Propofol for treatment resistant depression: A randomized controlled trial.

Background: Anesthetic agents including ketamine and nitrous oxide have shown antidepressant properties when appropriately dosed. Our recent open-label trial of propofol, an intravenous anesthetic known to elicit transient positive mood effects, suggested that it may also produce robust and durable antidepressant effects when administered at a high dose that elicits an electroencephalographic (EEG) burst-suppression state. Here we report findings from a randomized controlled trial ( NCT03684447 ) that compared two doses of propofol. We hypothesized greater improvement with a high dose that evoked burst suppression versus a low dose that did not. Methods: Participants with moderate-to-severe, treatment-resistant depression were randomized to a series of 6 treatments at low versus high dose (n=12 per group). Propofol infusions were guided by real-time processed frontal EEG to achieve predetermined pharmacodynamic criteria. The primary and secondary depression outcome measures were the 24-item Hamilton Depression Rating Scale (HDRS-24) and the Patient Health Questionnaire (PHQ-9), respectively. Secondary scales measured suicidal ideation, anxiety, functional impairment, and quality of life. Results: Treatments were well tolerated and blinding procedures were effective. The mean [95%-CI] change in HDRS-24 score was -5.3 [-10.3, -0.2] for the low-dose group and -9.3 [-12.9, -5.6] for the high-dose group (17% versus 33% reduction). The between-group effect size (standardized mean difference) was -0.56 [-1.39, 0.28]. The group difference was not statistically significant (p=0.24, linear model). The mean change in PHQ-9 score was -2.0 [-3.9, -0.1] for the low dose and -4.8 [-7.7, -2.0] for the high dose. The between-group effect size was -0.73 [-1.59, 0.14] (p=0.09). Secondary outcomes favored the high dose (effect sizes magnitudes 0.1 - 0.9) but did not generally reach statistical significance (p>0.05). Conclusions: The medium-sized effects observed between doses in this small, controlled, clinical trial suggest that propofol may have dose-dependent antidepressant effects. The findings also provide guidance for subsequent trials. A larger sample size and additional treatments in series are likely to enhance the ability to detect dose-dependent effects. Future work is warranted to investigate potential antidepressant mechanisms and dose optimization.

Pharmacist interventions to deprescribe opioids and benzodiazepines in older adults: A rapid review.

BACKGROUND: Many older adults are prescribed opioids and benzodiazepines (BZDs), despite increased susceptibility to adverse events. Challenges of deprescribing include fragmented care and lack of knowledge or time. Pharmacists are well-positioned to overcome these challenges and facilitate deprescribing of these medications. OBJECTIVES: We sought to evaluate interventions utilizing pharmacists to deprescribe opioids and BZDs in older adults. METHODS: We conducted a rapid review following a comprehensive literature search to identify interventions with pharmacist involvement for deprescribing opioids and BZDs in older adults. Studies were included based on: (1) inclusion of patients ≥ 65 years old receiving BZDs and/or opioids, (2) evaluation of feasibility or outcomes following deprescribing (3) pharmacists as part of the intervention. We included randomized, observational, cohort, and pilot studies. Studies that did not report specific results for BZD or opioids were excluded. RESULTS: We screened 687 abstracts and included 17 studies. Most (n = 13) focused on BZD deprescribing. Few studies focused on opioids (n = 2) or co-prescribing of opioids and BZDs (n = 2). The most common intervention was educational brochures (n = 8), majority being the EMPOWER brochure for deprescribing BZDs. Other interventions included chart review with electronic notes (n = 4), pharmacist-led programs/services (n = 2), and multifactorial interventions (n = 3). Many studies were underpowered or lacked suitable control groups. Generally speaking, interventions utilizing educational materials and those in which pharmacists engaged with patients and providers were more effective. Interventions relying on electronic communication by pharmacists were less successful, due to low acceptance or acknowledgement. CONCLUSIONS: We identified a number of feasible interventions to reduce BZD use, but fewer interventions to reduce opioid use in older adults. An optimal approach for deprescribing likely requires pharmacists to engage directly with patients and providers. Larger well-designed studies are needed to evaluate the effectiveness of deprescribing interventions beyond feasibility.

Integrating targeted consultant pharmacists into a new collaborative care model to reduce the risk of falls in older adults owing to the overuse of opioids and benzodiazepines.

Using central nervous system (CNS)-active medications increases older adults' risk for falls and fall-related injuries. Opioids and benzodiazepines are among the most widely used CNS-active medications and because of their addictive potential and widespread use for common ailments such as chronic pain, anxiety, or sleep, are also among the most difficult to deprescribe. Reducing the dose burden of these 2 medication classes in older adults-to balance safety with efficacy-is a challenge that requires persistence and strategic support structures to be successful. We propose a novel care model that uses the support of targeted consultant pharmacist services to help primary care providers reduce the unnecessary use of opioids and benzodiazepines in their patients who are older adults. This care model holds promise to not only offer providers additional time-saving clinical support but to help their practices improve patient outcomes, such as a reduction in medication-related falls and excess opioid use.

GeriWard Falls: An Interprofessional Team-Based Curriculum on Falls in the Hospitalized Older Adult.

