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When discussing neurotransmitters whose signaling plays an important role in psychiatric illnesses, serotonin and dopamine may be the first that come to mind. Although serotonin and dopamine have significant roles, the impact of norepinephrine signaling is often overlooked. A growing body of evidence suggests that hyperactivity of norepinephrine signaling is an underlying issue in psychiatric disorders; conversely, there is evidence to suggest that deficits in the noradrenergic system are just as significant. Hence, alterations in noradrenergic activity are better characterized as dysregulation rather than a reductive, outdated formulation of "too much" or "too little" activity. Therefore, symptoms such as agitation, irritability, hyperarousal, and insomnia could be treated by targeting the underlying pathophysiology related to noradrenergic dysregulation with targeted treatments. In a recent consensus panel meeting, 5 experts reviewed the available evidence of altered noradrenergic activity and its potential role in some of the most common psychiatric disorders. This Academic Highlights article summarizes their discussion and presents the panel's conclusions., (© Copyright 2024 Physicians Postgraduate Press, Inc.)

Introduction: Medications for opioid use disorders (MOUD) remain the gold standard for treating OUD, but treatment initiation and adherence remain challenging. Exclusive utilization of pharmacotherapy as a treatment modality for OUD is sub-optimal, and a combination of psychotherapies and pharmacotherapies is recommended. General trends indicate the benefits of peer mentoring and MBRP separately. Therefore, we hypothesize that the combined effect of MBRP and Peer mentoring will produce synergistic improvements in MOUD adherence compared to an enhanced twelve-step facilitation (TSF)., Methods: This paper describes the methods and baseline characteristics of a multi-site randomized controlled trial evaluating the effectiveness of a combination of MBRP and peer support (MiMP) compared to an enhanced TSF in improving adherence to MOUD. Both MiMP and TSF are 12-week manualized protocols that utilize licensed therapists. The interventions are delivered in weekly group sessions that last about 75-90 minutes per session. The primary outcome is MOUD adherence. Secondary and exploratory outcomes include relapse, cravings, depression, anxiety, stress, quality of life, and pain catastrophizing., Results: The participants' ages ranged from 21 years to 77 years, with a mean age of 44.5 (SD ± 11.5 years). There was an almost equal distribution of gender and place of residence. Overall, 51.9% (n=54) of participants identified as female and 48.1% (n=50) were male. Similarly, 51.9% (n=54) of participants resided in urban areas, while 48.1% (n=50) resided in rural areas. Participants identified as either black or white, with over three-quarters identifying as white (77.9%, n= 81) and 22.1% (n= 23) as black. Most participants randomized to the 12-step facilitation group were white (93.1%). Relationships and employment status were well distributed between categories. Over half of the participants reported some college or higher education. Over 90% of the participants made less than $75,000 per year. Some participants indicated that they had both public and private health insurance., Discussion and Conclusion: This study is innovative in several ways including combining MBRP and peer support, addressing comorbid mental health issues among individuals with OUD, utilizing manualized protocols, and evaluating of both physiological and self-reported measures in assessing cortisol reactivity as a predictor of relapse and treatment outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mumba, Mugoya, Allen, Glenn, Richman, Ghera, Butler, Rogers, Granger and Davis.)

Introduction: Post-traumatic stress disorder (PTSD) is a psychiatric disorder triggered by exposure to a life-threatening or sexually violent traumatic event, and is characterized by symptoms involving intrusive re-experiencing, persistent avoidance of associated stimuli, emotional and cognitive disturbances, and hyperarousal for long periods after the trauma has occurred. These debilitating symptoms induce occupational and social impairments that contribute to a significant clinical burden for PTSD patients, and substantial socioeconomic costs, reaching approximately $20,000 dollars per individual with PTSD each year in the US. Despite increased translational research focus in the field of PTSD, the development of novel, effective pharmacotherapies for its treatment remains an important unmet clinical need., Observations: In this review, we summarize the evidence implicating dysfunctional activity of the amygdala in the pathophysiology of PTSD. We identify the transient receptor potential canonical (TRPC) ion channels as promising drug targets given their distribution in the amygdala, and evidence from animal studies demonstrating their role in fear response modulation. We discuss the evidence-based pharmacotherapy and psychotherapy treatment approaches for PTSD., Discussion: In view of the prevalence and economic burden associated with PTSD, further investigation is warranted into novel treatment approaches based on our knowledge of the involvement of brain circuitry and the role of the amygdala in PTSD, as well as the potential added value of combined pharmacotherapy and psychotherapy to better manage PTSD symptoms., Competing Interests: MBH has received funding from Boehringer Ingelheim Pharmaceuticals Inc. (BIPI), the US Department of Defense and the US Department of Veteran Affairs. In the past 2 years, LLD has received consulting fees from Otsuka, Signant Health, and Boehringer Ingelheim; research funding or materials from the US Department of Veteran Affairs, Alkermes, Aptinyx, Tonix, US Department of Defense, Social Finance, and Westat; and honorarium from Clinical Care Options. BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. To ensure independent interpretation of clinical study results and enable authors to fulfil their role and obligations under the ICMJE criteria, Boehringer Ingelheim grants all external authors access to clinical study data pertinent to the development of the publication., (Copyright © 2024 Davis and Hamner.)

Background: There is limited research on outcomes of patients with posttraumatic stress disorder (PTSD) who also develop stroke, particularly regarding racial disparities. Our goal was to determine whether PTSD is associated with the risk of hospital readmission after stroke and whether racial disparities existed., Methods: The analytical sample consisted of all veterans receiving care in the Veterans Health Administration who were identified as having a new stroke requiring inpatient admission based on the International Classification of Diseases codes. PTSD and comorbidities were identified using the International Classification of Diseases codes and given the date of first occurrence. The retrospective cohort data were obtained from the Veterans Affairs Corporate Data Warehouse. The main outcome was any readmission to Veterans Health Administration with a stroke diagnosis. The hypothesis that PTSD is associated with readmission after stroke was tested using Cox regression adjusted for patient characteristics including age, sex, race, PTSD, smoking status, alcohol use, and comorbidities treated as time-varying covariates., Results: Our final cohort consisted of 93 651 patients with inpatient stroke diagnosis and no prior Veterans Health Administration codes for stroke starting from 1999 with follow-up through August 6, 2022. Of these patients, 12 916 (13.8%) had comorbid PTSD. Of the final cohort, 16 896 patients (18.0%) with stroke were readmitted. Our fully adjusted model for readmission found an interaction between African American veterans and PTSD with a hazard ratio of 1.09 ([95% CI, 1.00-1.20] P =0.047). In stratified models, PTSD has a significant hazard ratio of 1.10 ([95% CI, 1.02-1.18] P =0.01) for African American but not White veterans (1.05 [95% CI, 0.99-1.11]; P =0.10)., Conclusions: Among African American veterans who experienced stroke, preexisting PTSD was associated with increased risk of readmission, which was not significant among White veterans. This study highlights the need to focus on high-risk groups to reduce readmissions after stroke., Competing Interests: Disclosures Dr Davis reports compensation from Boehringer Ingelheim and Otsuka Pharmaceutical for consultant services. The other authors report no conflicts.

