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Kyle AB Lapidus, Laili Soleimani, James W MurroughMood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USAAbstract: Mood disorders are common and debilitating, resulting in a significant public health burden. Current treatments are only partly effective and patients who have failed to respond to trials of existing antidepressant agents (eg, those who suffer from treatment-resistant depression [TRD]) require innovative therapeutics with novel mechanisms of action. Although neuroscience research has elucidated important aspects of the basic mechanisms of antidepressant action, most antidepressant drugs target monoaminergic mechanisms identified decades ago. Glutamate, the major excitatory neurotransmitter in the central nervous system, and glutamatergic dysfunction has been implicated in mood disorders. These data provide a rationale for the pursuit of glutamatergic agents as novel therapeutic agents. Here, we review preclinical and clinical investigations of glutamatergic agents in mood disorders with a focus on depression. We begin with discussion of evidence for the rapid antidepressant effects of ketamine, followed by studies of the antidepressant efficacy of the currently marketed drugs riluzole and lamotrigine. Promising novel agents currently in development, including N-methyl-D-aspartate (NMDA) receptor modulators, 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid (AMPA) receptor modulators, and drugs with activity at the metabotropic glutamate (mGlu) receptors are then reviewed. Taken together, both preclinical and clinical evidence exists to support the pursuit of small molecule modulators of the glutamate system as novel therapeutic agents in mood disorders. It is hoped that by targeting neural systems outside of the monoamine system, more effective and perhaps faster acting therapeutics can be developed for patients suffering from these disabling disorders.Keywords: glutamate, mood disorders, major depressive disorder, ketamine, NMDA, AMPA

Currently available drugs for unipolar major depressive disorder (MDD), which target monoaminergic systems, have a delayed onset of action and significant limitations in efficacy. Antidepressants with primary pharmacological targets outside the monoamine system may offer the potential for more rapid activity with improved therapeutic benefit. The glutamate system has been scrutinized as a target for antidepressant drug discovery. The purpose of this article is to review emerging literature on the potential rapid-onset antidepressant properties of the glutamate NMDA receptor antagonist ketamine, an established anaesthetic agent. The pharmacology of ketamine and its enantiomer S-ketamine is reviewed, followed by examples of its clinical application in chronic, refractory pain conditions, which are commonly co-morbid with depression. The first generation of studies in patients with treatment-resistant depression (TRD) reported the safety and acute efficacy of a single subanaesthetic dose (0.5 mg/kg) of intravenous ketamine. A second generation of ketamine studies is focused on testing alternate routes of drug delivery, identifying methods to prevent relapse following resolution of depressive symptoms and understanding the neural basis for the putative antidepressant actions of ketamine. In addition to traditional depression rating endpoints, ongoing research is examining the impact of ketamine on neurocognition. Although the first clinical report in MDD was published in 2000, there is a paucity of adequately controlled double-blind trials, and limited clinical experience outside of research settings. Given the potential risks of ketamine, safety considerations will ultimately determine whether this old drug is successfully repositioned as a new therapy for TRD. [ABSTRACT FROM AUTHOR]

Background: Harmine is a component of the hallucinogenic brew, Ayahuasca, which also contains the psychoactive compound, N , N -dimethyltryptamine. Whether pharmaceutical-grade harmine hydrochloride (HCl) has psychoactive effects, the doses at which these might occur, and the dose-response relationship to side effects and safety in humans are unknown., Methods: We conducted a Phase 1, open-label single ascending dose trial in healthy adults with normal body mass index and no prior psychiatric illness. The primary goal was to determine the maximum tolerated dose (MTD) of oral pharmaceutical-grade harmine HCl and to characterize safety and tolerability. A secondary goal was to ascertain whether any oral dose has psychoactive effects., Results: Thirty-four adult participants, aged 18-55 years, were screened for study eligibility. Twenty-five participants met eligibility criteria and were randomized to a single dose of 100, 200, 300, or 500 mg of harmine HCl, respectively, using a continuous reassessment method. The most common adverse events (AEs) observed were gastrointestinal and/or neurological, dose-related, and of mild to moderate severity. The MTD was determined to be between 100 and 200 mg and is weight-based, with 90% of those participants receiving >2.7 mg/kg experiencing a dose-limiting toxicity. No serious AEs of harmine HCl were identified., Conclusions: Harmine HCl can be orally administered to healthy participants in doses <2.7 mg/kg with minimal or no AEs. Doses >2.7 mg/kg are associated with vomiting, drowsiness, and limited psychoactivity. This study is the first to systematically characterize the psychoactive effects of pharmaceutical quality harmine in healthy participants.

