehicles offers a significant and as yet unfulfilled promise to expand delivery of high-quality psychological therapies, regardless of clinician and patient location.

Meaning-centered group psychotherapy for patients with advanced cancer: a pilot randomized controlled trial.

OBJECTIVES: An increasingly important concern for clinicians who care for patients at the end of life is their spiritual well-being and sense of meaning and purpose in life. In response to the need for short-term interventions to address spiritual well-being, we developed Meaning Centered Group Psychotherapy (MCGP) to help patients with advanced cancer sustain or enhance a sense of meaning, peace and purpose in their lives, even as they approach the end of life. METHODS: Patients with advanced (stage III or IV) solid tumor cancers (N=90) were randomly assigned to either MCGP or a supportive group psychotherapy (SGP). Patients were assessed before and after completing the 8-week intervention, and again 2 months after completion. Outcome assessment included measures of spiritual well-being, meaning, hopelessness, desire for death, optimism/pessimism, anxiety, depression and overall quality of life. RESULTS: MCGP resulted in significantly greater improvements in spiritual well-being and a sense of meaning. Treatment gains were even more substantial (based on effect size estimates) at the second follow-up assessment. Improvements in anxiety and desire for death were also significant (and increased over time). There was no significant improvement on any of these variables for patients participating in SGP. CONCLUSIONS: MCGP appears to be a potentially beneficial intervention for patients' emotional and spiritual suffering at the end of life. Further research, with larger samples, is clearly needed to better understand the potential benefits of this novel intervention.

Measuring depression at the end of life: is the Hamilton Depression Rating Scale a valid instrument?

Depression at the end of life is a common mental health issue with serious implications for quality of life and decision making. This study investigated the reliability and validity of one of the most frequently used measures of depression, the Hamilton Depression Rating Scale (HAM-D) in 422 patients with terminal cancer admitted to a palliative care hospital. The HAM-D demonstrated high reliability and concurrent validity with depression diagnosis, based on Structured Clinical Interview for DSM-IV Axis I Disorders, non-patient research version (SCID-I/NP Depression Module). Receiver Operating Characteristic (ROC) analyses generated an area under the curve of .91, indicating high sensitivity and specificity. The HAM-D strongly correlated with several measures of distress (e.g., hopelessness, desire for hastened death, and suicidal ideation). Factor analysis generated 4 factors (anxiety, depressed mood, insomnia, and somatic symptoms), accounting for 42% of the variance. Implications for assessing depression in this population are discussed.

Clinical assessment of depression in terminally ill cancer patients: a practical guide.

Depression is commonly experienced by cancer patients at the end of life. The identification of patients suffering from depression is essential to provide clinicians with an opportunity to relieve considerable suffering. However, the assessment of depressive symptoms is complex and often challenging in a terminally ill cancer population. This article offers practical guidelines to assist clinicians with the diagnosis of depression, reviews the defining symptoms of depression and their unique presentation in patients at the end of life, suggests modifications of the standard diagnostic interview, and provides examples of specific assessment questions to target depressive symptoms at the end of life.