Sleep disturbances in posttraumatic stress disorder (PTSD) are a potential target for improving PTSD severity with pharmacotherapy. TNX-102 SL is a bedtime sublingual formulation of cyclobenzaprine with potent binding and antagonist activity at 5-HT 2A , α 1 -adrenergic, H 1 histaminergic, and M 1 muscarinic receptors, which play roles in the pharmacological management of sleep disturbances. This Phase 3 trial evaluated the efficacy and safety of TNX-102 SL in patients with military-related PTSD. Early and sustained improvements in sleep were associated with TNX-102 SL treatment by PROMIS Sleep Disturbance scale and Clinician Administered PTSD Scale (CAPS-5) "sleep disturbance" item, establishing a sleep quality benefit. Primary analysis comparing change from baseline in CAPS-5 total severity between TNX-102 SL and placebo at week 12 was not significant; however, week 4 was associated with an improvement. Secondary analyses showed TNX-102 SL treatment was associated with benefits on the Clinician Global Impression of Improvement at week 4 and the Patient Global Impression of Change at week 12. Time since trauma exposure was a discriminator of CAPS-5 treatment response in the subgroup ≤ 9 years since the index event. This study provides preliminary evidence that TNX-102 SL is well-tolerated and may promote recovery from PTSD by addressing sleep-related symptoms., Competing Interests: Declaration of competing interest MP consulted with Tonix on the preparation, creation, and presentation of the published work. SL and GMS are employees of Tonix Pharmaceuticals, Inc. (Tonix) and own stock and/or have options in the company. JE is an employee of Tonix and previously consulted on the statistical analyses in the study. BV is the primary statistician consulting for Tonix as an employee of Rho, Inc. LLD has received income as consultant from Otsuka, Lundbeck, Signant Health, and Boehringer Ingelheim and has received research funding or materials from Tonix, Alkermes, Aptinyx, Social Finance, and Westat., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Major depressive disorder (MDD) contributes to suicide risk. Treating MDD effectively is considered a key suicide prevention intervention. Yet many patients with MDD do not respond to their initial medication and require a 'next-step'. The relationship between next-step treatments and suicidal thoughts and behaviors is uncharted., Method: The VA Augmentation and Switching Treatments for Depression trial randomized 1522 participants to one of three next-step treatments: Switching to Bupropion, combining with Bupropion, and augmenting with Aripiprazole. In this secondary analysis, features associated with lifetime suicidal ideation (SI) and attempts (SA) at baseline and current SI during treatment were explored., Results: Compared to those with SI only, those with lifetime SI + SA were more likely to be female, divorced, or separated, unemployed; and to have experienced more childhood adversity. They had a more severe depressive episode and were more likely to respond to 'next-step' treatment. The prevalence of SI decreased from 46.5% (694/1492) at baseline to 21.1% (315/1492) at end-of-treatment. SI during treatment was associated with baseline SI; low positive mental health, more anxiety, greater severity and longer duration of current MDD episode; being male and White; and treatment with S-BUP or C-BUP as compared to A-ARI., Conclusion: SI declines for most patients during next-step medication treatments. But about 1 in 5 experienced emergent or worsening SI during treatment, so vigilance for suicide risk through the entire 12-week acute treatment period is necessary. Treatment selection may affect the risk of SI.

Objective: To assess the journey of individuals from experiencing a traumatic event through onset of symptoms, diagnosis, and treatment of posttraumatic stress disorder (PTSD)., Methods: Patient- and psychiatrist-level data was collected (02/2022-05/2022) from psychiatrists who treated ≥1 civilian adult diagnosed with PTSD. Eligible charts covered civilian adults diagnosed with PTSD (2016-2020), receiving ≥1 PTSD-related treatment (selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], atypical antipsychotics [AAs]), and having ≥1 medical visit in the last 12 months. Collected information included clinical and treatment characteristics surrounding the PTSD diagnosis., Results: A total of 273 psychiatrists contributed data on 687 patients with PTSD (average age 36.1; 60.4% female). On average, the traumatic event and symptom onset occurred 8.7 years and 6.5 years prior to PTSD diagnosis, respectively. In the 6 months before diagnosis, 88.9% of patients had received a PTSD-related treatment. At time of diagnosis, 87.8% of patients had intrusion symptoms and 78.9% had alterations in cognition/mood; 41.2% had depressive disorder and 38.7% had anxiety. Diagnosis prompted treatment changes for 79.3% of patients, receiving treatment within 1.9 months on average, often with a first-line SSRI as either monotherapy (52.8%) or combination (24.9%). At the end of the 24-month study period, 34.4% of patients achieved psychiatrist-recorded remission. A total of 23.0% of psychiatrists expressed dissatisfaction with approved PTSD treatments, with 88.3% at least somewhat likely to prescribe AAs despite lack of FDA approval., Conclusion: PTSD presents heterogeneously, with an extensive journey from trauma to diagnosis with low remission rates and limited treatment options.

Background: Each year about one in five adults experiences mental illness. Although the independent physical and mental health consequences of alcohol misuse and cigarette smoking are well documented, little is known on how substance use moderates the relationship between physical and mental well-being., Aim: The purpose of this study was to examine whether substance use moderates the relationship between physical activity and mental health in adults., Methods: This was a secondary analysis of data provided by the Behavioral Risk Factor Surveillance System (BRFSS)., Results: Participants ( N = 450,016) were adults who completed the BRFSS in 2017. Those who did not drink alcohol had fewer mental health problems when they indicated greater amounts of time spent doing physical activities each week. Last, smokers' number of mental health problems decreased as they engaged in more physical activity, whereas nonsmokers' number of mental health problems increased as they engaged in more physical activity., Conclusions: The relationship between physical activity and mental health outcomes is well established and cannot be overemphasized. Nonetheless, substance abuse can moderate this relationship and should be routinely screened for by health care providers regardless of treatment setting., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Childhood sexual abuse is the leading cause of posttraumatic stress disorder (PTSD) in women, and is a prominent cause of morbidity and loss of function for which limited treatments are available. Understanding the neurobiology of treatment response is important for developing new treatments. The purpose of this study was to assess neural correlates of personalized traumatic memories in women with childhood sexual abuse with and without PTSD, and to assess response to treatment., Methods: Women with childhood sexual abuse with ( N = 28) and without ( N = 17) PTSD underwent brain imaging with High-Resolution Positron Emission Tomography scanning with radiolabeled water for brain blood flow measurements during exposure to personalized traumatic scripts and memory encoding tasks. Women with PTSD were randomized to paroxetine or placebo followed by three months of double-blind treatment and repeat imaging with the same protocol., Results: Women with PTSD showed decreases in areas involved in the Default Mode Network (DMN), a network of brain areas usually active when the brain is at rest, hippocampus and visual processing areas with exposure to traumatic scripts at baseline while women without PTSD showed increased activation in superior frontal gyrus and other areas ( p < 0.005). Treatment of women with PTSD with paroxetine resulted in increased anterior cingulate activation and brain areas involved in the DMN and visual processing with scripts compared to placebo ( p < 0.005)., Conclusion: PTSD related to childhood sexual abuse in women is associated with alterations in brain areas involved in memory and the stress response and treatment with paroxetine results in modulation of these areas., Competing Interests: Declaration of Competing Interest No authors report potential conflicts of interests.

Objective: To describe post-traumatic stress disorder (PTSD)-related symptoms and frequent psychiatric comorbidities, treatments received, healthcare resource utilization (HRU), and healthcare costs pre- and post-PTSD diagnosis among adults in the United States., Methods: Adults with PTSD who received a PTSD-related pharmacological treatment (selective serotonin reuptake inhibitor [SSRI], serotonin-norepinephrine reuptake inhibitor [SNRI], atypical antipsychotic [AA]) within 24 months of the first observed PTSD diagnosis (index date) were identified using MarketScan Commercial Database (2015-2020). Study outcomes were assessed during the 6-month pre-diagnosis and 24-month post-diagnosis periods. Subgroup analyses included patients treated or not treated with AAs post-PTSD diagnosis., Results: Of the overall patients ( N  = 26,306; mean age at diagnosis 39.5 years; 73.3% female), 85.9% had PTSD-related symptoms and frequent psychiatric comorbidities during the 6 months pre-diagnosis. Patients treated with AAs post-PTSD diagnosis ( N  = 9,298) tended to have higher rates of PTSD-related symptoms and comorbidities at diagnosis than those not treated with AAs ( N  = 7,011). Following diagnosis, the most commonly observed first-line treatments were SSRI (67.4%), AA (23.4%), and SNRI (22.6%). The rate of PTSD-related symptoms and comorbidities, psychotherapy and pharmacological treatments received, HRU, and healthcare costs increased during the 6 months post-diagnosis relative to the 6 months pre-diagnosis and then declined over time during the 24 months post-diagnosis., Conclusions: The PTSD diagnosis was associated with increased rates of symptoms and frequent psychiatric comorbidities, psychotherapy and pharmacological treatments received, HRU, and healthcare costs, pointing to increased patient monitoring. Within 6 to 12 months after the PTSD diagnosis, these outcomes tended to reduce, perhaps as patients were obtaining targeted and effective care.

