Propranolol treatment during repetitive mild traumatic brain injuries induces transcriptomic changes in the bone marrow of mice.

Introduction: There are 1.5 million new mild traumatic brain injuries (mTBI) annually in the US, with many of the injured experiencing long-term consequences lasting months after the injury. Although the post injury mechanisms are not well understood, current knowledge indicates peripheral immune system activation as a causal link between mTBI and long-term side effects. Through a variety of mechanisms, peripheral innate immune cells are recruited to the CNS after TBI to repair and heal the injured tissue; however, the recruitment and activation of these cells leads to further inflammation. Emerging evidence suggests sympathetic nervous system (SNS) activity plays a substantial role in the recruitment of immune cells post injury. Methods: We sought to identify the peripheral innate immune response after repeated TBIs in addition to repurposing the nonselective beta blocker propranolol as a novel mTBI therapy to limit SNS activity and mTBI pathophysiology in the mouse. Mice underwent repetitive mTBI or sham injury followed by i.p. saline or propranolol. Isolated mRNA derived from femur bone marrow of mice was assayed for changes in gene expression at one day, one week, and four weeks using Nanostring nCounter® stem cell characterization panel. Results: Differential gene expression analysis for bone marrow uncovered significant changes in many genes following drug alone, mTBI alone and drug combined with mTBI. Discussion: Our data displays changes in mRNA at various timepoints, most pronounced in the mTBI propranolol group, suggesting a single dose propranolol injection as a viable future mTBI therapy in the acute setting.

Repeated mild traumatic brain injury in mice elicits long term innate immune cell alterations in blood, spleen, and brain.

Mild traumatic brain injury is an insidious event whereby the initial injury leads to ongoing secondary neuro- and systemic inflammation through various cellular pathways lasting days to months after injury. Here, we investigated the impact of repeated mild traumatic brain injury (rmTBI) and the resultant systemic immune response in male C57B6 mice using flow cytometric methodology on white blood cells (WBCs) derived from the blood and spleen. Isolated mRNA derived from spleens and brains of rmTBI mice was assayed for changes in gene expression at one day, one week, and one month following the injury paradigm. We observed increases in Ly6C+, Ly6C-, and total monocyte percentages in both blood and spleen at one month after rmTBI. Differential gene expression analysis for the brain and spleen tissues uncovered significant changes in many genes, including csf1r, itgam, cd99, jak1,cd3ε, tnfaip6, and nfil3. Additional analysis revealed alterations in several immune signaling pathways over the course of one month in the brain and spleen of rmTBI mice. Together, these results indicate that rmTBI produces pronounced gene expression changes in the brain and spleen. Furthermore, our data suggest that monocyte populations may reprogram towards the proinflammatory phenotype over extended periods of time after rmTBI.

A clinical trial comparing trauma-informed guilt reduction therapy (TrIGR), a brief intervention for trauma-related guilt, to supportive care therapy.

INTRODUCTION: Trauma-related guilt is common, associated with posttraumatic mental health problems, and can persist after posttraumatic stress disorder (PTSD) treatment. We compared the efficacy of two six-session psychotherapies, Trauma-Informed Guilt Reduction (TrIGR) and Supportive Care Therapy (SCT), for reducing trauma-related guilt. TrIGR helps patients accurately appraise their role in the trauma and re-engage in values. In SCT, patients guide session content. METHODS: A total of 184 veterans seeking VA mental health services were enrolled across two sites; 145 veterans (mean age: 39.2 [8.1]; 92.4% male; 84.8% with PTSD) who endorsed guilt related to a traumatic event that occurred during a post 9/11 Iraq or Afghanistan deployment were randomized and assessed at baseline, posttreatment, 3- and 6-month follow-up. RESULTS: Linear mixed models using intent-to-treat analyses showed guilt decreased in both conditions with a greater decrease for TrIGR (treatment × time, -0.22; F 1, 455.2 = 18.49, p = .001; d = 0.92) than supportive therapy. PTSD and depressive symptoms showed the same pattern. TrIGR had significantly higher likelihood of PTSD treatment response (67% vs. 40%), loss of PTSD diagnosis (50% vs. 14%), and meaningful change in depression (54% vs. 27%) than supportive therapy. Psychological distress and trait shame improved in both conditions. Quality of life did not change. CONCLUSIONS: Targeting guilt appears to be an effective means for reducing posttraumatic symptoms and distress.

Examining attendance patterns across integrated therapies for posttraumatic stress disorder and alcohol use disorder.