INTRODUCTION: Interprofessional (IP) collaboration is key in caring for older adults and a critical part of health professions education. Falls are a source of significant morbidity and mortality in older adults. GeriWard, an innovative curriculum, emphasizes IP collaboration during a clinical encounter with a hospitalized older adult. GeriWard Falls expands on the existing GeriWard curriculum, allowing medical, pharmacy, physical therapy, and nursing students to conduct a comprehensive falls risk evaluation at the bedside. METHODS: The 2-hour exercise consists of participation in a team-based falls risk assessment at the bedside of a hospitalized older adult, development of a falls care plan and communication with the patient and primary inpatient physicians, and completion of clinical questions focused on systems-based interventions to reduce fall risk. RESULTS: A total of 39 students participated in two sessions. Ninety-seven percent of students were likely to change their clinical activities as a result of the session. Faculty facilitators cited the students' ability to effectively collaborate, identify risk factors for falls, and propose systems-based interventions to reduce falls risk. Seventy-eight percent of primary inpatient physicians planned to implement at least one of the IP team recommendations; 89% agreed that the IP team recommendations were helpful. DISCUSSION: The activity was engaging for students and helped them achieve competency with fall risk assessment. Communication of the students' assessment to the primary medical team not only was useful to the primary team but also helped students understand how systems can affect patient care.

Association of shock, coagulopathy, and initial vital signs with massive transfusion in combat casualties.

BACKGROUND: Timely initiation of a massive transfusion (MT) protocol is associated with improved survival and reduced transfusion for patients requiring MT; however, a priori identification of this population is difficult. The objective of this study was to compare the results of an MT prediction model and actual MT incidence in combat casualties. METHODS: We performed a retrospective review of the Joint Theater Trauma Registry transfusion database for all US service personnel injured in combat during overseas contingency operations who received at least 1 unit of blood. Systolic blood pressure at the time of admission, heart rate, hemoglobin, international normalized ratio, and base deficit were used in a previously developed prediction model for MT. RESULTS: Casualties (n = 1124) were identified who had received at least 1 unit of blood and had all data points. Of these patients, 420 patients (37%) received an MT. Subjects presenting with any two of four possible variables (heart rate >110, systolic blood pressure <110 mm Hg, base deficit < or = -6, and hemoglobin <11) had a 54% incidence of MT with a model sensitivity of 69%. Patients predicted but not observed to receive an MT had earlier time of death and an increased incidence of head injuries compared with those predicted and observed to receive an MT. Patients not predicted but observed to receive an MT had increased chest, abdominal, and extremity injuries than those neither predicted nor observed to receive an MT. CONCLUSION: The decision to implement an MT seems to rely heavily on clinical evaluation of severity of abdominal and extremity injury rather than physiologic derangement. Using a model based on the physiologic parameters--a more objective measure--may decrease mortality in combat casualties.

The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease.

Autosomal-dominant polycystic kidney disease (ADPKD) is a common genetic disorder that frequently leads to renal failure. Mutations in polycystin-1 (PC1) underlie most cases of ADPKD, but the function of PC1 has remained poorly understood. No preventive treatment for this disease is available. Here, we show that the cytoplasmic tail of PC1 interacts with tuberin, and the mTOR pathway is inappropriately activated in cyst-lining epithelial cells in human ADPKD patients and mouse models. Rapamycin, an inhibitor of mTOR, is highly effective in reducing renal cystogenesis in two independent mouse models of PKD. Treatment of human ADPKD transplant-recipient patients with rapamycin results in a significant reduction in native polycystic kidney size. These results indicate that PC1 has an important function in the regulation of the mTOR pathway and that this pathway provides a target for medical therapy of ADPKD.

Polycystin-1, STAT6, and P100 function in a pathway that transduces ciliary mechanosensation and is activated in polycystic kidney disease.

Primary cilia are implicated in the pathogenesis of autosomal-dominant polycystic kidney disease (ADPKD), which results from defects in polycystin-1 (PC1), but the function of PC1 remains poorly understood. Here, we show that PC1 undergoes proteolytic cleavage that results in nuclear translocation of its cytoplasmic tail. The PC1 tail interacts with the transcription factor STAT6 and the coactivator P100, and it stimulates STAT6-dependent gene expression. Under normal conditions, STAT6 localizes to primary cilia of renal epithelial cells. Cessation of apical fluid flow results in nuclear translocation of STAT6. Cyst-lining cells in ADPKD exhibit elevated levels of nuclear STAT6, P100, and the PC1 tail. Exogenous expression of the human PC1 tail results in renal cyst formation in zebrafish embryos. These results identify a novel mechanism of cilia function in the transduction of a mechanical signal to changes of gene expression involving PC1 and show that this pathway is inappropriately activated in ADPKD.

Analysis of electrically induced reentrant circuits in a sheet of myocardium.

Understanding the complex spatiotemporal dynamics of action potential propagation in the heart during arrhythmia is exceedingly difficult. This study applies nonlinear dynamics tools to simplify this task. Using the results of a simulation of an electrical induction of reentry in a sheet of myocardium represented as a bidomain, transmembrane voltage maps are processed to obtain: (i) spatial maps of phase angle and phase singularity trajectories, (ii) state scatter plots, and (iii) spatial maps of even phase resetting, wave fronts and wave tails. Tracking the phase singularities allows us to identify the "seeds" of reentry before the reentrant circuit is formed and to characterize the spatiotemporal evolution of the organizing center of the reentrant circuit. The state scatter plots demonstrate the effect of the shock on the instantaneous state of the system. The spatial maps of even phase resetting allow us to identify the shock-induced excitable gaps (regions of regenerative repolarization) as well as the regions directly activated by the shock. These nontraditional approaches to the analysis of electrophysiological phenomena greatly enhance our ability to conceptualize the dynamics of arrhythmias.