Background: Effective pharmacologic treatments for comorbid alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD) are lacking. Kappa (κ) opioid receptor antagonists may address this unmet need. Buprenorphine is a κ-opioid antagonist and a partial agonist of mu (μ) opioid receptors. Whereas naltrexone blocks all μ-mediated effects combining it with buprenorphine yields a pharmacologic net effect of opioid receptor antagonism. Because no κ-opioid receptor antagonist it available for clinical use, we tested this combination in a proof-of-concept study., Methods: Consenting participants were enrolled in a Phase II, multisite, double-blind, randomized, placebo-controlled trial evaluating the effectiveness of sublingual (SL) buprenorphine combined with extended-release (XR) injectable naltrexone for the treatment of comorbid AUD and PTSD. Eligible participants (n = 75) were randomized (1:1:1) to receive either buprenorphine 2 mg/day plus naltrexone-XR (n = 35), buprenorphine 8 mg/day plus naltrexone-XR (n = 6) or SL plus injectable placebo (n = 34) for 12 weeks. The buprenorphine 8 mg/day plus naltrexone-XR arm was dropped early in the trial due to the negative impact of COVID-19 on enrollment. A binary primary outcome of response at week 8 was defined as a decrease from baseline of ≥10 points on the past week Clinician-Administered PTSD Scale (CAPS-5) and a reduction of ≥1 of past month alcohol risk level, as defined by the World Health Organization (WHO) and measured by the Timeline Follow-Back., Results: Based on the results of a futility analysis, enrollment was stopped prior to reaching the initial goal of 90 participants. At the week eight primary timepoint, there were no statistically significant differences between buprenorphine plus naltrexone-XR and placebo group for the primary composite outcome (OR = 0.63; p-value = 0.52), or the subcomponents of the PTSD outcome (OR = 0.76; p-value = 0.69) and AUD outcome (OR = 0.17; p-value = 0.08). The placebo arm had a significantly higher proportion of participants with ≥1 WHO risk level reduction than the buprenorphine plus naltrexone-XR arm (OR = 0.18, p value = 0.02)., Conclusions: This is the first study to evaluate the potential of κ-opioid receptor antagonism for the treatment of comorbid AUD and PTSD. The combination of buprenorphine and naltrexone-XR showed no significant improvement over placebo for the composite, PTSD, or alcohol measures., (© 2023 The Authors. Alcohol: Clinical and Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcohol. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Complementary integrative medicine, such as mindfulness-based interventions, (MBI) have demonstrated efficacy in the treatment of depression, anxiety, substance use disorders (SUDs), and pain. Mindfulness-based relapse prevention (MBRP) is an aftercare intervention targeting SUD relapse that integrates cognitive-behavioral relapse prevention and mindfulness meditation practices, raising awareness of substance use triggers and reactive behavioral patterns. This study evaluated the efficacy of MBRP in reducing relapse in veterans following completion of an SUD treatment program., Methods: This study was a two-site, randomized controlled trial comparing MBRP to 12-step facilitation (TSF) aftercare in military veterans following completion of intensive treatment for SUDs. The 8 weeks of 90-minute, group-based MBRP or TSF sessions were followed by 3-, 6- and 10-month follow-up periods with assessments of alcohol/substance use and secondary outcomes of depression, anxiety, and mindfulness., Results: Forty-seven percent of veterans attended ≥75 % of sessions. Veterans in both the MBRP and TSF aftercare groups maintained reductions in alcohol and illicit substance use during the aftercare treatment. Nineteen participants (11 %; 19/174) reported returning to alcohol use during the study treatment period and the study found no difference between study groups [MBRP: 9 % vs. TSF 13 %; p = 0.42]. Thirteen participants (7.5 %; 13/174) reported a return to illicit substance use during study treatment [MBRP: 5.4 % vs. TSF 10.3 % p = 0.34]. The number of days of drinking and illicit substance use was not different between groups (alcohol, p = 0.53; illicit substance use, p = 0.28)., Conclusion: Although retention in treatment limits interpretation of the findings, both MBRP and TSF were effective in maintenance of treatment gains following an intensive treatment program for veterans with SUDs. Future studies should focus on strategies to improve treatment participation., Competing Interests: Declaration of competing interest The authors have no conflicts of interest. Sarah Bowen is the developer of manualized therapy and author of “Mindfulness Based Relapse Prevention: A clinician's guide.”, (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: In this secondary analysis of the VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) study we used antidepressant response trajectories to assess the association of treatment and multiple clinical/demographic factors with the probability of response., Methods: Using data from VAST-D, a multi-site, randomized, single-blind trial with parallel-assignment to one of three treatment interventions in 1522 Veterans whose major depressive disorder was unresponsive to at least one antidepressant trial, we evaluated response patterns using group-based trajectory modeling (GBTM). A weighted multinomial logistic regression analysis with backward elimination and additional exploratory analyses were performed to evaluate the association of multiple clinical/demographic factors with the probability of inclusion into specific trajectories. Additional exploratory analyses were used to identify factors associated with trajectory group membership that could have been missed in the primary analysis., Results: GBTM showed the best fit for depression symptom change was comprised of six trajectories, with some trajectories demonstrating minimal improvement and others showing a high probability of remission. High baseline depression and anxiety severity scores decreased, and early improvement increased, the likelihood of inclusion into the most responsive trajectory in both the GBTM and exploratory analyses., Conclusion: While multiple factors influence responsiveness, the probability of inclusion into a specific depression symptom trajectory is most strongly influenced by three factors: baseline depression, baseline anxiety, and the presence of early improvement., (© 2023 The Authors. Psychiatric Research and Clinical Practice published by Wiley Periodicals LLC on behalf of American Psychiatric Association.)

Stimulant use disorders are emerging as a serious global threat to health. Although research, clinical, and policy efforts have largely concentrated on opioid use disorders over the past decade, exponential rises in prevalence and overdose deaths attributable to stimulant use disorders warrant renewed attention. To date, no approved medications are available to treat stimulant use disorders; however, behavioral interventions have been effective and should be proactively promoted. Similarly, complementary and integrative therapies and harm reduction services have emerging evidence for effectiveness in treating these conditions. Research, practice, and policy interventions should address stigma for medications for stimulant use disorders when available, vaccine hesitancy if vaccines are approved and safe, environmental surveillance to reduce population exposure to toxic effects of methamphetamines, and educational interventions for health providers to increase competency to reduce the long-term effects on various body systems. [ Journal of Psychosocial Nursing and Mental Health Services, 61 (3), 13-18.].

Objective: Among veterans with posttraumatic stress disorder (PTSD), supported employment that utilizes the individual placement and support (IPS) model has resulted in consistently better employment and functional outcomes than usual vocational rehabilitation services. This study aimed to compare these two approaches in terms of health services use and associated costs., Methods: A secondary analysis of a multisite randomized controlled trial of 541 unemployed veterans with PTSD used archival data from electronic medical records to assess the use and costs of health services of IPS and usual care (i.e., a transitional work [TW] program) over 18 months. Comparisons were also made to an 18-month postintervention period., Results: The two study groups did not differ in number of inpatient days or in utilization or cost of high-intensity services. Annual per-person costs of health services were approximately 20% higher for IPS than for TW participants (mean difference=$4,910 per person per year, p<0.05) during the intervention period, largely driven by higher utilization and costs for vocational services in the IPS group (p<0.001). These costs declined postintervention to nonsignificant differences. The mean annual per-person vocational service cost was $6,388 for IPS and $2,549 for TW (mean difference=$3,839, p<0.001) during the intervention period., Conclusions: In keeping with IPS’s intensive case management approach, veterans receiving IPS used more vocational services and had correspondingly higher costs than veterans receiving TW. The two groups did not differ in use or cost of other types of health services. Future research should examine whether higher short-term costs associated with IPS relative to usual care result in long-term cost savings or higher quality of life for persons with PTSD.

Objectives: This study evaluates the effects of treatment with mindfulness-based stress reduction (MBSR) compared to the active control, present-centered group therapy (PCGT), on morning plasma cortisol, interleukin-6 (IL-6), and C-reactive protein (CRP) in veterans diagnosed with post-traumatic stress disorder (PTSD)., Methods: In a post hoc exploratory analysis, we pooled biomarkers and clinical outcomes of mindfulness, PTSD, and depression from two randomized controlled trials comparing MBSR ( n = 104) to PCGT ( n = 106) in U.S. military veterans diagnosed with PTSD. Linear mixed-effects modeling was used to evaluate associations between changes in biomarkers and clinical outcomes from baseline to 9-week primary endpoint and 16-week follow-up endpoint., Results: Cortisol levels were inversely related to self-reported PTSD symptoms at baseline ( p = 0.02). Cortisol increased from baseline to 9-week endpoint for both groups, but significantly less so in the MBSR group compared to PCGT group (mean difference 1.69 ± 0.8 SE; p = 0.035). Changes in IL-6 and CRP did not differ between groups at either baseline or week 9. From baseline to week 9, increased mindfulness was significantly associated with increased cortisol ( p = 0.02) and decreased PTSD and depression severity ( p < 0.01). Increased IL-6 and CRP were significantly associated with decreased PTSD severity ( p < 0.05), but not depression. Pooled analysis corroborated earlier findings that MBSR is significantly better than PCGT in improving clinical outcomes. Increased mindfulness was strongly associated with improved symptoms., Conclusions: Increased mindfulness is associated with a recalibration of cortisol levels which may be indicative of therapeutic response, especially in patients with lower baseline cortisol. Furthermore, mindfulness-based practices improve symptoms of PTSD and depression in a significant correlation with self-reported levels of mindfulness., Clinical Trial Registration Clinicaltrialsgov: NCT01532999 and NCT01548742., Competing Interests: Conflict of Interest The authors declare no competing interests.