A substantial body of evidence supports the use of integrated treatments for posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD). Integrated trauma-focused exposure therapies reduce PTSD symptoms more than comparison treatments, including integrated coping skills therapies, but demonstrate lower attendance, raising questions regarding the relationships between attendance, outcomes, and treatment type. We aimed to examine these relationships in a RCT comparing integrated prolonged exposure (Concurrent Treatment for PTSD and Substance Use Disorders Using Prolonged Exposure, COPE; n = 58), to integrated coping skills therapy (Seeking Safety, SS; n = 52) offered in 12 sessions, with an option to extend up to four additional sessions. Participants were categorized based on number of sessions attended (0-4; 5-8; 9-12; 13-16). Multilevel modeling revealed that only when examining therapy attendance segments individually, clinical outcomes were comparable across treatments except in the 9-12 group, with COPE resulting in greater reductions in PTSD symptoms (p < 0.001), but not in alcohol use. Extending past 12 sessions was not associated with additional clinically meaningful symptom improvement for either treatment. These results suggest that attending a complete or near complete course of exposure therapy may enhance PTSD outcomes relative to non-trauma-focused therapies.

Substance use predictors of attendance among veterans in integrated PTSD and alcohol use disorder treatment.

Comorbid post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) is common, defined by greater severity and impairment than either disorder alone, and associated with poor treatment attendance. Exposure therapies are effective in treating PTSD+AUD, yet substance use is still cited as a potential contraindication for exposure. This study examined substance use-related predictors of session attendance among veterans (N = 119) randomized to receive integrated exposure therapy (Concurrent Treatment of PTSD and Substance Use Disorders using Prolonged Exposure [COPE]; Back et al., 2015) or integrated coping skills therapy (Seeking Safety [SS]; Najavits, 2002) in a clinical trial for comorbid PTSD+AUD (Norman et al., 2019). At baseline, greater percentage of heavy drinking days (ß = -0.23, p = .011) and greater AUD severity per structured clinical interview for DSM-IV-TR (ß = -0.21, p = .019) predicted fewer sessions across both treatments. Treatment type did not moderate the relationship between predictors and attendance, except for a trend for craving (p = .057), where greater craving predicted fewer sessions in SS (ß = -0.31, p = .02) but not COPE (ß = 0.14, p = .28). Percentage of abstinence days, AUD duration, and living in a controlled environment (e.g., recovery home) at the start of therapy were not associated with attendance in either treatment condition. Only a subset of substance use characteristics predicted attendance. Findings did not support the notion that alcohol use leads to lower attendance in exposure therapy compared to nonexposure therapy.

Does exposure exacerbate symptoms in veterans with PTSD and alcohol use disorder?

OBJECTIVE: Patients with posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) are often not offered exposure therapy for PTSD due to concerns that symptoms may worsen. This study examined whether initiating exposure would cause exacerbation of PTSD, alcohol use, depression, or suicidal ideation (SI) among patients with PTSD/AUD participating in exposure therapy for PTSD. METHOD: Veterans were randomized to either concurrent treatment of PTSD and substance use disorders using prolonged exposure (COPE) or seeking safety, a nonexposure intervention, and were included in this study if they had data to at least Session 5 available (n = 81). They completed measures of PTSD, alcohol use, and depression/SI symptom severity throughout treatment and posttreatment. The reliable exacerbation method examined the number of participants who demonstrated clinically meaningful symptom exacerbation from Sessions 3 to 5 (capturing the prepost window for the start of exposure in COPE). Hierarchical/logistic regressions examined whether treatment condition predicted exacerbation of symptoms. T tests/chi-square analyses examined whether clinical exacerbation led to worse posttreatment outcomes. RESULTS: Few participants endorsed exacerbation in symptoms of PTSD (15.8%), alcohol use (5.1%), depression (10.2%), or SI (12.8%). No significant treatment condition differences existed. Participants who experienced symptom exacerbation had higher rates of depression posttreatment compared to those who did not experience symptom exacerbation, but there were no differences in PTSD, alcohol use, or SI. CONCLUSIONS: Exposure therapy did not lead to more clinical exacerbation than nonexposure therapy during the course of treatment, providing support that exposure therapy should not be withheld from patients with PTSD/AUD. This was a secondary analysis. and future studies that are sufficiently powered may demonstrate different results. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

A model for treating COVID-19-related guilt, shame, and moral injury.

During the unprecedented COVID-19 pandemic, people around the world have faced a myriad of heart-rending and ethically difficult scenarios (e.g., not being able to tend to a sick or dying loved one) that may lead to subsequent guilt, shame, or moral injury. Trauma-informed guilt reduction therapy is a brief intervention that helps clients accurately appraise their role in a stressful event (such as those experienced during the COVID-19 pandemic) and find positive ways to express important values going forward. Future studies of trauma-informed guilt reduction therapy with those affected by COVID-19 will be helpful for clarifying its effectiveness with this population. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Residual Symptoms of Posttraumatic Stress Disorder and Alcohol Use Disorder Following Integrated Exposure Treatment Versus Coping Skills Treatment.