Background: Research suggests that healthcare workers are at greater risk for suicide than other occupations, but most published studies focus on physicians. This study examines the prevalence of suicidal ideation (SI) and associated occupational factors among a broad group of non-physician healthcare staff., Methods: An anonymous online survey was sent to a random sample of 30 % of non-physician healthcare staff at a large urban healthcare system between September and November 2022. Weighted multivariable binary logistic regressions were conducted to determine the workplace and mental health factors associated with SI., Results: The 1084 respondents included nurses, administrative staff, research staff, medical assistants, nurse practitioners, physician assistants, and other roles. Of the sample, 8.8 % endorsed having SI over the prior two weeks. Results of the regression indicated that, after adjusting for demographic factors, greater odds of SI were associated with physical violence experienced from a patient or visitor (odds ratio [OR] = 2.15, 95 % confidence interval [CI] = 1.06-4.37), lower perceived leadership support (OR = 0.95, 95 % CI = 0.92-0.98), and positive screening for depression (OR = 4.66, 95 % CI = 2.45-8.86). Exploratory analysis suggests that depression may be a mediating factor between workplace stressors and SI., Limitations: Limitations include the response rate, the use of a single item to assess SI, and the cross-sectional design., Conclusion: Findings suggest that workplace violence and leadership support are important occupational factors associated with SI among healthcare workers. Reducing and mitigating workplace violence, enhancing leadership support, and improving access to mental health care should be considered targets for interventions to decrease suicide risk in this population., Competing Interests: Declaration of competing interest Jonathan M. DePierro receives book royalties from Cambridge University Press and compensation related to an editor in chief role with Springer Press; and is named on a U.S. patent application for a digital health intervention, an intellectual property that that has yet to be licensed. He has received honoraria from New York University, University of New Mexico, Ro Health Ventures Inc., the Canadian Institutes of Health Research, and the US Department of State. Lauren Peccoralo received honoraria from Atrium Health Wake Forest Baptist, American Society of Health-System Pharmacists, Stanford University, University of Montana and Baylor, Scott & White Health. Jonathan Ripp received honoraria for numerous speaking engagements at professional societies, academic medical centers, health care institutions; serves as a course director for the Institute for Healthcare Improvement, worked as a consultant for the well-being program at the NYU School of Medicine Long Island; served as a non-fiduciary board member of the Lorna Breen Foundation; and served on a temporary advisory board established by PEPSICO to inform employee well-being efforts, and provides consultation to Marvin Behavioral Health, Inc. The remaining authors have no conflict of interest to disclose., (Published by Elsevier B.V.)