Background: The proportion of patients with post-traumatic stress disorder (PTSD) that remain undiagnosed may be substantial. Without an accurate diagnosis, these patients may lack PTSD-targeted treatments and experience adverse health outcomes. This study used a machine learning approach to identify and describe civilian patients likely to have undiagnosed PTSD in the US commercial population., Methods: The IBM® MarketScan® Commercial Subset (10/01/2015-12/31/2018) was used. A random forest machine learning model was developed and trained to differentiate between patients with and without PTSD using non-trauma-based features. The model was applied to patients for whom PTSD status could not be confirmed to identify individuals likely and unlikely to have undiagnosed PTSD. Patient characteristics, symptoms and complications potentially related to PTSD, treatments received, healthcare costs, and healthcare resource utilization were described separately for patients with PTSD (Actual Positive PTSD cohort), patients likely to have PTSD (Likely PTSD cohort), and patients without PTSD (Without PTSD cohort)., Results: A total of 44,342 patients were classified in the Actual Positive PTSD cohort, 5683 in the Likely PTSD cohort, and 2,074,471 in the Without PTSD cohort. While several symptoms/comorbidities were similar between the Actual Positive and Likely PTSD cohorts, others, including depression and anxiety disorders, suicidal thoughts/actions, and substance use, were more common in the Likely PTSD cohort, suggesting that certain symptoms may be exacerbated among those without a formal diagnosis. Mean per-patient-per-6-month healthcare costs were similar between the Actual Positive and Likely PTSD cohorts ($11,156 and $11,723) and were higher than those of the Without PTSD cohort ($3616); however, cost drivers differed between cohorts, with the Likely PTSD cohort experiencing more inpatient admissions and less outpatient visits than the Actual Positive PTSD cohort., Conclusions: These findings suggest that the lack of a PTSD diagnosis and targeted management of PTSD may result in a greater burden among undiagnosed patients and highlights the need for increased awareness of PTSD in clinical practice and among the civilian population., (© 2022. The Author(s).)

Transitioning from military service is stressful for veterans with service-connected disabilities seeking civilian employment. This descriptive study examined self-assessed mental health, well-being, and substance use of men and women shortly before or after transition from US military service, compared to norms from community and military samples. As part of a prospective study evaluating an innovative employment program, researchers interviewed 229 current and former service members with service-connected disabilities transitioning from U.S. military service. Compared to published norms, respondents reported significantly poorer outcomes on 5 of 6 standardized measures, indicating less life satisfaction, poorer mental health, more symptoms of depression and posttraumatic stress disorder, and greater financial distress. In the previous year, 42% were prescribed opioid medications, over twice the annual opioid prescription rate of 19% in the general US population. Systematic strategies are needed to ensure access for transitioning veterans with serious behavioral health issues to appropriate evidence-based practices., (© 2021. The Author(s).)

Objectives: Mental health issues can cause serious problems in occupational functioning, including higher rates of unemployment. Individual placement and support (IPS) is an evidence-based supported employment intervention that is typically integrated within a mental health setting; however, many primary care patients view referral to a mental health clinic as stigmatizing. Thus, this study examined whether delivery of IPS in a primary care setting provides an effective treatment option and avoids unnecessary delays in obtaining competitive employment., Methods: U.S. military veterans (N=119) who had a diagnosis in a broad range of nonpsychotic psychiatric disorders and who were receiving care from Veterans Health Administration (VHA) patient-aligned care teams were prospectively randomly assigned to IPS (N=58) or standard VHA non-IPS vocational rehabilitation (VR) (N=61). The primary outcome was achievement of steady worker status, defined as holding a competitive job for ≥6 months of the 12-month follow-up., Results: As hypothesized, a significantly greater proportion of IPS participants achieved steady worker status (45%), compared with VR participants (25%) (p=0.02; odds ratio=2.49, 95% confidence interval=1.14-5.43). On average, the IPS participants worked significantly more weeks (p=0.003) and earned significantly more income (p=0.033) from competitive jobs, compared with VR participants., Conclusions: The results provide supporting evidence for offering IPS within primary care with the aim of restoring meaningful and sustained competitive employment for veterans living with a mental disorder. Such modifications could improve veterans' vocational outcomes, moving a significantly greater number of disabled veterans back to full and productive lives in the community.

Abstract: Military personnel face numerous challenges transitioning from military jobs to meaningful civilian employment. The Independence Project compared an innovative employment program (National Career Coach Program) with standard employment services (Local Community Resources) in a randomized controlled trial. Study participants were transitioning veterans with self-reported service-connected disabilities seeking permanent employment. The primary outcomes were paid employment and disability ratings over 1 year. Secondary outcomes included health and well-being. At 1-year follow-up, National Career Coach Program participants were significantly more likely to work, had significantly greater earnings, and reported significantly greater improvements in physical and mental health compared with participants assigned to Local Community Resources. Both groups increased in disability ratings over 12 months, with no difference between groups. Multifaceted supports delivered by the National Career Coach Program increased employment, earnings, mental health, and physical health over 1 year. These significant differences appeared even though control group participants achieved considerable employment success., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Examine how specific types of childhood adversity are associated with clinical features and treatment in adults with Major Depressive Disorder (MDD)., Method: This is a secondary analysis of the 35-site VA Augmentation and Switching Treatments for Improving Depression Outcomes study. A 10-item Adverse Childhood Events (ACE) survey was administered at baseline., Results: 83% experienced at least one of the 10 ACEs and 20.7% experienced 6 or more. Participants with childhood adversities were more likely to be younger, female, unemployed, single or divorced, and to have had more severe depression and anxiety, more lifetime episodes, a younger age of first diagnosed MDD, more comorbid PTSD, worse quality of life, and more suicidal ideation than those no or fewer adversities. Neither the overall number nor any of the specific types of adversities were associated with lower remission rates after administration of standard "next-step" treatment strategies, while histories of different specific types were associated with lower depression severity, better quality of life, and less suicidal ideation post-treatment., Conclusions: Attention to different forms of childhood adversity and to diverse clinical outcomes beyond remission and relapse are important considerations when treating individuals with MDD with histories of childhood maltreatment., Clinicaltrials: gov identifier: NCT01421342., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Post-traumatic stress disorder (PTSD) leads to significant disability, unemployment, and substantial healthcare costs. The cost-effectiveness of vocational rehabilitation (VR) interventions is important to consider when determining which services to offer. This study assesses the cost-effectiveness and return on investment of Individual Placement and Support (IPS) compared to transitional work (TW) programs. Employment outcomes from a multisite randomized trial comparing IPS to TW in military veterans with PTSD (n = 541) were linked to Veterans Health Administration (VHA) archival medical record databases to examine the comparative cost-effectiveness and return on investment. Effectiveness was defined as hours worked and income earned in competitive jobs. Costs for VR, mental health, and medical care and income earned from competitive sources were annualized and adjusted to 2019 US dollars. The annualized mean cost per person of outpatient (including vocational services) were $3970 higher for IPS compared to TW ($23,245 vs. $19,276, respectively; P = 0.004). When TW income was included in costs, mean grand total costs per person per year were similar between groups ($29,828 IPS vs. $26,772 TW; P = 0.17). The incremental cost-effectiveness analysis showed that while IPS is more costly, it is also more effective. The return on investment (excluding TW income) was 32.9% for IPS ($9762 mean income/$29,691 mean total costs) and 29.6% for TW ($7326 mean income/$24,781 mean total costs). IPS significantly improves employment outcomes for individuals with PTSD with negligible increase in healthcare costs and yields very good return on investment compared to non-IPS VR services., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Objective: To estimate the economic burden of posttraumatic stress disorder (PTSD) in the United States civilian and military populations from a societal perspective., Methods: A prevalence-based and human capital approach was used to estimate the total excess costs of PTSD in 2018 from insurance claims data, academic literature, and governmental publications. Excess direct health care costs (pharmacy, medical), direct non-health care costs (research and training, substance use, psychotherapy, homelessness, disability), and indirect costs (unemployment, productivity loss, caregiving, premature mortality) associated with PTSD were compared between adults with PTSD and adults without PTSD, or the general population if information was not available for adults without PTSD., Results: The total excess economic burden of PTSD in the US was estimated at $232.2 billion for 2018 ($19,630 per individual with PTSD). Total excess costs were $189.5 billion (81.6%) in the civilian population and $42.7 billion (18.4%) in the military population, corresponding to $18,640 and $25,684 per individual with PTSD in the civilian and military populations, respectively. In the civilian population, the excess burden was driven by direct health care ($66.0 billion) and unemployment ($42.7 billion) costs. In the military population, the excess burden was driven by disability ($17.8 billion) and direct health care ($10.1 billion) costs., Conclusions: The economic burden of PTSD goes beyond direct health care costs and has been found to rival costs for other costly mental health conditions. Increased awareness of PTSD, development of more effective therapies, and expansion of evidence-based interventions may be warranted to reduce the large clinical and economic burden of PTSD., (© Copyright 2022 Physicians Postgraduate Press, Inc.)

