Impact of SARS-CoV-2 Infection on Long-Term Depression Symptoms among Veterans.

BACKGROUND: Prior research demonstrates that SARS-COV-2 infection can be associated with a broad range of mental health outcomes including depression symptoms. Veterans, in particular, may be at elevated risk of increased depression following SARS-COV-2 infection given their high rates of pre-existing mental and physical health comorbidities. However, few studies have tried to isolate SARS-COV-2 infection associations with long term, patient-reported depression symptoms from other factors (e.g., physical health comorbidities, pandemic-related stress). OBJECTIVE: To evaluate the association between SARS-COV-2 infection and subsequent depression symptoms among United States Military Veterans. DESIGN: Survey-based non-randomized cohort study with matched comparators. PARTICIPANTS: A matched-dyadic sample from a larger, stratified random sample of participants with and without known to SARS-COV-2 infection were invited to participate in a survey evaluating mental health and wellness 18-months after their index infection date. Sampled participants were stratified by infection severity of the participant infected with SARS-COV-2 (hospitalized or not) and by month of index date. A total of 186 participants in each group agreed to participate in the survey and had sufficient data for inclusion in analyses. Those in the uninfected group who were later infected were excluded from analyses. MAIN MEASURES: Participants were administered the Patient Health Questionnaire-9 as part of a phone interview survey. Demographics, physical and mental health comorbidities were extracted from VHA administrative data. KEY RESULTS: Veterans infected with SARS-COV-2 had significantly higher depression symptoms scores compared with those uninfected. In particular, psychological symptoms (e.g., low mood, suicidal ideation) scores were elevated relative to the comparator group (MInfected = 3.16, 95%CI: 2.5, 3.8; MUninfected = 1.96, 95%CI: 1.4, 2.5). Findings were similar regardless of history of depression. CONCLUSION: SARS-COV-2 infection was associated with more depression symptoms among Veterans at 18-months post-infection. Routine evaluation of depression symptoms over time following SARS-COV-2 infection is important to facilitate adequate assessment and treatment.

Risk of Suicide-Related Outcomes After SARS-COV-2 Infection: Results from a Nationwide Observational Matched Cohort of US Veterans.

BACKGROUND: Negative mental health-related effects of SARS-COV-2 infection are increasingly evident. However, the impact on suicide-related outcomes is poorly understood, especially among populations at elevated risk. OBJECTIVE: To determine risk of suicide attempts and other self-directed violence (SDV) after SARS-COV-2 infection in a high-risk population. DESIGN: We employed an observational design supported by comprehensive electronic health records from the Veterans Health Administration (VHA) to examine the association of SARS-COV-2 infection with suicide attempts and other SDV within one year of infection. Veterans with SARS-COV-2 infections were matched 1:5 with non-infected comparators each month. Three periods after index were evaluated: days 1-30, days 31-365, and days 1-365. PARTICIPANTS: VHA patients infected with SARS-COV-2 between March 1, 2020 and March 31, 2021 and matched non-infected Veteran comparators. MAIN MEASURES: Suicide attempt and other SDV events for the COVID-19 and non-infected comparator groups were analyzed using incidence rates per 100,000 person years and hazard ratios from Cox regressions modeling time from matched index date to first event. Subgroups were also examined. KEY RESULTS: 198,938 veterans with SARS-COV-2 (COVID-19 group) and 992,036 comparators were included. Unadjusted one-year incidence per 100,000 for suicide attempt and other SDV was higher among the COVID-19 group: 355 vs 250 and 327 vs 235, respectively. The COVID-19 group had higher risk than comparators for suicide attempts: days 1-30 hazard ratio (HR) = 2.54 (CI:2.05, 3.15), days 31-365 HR = 1.30 (CI:1.19, 1.43) and days 1-365 HR = 1.41 (CI:1.30, 1.54), and for other SDV: days 1-30 HR = 1.94 (CI:1.51, 2.49), days 31-365 HR = 1.32 (CI:1.20, 1.45) and days 1-365 HR = 1.38 (CI:1.26, 1.51). CONCLUSIONS: COVID-19 patients had higher risks of both suicide attempts and other forms of SDV compared to uninfected comparators, which persisted for at least one year after infection. Results support suicide risk screening of those infected with SARS-COV-2 to identify opportunities to prevent self-harm.

