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Objective: To conduct a meta-analysis of studies of vortioxetine in adults with major depressive disorder (MDD). DataSources: Abstracts were identified using PubMed by cross-referencing vortioxetine with placebo and randomized. No language or publication year restrictions were used. Study Selection: Randomized, double-blind, placebo-controlled clinical trials comparing oral vortioxetine monotherapy with placebo for acute treatment of MDD. Data Extraction: Data were extracted with a pre-coded form, as follows: number of patients randomized, treatment group, Montgomery-Asberg Depression Rating Scale (MADRS) response and remission rates, and mean change in scores from baseline and standard errors for the MADRS, Hamilton Anxiety Rating Scale (HARS), and Digit Symbol Substitution Test (DSST). Results: 7,269 subjects randomized to vortioxetine (n = 3,630) or placebo (n = 3,639) from 17 studies were included. The probability of receiving placebo did not predict difference in change in MADRS scores between vortioxetine and placebo (estimate = 4.1, P = .54). The standardized mean difference (SMD) (95% CI) for change in MADRS score for vortioxetine overall versus placebo was 0.33 (0.24 to 0.41) and was 0.24 (0.08 to 0.39), 0.33 (0.19 to 0.47), 0.26 (-0.06 to 0.58), and 0.44 (0.27 to 0.62) for 5-mg, 10-mg, 15-mg, and 20-mg doses, respectively. Greater difference in efficacy between drug and placebo was observed in studies with a low rather than a high placebo response rate. Conclusions: Vortioxetine is more effective than placebo in improving depression, anxiety, and cognition. Less informative or uninformative studies obscured the true treatment effect.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic has led to an increased risk of psychiatric symptoms among frontline health care workers (FHCWs). In the current study, a novel "symptomics" approach was employed to examine the association between acute transdiagnostic symptoms of posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and generalized anxiety disorder (GAD) and burnout and work and relationship difficulties in FHCWs at an urban tertiary care hospital in New York City. METHODS: Symptoms of COVID-19-related PTSD (4-item PTSD Checklist-5), MDD (Patient Health Questionnaire-8), GAD (Generalized Anxiety Disorder-7), burnout (Single-Item Mini-Z Burnout Assessment), and functional difficulties (Brief Inventory of Psychosocial Functioning) were assessed. Relative importance analyses were conducted to identify PTSD, MDD, and GAD symptoms associated with burnout and functional difficulties. RESULTS: The total number of eligible participants included 6,026 presumed FHCWs, of which 3,360 (55.8%) completed the survey and 2,579 (76.8%) of whom endorsed directly treating patients with COVID-19 and provided sufficient responses to our outcome variables for analysis. Feeling tired/having little energy, being easily annoyed or irritable, and feeling nervous, anxious, or on edge were most strongly associated with burnout; feeling tired/having little energy accounted for the greatest amount of explained variance (> 15%). Negative expectations of oneself or the world, trouble concentrating, and feeling easily annoyed or irritable were most strongly associated with work difficulties; negative expectations of oneself or the world accounted for the greatest amount of explained variance (> 9%). Feeling easily annoyed or irritable, negative expectations about oneself or the world, and feeling bad about oneself were most strongly associated with relationship difficulties; feeling easily annoyed or irritable accounted for the greatest amount of explained variance (> 10%). CONCLUSIONS: Results of this study underscore the importance of a transdiagnostic, symptom-based approach when examining associations between acute psychopathology and burnout and functional difficulties in FHCWs. Further work is needed to determine if early interventions aimed at ameliorating specific psychiatric symptoms may help mitigate risk for peri- and posttraumatic burnout and functional difficulties in this population.

Listen to experts and view their slides from a panel session at the American Society of Clinical Psychopharmacology (ASCP) meeting, held on May 29, 2019, in Scottsdale, Arizona. Dr Murrough described the current understanding of depression etiology and new insights into antidepressant development. Dr Goldberg shared his expertise about whether antidepressant drugs with novel mechanisms of action can improve outcomes in patients with major depressive disorder. Dr Gaynes reviewed the link between major depressive disorder and elevated mortality risk and whether recovery from depression can reverse patients' mortality risk. Dr Citrome discussed current best practices and new medications for the treatment of depression. Finally, Dr Ketter provided his thoughts on his colleagues' presentations.

OBJECTIVE Esketamine, the S-enantiomer of ketamine, was recently approved as a rapid-acting intranasal therapy for depression and is currently under development for suicidality. The authors sought to determine the efficacy of adjunctive intranasal esketamine in major depressive disorder (MDD). DATA SOURCES A systematic search of PubMed/MEDLINE was conducted up to January 2019, in addition to abstracts of major psychiatric meetings held since 2010. Searches were conducted by cross-referencing the term intranasal with the term esketamine. Where necessary, authors and/or study sponsors were contacted in order to obtain a copy of the presentation as well as any pertinent study details. STUDY SELECTION 241 study abstracts were initially identified and reviewed. Selected studies were randomized, double-blind clinical trials comparing adjunctive intranasal esketamine to adjunctive placebo for MDD. DATA EXTRACTION Data were extracted independently by two of the authors. A random effects model was used to calculate the standardized mean difference (SMD) between esketamine and placebo (intranasal saline) in the Montgomery-Asberg Depression Rating Scale (MADRS) score change from baseline to endpoint, serving as the primary outcome of the study. RESULTS Five trials with 774 patients were pooled. Adjunctive esketamine was significantly more effective than placebo for MADRS score change, response, and remission (N = 774, SMD = 0.36, 95% CI = 0.24-0.49, P < .0001; response: risk ratio [RR] = 1.40, 95% CI = 1.22-1.61, P < .0001; remission: RR = 1.45, 95% CI = 1.20-1.75, P < .0001). Results remained statistically significant regardless of differences in the study sample, fixed vs new/optimized baseline antidepressants. CONCLUSIONS Adjunctive intranasal esketamine for patients with MDD who are either treatment-resistant or acutely suicidal appears to be an effective treatment strategy.

Objective: Ketamine has demonstrated rapid antidepressant effects in patients with treatmentresistant depression (TRD); however, the safety and tolerability of ketamine in this population have not been fully described. Herein we report the largest study to date of the safety, tolerability, and acceptability of ketamine in TRD. Method: Data from 205 intravenous (IV) ketamine infusions (0.5 mg/kg over 40 minutes) in 97 participants with DSM-IV‐defined major depressive disorder (MDD) were pooled from 3 clinical trials conducted between 2006 and 2012 at 2 academic medical centers. Safety and tolerability measures included attrition, adverse events (AEs), hemodynamic changes, and assessments of psychosis and dissociation. Results: The overall antidepressant response rate, defined as a ≥ 50% improvement in MontgomeryAsberg Depression Rating Scale score, was 67% (65 of 97 participants). Four of 205 infusions (1.95%) were discontinued due to AEs. The overall attrition rate was 3.1% (3 of 97). In the first 4 hours after the infusion, the most common general AEs were drowsiness, dizziness, poor coordination, blurred vision, and feeling strange or unreal. Approximately one third of individuals experienced protocol-defined hemodynamic changes. Ketamine resulted in small but significant increases in psychotomimetic and dissociative symptoms (all P < .05). There were no cases of persistent psychotomimetic effects, adverse medical effects, or increased substance use in a subgroup of patients with available long-term follow-up information. Conclusions: In this relatively large group of patients with TRD, ketamine was safe and well tolerated. Further research investigating the safety of ketamine in severe and refractory depression is warranted. Trial Registration: ClinicalTrials.gov identifiers: NCT00419003, NCT00548964, and NCT00768430.