Faculty Bibliography

BACKGROUND:Patients with bipolar disorder have higher rates of cardiometabolic comorbidities and mortality. Although guidelines emphasize the importance of cardiovascular monitoring, few studies characterized the cardiometabolic risk profile during treatment and their relation to symptomatology and treatment response. METHODS:We analyzed data from two similar 24-weeks comparative effectiveness trials, with a combined sample of 770 participants randomized to two different lithium doses, quetiapine (300 mg/day), or standard treatment without lithium. Glucose, lipids and vital signs were measured before and after 24 weeks of treatment. We calculated several cardiovascular risk scores, assessed baseline correlations and compared the four treatment arms via multiple linear regression models. RESULTS:Higher cholesterol and LDL levels were associated with greater depression severity, showing differential correlations to specific symptoms, particularly agitation, low energy and suicidality. Those randomized to quetiapine showed a significant worsening of cardiometabolic markers during the 24-week trial. Neither baseline nor change in lipid levels correlated with differential treatment response. LIMITATIONS:Study duration was short from the perspective of cardiometabolic risk markers, and all treatment arms included patients taking adjunct antipsychotics. The trials compared quetiapine to lithium, but not to other medications known to affect similar risk factors. CONCLUSIONS:Treatment with 300 mg/day quetiapine for 24 weeks, representing a short and common dose course, resulted in increased cardiometabolic risk markers, emphasizing the importance of monitoring during mood-stabilizing treatment. The symptom-specific associations are in line with previous studies in unipolar depression, suggesting a cardiometabolic-depression link that needs to be further studied in bipolar depression.

Objective: Ketamine is a novel and rapidly acting treatment for major depressive disorder (MDD). Benzodiazepines are commonly coprescribed with antidepressants in MDD. This study sought to examine data from a randomized clinical trial that compared a single infusion of intravenous (IV) ketamine to midazolam placebo in treatment-resistant depression (DSM-IV-TR MDD) and to assess whether the use of concomitant oral benzodiazepines differentially affected treatment response to ketamine versus midazolam. Methods: This trial ran from December 2015 to December 2016. Subjects who were taking oral benzodiazepines (n = 44) were compared to those who were not (n = 55). A significant treatment-by-benzodiazepine effect could be interpreted as a possible moderator of differential treatment response to ketamine versus midazolam. Benzodiazepine use was examined as both a binary and a continuous predictor, to assess the impact of dosage. Results: Benzodiazepine users did not differ from non-users on the original study's primary outcome measure, score on the 6-item Hamilton Depression Rating Scale (HDRS-6), at baseline, but the former had more severe anxiety. When oral benzodiazepine use was modeled as a binary predictor, benzodiazepine use did not impact differential treatment response. However, when benzodiazepine dosage was considered, there was a significant impact of benzodiazepine use on differential treatment response. Oral benzodiazepines significantly impacted HDRS-6 (P = .018) and Clinical Global Impressions-Severity of Illness scale (CGI-S; P = .008) scores at day 1 (24 hours post treatment); effects were nonsignificant for all day 3 outcomes. Among ketamine subjects, higher doses of benzodiazepines were associated with less improvement in depression scores at day 1. Conclusions: Concomitant oral benzodiazepines at higher doses may attenuate the antidepressant effects of IV ketamine at day 1 but not day 3 post-infusion.

BACKGROUND:Burnout, by definition, is related to adverse chronic workplace stressors. Life events outside the workplace have been associated with an increased risk of psychiatric morbidity. However, it is unknown whether life events outside the workplace increase the severity of burnout. PURPOSE/OBJECTIVE:The aim of the study was to investigate the association between burnout and life events outside the workplace in nursing assistants. METHODS:In an observational, cross-sectional, single-site study of 521 nursing assistants at a university hospital, we assessed burnout with the Maslach Burnout Inventory-Human Services Survey, and life events with the Social Readjustment Rating Scale. We constructed equations of multiple linear regression analyses that included each burnout subscale as the dependent variable and a domain of life events as the independent variable. Results were adjusted for potential confounders, including gender, no religion or faith, years of work, and depression. RESULTS:An increase in the number of life events in the domain of personal changes or difficulties (e.g., personal injury or illness, sexual difficulties, change in recreation, church activities, social activities, sleeping habits, eating habits and revision of personal habits) was associated with increased severity of emotional exhaustion. An increase in the number of life events in the domain of changes in familial situation and in the domains of death of relatives or friends were associated with increased severity of depersonalization. Those associations were independent of work-related life events and other potential confounders. CONCLUSIONS:Life events outside the workplace may increase the levels of burnout in nursing assistants.