Optimizing the Equitable Deployment of Virtual Care for Women: Protocol for a Qualitative Evidence Synthesis Examining Patient and Provider Perspectives Supplemented with Primary Qualitative Data.

Introduction: Women experience numerous barriers to patient-centered health care (e.g., lack of continuity). Such barriers are amplified for women from marginalized communities. Virtual care may improve equitable access. We are conducting a partner-engaged, qualitative evidence synthesis (QES) of patients' and providers' experiences with virtual health care delivery for women. Methods: We use a best-fit framework approach informed by the Non-adoption, Abandonment, Scale-up, Spread, and Sustainability framework and Public Health Critical Race Praxis. We will supplement published literature with qualitative interviews with women from underrepresented communities and their health care providers. We will engage patients and other contributors through multiple participatory methods. Results: Our search identified 5525 articles published from 2010 to 2022. Sixty were eligible, of which 42 focused on women and 24 on provider experiences. Data abstraction and analysis are ongoing. Discussion: This work offers four key innovations to advance health equity: (1) conceptual foundation rooted in an antiracist action-oriented praxis; (2) worked example of centering QES on marginalized communities; (3) supplementing QES with primary qualitative information with populations historically marginalized in the health care system; and (4) participatory approaches that foster longitudinal partnered engagement. Health Equity Implications: Our approach to exploring virtual health care for women demonstrates an antiracist praxis to inform knowledge generation. In doing so, we aim to generate findings that can guide health care systems in the equitable deployment of comprehensive virtual care for women.

Time doesn't heal all: PTSD symptoms exacerbate the relationship between age and pain intensity.

Objective: Posttraumatic stress disorder (PTSD) symptoms and pain interfere with daily functioning and quality of life for many combat Veterans. As individuals age, pain symptoms tend to increase whereas PTSD symptoms tend to decrease. PTSD symptoms exacerbate pain, but the nature of this relationship across the aging process is unclear. The purpose of this study was to determine how PTSD symptoms affect the association between age and pain intensity. Methods: Participants in this cross-sectional study included 450 Veterans (80% male) who served after September 11, 2001. PTSD and pain intensity ratings were assessed by the PTSD Checklist for DSM-5 (PCL-5) and the Brief Pain Inventory (BPI), respectively. Hierarchical multiple linear regression evaluated main and interaction effects between age, PTSD symptoms, and pain intensity. Results: Age (B = 0.04, p < 0.001) and PTSD symptoms (B = 0.05, p < 0.001) were positively associated with pain intensity. Age and PTSD symptoms were inversely correlated (r = -0.16, p < 0.001). PTSD symptoms exacerbated the relationship between age and pain intensity (ΔR2 = 0.01, p = 0.036). Specifically, when greater PTSD symptoms were reported at older ages, pain intensity was significantly higher. Conclusion: Results of these analyses suggests that age is important when considering the effects of PTSD symptoms on pain intensity ratings. Specifically, pain intensity ratings are higher in older Veterans with PTSD symptoms. These findings underscore the importance for clinical providers to evaluate trauma history and PTSD symptoms in older Veterans reporting pain symptoms.

White Matter Microstructure Is Associated with Serum Neuroactive Steroids and Psychological Functioning.