In 2021, drug overdose deaths exceeded 100,000 for the first time in U.S. history, mostly attributable to opioid overdoses. Medications for opioid use disorders are considered the gold standard for treatment; however, treatment initiation and adherence remain a challenge. Mindfulness-based interventions show efficacy for substance use disorders, and peer support has been shown to improve treatment outcomes. The purpose of the current study was to examine the feasibility and acceptability of the Minds and Mentors Program. Enrollment, randomization, and retention rates were 36%, 49%, and 57%, respectively. Client satisfaction scores ranged from 84.4% to 100%. Approximately 64% of participants attended 10 of 12 treatment sessions, representing treatment adherence. Qualitative analysis revealed four main domains: Permission to Be Honest and Open , Applicability for Everyday Life , Hope Restored , and Changing the Way I Think . [ Journal of Psychosocial Nursing and Mental Health Services, 60 (3), 11-14.].

Objective: This study synthesized evidence regarding the prevalence of post-traumatic stress disorder (PTSD) in the United States (US)., Methods: A systematic literature review (SLR) identified recently published (2015-2019) observational studies of PTSD prevalence in the US via the MEDLINE, EMBASE, and PsycINFO databases. Eligible studies' most recent data were collected no earlier than 2013. Data elements extracted included study design, sample size, location, data source/year(s), study population(s), traumatic event type, prevalance estimates with corresponding look-back periods, and clinical metrics., Results: Data from 38 identified articles were categorized by population, diagnostic criteria, and lookback period. Among civilians, point prevalence ranged from 8.0% to 56.7%, 1-year prevalence from 2.3% to 9.1%, and lifetime prevalence from 3.4% to 26.9%. In military populations, point prevalence ranged from 1.2% to 87.5%, 1-year prevalence from 6.7% to 50.2%, and lifetime prevalence from 7.7% to 17.0%. Within these ranges, several estimates were derived from relatively high quality data; these articles are highlighted in the review. Prevalence was elevated in subpopulations including emergency responders, refugees, American Indian/Alaska Natives, individuals with heavy substance use, individuals with a past suicide attempt, trans-masculine individuals, and women with prior military sexual trauma. Female sex, lower income, younger age, and behavioral health conditions were identified as risk factors for PTSD., Conclusions: PTSD prevalence estimates varied widely, partly due to different study designs, populations, and methodologies, and recent nationally representative estimates were lacking. Efforts to increase PTSD screening and improve disease awareness may allow for a better detection and management of PTSD.

There are currently no validated pharmacotherapies for posttraumatic stress disorder (PTSD)-related insomnia. The purpose of the National Adaptive Trial for PTSD-Related Insomnia (NAP Study) is to efficiently compare to placebo the effects of three insomnia medications with different mechanisms of action that are already prescribed widely to veterans diagnosed with PTSD within U.S. Department of Veterans Affairs (VA) Medical Centers. This study plans to enroll 1224 patients from 34 VA Medical Centers into a 12- week prospective, randomized placebo-controlled clinical trial comparing trazodone, eszopiclone, and gabapentin. The primary outcome measure is insomnia, assessed with the Insomnia Severity Index. A novel aspect of this study is its adaptive design. At the recruitment midpoint, an interim analysis will be conducted to inform a decision to close recruitment to any "futile" arms (i.e. arms where further recruitment is very unlikely to yield a significant result) while maintaining the overall study recruitment target. This step could result in the enrichment of the remaining study arms, enhancing statistical power for the remaining comparisons to placebo. This study will also explore clinical, actigraphic, and biochemical predictors of treatment response that may guide future biomarker development. Lastly, due to the COVID-19 pandemic, this study will allow the consenting process and follow-up visits to be conducted via video or phone contact if in-person meetings are not possible. Overall, this study aims to identify at least one effective pharmacotherapy for PTSD-related insomnia, and, perhaps, to generate definitive negative data to reduce the use of ineffective insomnia medications. NATIONAL CLINICAL TRIAL (NCT) IDENTIFIED NUMBER: NCT03668041., (Published by Elsevier Inc.)

Abstract: Substance use treatment inequities among rural populations are well documented and the COVID-19 pandemic has exacerbated these inequalities, forcing healthcare providers to be creative in the delivery of treatment. Systematic reviews on the use of telehealth to treat patients with substance use disorder indicate that it is a promising alternative to in-person services. This article examines the evidence supporting the use of telehealth in treating patients with opioid use disorder and explores other promising options that can help overcome pandemic-related barriers to treatment., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

International Society for CNS Clinical Trials and Methodology convened an expert Working Group that assembled consistency/inconsistency flags for the Personal and Social Performance Scale (PSP). One hundred and forty seven flags were identified, 16 flag errors in deriving the PSP decile (i.e., total) score from the four individual domain scores, 74 flag inconsistencies between domain scores relative to Positive and Negative Symptom Scale (PANSS) item ratings and 57 flag inconsistencies between PSP decile score and PANSS items ratings. The flags were applied to assessments from randomized clinical trial data of antipsychotics in schizophrenia from almost 18,000 ratings. Twenty-two flags were raised in at least 5 of 1000 ratings. Nearly 20% of the PSP ratings had at least one inconsistency flag raised. Application of flags to clinical ratings may improve the reliability of ratings and validity of trials., Competing Interests: Declaration of competing interest Jonathan Rabinowitz has received research grant(s) support and/or travel support and/or speaker fees and/or consultant fees from Janssen Research and Development (J&J), Eli Lilly and Company, Pfizer, Lundbeck, Roche, Abraham Pharmaceuticals, Pierre Fabre, Intra-cellular Therapies, Minerva Foundation, Takeda and Amgen. Mark Opler is an employee and shareholder of WCG MedAvante-ProPhase Inc. and has received grant funding from Stanley Foundation, QNRF, and NIH. Alon A. Rabinowitz has no conflicts of interest to disclose. Selam Negash is an employee of WCG – MedAvante-ProPhase. Ariana Anderson has received grants or contracts from Janssen Research and Development and BlackThorn Therapeutics. Dong-Jing Fu is an employee of Janssen Research & Development, LLC and a stockholder of Johnson & Johnson. David Williamson is an employee of Janssen Scientific Affairs, LLC and a stockholder of Johnson & Johnson. Alan Kott is a Full time Employee of Signant Health, LLC. Lori L. Davis reports consulting income from Lundbeck, Otsuka, Janssen and research support from Alkermes, Aptinyx, Tonix. Nina R. Schooler has received honoraria and travel support for attendance at advisory board meetings or consultation from Alkermes, GW Pharmaceuticals, Intracellular Therapies, Lundbeck and Otsuka. She has received grant support from Otskua., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: The aim of this study was to determine the efficacy of mirtazapine, a tetracyclic antidepressant, as monotherapy for the treatment of posttraumatic stress disorder (PTSD)., Methods: This multisite, randomized, double-blind, placebo-controlled trial was conducted between April 2006 and November 2010 at the Tuscaloosa and Birmingham Veterans Affairs Medical Centers in Alabama. US military veterans who met DSM-IV criteria for PTSD were randomly assigned to placebo (n = 39) or mirtazapine (n = 39) titrated up to 45 mg/d for an 8-week double-blind period followed by an 8-week open-label phase of mirtazapine treatment. The primary outcome efficacy measure was the Structured Interview for Posttraumatic Stress Disorder (SIP). Secondary measures included other measures of PTSD, depression, and sleep. Analyses of treatment groups involved mixed-model procedures using a random intercept to test the hypotheses that mirtazapine would be more effective than placebo in reducing symptoms of PTSD and depression and improving quality of sleep., Results: Seventy-eight participants were randomized with 61 completing the 8-week controlled phase and 48 completing the open-label phase. No significant differences were observed between groups on the primary outcome of SIP scores during the controlled phase (P = .418). In secondary outcomes, significant improvements per the Clinical Global Impressions-Improvement scale were found for the mirtazapine group compared to the placebo group (P = .041). The 8-week open-label phase demonstrated significant symptom improvement in SIP total score (P = .0003) and in scores on the SIP re-experiencing (P = .0007), avoidance (P = .0309), and hyperarousal (P = .0014) subscales. There were no significant differences in the occurrence of adverse events between groups., Conclusions: This study did not show efficacy of mirtazapine monotherapy in the treatment of PTSD. Identification of more effective treatments, either as monotherapy or adjunctive, for PTSD is imperative., Trial Registration: ClinicalTrials.gov identifier: NCT00302107., (© Copyright 2020 Physicians Postgraduate Press, Inc.)

