Venlafaxine is a structurally novel, nontricyclic compound that is being evaluated for the treatment of various depressive disorders. A randomized three-period crossover study was conducted to obtain pharmacokinetic and dose proportionality data on the drug and its active metabolite, O-desmethylvenlafaxine. Eighteen healthy young men received single doses of venlafaxine 25, 75, and 150 mg followed by 3 days of administration every 8 hours (q8h). Steady-state elimination half-life was 3 to 4 hours for venlafaxine and 10 hours for O-desmethylvenlafaxine; both were independent of dose. Venlafaxine had a high oral-dose clearance, ranging from 0.58 to 2.63 L/hr/kg across doses with the lowest mean clearance, 0.98 L/hr/kg, at the highest dose. The apparent clearance of O-desmethylvenlafaxine was lower than venlafaxine, ranging from 0.21 to 0.66 L/hr/kg, and the lowest mean clearance, 0.33 L/hr/kg, occurred at the lowest dose. The area under the metabolite curve was two to three times greater than that for venlafaxine. Each compound had linear dose proportionality up to 75 mg q8h. A composite parameter incorporating venlafaxine plus O-desmethylvenlafaxine was introduced (i.e., AUC [area under the curve] + activity factor.AUCm), which extended linearity to 150 mg q8h. In summary, venlafaxine is a high-clearance drug that forms a metabolite with almost equal activity and demonstrates linear dose-proportionality.

ImportanceTo date, few multisite investigations have evaluated early interventions for injured patients with posttraumatic stress disorder (PTSD) symptoms.ObjectiveTo simultaneously assess the effectiveness and implementation of a brief stepped collaborative care intervention targeting PTSD and comorbidity.Design, Setting, and ParticipantsA stepped-wedge cluster randomized clinical trial was conducted at 25 US level I trauma centers. Participants included hospitalized survivors of physical injury who underwent a 2-step evaluation for PTSD symptoms. Patients reporting high levels of distress on the PTSD Checklist (PCL-C) were randomized (N = 635) per the stepped-wedge protocol to enhanced usual care control (n = 370) or intervention (n = 265) conditions. The study was conducted from January 4, 2016, through November 2019. Data analysis was performed from November 4, 2019, to December 8, 2020.InterventionsThe Trauma Survivors Outcomes and Support collaborative care intervention included proactive injury case management that assisted patients transitioning from hospital inpatient to outpatient and community settings. The intervention also integrated evidence-based pharmacotherapy and psychotherapeutic elements targeting PTSD symptoms and comorbidity.Main Outcomes and MeasuresThe primary study outcome was PTSD symptoms assessed with the PCL-C at baseline in the surgical ward and at 3, 6, and 12 months postinjury. Secondary outcomes included depressive symptoms, alcohol use, and physical function. Subgroup analyses examined the effect of baseline risk factors for enduring PTSD and quality of protocol implementation on study outcomes. Primary statistical analyses were conducted using the intent-to-treat sample.ResultsA total of 327 men (51.5%) were included in analysis; mean (SD) age was 39.0 (14.2) years. The investigation attained follow-up of 75% to 80% of the participants at 3 to 12 months. The intervention lasted a mean (SD) of 122 (132) minutes. Mixed model regression analyses revealed statistically significant changes in PCL-C scores for intervention patients compared with control patients at 6 months (difference, −2.57; 95% CI, −5.12 to −0.03; effect size, 0.18; P < .05) but not 12 months (difference, −1.27; 95% CI, −4.26 to 1.73; effect size, 0.08; P = .35). Subgroup analyses revealed larger PTSD treatment effects for patients with 3 or more baseline risk factors for enduring PTSD and for patients, including firearm injury survivors, treated at trauma centers with good or excellent protocol implementation. Intervention effects for secondary outcomes did not attain statistical significance.Conclusions and RelevanceA brief stepped collaborative care intervention was associated with significant 6-month but not 12-month PTSD symptom reductions. Greater baseline PTSD risk and good or excellent trauma center protocol implementation were associated with larger PTSD treatment effects. Orchestrated efforts targeting policy and funding should systematically incorporate the study findings into national trauma center requirements and verification criteria.Trial RegistrationClinicalTrials.gov Identifier: NCT02655354

ObjectivesAssess the impacts of the COVID-19 pandemic on service delivery by frontline healthcare providers in acute care medical and emergency department settings and identify strategies used to cope with pandemic-related physical and mental health demands.DesignRapid clinical ethnography of patient–provider encounters during an initial pandemic ‘surge’ conducted by a team of clinician–researchers using a structured protocol for qualitative data collection and analysis.SettingLevel 1 trauma centre at Harborview Hospital in Seattle Washington in April 2020.ParticipantsFrontline clinical providers serving as participant observers during performance of their clinical duties recorded observations and summaries of conversations with other providers and patients.ResultsWe identified four different kinds of impacts: procedural, provider, patient and overall. Each impact highlighted two or more levels of a socioecological model of services delivery: (1) the epidemiology of COVID-19, (2) outer setting, (3) inner or organisational setting and (4) individual patient and provider. Despite significant changes in procedures that included COVID-19 screening of all admitted patients, social distancing and use of personal protective equipment, as well as changes in patient and provider behaviour, the overall impact of the pandemic on the emergency department and acute care service delivery was minimal. This is attributed to having a smaller surge than expected, a quick response by the healthcare system to anticipated demands for service delivery and protection of patients and providers, adequate supplies and high provider morale.ConclusionsAlthough limited to one setting in one healthcare system in one community, the findings offer some important lessons for healthcare systems that have yet to be impacted as well as systems that have been more severely impacted. Each of the socioecological framework levels was found to impact service delivery to patients, and variations at each of these levels account for variations in that quality of care globally.

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BACKGROUND Posttraumatic stress disorder (PTSD) symptoms, firearm violence events, alcohol and drug use problems, and major depression and suicidal ideation are endemic among patients admitted to US trauma centers. Despite increasing policy importance, the current availability of screening and intervention services for this constellation of conditions in US trauma centers is unknown. STUDY DESIGN Trauma program staff at all Level I and Level II trauma centers in the US. (N = 627) were contacted to complete a survey describing screening and intervention procedures for alcohol and drug use problems, PTSD symptoms, depression and suicidality, and firearm violence. Additional questions asked trauma centers about the delivery of peer interventions and information technology capacity for screening and intervention procedures. RESULTS: Fifty-one percent of trauma centers (n = 322) responded to the survey. More than 95% of responding sites endorsed routinely screening and/or intervening for alcohol use problems. Routine services addressing PTSD were less common, with 28% of centers reporting routine screening. More than 50% of sites that screened for PTSD used previously established trauma center alcohol use services. Programmatic screening and intervention for firearm injury sequelae was occurring at 30% of sites. CONCLUSION Alcohol screening and intervention is occurring frequently at US trauma centers and appears to be responsive to American College of Surgeons Committee on Trauma verification requirements. Routine screening and intervention services for PTSD and firearm injury were occurring less frequently. Regular national surveys may be a key element of tracking progress in national mental health and substance use screening, intervention, and referral policy.