Military service members are at increased risk for mental health issues, and comorbidity with mild traumatic brain injury (mTBI) is common. Largely overlapping symptoms between conditions suggest a shared pathophysiology. The present work investigates the associations among white matter microstructure, psychological functioning, and serum neuroactive steroids that are part of the stress-response system. Diffusion-weighted brain imaging was acquired from 163 participants (with and without military affiliation) and free-water-corrected fractional anisotropy (FAT) was extracted. Associations between serum neurosteroid levels of allopregnanolone (ALLO) and pregnenolone (PREGNE), psychological functioning, and whole-brain white matter microstructure were assessed using regression models. Moderation models tested the effect of mTBI and comorbid post-traumatic stress disorder (PTSD) and mTBI on these associations. ALLO is associated with whole-brain white matter FAT (ß = 0.24, t = 3.05, p = 0.006). This association is significantly modulated by PTSD+mTBI comorbidity (ß = 0.00, t = 2.50, p = 0.027), although an mTBI diagnosis alone did not significantly impact this association (p = 0.088). There was no significant association between PREGNE and FAT (p = 0.380). Importantly, lower FAT is associated with poor psychological functioning (ß = -0.19, t = -2.35, p = 0.020). This study provides novel insight into a potential common pathophysiological mechanism of neurosteroid dysregulation underlying the high risk for mental health issues in military service members. Further, comorbidity of PTSD and mTBI may bring the compensatory effects of the brain's stress response to their limit. Future research is needed to investigate whether neurosteroid regulation may be a promising tool for restoring brain health and improving psychological functioning.

Cost Analysis of Providing Overtime to Current Nurses Versus Hiring a Dedicated Nurse for COVID-19 Management in a Processing Plant.

BACKGROUND: U.S. meat and poultry processing workers experienced a disproportionate burden of COVID-19 illness following the declaration of the COVID-19 pandemic. Managing prevention and surveillance activities for COVID-19 prevention required additional work for occupational health nurses. The purpose of this project was to conduct a cost analysis for two staffing options to address the increased workload for occupational health nurses. METHODS: An economic quality improvement design was used for this study. The project was performed at a meat and poultry processing plant with 1,800 employees and six occupational health nurses. Two staffing options were considered. Option 1 was to continue to pay current occupational health nurses overtime, and Option 2 was to hire a COVID-dedicated nurse to manage the increased workload. A cost analysis was conducted for wages per hour plus benefits at three time points: 3 months, 1 year, and 3 years. FINDINGS: Costs for Option 1 (continuing overtime) at 3 months, 1 year, and 3 years were estimated at US$27,370, US$109,517, and US$328,550, respectively. Costs for Option 2 (hiring a COVID-dedicated nurse) at 3 months, 1 year, and 3 years were estimated at US$44,279, US$94,979, and US$230,179, respectively. CONCLUSIONS/APPLICATION TO PRACTICE: Hiring a dedicated COVID nurse would save the processing plant extensive salary costs by Year 3. Reducing overtime had the potential to decrease the COVID-19-related workload and potential experiences of fatigue and burnout in occupational health nurses.

Moral Injury as a Mediator of the Associations Between Sexual Harassment and Mental Health Symptoms and Substance Use Among Women Veterans.

Moral injury is an array of symptoms theorized to develop in response to morally injurious events, defined as events that challenge one's core moral beliefs and expectations about the self, others, and world. Recent measures of moral injury have distinguished self-directed moral injury (e.g., moral injury symptoms that emerge following the perpetration of morally injurious events) from other-directed moral injury, the symptoms of which are believed to stem from one's response to actions that others have committed (e.g., within-rank violence, failures of leadership, and acts of betrayal committed by trusted others or institutions). Using a convenience sample of 154 primarily former military women, the present study examined if other-directed moral injury symptoms (e.g., anger, betrayal, and mistrust) associated with military experience would mediate the association between military sexual harassment and mental health and substance abuse symptoms. Results demonstrated that 85.8% (n = 127) of the of this sample of women veterans reported experiencing sexual harassment during their military service. Using a single mediation model, we further demonstrated that other-directed moral injury mediated the association between sexual harassment experience and mental health symptoms. Given the percentage of women veterans who reported sexual harassment, these results suggest that additional training for military members, and particularly, military leaders, is necessary to begin to reduce sexual harassment. In addition, mental health providers who work with current and former military members should consider how other-directed moral injury may be associated with mental health symptoms among women veterans who have experienced sexual harassment while in the military.