Although some studies have demonstrated residual symptoms in patients who have participated in posttraumatic stress disorder (PTSD) treatment, no studies to date have assessed residual PTSD symptoms following treatment for comorbid alcohol use disorder (AUD) and PTSD (PTSD/AUD). We examined residual symptoms of PTSD and AUD in 73 veterans with PTSD/AUD who completed a posttreatment assessment after being randomized to receive either Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure (COPE) or Seeking Safety (SS). We used logistic regression to identify differences (a) in residual PTSD and AUD symptoms among participants randomized to COPE versus SS and (b) among those with versus without a posttreatment PTSD/AUD diagnosis within both treatment conditions. Participants randomized to SS were more likely to report persistent avoidance, inability to experience positive emotions, hypervigilance, difficulty concentrating, and difficulty sleeping, ORs = 3.74-6.21. There were no differences between COPE and SS regarding the likelihood of persistent AUD symptoms. Participants without a posttreatment PTSD diagnosis had lower conditional probabilities of most symptoms, although exaggerated startle, OR = 0.71, and irritability/aggression, OR = 0.58, were most likely to persist. Participants without a posttreatment AUD diagnosis had lower conditional probabilities of most symptoms, although withdrawal, OR = 0.21; unsuccessful quit attempts, OR = 0.04; and higher intake, OR = 0.01, were most likely to persist. Findings indicate hyperarousal may warrant additional intervention following PTSD treatment. Residual AUD symptoms may relate to the enduring nature of some AUD symptoms rather than a lack of treatment efficacy.

Comparing Exposure- and Coping Skills-Based Treatments on Trauma-Related Guilt in Veterans With Co-Occurring Alcohol Use and Posttraumatic Stress Disorders.

Posttraumatic stress disorder (PTSD) and substance use disorders (SUD) commonly co-occur, and this comorbidity (PTSD-SUD) is associated with more severe symptoms and functional impairment than either disorder alone. Growing evidence indicates that trauma-related guilt, typically concerning negative appraisals of one's actions or inaction during a traumatic event, is associated with PTSD, depression, suicidality, and, possibly, substance use. The present study examined whether integrated treatment for PTSD-SUD was effective in reducing trauma-related guilt as measured by the Trauma-Related Guilt Inventory. Data were drawn from a randomized clinical trial comparing the effectiveness of two integrated therapies on treatment outcomes in a sample of U.S. veterans (N = 119) with comorbid PTSD and SUD. Participants were randomized to receive either Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure (COPE; n = 63) or Seeking Safety (SS; n = 56). The results indicated that global guilt decreased over time for the whole sample. However, there was a significant Treatment × Time interaction, such that participants in the COPE condition reported lower rates of global guilt, d = 0.940, over time compared to those in the SS condition, d = .498. To our knowledge, this was the first study to examine the effects of integrated PTSD-SUD treatment on trauma-related guilt. The findings highlight that exposure-based, trauma-focused treatment for comorbid PTSD-SUD can be more effective in decreasing trauma-related guilt, with potentially longer-lasting effects, than non-exposure-based treatment, adding evidence that patients with PTSD-SUD should be offered such treatment.

Understanding the impact of attachment insecurity on PTSD symptoms among male Veterans and military personnel.

Attachment insecurity (i.e., attachment anxiety and attachment avoidance) has been found to contribute to PTSD symptom severity in Veterans. However, little is known of the unique contribution of attachment insecurity on individual PTSD symptom clusters. In a community sample of 106 combat-deployed Veterans, active duty service members, and reservists, this study examined: (1) the relationships between childhood family experience, combat experience, attachment insecurity, and PTSD symptom clusters, and (2) the influence of attachment insecurity on PTSD symptom clusters. Results revealed significant correlations between attachment anxiety and all PTSD symptom clusters (rs = .22 -.43) and attachment avoidance and PTSD symptom clusters, except the avoidance cluster (rs = .21 -.36). Four multiple regression analyses were employed to address the second study aim. Childhood family experiences predicted negative alterations in cognitions and mood (ß = -.30) and alterations in arousal and reactivity (ß = -.20). Further, combat experience significantly predicted each symptom cluster of PTSD (ßs = .03 -.44). In the second step, attachment anxiety and attachment avoidance were added to each model. Attachment anxiety and attachment avoidance predicted negative alterations in cognitions and mood (ßs = .22 and .35) and alterations in arousal and reactivity (ßs = .27 and .17). Inconsistent with previous research, attachment insecurity did not predict symptoms of avoidance. These results highlight the impact of attachment among a diverse sample of trauma exposed individuals and may provide insights for clinical implications and therapeutic approaches when working with Veterans and military personnel high in attachment insecurity.