Background: This article describes the design and baseline sample of a single-site trial comparing Individual Placement and Support (IPS) supported employment delivered within a Veterans Health Administration (VHA) primary care Patient Aligned Care Team (PACT) to treatment-as-usual vocational rehabilitation (TAU-VR) that includes transitional work., Methods: Unemployed U.S. military veterans receiving care in a VHA PACT who were seeking competitive work, otherwise eligible for vocational rehabilitation, and diagnosed with a mental health condition other than a psychotic or bipolar I disorder were prospectively randomized to receive either IPS or TAU-VR. Employment outcomes and measures of quality of life, self-esteem, and community reintegration are being collected for 12 months., Results: The participant sample (n = 119) is comprised of 17.6% female, 73.1% African-Americans, and 1.7% Hispanic. Average age is 38.2 (SD ± 8.41) years; 80.7% served in the military since 2001; 78% are receiving or applying for U.S. Department of Veterans Affairs (VA) service-connected disability; 26.9% have not held a competitive job in the past 3 years; and the average length of pre-randomization unemployment is 1.4 (SD ± 2.3) years., Conclusions: Unique design features include evaluating the efficacy of evidenced-based IPS within the primary care setting, having broad diagnostic eligibility, and defining the primary outcome criterion as "steady employment", i.e. holding a competitive job for ≥26 weeks of the 12-month follow-up period. The findings illustrate the characteristics of a primary care veteran sample in need of employment services., Trial Registration: www.clinicaltrials.gov Identifier: NCT02400736.

The Montreal Cognitive Assessment (MoCA) is a free, easily accessible screener ideal for rural areas where resources are limited. We examined administration and scoring by Veteran Community Outreach Health Workers (VCOHWs); compared positive screening rates using two cutoff scores; and examined predictors of education-adjusted scores in N = 168 rural military Veterans from the Alabama Veteran Rural Health Initiative. Accuracy of administration (95 percent) and scoring (68 percent) was calculated and recommendations are offered. Higher than expected rates of positive screens were observed (40 percent using 24/30 cutoff) in this relatively young (M = 55 years) community-dwelling sample. Age, education, and race but not subjective health predicted differences in domain and total education-adjusted scores on multivariate and univariate tests. This study advances social science research in rural communities by being the first to: (1) examine MoCA scores in a rural, Deep South U.S. sample; and (2) report fidelity administration data for VCOHWs., Competing Interests: DISCLOSURE STATEMENT No potential conflict of interest was reported by the authors.

Objective: In this secondary analysis of data from the Veterans Affairs Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) study, the authors sought to determine the effectiveness of early improvement (or lack thereof) for predicting remission from depression with antidepressant therapy., Methods: This study used data from the VAST-D study, a multisite, randomized, single-blind trial with parallel assignment to one of three medication interventions for 1,522 veterans whose major depressive disorder was unresponsive to at least one course of antidepressant treatment meeting minimal standards for dosage and duration. The authors calculated the positive predictive value (PPV) and negative predictive value (NPV) of early improvement on remission, response, or greater than minimal improvement from depression for various degrees of improvement (10%-50%) on the Quick Inventory of Depressive Symptomatology-Clinician Rated (QIDS-C) at 1, 2, 4, and 6 weeks., Results: The end of week 2 of treatment was identified as the best time to evaluate early improvement. The presence of a ≥20% drop from the baseline QIDS-C score by the end of week 2 resulted in a PPV for remission of 38% and an NPV of 93% by week 12. Extending the observational window to week 6 minimally improved NPV (97%). This association did not differ across treatment groups., Conclusions: A lack of early improvement at the end of week 2 of antidepressant therapy can be used to inform clinical decisions on the likelihood of nonremission of depression during the subsequent 10 weeks, even when dosage optimization is incomplete., (© 2019 American Psychiatric Association.)

Objective: Posttraumatic stress disorder (PTSD) is often difficult to treat, and many patients do not achieve full remission. Complementary and integrative health approaches, such as mindfulness meditation, are intended to be integrated with evidence-based treatment. This study examined the efficacy of mindfulness-based stress reduction (MBSR) in the treatment of PTSD in U.S. military veterans., Methods: Veterans with a diagnosis of PTSD (N=214) were randomly assigned to either 90-minute group MBSR or present-centered group therapy (PCGT) for eight weeks. Follow-up assessments were obtained at baseline and weeks 3, 6, 9 (primary endpoint), and 16., Results: Both the MBSR and PCGT groups achieved significant improvement in PTSD as measured by the Clinician-Administered PTSD Scale for DSM-IV (CAPS-IV), with no statistically significant differences between groups. However, compared with PCGT, the MBSR group showed a statistically significant improvement in PTSD on the self-reported PTSD Checklist for DSM-IV over the nine weeks. This difference was not maintained posttreatment, at week 16. Strengths of the study include its large sample size, multisite design, active control group, single-blind outcome ratings, fidelity monitoring, large minority representation, and randomized approach. The study was limited by its high attrition rate and low representation of women., Conclusion: Both MBSR and PCGT appear to have beneficial effects in treating PTSD in veterans, with greater improvement observed in self-reported PTSD symptoms in the MBSR group. No differences between groups were observed on the CAPS-IV scale.

Objective: Posttraumatic stress disorder (PTSD) has significant negative effects on occupational, interpersonal, and social functioning. Supported employment is highly effective in helping people with a diagnosis of PTSD obtain and maintain competitive employment. However, less is known about the impact of supported employment on functioning in work or school, social, and interpersonal areas as specifically related to the symptoms of PTSD., Method: The Veterans Individual Placement and Support Toward Advancing Recovery study was a prospective, multisite, randomized, controlled trial that compared Individual Placement and Support (IPS) supported employment with a stepwise vocational rehabilitation involving transitional work (TW) assignments with unemployed veterans with PTSD diagnoses (n = 541) at 12 Veterans Administration (VA) medical centers. This analysis focuses on the PTSD-related functional outcomes over the 18-month follow-up period., Results: Compared with those randomized to TW, the PTSD Related Functioning Inventory (PRFI) total score significantly improved for participants randomized to IPS (LSMeans difference = -3.92, 95% CI [-7.49, -.36]; p = .03) over 18 months. When the Work/School subscale of the PRFI was removed from the analysis, the IPS group continued to show significant improvements compared with the TW group on the PRFI relationship and lifestyle domains (LSMeans difference = -2.37, 95% CI [-4.74, .00]; p = .05), suggesting a positive impact of IPS beyond work/school functioning., Conclusion: Compared with the usual-care VA vocational services for veterans with PTSD, IPS supported employment is associated with greater improvement in overall PTSD-related functioning, including occupational, interpersonal, and lifestyle domains. In addition to superior employment outcomes, IPS has a positive impact on occupational-psychosocial functioning outcomes. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Objective: Transitional work (TW) for veterans with psychiatric disabilities is the predominant model of vocational rehabilitation in the Veterans Health Administration (VA). Although, on average, TW employment outcomes have been demonstrated to be inferior to supported employment, little is known about the potential subgroup of veterans for which TW may be most effective. This study of veterans with posttraumatic stress disorder (PTSD) examines differences in competitive employment outcomes and identifies characteristics of veterans who chose to engage in TW compared with those who did not., Method: A post hoc comparative subgroup analysis of veterans with PTSD randomly assigned to TW as part of a randomized controlled trial was conducted. Veterans were divided into 2 subgroups: those who engaged in TW (n = 141) and nonengagers (n = 129). Differences in baseline characteristics were examined and 18-month employment outcomes were compared., Results: There were no differences in 18-month employment outcomes between TW engagers and nonengagers. Compared with TW engagers, those that did not engage in TW were 2.5 times more likely to get a competitive job within the first 6 months and were less likely to obtain lower skilled jobs. Younger age, adequate housing, personal means of transportation, and recent work history factor into the odds of gaining and maintaining competitive work., Conclusions and Implications for Practice: Consistent with past research, engagement in TW did not result in improved long-term competitive employment outcomes for veterans with PTSD. Those who did not engage in TW were more likely to gain a competitive job within the first 6 months. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Adults who complete an advance directive (AD) are not consistently offered information about the risks, benefits, or alternatives (RBA) of the life-sustaining medical procedures addressed on standardized forms. The current article describes a new patient-centered nurse-supported advance care planning (NSACP) intervention focused on providing information about RBA of life-sustaining procedures. Fifty participants (mean age = 50.26 years) at a Veterans Affairs medical center were randomized to the NSACP intervention or a comparison condition. Before randomization, 78% (n = 39) expressed interest in RBA information. Of participants in the NSACP group, 94% (n = 30) completed an AD. Participants who received NSACP made more decisions to decline life-sustaining treatment than those who were randomized to the comparison group. Promising feasibility data include brevity (mean = 46 minutes), high patient satisfaction, participant retention, and treatment fidelity. The NSACP holds promise as a brief, educational intervention to support patients in completing an AD. [Journal of Gerontological Nursing, 44(7), 31-42.]., (Copyright 2018, SLACK Incorporated.)