Reciprocal Effects Between Depressive Symptoms and Pain in Veterans over 50 Years of Age or Older.

OBJECTIVE: Depression and chronic pain are major problems in American veterans, yet there is limited long-term research examining how they relate to one another in this population. This study examined the relationship between depressive symptoms and pain in U.S. veterans 50 years of age or older. METHODS: This study used data on veterans from the 2002-2016 waves of the Health and Retirement Study (n = 4,302), a large-scale observational study of Americans 50 years of age or older. Measures included a short form of the Center for Epidemiologic Studies Depression scale and two items assessing the presence and degree of pain. Analyses included random-intercept cross-lagged panel models (RI-CLPM). RESULTS: In the RI-CLPM, there were roughly equivalent cross-lagged effects between depressive symptoms and pain. There was also evidence that depressive symptoms and pain have a trait-like component and that these trait-like characteristics are associated. CONCLUSIONS: These findings indicate that depressive symptoms and pain in veterans are stable characteristics in American veterans 50 years of age or older. There appear to be reciprocal effects between the two, whereby deviations in one's typical depressive symptoms predict subsequent deviations in one's pain level and vice versa; however, the size of these effects is very small. These findings suggest that clinicians should treat both depressive symptoms and pain, rather than assume that treatment benefits in one domain will lead to major benefits in another.

Cerebral Venous Thrombosis Presenting as a Subacute Headache in a Young Man With Undiagnosed Factor V Leiden Mutation.

Cerebral venous sinus thrombosis (CVT) is a rare but potentially life-threatening condition that presents with non-specific symptoms. This condition is more common in women and can be associated with local infection and hypercoagulable conditions, including protein C and S deficiency, factor V Leiden mutation, anti-thrombin III deficiency, thrombophilia, vasculitis, and malignancy. We report the case of a 24-year-old man who presented with a left temporal headache and right upper and lower extremity paresthesia. He also experienced impaired vision (altered spatial sensation), dental pain, bruxism, nausea, and vomiting. Magnetic resonance imaging and magnetic resonance venography of the brain revealed widespread thrombosis of the cerebral sinuses as well as left superior cerebral cortical veins bilaterally. No evidence of venous infarct was found. Subsequent hematologic evaluation showed the presence of heterozygous factor V Leiden mutation. Testing of family members subsequently revealed the presence of this same mutation in his mother and all three siblings, although there was no family history of stroke, hypercoagulability, or atypical headaches. The patient was started on low-molecular-weight heparin and later transitioned to apixaban. Progression of his headache and visual abnormalities led to the discovery of increased intracranial pressure as demonstrated by papilledema and characteristic findings on computed tomography scan. He was treated with acetazolamide with improvement of his symptoms. CVT is uncommon and can be a diagnostic challenge due to its atypical presentation. Clinicians should consider this diagnosis in patients with a subacute onset of atypical headache, especially when accompanied by seizures, focal neurological deficits, or altered consciousness.

An assessment of ergonomic issues in the home offices of university employees sent home due to the COVID-19 pandemic.

BACKGROUND: As millions of workers have shifted to telework, special accommodations for workers with respect to ergonomics may be required to ensure the workforce remains healthy. METHODS: A survey about home office ergonomics and discomfort was sent to faculty, staff, and administrators by email and was completed by 843 individuals. RESULTS: Over 40%of the participants reported moderate to severe discomfort (severe low/middle back pain, moderate discomfort in eyes/neck/head, and discomfort in the upper back/shoulders). Laptops (always and often) were widely used (85%) with most using the laptop monitor (55%) of all respondents. Further, less than 45%of the seating conditions were reported as having adjustable arm rests. CONCLUSION: As teleworking in makeshift offices becomes more common, the risk of significant discomfort and potentially more serious musculoskeletal disorders may result from poor static postures. Companies may need to accommodate workers by allowing them to take home office chairs, external monitors, keyboards, and mice as laptops are insufficient, ergonomically.

Sex differences in predictors of recurrent major depression among current-era military veterans.