Background: Mood and anxiety disorders are highly prevalent and comorbid worldwide, with variability in symptom severity that fluctuates over time. Digital phenotyping, a growing field that aims to characterize clinical, cognitive and behavioral features via personal digital devices, enables continuous quantification of symptom severity in the real world, and in real-time., Methods: In this study, N=114 individuals with a mood or anxiety disorder (MA) or healthy controls (HC) were enrolled and completed 30-days of ecological momentary assessments (EMA) of symptom severity. Novel real-world measures of anxiety, distress and depression were developed based on the established Mood and Anxiety Symptom Questionnaire (MASQ). The full MASQ was also completed in the laboratory (in-lab). Additional EMA measures related to extrinsic and intrinsic motivation, and passive activity data were also collected over the same 30-days. Mixed-effects models adjusting for time and individual tested the association between real-world symptom severity EMA and the corresponding full MASQ sub-scores. A graph theory neural network model (D EP NA) was applied to all data to estimate symptom interactions., Results: There was overall good adherence over 30-days (MA=69.5%, HC=71.2% completion), with no group difference (t (58) =0.874, p=0.386). Real-world measures of anxiety/distress/depression were associated with their corresponding MASQ measure within the MA group (t's > 2.33, p's < 0.024). Physical activity (steps) was negatively associated with real-world distress and depression (IRRs > 0.93, p's ≤ 0.05). Both intrinsic and extrinsic motivation were negatively associated with real-world distress/depression (IRR's > 0.82, p's < 0.001). D EP NA revealed that both extrinsic and intrinsic motivation significantly influenced other symptom severity measures to a greater extent in the MA group compared to the HC group (extrinsic/intrinsic motivation: t (46) = 2.62, p < 0.02, q FDR < 0.05, Cohen's d = 0.76; t (46) = 2.69, p < 0.01, q FDR < 0.05, Cohen's d = 0.78 respectively), and that intrinsic motivation significantly influenced steps (t (46) = 3.24, p < 0.003, q FDR < 0.05, Cohen's d = 0.94)., Conclusions: Novel real-world measures of anxiety, distress and depression significantly related to their corresponding established in-lab measures of these symptom domains in individuals with mood and anxiety disorders. Novel, exploratory measures of extrinsic and intrinsic motivation also significantly related to real-world mood and anxiety symptoms and had the greatest influencing degree on patients' overall symptom profile. This suggests that measures of cognitive constructs related to drive and activity may be useful in characterizing phenotypes in the real-world.

Grape and grape derived products contain many bioactive phenolics which have a variety of impacts on health. Following oral ingestion, the phenolic compounds and their metabolites may be detectable in human urine. However, developing a reliable method for the analysis of phenolic compounds in urine is challenging. In this work, we developed and validated a new high-throughput, sensitive and reproducible analytical method for the simultaneous analysis of 31 grape phenolic compounds and metabolites using Oasis PRiME HLB cleanup for sample preparation combined with ultra-performance liquid chromatography with triple quadrupole tandem mass spectrometry (UHPLC-QqQ-MS/MS). Using this new method, the accuracy achieved was 69.3 % ∼ 134.9 % (except for six compounds), and the recovery achieved was 52.4 % ∼ 134.7 % (except for two very polar compounds). For each of the 31 target analytes, the value of intra-day precision was less than 14.3 %. The value of inter-day precision was slightly higher than intra-day precision, with a range of 0.7 % ∼ 19.1 %. We report for the first time on the effect of gender and BMI on the accuracy and recovery of human urine samples, and results from analysis of variance (ANOVA), and principal component analysis (PCA) indicated there was no difference in the value of accuracy and recovery between different gender or BMI (>30) using our purposed cleanup and UHPLC-QqQ-MS/MS method. Overall, this newly developed method could serve as a powerful tool for analyzing grape phenolic compounds and metabolites in human urine samples., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, CYP2D6 and CYP2C19. However, the effectiveness of prospectively using pharmacogenetic variants to select or dose SSRIs for depression is uncertain in routine clinical practice. The objective of this prospective, multicenter, pragmatic randomized controlled trial is to determine the effectiveness of genotype-guided selection and dosing of antidepressants on control of depression in participants who are 8 years or older with ≥3 months of depressive symptoms who require new or revised therapy. Those randomized to the intervention arm undergo pharmacogenetic testing at baseline and receive a pharmacy consult and/or automated clinical decision support intervention based on an actionable phenotype, while those randomized to the control arm have pharmacogenetic testing at the end of 6-months. In both groups, depression and drug tolerability outcomes are assessed at baseline, 1 month, 3 months (primary), and 6 months. The primary end point is defined by change in Patient-Reported Outcomes Measurement Information System (PROMIS) Depression score assessed at 3 months versus baseline. Secondary end points include change inpatient health questionnaire (PHQ-8) measure of depression