Importance: Posttraumatic stress disorder (PTSD) often interferes with a person's ability to obtain or sustain employment, which leads to premature exit from the labor force and reduced income., Objective: To determine whether individual placement and support (IPS)-supported employment is more effective than stepwise vocational rehabilitation involving transitional work assignments at helping veterans with PTSD attain steady, competitive employment., Design, Setting, and Participants: The Veterans Individual Placement and Support Toward Advancing Recovery (VIP-STAR) study was a prospective, multisite, randomized clinical trial that included 541 unemployed veterans with PTSD at 12 Veterans Affairs medical centers. Data were collected from December 23, 2013, to May 3, 2017. Intent-to-treat analysis was performed., Interventions: Individual placement and support is a supported employment intervention that rapidly engages people with disabilities in community job development to obtain work based on their individual job preferences. Transitional work is a stepwise vocational rehabilitation intervention that assigns people temporarily to noncompetitive jobs as preparation for competitive employment in the community., Main Outcomes and Measures: A priori hypotheses were that, compared with those in transitional work, more participants in the IPS group would become steady workers (primary) and earn more income from competitive jobs (secondary) over 18 months. Steady worker was defined as holding a competitive job for at least 50% of the 18-month follow-up period., Results: A total of 541 participants (n = 271 IPS; n = 270 transitional work) were randomized. Mean (SD) age was 42.2 (11) years; 99 (18.3%) were women, 274 (50.6%) were white, 225 (41.6%) were African American, and 90 (16.6%) were of Hispanic, Spanish, or Latino ethnicity. More participants in the IPS group achieved steady employment than in the transitional work group (105 [38.7%] vs 63 [23.3%]; odds ratio, 2.14; 95% CI, 1.46-3.14). A higher proportion of IPS participants attained any competitive job (186 [68.6%] vs 154 [57.0%]; P = .005) and had higher cumulative earnings from competitive jobs (median [interquartile range] $7290 [$23 174] in IPS vs $1886 [$17 167] in transitional work; P = .004)., Conclusions and Relevance: This multisite trial demonstrated significantly greater effectiveness of IPS-supported employment over stepwise transitional work vocational rehabilitation for veterans living with chronic PTSD. The results provide supporting evidence for increasing access to IPS for veterans living with PTSD., Trial Registration: clinicaltrials.gov Identifier: NCT01817712.

Objective: This article describes the methodology and the baseline characteristics of veterans with posttraumatic stress disorder (PTSD) enrolled in a multisite trial comparing supported employment individual placement and support (IPS) to a stepwise vocational transitional work program (TWP)., Method: The Veterans Affairs Cooperative Studies Program randomized 541 veterans with PTSD across 12 Veterans Affairs Medical Centers to either IPS or TWP. Demographic and clinical characteristics were evaluated at baseline., Results: Participants averaged 42 (SD ± 11) years of age and had PTSD for 13 (SD ± 11) years. The group was comprised of 18% female, 42% African Americans, and 16% Latino participants. Approximately 60% of participants served in the military since 2001, 89% were receiving or applying for service-connected disability, 60% had PTSD from nonsexual combat-related trauma, and 17% had PTSD from military sexual trauma. One third had not held a competitive job in the past 3 years; the average length of unemployment was 2.8 (SD ± 4) years. Unique study features included the focus on veterans with PTSD, a comparison of a promising practice with a usual-care practice, and the outcome criterion of achieving steady competitive employment. Conclusions and Implication for Practice: This study is the first large-scale randomized trial of IPS in a PTSD population. These baseline findings illustrate the characteristics of the study sample, which are representative of a veteran population in need of vocational rehabilitation services and can be used to help guide the implementation of tailored veteran-centered programs. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Sea otters represent an interesting model for studies of mammalian feeding evolution. Although they are marine mammals, sea otters returned to the sea relatively recently and feed at the surface. Therefore, they represent a transitional stage of aquatic adaptation. Currently no feeding performance studies of sea otters have been conducted. The main objective of this study was to characterize the feeding kinematic profile in sea otters. It was hypothesized that sea otters would exhibit a terrestrial feeding behavior and that they forcefully crush hard prey at large gapes. As a result, biting kinematics would be congruent with biting behavior reported for their terrestrial ancestors, thus providing additional evidence that raptorial biting is a conserved behavior even in recently aquatic mammals. Sea otters consistently used a durophagous raptorial biting mode characterized by large gapes, large gape angles and lack of lateral gape occlusion. The shorter skulls and mandibles of sea otters, along with increased mechanical advantages of the masseter and increased bite force, form a repertoire of functional traits for durophagy. Here we consider durophagy to be a specialized raptorial biting feeding mode. A comparison of feeding kinematics of wild versus captive sea otters showed no significant differences in lateral kinematic profiles, and only minor differences in three frontal kinematic profiles, which included a slower maximum opening gape velocity, a slower maximum gape opening velocity, and a slower maximum closing gape velocity in captive sea otters. Data indicate functional innovations for producing large bite forces at wide gape and gape angles., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)

Objective: Brain imaging studies in patients with post-traumatic stress disorder (PTSD) have implicated a circuitry of brain regions including the medial prefrontal cortex, amygdala, hippocampus, parietal cortex, and insula. Pharmacological treatment studies have shown a reversal of medial prefrontal deficits in response to traumatic reminders. Mindfulness-based stress reduction (MBSR) is a promising non-pharmacologic approach to the treatment of anxiety and pain disorders. The purpose of this study was to assess the effects of MBSR on PTSD symptoms and brain response to traumatic reminders measured with positron-emission tomography (PET) in Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) combat veterans with PTSD. We hypothesized that MBSR would show increased prefrontal response to stress and improved PTSD symptoms in veterans with PTSD., Method: Twenty-six OEF/OIF combat veterans with PTSD who had recently returned from a combat zone were block randomized to receive eight sessions of MBSR or present-centered group therapy (PCGT). PTSD patients underwent assessment of PTSD symptoms with the Clinician-Administered PTSD Scale (CAPS), mindfulness with the Five Factor Mindfulness Questionnaire (FFMQ) and brain imaging using PET in conjunction with exposure to neutral and Iraq combat-related slides and sound before and after treatment. Nine patients in the MBSR group and 8 in the PCGT group completed all study procedures., Results: Post-traumatic stress disorder patients treated with MBSR (but not PCGT) had an improvement in PTSD symptoms measured with the CAPS that persisted for 6 months after treatment. MBSR also resulted in an increase in mindfulness measured with the FFMQ. MBSR-treated patients had increased anterior cingulate and inferior parietal lobule and decreased insula and precuneus function in response to traumatic reminders compared to the PCGT group., Conclusion: This study shows that MBSR is a safe and effective treatment for PTSD. Furthermore, MBSR treatment is associated with changes in brain regions that have been implicated in PTSD and are involved in extinction of fear responses to traumatic memories as well as regulation of the stress response.

Importance: Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant., Objective: To determine the relative effectiveness and safety of 3 common alternate treatments for MDD., Design, Setting, and Participants: From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks., Interventions: Switch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase)., Main Outcomes and Measures: The primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects., Results: Among 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain., Conclusions and Relevance: Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach., Trial Registration: clinicaltrials.gov Identifier: NCT01421342.

We present an evidence-based review of post-trauma interventions used to prevent posttraumatic stress disorder (PTSD). Literature search of PubMed from 1988 to March 2016 using keywords "Early Intervention AND Prevention of PTSD" yielded 142 articles, of which 52 intervention studies and 6 meta-analyses were included in our review. Trauma-focused cognitive behavioral therapy and modified prolonged exposure delivered within weeks of a potentially traumatic event for people showing signs of distress have the most evidence in the treatment of acute stress and early PTSD symptoms, and the prevention of PTSD. Even though several pharmacological agents have been tried, only hydrocortisone prior to high-risk surgery, severe traumatic injury, or during acute sepsis has adequate evidence for effectiveness in the reduction of acute stress symptoms and prevention of PTSD. There is an urgent need to determine the best targets for interventions after trauma to accelerate recovery and prevent PTSD.