Although major depressive disorder (MDD) is a frequent diagnosis among women seeking care in the Veterans Health Administration, little is known about its course. For example, recurrence of MDD and its predictors have been investigated in civilians, but not among female veterans. Because female veterans differ from their civilian counterparts and from male veterans on demographic variables, including race, ethnicity, marital status, and educational level, it is important to identify factors affecting MDD course within this population. We investigated frequency and correlates of recurrent MDD among female veterans and their male counterparts. From a postdeployment research registry of 3,247 participants (660 women and 2,587 men), we selected those with a current episode of MDD (141 women and 462 men). For each sex, we compared those diagnosed with recurrent MDD with those experiencing a single episode on demographics, comorbid diagnoses, family history of mental illness, traumatic experiences, combat exposure, and social support. In contrast to findings in most civilian samples, recurrent MDD was significantly more frequent in female (70.2%) than in male (45.2%) depressed veterans, χ²(1) = 26.96, p < .001. In multivariable analyses, recurrence among women was associated with greater experiences of childhood abuse and more trauma during military service and with lower rates of posttraumatic stress disorder. Among men, recurrence was associated with older age, family history of psychiatric hospitalization, more postmilitary trauma, and lifetime anxiety disorder and with lower likelihood of war zone deployment. Trauma was associated with recurrence in both sexes, but the features of traumatic events differed in women and men. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Improving Veteran Access to Integrated Management of Back Pain (AIM-Back): Protocol for an Embedded Pragmatic Cluster-Randomized Trial.

BACKGROUND: Coordinated efforts between the National Institutes of Health, the Department of Defense, and the Department of Veterans Affairs have built the capacity for large-scale clinical research investigating the effectiveness of nonpharmacologic pain treatments. This is an encouraging development; however, what constitutes best practice for nonpharmacologic management of low back pain (LBP) is largely unknown. DESIGN: The Improving Veteran Access to Integrated Management of Back Pain (AIM-Back) trial is an embedded pragmatic cluster-randomized trial that will examine the effectiveness of two different care pathways for LBP. Sixteen primary care clinics will be randomized 1:1 to receive training in delivery of 1) an integrated sequenced-care pathway or 2) a coordinated pain navigator pathway. Primary outcomes are pain interference and physical function (Patient-Reported Outcomes Measurement Information System Short Form [PROMIS-SF]) collected in the electronic health record at 3 months (n=1,680). A subset of veteran participants (n=848) have consented to complete additional surveys at baseline and at 3, 6, and 12 months for supplementary pain and other measures. SUMMARY: AIM-Back care pathways will be tested for effectiveness, and treatment heterogeneity will be investigated to identify which veterans may respond best to a given pathway. Health care utilization patterns (including opioid use) will also be compared between care pathways. Therefore, the AIM-Back trial will provide important information that can inform the future delivery of nonpharmacologic treatment of LBP.

Neuroendocrine biomarkers of prolonged exposure treatment response in military-related PTSD.

Posttraumatic stress disorder (PTSD) is associated with dysregulation of the neuroendocrine system, including cortisol, allopregnanolone, and pregnanolone. Preliminary evidence from animal models suggests that baseline levels of these biomarkers may predict response to PTSD treatment. We report the change in biomarkers over the course of PTSD treatment. Biomarkers were sampled from individuals participating in (1) a randomized controlled trial comparing a web-version of Prolonged Exposure (Web-PE) therapy to in-person Present-Centered Therapy (PCT) and (2) from individuals participating in a nonrandomized effectiveness study testing PE delivered in-person as part of an intensive outpatient PTSD program. We found that higher cortisol reactivity during script-driven imagery was associated with higher baseline PTSD severity and that baseline allopregnanolone, pregnanolone, and cortisol reactivity were associated with PTSD treatment responder status over the course of intensive outpatient treatment. These findings demonstrate that peripherally assessed biomarkers are associated with PTSD severity and likelihood of successful treatment outcome of PE delivered daily over two weeks. These assessments could be used to determine which patients are likely to respond to treatment and which patients require augmentation to increase the likelihood of optimal response to PTSD treatment.