severity, remission rates defined by PROMIS score < 16, medication adherence, and medication side effects. The primary analysis will compare the PROMIS score difference between trial arms among those with an actionable CYP2D6 or CYP2C19 genetic result or a CYP2D6 drug-drug interaction. The trial has completed accrual of 1461 participants, of which 562 were found to have an actionable phenotype to date, and follow-up will be complete in April of 2024., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background and Aims: Chronic stress associates with cardiovascular disease, but mechanisms remain incompletely defined. Advanced imaging was used to identify stress-related neural imaging phenotypes associated with atherosclerosis., Methods: Twenty-seven individuals with post-traumatic stress disorder (PTSD), 45 trauma-exposed controls without PTSD, and 22 healthy controls underwent 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI). Atherosclerotic inflammation and burden were assessed using 18F-FDG PET (as maximal target-to-background ratio, TBR max) and MRI, respectively. Inflammation was assessed using high-sensitivity C-reactive protein (hsCRP) and leucopoietic imaging (18F-FDG PET uptake in spleen and bone marrow). Stress-associated neural network activity (SNA) was assessed on 18F-FDG PET as amygdala relative to ventromedial prefrontal cortex (vmPFC) activity. MRI diffusion tensor imaging assessed the axonal integrity (AI) of the uncinate fasciculus (major white matter tract connecting vmPFC and amygdala)., Results: Median age was 37 years old and 54% of participants were female. There were no significant differences in atherosclerotic inflammation between participants with PTSD and controls; adjusted mean difference in TBR max (95% confidence interval) of the aorta 0.020 (-0.098, 0.138), and of the carotids 0.014 (-0.091, 0.119). Participants with PTSD had higher hsCRP, spleen activity, and aorta atherosclerotic burden (normalized wall index). Participants with PTSD also had higher SNA and lower AI. Across the cohort, carotid atherosclerotic burden (standard deviation of wall thickness) associated positively with SNA and negatively with AI independent of Framingham risk score., Conclusions: In this study of limited size, participants with PTSD did not have higher atherosclerotic inflammation than controls. Notably, impaired cortico-limbic interactions (higher amygdala relative to vmPFC activity or disruption of their intercommunication) associated with carotid atherosclerotic burden. Larger studies are needed to refine these findings., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: The construct of psychological resilience has received increasing attention in the mental health field. This article describes the development and initial validation of a novel self-report resilience scale, which addresses gaps in the resilience measurement literature by assessing thoughts and behaviors that help promote resilience rather than traits, and simultaneously evaluating multiple factors previously associated with resilience., Method: Following consensus meetings focused on scale development, we conducted an online study ( n = 1,864) of U.S. adults to develop and validate an initial version of the Mount Sinai Resilience Scale (MSRS)., Results: An exploratory factor analysis in a random 50% of the sample suggested a seven-factor solution; this solution was then generally supported by a follow-up confirmatory factor analysis in the remaining 50% of the sample. After removing poor-fitting items, a revised 24-item scale correlated in the expected directions with established measures of perceived resilience and resilience-related constructs (e.g., social support and optimism)., Conclusions: Collectively, the results of this study provide initial support for the convergent and discriminant validity of the MSRS and describe its factor structure. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Psychosocial stress has profound effects on the body, including the immune system and the brain 1,2 . Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD) 3 , the underlying mechanisms are not well understood. Here we show that expression of a circulating myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is increased in the serum of humans with MDD as well as in stress-susceptible mice following chronic social defeat stress (CSDS). In mice, we show that this increase leads to alterations in extracellular space and neurophysiological changes in the nucleus accumbens (NAc), as well as altered social behaviour. Using a combination of mass cytometry and single-cell RNA sequencing, we performed high-dimensional phenotyping of immune cells in circulation and in the brain and demonstrate that peripheral monocytes are strongly affected by stress. In stress-susceptible mice, both circulating monocytes and monocytes that traffic to the brain showed increased Mmp8 expression following chronic social defeat stress. We further demonstrate that circulating MMP8 directly infiltrates the NAc parenchyma and controls the ultrastructure of the extracellular space. Depleting MMP8 prevented stress-induced social avoidance behaviour and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a mechanism by which peripheral immune factors can affect central nervous system function and behaviour in the context of stress. Targeting specific peripheral immune cell-derived matrix metalloproteinases could constitute novel therapeutic targets for stress-related neuropsychiatric disorders., (© 2024. The Author(s).)