OBJECTIVE:Adiponectin, which is secreted from adipose tissue, is a protein hormone. Although a large body of studies have found that circulating adiponectin levels increase in anorexia nervosa (AN) and caloric restriction, the effect of subtypes of AN and modifiers of adiponectin in AN are not yet known. METHODS:A systematic search of electronic databases was performed using the search terms "adiponectin," "anorexia nervosa," and "eating disorder" up to January 2021. All studies published in peer-reviewed journals, which included cases and control groups, were selected. The main outcome was the pooled standardized mean difference (SMD) in adiponectin levels between cases and controls, using the random-effects model. Modifiers of SMD were tested via meta-regression. Heterogeneity and publication bias were evaluated. RESULTS:Thirty-four studies met all eligibility criteria. The total sample of AN participants (Hedges' g = .765, p < .0001), and specifically the binge-eating/purging (Hedges' g = 1.211, p < .00001) and restrictive subtypes (Hedges' g = .913, p < .00001) of AN have increased adiponectin plasma levels compared with healthy controls. Meta-regression determined that insulin, IGF-1, BMI, triglyceride, resistin, glucose, IL-6 levels are significant modifiers of adiponectin levels. DISCUSSION/CONCLUSIONS:Compared with controls, adiponectin levels are higher in AN overall, and specifically in the binge-eating/purging and the restrictive AN subtypes. Many of metabolic parameters of glucose metabolism and pro-inflammatory molecules modify the relationship between AN and adiponectin levels. Adipose tissue is important to maintain metabolic stability. PUBLIC SIGNIFICANCE/UNASSIGNED:Anorexia nervosa is a psychiatric disorder associated with a severe decrease in body weight and multiple metabolic abnormalities, including an increase in the hormone adiponectin. In this paper, we used meta-analysis, a powerful statistical method, to aggregate data from 34 rigorously selected research reports. This enabled us to understand the value of adiponectin to differentiate clinical subtypes of anorexia nervosa and the relations between adiponectin and other important metabolic parameters.

OBJECTIVE/UNASSIGNED:Altered glutamatergic neurotransmission is implicated in the pathogenesis of major depressive disorder. AXS-05 (dextromethorphan-bupropion) is an oral NMDA receptor antagonist and sigma-1 receptor agonist, which utilizes inhibition of CYP2D6 to increase its bioavailability. This phase 2 trial assessed the efficacy and safety of dextromethorphan-bupropion in the treatment of major depressive disorder. METHODS/UNASSIGNED:This randomized, double-blind, multicenter, parallel-group trial evaluated dextromethorphan-bupropion versus the active comparator sustained-release bupropion in patients 18-65 years old with a diagnosis of major depressive disorder of moderate or greater severity. Patients were randomly assigned to receive either dextromethorphan-bupropion (45 mg/105 mg tablet) or bupropion (105 mg tablet), once daily for the first 3 days and twice daily thereafter, for a total of 6 weeks. The primary endpoint was overall treatment effect on Montgomery-Åsberg Depression Rating Scale (MADRS) score (average of the change from baseline for weeks 1-6), assessed in all randomized patients whose diagnosis and severity were confirmed by an independent assessor and who received at least one dose of study medication and had at least one postbaseline assessment. RESULTS/UNASSIGNED:Of 97 patients randomized, 17 did not have a confirmed diagnosis and severity based on the independent assessment, resulting in 80 patients in the efficacy population (dextromethorphan-bupropion, N=43; bupropion, N=37). The mean change from baseline in MADRS score over weeks 1-6 (overall treatment effect) was significantly greater with dextromethorphan-bupropion than with bupropion (-13.7 points vs. -8.8 points; least-squares mean difference=-4.9; 95% CI=-3.1, -6.8). MADRS score change with dextromethorphan-bupropion was significantly greater than with bupropion at week 2 and every time point thereafter (week 6: -17.3 vs. -12.1 points; least-squares mean difference=-5.2, 95% CI=-1.1, -9.3). Remission rates were significantly greater with dextromethorphan-bupropion at week 2 and every time point thereafter (week 6: 46.5% vs. 16.2%; least-squares mean difference=30.3%, 95% CI=11.2, 49.4). Response rates (≥50% decrease in MADRS score from baseline) at week 6 were 60.5% with dextromethorphan-bupropion and 40.5% with bupropion (least-squares mean difference=19.9%, 95% CI=-1.6, 41). Most secondary outcomes favored dextromethorphan-bupropion. The most common adverse events with dextromethorphan-bupropion were dizziness, nausea, dry mouth, decreased appetite, and anxiety. Dextromethorphan-bupropion was not associated with psychotomimetic effects, weight gain, or sexual dysfunction. CONCLUSIONS/UNASSIGNED:In patients with major depression, dextromethorphan-bupropion (AXS-05) significantly improved depressive symptoms compared with bupropion and was generally well tolerated.