Serum Neurosteroid Levels Are Associated With Cortical Thickness in Individuals Diagnosed With Posttraumatic Stress Disorder and History of Mild Traumatic Brain Injury.

Posttraumatic stress disorder (PTSD) co-occurring with mild traumatic brain injury (mTBI) is common in veterans. Worse clinical outcome in those with PTSD has been associated with decreased serum neurosteroid levels. Furthermore, decreased cortical thickness has been associated with both PTSD and mTBI. However, it is not known whether decreased neurosteroids are associated with decreased cortical thickness in PTSD co-occurring with mTBI. This study included 141 individuals divided into the following groups: (a) mTBI group (n = 32 [10 female, 22 male] veterans with a history of mTBI); (b) PTSD + mTBI group (n = 41 [6 female, 35 male] veterans with current PTSD with a history of mTBI); and (c) control group (n = 68 [35 female, 33 male] control participants), which were acquired through the Injury and Traumatic Stress (INTRuST) Clinical Consortium. Subjects underwent clinical assessment, magnetic resonance imaging at 3 T, and serum neurosteroid quantifications of allopregnanolone (ALLO) and pregnenolone (PREGN). Group differences in cortical thickness and associations between serum neurosteroid levels and cortical thickness were investigated. Cortical thickness was decreased in the PTSD + mTBI group compared with the other groups. In the PTSD + mTBI group, decreased cortical thickness was also associated with lower serum ALLO (right superior frontal cortex) and lower serum PREGN (left middle temporal and right orbitofrontal cortex). Cortical thickness in the middle temporal and orbitofrontal cortex was associated with PTSD symptom severity. There were no significant associations between neurosteroids and cortical thickness in the mTBI or control groups. Decreased cortical thickness in individuals with PTSD + mTBI is associated with decreased serum neurosteroid levels and greater PTSD symptom severity. Causality is unclear. However, future studies might investigate whether treatment with neurosteroids could counteract stress-induced neural atrophy in PTSD + mTBI by potentially preserving cortical thickness.

Effect of Pregnenolone vs Placebo on Self-reported Chronic Low Back Pain Among US Military Veterans: A Randomized Clinical Trial.

Importance: In response to the national opioid public health crisis, there is an urgent need to develop nonopioid solutions for effective pain management. Neurosteroids are endogenous molecules with pleotropic actions that show promise for safe and effective treatment of chronic low back pain. Objective: To determine whether adjunctive pregnenolone has therapeutic utility for the treatment of chronic low back pain in Iraq- and Afghanistan-era US military veterans. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled clinical trial that enrolled for 42 months, from September 2013 to April 2017. Participants were Iraq- and Afghanistan-era veterans aged 18 to 65 years with chronic low back pain who received treatment in the Durham VA Health Care System in Durham, North Carolina, over 6 weeks. Data analysis began in 2018 and was finalized in March, 2019. Interventions: Following a 1-week placebo lead-in, participants were randomized to pregnenolone or placebo for 4 weeks. Pregnenolone and placebo were administered at fixed, escalating doses of 100 mg for 1 week, 300 mg for 1 week, and 500 mg for 2 weeks. Main Outcomes and Measures: The primary outcome measure was the change in mean pain intensity ratings from a daily pain diary (numerical rating scale, 0-10) between visit 3 (baseline) and visit 6. Secondary outcomes included pain interference scores (Brief Pain Inventory, Short Form). Preintervention and postintervention neurosteroid levels were quantified by gas chromatography with tandem mass spectrometry. Hypotheses tested were formulated prior to data collection. Results: A total of 94 participants (84 [89.4%] male; mean [SD] age, 37.5 [9.8] years; 53 [56.4%] of self-reported Caucasian race and 31 [33.0%] of self-reported African American race) were included. Forty-eight participants were randomized to pregnenolone and 52 to placebo, of whom 45 and 49, respectively, were included in baseline demographic characteristics secondary to noncompliance with medications as per protocol. Veterans randomized to pregnenolone reported significant reductions in low back pain relative to those randomized to placebo. Baseline unadjusted mean (SE) pain diary ratings were 4.83 (0.23) and 5.24 (0.22) for the placebo- and pregnenolone-treated groups, respectively (baseline unadjusted mean [SE] ratings for pain recall were 4.78 [0.24] and 5.15 [0.23], respectively). Unadjusted mean (SE) ratings following treatment (visit 6) were 4.74 (0.26) in the placebo group and 4.19 (0.30) in the pregnenolone-treated group. Unadjusted mean (SE) ratings for pain recall following treatment were 4.86 (0.27) for placebo and 4.18 (0.29) for pregnenolone. Least-square mean (LSM) analysis showed that pain scores significantly improved in the pregnenolone-treated group compared with placebo (LSM [SE] change in pain diary rating, -0.56 [0.25]; P = .02; LSM [SE] change in pain recall, -0.70 [0.27]; P = .01). Pain interference scores for work (LSM [SE] change, 0.71 [0.12]; P = .04) and activity (LSM [SE] change, 0.71 [0.11]; P = .03) were also improved in veterans randomized to pregnenolone compared with placebo. Pregnenolone was well tolerated. Conclusions and Relevance: Participants receiving pregnenolone reported a clinically meaningful reduction in low back pain and 2 pain interference domains compared with those receiving placebo. Pregnenolone may represent a novel, safe, and potentially efficacious treatment for the alleviation of chronic low back pain in Iraq- and Afghanistan-era veterans. Trial Registration: ClinicalTrials.gov Identifier: NCT01898013.