Clinical studies have revealed a high comorbidity between autoimmune diseases and psychiatric disorders, including major depressive disorder (MDD). However, the mechanisms connecting autoimmunity and depression remain unclear. Here, we aim to identify the processes by which stress impacts the adaptive immune system and the implications of such responses to depression. To examine this relationship, we analyzed antibody responses and autoimmunity in the chronic social defeat stress (CSDS) model in mice, and in clinical samples from patients with MDD. We show that socially stressed mice have elevated serum antibody concentrations. We also confirm that social stress leads to the expansion of specific T and B cell populations within the cervical lymph nodes, where brain-derived antigens are preferentially delivered. Sera from stress-susceptible (SUS) mice exhibited high reactivity against brain tissue, and brain-reactive immunoglobulin G (IgG) antibody levels positively correlated with social avoidance behavior. IgG antibody concentrations in the brain were significantly higher in SUS mice than in unstressed mice, and positively correlated with social avoidance. Similarly, in humans, increased peripheral levels of brain-reactive IgG antibodies were associated with increased anhedonia. In vivo assessment of IgG antibodies showed they largely accumulate around blood vessels in the brain only in SUS mice. B cell-depleted mice exhibited stress resilience following CSDS, confirming the contribution of antibody-producing cells to social avoidance behavior. This study provides mechanistic insights connecting stress-induced autoimmune reactions against the brain and stress susceptibility. Therapeutic strategies targeting autoimmune responses might aid in the treatment of patients with MDD featuring immune abnormalities., Competing Interests: Competing interests statement:Y.S. is currently a full time employee of Shionogi & Co., Ltd. This work is independent of Y.S.’s affiliation with Shionogi & Co., Ltd and was performed solely while serving as a visiting scholar at Mount Sinai.

Background: Depression symptoms are prevalent in multiple sclerosis (MS) and associated with poorer cognition in cross-sectional studies; it is unknown whether changes in depression symptoms track with cognitive changes longitudinally., Objective: Investigate whether changes in depression symptoms correspond with cognitive changes over time in MS, and identify specific cognitive functions related to depression symptoms., Method: Persons with early relapse-onset MS ( n = 165) completed a depression questionnaire (Beck Depression Inventory FastScreen) and tests of cognitive speed, executive control, and memory at baseline and 3-year follow-up. One-way ANOVAs assessed differences in cognitive change across participants with worsened, stable, or improved depression symptoms from baseline to year 3., Results: Change in depression symptoms was related to change in executive control ( p = 0.001, η p 2 = 0.08; worsened mood with worsened executive control; improved mood with improved executive control), even when adjusting for cognitive speed ( p = 0.002, η p 2 = 0.08). There were no links to cognitive speed ( p = 0.826) or memory ( p = 0.243). Regarding individual depression symptoms, executive control was related to loss of pleasure and suicidal thoughts., Conclusions: Executive control tracks with depression symptoms, raising hope that management of mood may improve executive control. The specific link between executive control and anhedonia implicates dysfunctional reward processing as a key component of MS depression., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Growing evidence indicates that anhedonia is a multifaceted construct. This study examined the possibility of identifying subgroups of people with anhedonia using multiple reward-related measures to provide greater understanding the Research Domain Criteria's Positive Valence Systems Domain and pathways for developing treatments., Methods: Latent profile analysis of baseline data from a study that