Objective: Finding effective and lasting treatments for patients with Major Depressive Disorder (MDD) that fail to respond optimally to initial standard treatment is a critical public health imperative. Understanding the nature and characteristics of patients prior to initiating "next-step" treatment is an important component of identifying which specific treatments are best suited for individual patients. We describe clinical features and demographic characteristics of a sample of Veterans who enrolled in a "next-step" clinical trial after failing to achieve an optimal outcome from at least one well-delivered antidepressant trial., Methods: 1522 Veteran outpatients with nonpsychotic MDD completed assessments prior to being randomized to study treatment. Data is summarized and presented in terms of demographic, social, historical and clinical features and compared to a similar, non-Veteran sample., Results: Participants were largely male and white, with about half unmarried and half unemployed. They were moderately severely depressed, with about one-third reporting recent suicidal ideation. More than half had chronic and/or recurrent depression. General medical and psychiatric comorbidities were highly prevalent, particularly PTSD. Many had histories of childhood adversity and bereavement. Participants were impaired in multiple domains of their lives and had negative self-worth., Limitations: These results may not be generalizable to females, and some characteristics may be specific to Veterans of US military service. There was insufficient data on age of clinical onset and depression subtypes, and three novel measures were not psychometrically validated., Conclusions: Characterizing VAST-D participants provides important information to help clinicians understand features that may optimize "next-step" MDD treatments., (Published by Elsevier B.V.)

This paper is based upon a panel discussion "What I Have Changed My Mind About and Why" held on 5 November in New Orleans, Louisiana (USA), as part of the ISTSS 2015 annual meeting "Back to Basics: Integrating Clinical and Scientific Knowledge to Advance the Field of Trauma." The panel was chaired by Professor Dr. Rachel Yehuda of the Icahn School of Medicine at Mount Sinai and the James J. Peters Veterans Affairs, and included five clinician-scholars who exchanged thoughts about what they have changed their minds about over the years: Dr. David Spiegel, Dr. Steven Southwick, Dr. Lori Davis, Dr. Thomas Neylan, and Dr. John Krystal. This paper provides a summary of the salient points made by each expert and the questions and discussion that ensured. Major issues raised included the increasingly clear limitations to the fear-based model that has advanced the field. While treatments for PTSD have improved, there are some aspects of trauma exposure that cannot be entirely repaired. Research providing an evidence base to treatment has led to overly specific treatment guidelines that may obscure more general principles of effective treatment. Treatment might be viewed as a way to increase the plasticity of the brain in the context of processing social cues. A variety of novel and integrative therapies include comprehensive holistic care, exercise, returning to competitive work, logotherapy, mindfulness, enhancing well-being and resilience, and medications with novel mechanisms, such as ketamine., Competing Interests: and funding There is no conflict of interest in the present study for any of the authors.

Objective: Selective serotonin reuptake inhibitors (SSRIs) remain the first-line treatment for posttraumatic stress disorder (PTSD). However, adjunctive atypical antipsychotics are often used to target residual or refractory symptoms. Asenapine is a novel atypical antipsychotic that possesses a high serotonin (5-HT2A) to dopamine (D2) affinity ratio and alpha-adrenergic antagonism, which may be advantageous in treating PTSD. This pilot study aimed to identify the therapeutic potential of asenapine as an adjunctive treatment for PTSD., Method: Eighteen subjects initiated treatment in this single-site prospective, open-label, 12-week trial of flexibly-dosed asenapine in Veterans with PTSD who had not responded to an adequate course of treatment with an SSRI, venlafaxine, or mirtazapine. Subjects remained on their antidepressant medication and were started on adjunctive asenapine 5 mg sublingual at bedtime, which was gradually titrated to a maximum of 10 mg twice per day, as tolerated. The primary outcome measure was the Clinician Administered PTSD Scale (CAPS) for DSM-IV., Results: Fifteen subjects finished at least 4 weeks and eleven completed the 12 week study. There was a significant and clinically meaningful decrease in CAPS from baseline (77.56 ± 14.48) to week 4 (48.7 ± 30.6), and to week 12 (35.3 ± 19.7). Six participants experienced adverse events possibly related to asenapine; however, only three participants discontinued early due to related adverse events., Conclusion: This pilot study demonstrated that adjunctive treatment with asenapine may provide additional benefit to some patients experiencing residual PTSD symptoms in spite of optimal antidepressant therapy. A larger efficacy study may be warranted., Competing Interests: Conflicts of Interests Dr. Davis has served as a consultant for Tonix, Otsuka, Lundbeck, and Brackett.

Background: Major depressive disorder (MDD) with concurrent anxiety symptoms may signal a difficult-to-treat patient. Brexpiprazole is a serotonin-dopamine activity modulator: a partial agonist at 5-HT 1A and dopamine D 2 receptors at similar potency, and an antagonist at 5-HT 2A and noradrenaline alpha 1B/2C receptors. The objective of this Phase IIIb study was to explore effectiveness, safety, and tolerability of brexpiprazole adjunctive to antidepressant (ADT) monotherapy in patients with MDD and anxiety symptoms (NCT02013531)., Methods: Patients with MDD, Hamilton Anxiety Rating Scale (HAM-A) total score ≥ 20, and inadequate response to current ADT received open-label brexpiprazole 1-3 mg day -1 (target dose 2 mg day -1 ) + ADT for 6 weeks. Efficacy endpoints included change from baseline at Week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score, HAM-A total score, and Sheehan Disability Scale (SDS). Safety and tolerability assessments included adverse events (AEs)., Results: Of 37 participants enrolled, 32 (86.5%) completed the study. Baseline mean ( SD ) MADRS total score was 30.1 (5.1); mean HAM-A total score was 26.9 (5.0). Improvements from baseline were observed at Week 6 for least squares mean change in MADRS total score (-19.6, p  < .0001 vs. baseline), HAM-A total score (-17.8, p  < .0001) and mean ( SD ) SDS mean score [-3.6 (2.6)]. Brexpiprazole was well tolerated. The most frequent treatment-emergent AEs were increased appetite (13.5%) and diarrhea, dry mouth, and dizziness (all 10.8%)., Conclusions: These open-label results support the anxiolytic effects of adjunctive brexpiprazole in the treatment of patients with MDD.

Variation in terrestrial mammalian skull morphology is known to constrain feeding performance, which in turn influences dietary habits and ultimately fitness. Among mustelids, otters have evolved two feeding specializations: underwater raptorial capture of prey (mouth-oriented) and capture of prey by hand (hand-oriented), both of which have likely associations with morphology and bite performance. However, feeding biomechanics and performance data for otters are sparse. The first goal of this study was to investigate the relationships between feeding morphology and bite performance among two mouth-oriented piscivores (Pteronura brasiliensis and Lontra canadensis) and two hand-oriented invertebrate specialists (Enhydra lutris and Aonyx cinerea). Since other vertebrate taxa that are mouth-oriented piscivores tend to possess longer skulls and mandibles, with jaws designed for increased velocity at the expense of biting capability, we hypothesized that mouth-oriented otters would also possess long, narrow skulls indicative of high velocity jaws. Conversely, hand-oriented otters were expected to possess short, blunt skulls with adaptations to increase bite force and crushing capability. Concomitant with these skull shapes we hypothesized that sea otters would possess a greater mandibular bluntness index, providing for a greater mechanical advantage compared to other otter species investigated. A second goal was to examine morphological variation at a finer scale by assessing variation in cranial morphology among three sea otter subspecies. Since diet varies among these subspecies, and their populations are isolated, we hypothesized that the magnitude of mandibular bluntness and concomitant mechanical advantage, as well as occlusal surface area would also vary within species according to their primary food source (fish versus hard invertebrates). Functional expectations were met for comparisons among and within species. Among species the phylogeny suggests a deeply rooted transition to alternative foraging types. Yet within foraging types alternative species were also strongly variable, suggesting either selective differences in the extent or nature of realized foraging mode, or an accumulation of non-adaptive changes during the long independent evolutionary history. At the finest scale, variation among subspecies indicates that trophic adaptation occurred rapidly, making it interesting that we happened to find both deeply and shallowly-rooted transformations associated with diet type in otter species and subspecies.

Because two-thirds of patients with Major Depressive Disorder do not achieve remission with their first antidepressant, we designed a trial of three "next-step" strategies: switching to another antidepressant (bupropion-SR) or augmenting the current antidepressant with either another antidepressant (bupropion-SR) or with an atypical antipsychotic (aripiprazole). The study will compare 12-week remission rates and, among those who have at least a partial response, relapse rates for up to 6 months of additional treatment. We review seven key efficacy/effectiveness design decisions in this mixed "efficacy-effectiveness" trial., (Copyright © 2015. Published by Elsevier Ireland Ltd.)