Kappa opioid agonists reduce oxycodone self-administration in male rhesus monkeys.

RATIONALE: Combinations of mu and kappa opioid receptor (KOR) agonists have been proposed as potential analgesic formulations with reduced abuse liability. The current studies extend previous work by investigating the typical KOR agonist, salvinorin A, and the atypical KOR agonist, nalfurafine, as deterrents of oxycodone self-administration using a progressive ratio (PR) schedule of reinforcement. METHODS: In separate experiments, adult male rhesus monkeys (N = 4/experiment) were trained under a PR schedule of reinforcement to self-administer cocaine (0.1 mg/kg/injection) and saline on alternating days. Oxycodone (0.01-0.1 mg/kg/injection) alone and combined with salvinorin A (experiment 1; 0.006, 0.012 mg/kg/injection) or nalfurafine (experiment 2; 0.0001-0.00032 mg/kg/injection) were tested within the alternating cocaine and saline baseline. The mechanism of nalfurafine's effects on oxycodone self-administration was investigated via pretreatment with the KOR antagonist, nor-binaltorphimine (nor-BNI; 10 mg/kg; i.m.). RESULTS: All subjects self-administered oxycodone alone above saline levels at sufficiently large doses, and combining salvinorin A or nalfurafine with oxycodone reduced the mean number of injections per session to saline levels (experiment 1) or to levels that were significantly lower than oxycodone alone (experiment 2). The ability of nalfurafine to reduce oxycodone self-administration was reversed by pretreatment with nor-BNI. CONCLUSIONS: These results demonstrate that KOR agonists, including the clinically used KOR agonist, nalfurafine, can punish self-administration of a prescription opioid analgesic, oxycodone, in rhesus monkeys and that nalfurafine's punishing effect is KOR-dependent. Combinations of KOR agonists with prescription opioids may have reduced abuse liability.

Use of a physiologically-based pharmacokinetic model to explore the potential disparity in nicotine disposition between adult and adolescent nonhuman primates.