Efficacy of Integrated Exposure Therapy vs Integrated Coping Skills Therapy for Comorbid Posttraumatic Stress Disorder and Alcohol Use Disorder: A Randomized Clinical Trial.

Importance: Co-occurrence of posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) is common and associated with psychiatric and functional problems. Understanding whether exposure therapy is tolerable and efficacious for treating PTSD and AUD is critical to ensure that best practice treatments are available. Objective: To compare the efficacy of integrated (ie, targeting both PTSD and alcohol use) prolonged exposure (I-PE) therapy with present-centered integrated coping skills (I-CS) therapy, a more commonly available treatment, in reducing PTSD symptoms and alcohol use. Design, Setting, and Participants: This prospective randomized clinical trial with masked assessments considered 186 veterans seeking Veterans Affairs mental health services. A total of 119 veterans with PTSD and AUD were randomized. Data were collected from February 1, 2013, to May 31, 2017, before treatment, after treatment, and at 3- and 6-month follow-ups. Intention-to-treat analyses were performed. Interventions: Veterans underwent I-PE (Concurrent Treatment of PTSD and Substance Use Disorder Using Prolonged Exposure) or I-CS (Seeking Safety) therapy. Main Outcomes and Measures: A priori planned outcomes were PTSD symptoms (Clinician Administered PTSD Scale for DSM-5) and percentage of heavy drinking days (Timeline Follow-Back) before treatment, after treatment, and at 3- and 6-month follow-ups. Results: A total of 119 veterans (mean [SD] age, 41.6 [12.6] years; 107 [89.9%] male) were randomized. Linear mixture models found that PTSD symptoms decreased in both conditions, with a significantly greater decrease for I-PE treatment compared with I-CS treatment (treatment × time interaction, -2.83; F3,233.1 = 4.92; Cohen d = 0.41; P = .002). The percentage of heavy drinking days improved in both conditions but was not statistically different between I-PE and I-CS treatment (treatment × time interaction, 1.8%; F3,209.9 = 0.18; Cohen d = 0.04; P = .91). Conclusions and Relevance: The I-PE arm had a greater reduction in PTSD symptoms than the I-CS arm and comparable drinking decreases. The study provides evidence that exposure therapy is more efficacious in treating PTSD than a more commonly available integrated treatment without exposure for comorbid PTSD and AUD. Trial Registration: ClinicalTrials.gov identifier: NCT01601067.

Examining Pretreatment Differences Between Veterans in Residential Versus Outpatient Treatment for Alcohol Use Disorder and Comorbid Combat-Related PTSD.

OBJECTIVE: Veterans with alcohol use disorder (AUD) and co-occurring posttraumatic stress disorder (PTSD) have access to various residential and outpatient treatment programs through the VA Healthcare System. There is a need to better understand the characteristics and needs of veterans who engage in residential versus outpatient treatment in order to help inform veteran care and decisions about treatment services. METHODS: The present study examined whether veterans with both AUD and combat-related PTSD who were enrolled in residential (n = 103) or outpatient treatment programs (n = 76) differed on pretreatment psychiatric symptoms, substance use and associated problems/behaviors, or demographics. Veterans completed self-report measures (which referenced symptoms in the past 30 days or 2 weeks) within the first week of PTSD/AUD treatment. RESULTS: Veterans in residential treatment had slightly worse PTSD symptoms compared to outpatient veterans; the groups reported similar levels of depression symptoms. Residential veterans had higher frequency of drug use, were more confident in their ability to be abstinent, attended more self-help meetings, spent more time around risky people or places, were more satisfied with their progress toward recovery goals, were more bothered by arguments with family/friends, and spent fewer days at work or school compared to outpatient veterans; the groups did not differ on drinking (frequency of use, binge drinking) or cravings. With respect to demographics, residential veterans were more likely to be married and non-Hispanic Caucasian (rather than minority races/ethnicities) compared to outpatient veterans. CONCLUSIONS: The finding that PTSD symptoms were more severe among veterans in residential substance use treatment highlights the importance of taking advantage of this crucial opportunity to engage veterans in evidence-based PTSD treatment. Consistent with other research, findings also indicated that individuals entering residential care have a higher level of impairment than those beginning outpatient care.