The widespread use and high abuse liability of tobacco products has received considerable public health attention, in particular for youth, who are vulnerable to nicotine addiction. In this study, adult and adolescent squirrel monkeys were used to evaluate age-related metabolism and pharmacokinetics of nicotine after intravenous administration. A physiologically-based pharmacokinetic (PBPK) model was created to characterize the pharmacokinetic behaviors of nicotine and its metabolites, cotinine, trans-3'-hydroxycotinine (3'-OH cotinine), and trans-3'-hydroxycotinine glucuronide (3'-OH cotinine glucuronide) for both adult and adolescent squirrel monkeys. The PBPK nicotine model was first calibrated for adult squirrel monkeys utilizing in vitro nicotine metabolic data, plasma concentration-time profiles and cumulative urinary excretion data for nicotine and metabolites. Further model refinement was conducted when the calibrated adult model was scaled to the adolescents, because adolescents appeared to clear nicotine and cotinine more rapidly relative to adults. More specifically, the resultant model parameters representing systemic clearance of nicotine and cotinine for adolescent monkeys were approximately two- to three-fold of the adult values on a per body weight basis. The nonhuman primate PBPK model in general captured experimental observations that were used for both model calibration and evaluation, with acceptable performance metrics for precision and bias. The model also identified differences in nicotine pharmacokinetics between adolescent and adult nonhuman primates which might also be present in humans.

Widespread Cortical Thickness Is Associated With Neuroactive Steroid Levels.

BACKGROUND: Neuroactive steroids are endogenous molecules with regenerative and neuroprotective actions. Both cortical thickness and many neuroactive steroid levels decline with age and are decreased in several neuropsychiatric disorders. However, a systematic examination of the relationship between serum neuroactive steroid levels and in vivo measures of cortical thickness in humans is lacking. METHODS: Peripheral serum levels of seven neuroactive steroids were assayed in United States military veterans. All (n = 143) subsequently underwent high-resolution structural MRI, followed by parcellelation of the cortical surface into 148 anatomically defined regions. Regression modeling was applied to test the association between neuroactive steroid levels and hemispheric total gray matter volume as well as region-specific cortical thickness. False discovery rate (FDR) correction was used to control for Type 1 error from multiple testing. RESULTS: Neuroactive steroid levels of allopregnanolone and pregnenolone were positively correlated with gray matter thickness in multiple regions of cingulate, parietal, and occipital association cortices (r = 0.20-0.47; p < 0.05; FDR-corrected). CONCLUSION: Positive associations between serum neuroactive steroid levels and gray matter cortical thickness are found in multiple brain regions. If these results are confirmed, neuroactive steroid levels and cortical thickness may help in monitoring the clinical response in future intervention studies of neuroregenerative therapies.

Neurosteroid Levels in the Orbital Frontal Cortex of Subjects with PTSD and Controls: A Preliminary Report.

Background: Neurosteroids mediate stress signaling and have been implicated in the pathogenesis of post-traumatic stress disorder (PTSD) in both preclinical and clinical studies. Compared to controls, subjects with PTSD exhibit altered neurosteroid levels in peripheral blood and cerebrospinal fluid as well as hypoactivity in the medial orbital frontal cortex (mOFC). Therefore, the aim of this study was to compare neurosteroid levels in the mOFC of subjects with PTSD (n = 18) and controls (n = 35). Methods: Gray matter was dissected from fresh-frozen mOFC, and levels of the neurosteroids pregnenolone, allopregnanolone, pregnanolone, epiallopregnanolone, epipregnanolone, tetrahydrodeoxycorticosterone, and androsterone were determined by gas chromatography - tandem mass spectrometry (GC/MS/MS). Results: Analyses of unadjusted levels revealed that males with PTSD had significantly decreased levels of allopregnanolone (p = 0.03) compared to control males and females with PTSD had significantly increased levels of pregnenolone (p = 0.03) relative to control females. After controlling for age, postmortem interval, and smoking status, results showed that males with PTSD had significantly decreased levels of androsterone (t46 = 2.37, p = 0.02) compared to control males and females with PTSD had significantly increased levels of pregnanolone (t46 = -2.25, p = 0.03) relative to control females. Conclusions: To our knowledge, this is the first report of neurosteroid levels in postmortem brain tissue of subjects with PTSD. Although replication is required in other brain regions and in a larger cohort of subjects, the results suggest a dysregulation of allopregnanolone and androsterone in males with PTSD and pregnanolone in females with PTSD in the mOFC.