examined the effects of a novel kappa opioid receptor (KOR) antagonist drug on measures and biomarkers associated with anhedonia was used to identify subgroups. Measures included ventral striatal activation during the Monetary Incentive Delay task, response bias in the Probabilistic Reward Task, reward valuation scores from the Effort-Expenditure for Rewards Task, and scores from reward-related self-report measures., Results: Two subgroups were identified, which differed on self-report measures of reward. Participants in the subgroup reporting more anhedonia also reported more depression and had greater illness severity and functional impairments. Graphs of change with treatment showed a trend for the less severe subgroup to demonstrate higher response to KOR antagonist treatment on the neuroimaging measure, probabilistic reward task, and ratings of functioning; the subgroup with greater severity showed a trend for higher treatment response on reward-related self-report measures., Limitations: The main limitations include the small sample size and exploratory nature of analyses., Conclusions: Evidence of possible dissociation between self-reported measures of anhedonia and other measures with respect to treatment response emerged. These results highlight the importance for future research to consider severity of self-reported reward-related deficits and how the relationship across measurement methods may vary with severity., Competing Interests: Declaration of competing interest Darrow: reports no financial relationship with commercial interests. Pizzagalli: Over the past 3 years, Dr. Pizzagalli has received consulting fees from Albright Stonebridge Group, Boehringer Ingelheim, Compass Pathways, Engrail Therapeutics, Neumora Therapeutics (formerly BlackThorn Therapeutics), Neurocrine Biosciences, Neuroscience Software, Otsuka, Sunovion, and Takeda; he has received honoraria from the Psychonomic Society and American Psychological Association (for editorial work) and from Alkermes; he has received research funding from the Brain and Behavior Research Foundation, Dana Foundation, Wellcome Leap, Millennium Pharmaceuticals, and NIMH; he has received stock options from Compass Pathways, Engrail Therapeutics, Neumora Therapeutics, and Neuroscience Software; he has a financial interest in Neumora Therapeutics, which has licensed the copyright to the human version of the probabilistic reward task through Harvard University. No funding from these entities was used to support the current work, and all views expressed are solely those of the authors. Smoski: reports no financial relationships with commercial interests. Mathew: Dr. Mathew has been a consultant for Allergan, Alkermes, Axsome Therapeutics, BioXcel Therapeutics, Clexio Biosciences, Eleusis, EMA Wellness, Engrail Therapeutics, Intra-Cellular Therapies, Greenwich Biosciences, Janssen, Levo Therapeutics, Neurocrine, Perception Neuroscience, Praxis Precision Medicines, Relmada Therapeutics, Sage Therapeutics, Signant Health and Seelos Therapeutics, and received research support from Biohaven, Janssen, Merck, NIH, NeuroRx, PCORI, Sage Therapeutics, VA, and VistaGen Therapeutics, drug from Biohaven for NIMH-funded study, and support from the Michael E. Debakey VA Medical Center (Houston, TX) for use of resources and facilities and The Menninger Clinic, Houston, Texas. Nurnberger: J.N. has received research funding from Janssen and Assurex. Lisanby: S.H.L. is a co-inventor on a patent for TMS Technology, unrelated to this manuscript. S.H.L. contributed to this article while at Duke University, before joining the National Institute of Mental Health. The views expressed are her own and do not necessarily represent the views of the National Institutes of Health, the Department of Health, or the US government. Iosifescu: In the past 5 years, Dr. Iosifescu has received consulting fees from Alkermes, Axsome, Allergan, Biogen, the Centers for Psychiatric Excellence, Global Medical Education, MyndAnalytics (CNS Response), Jazz, Lundbeck, Otsuka, Precision Neuroscience, Sage, Sunovion; and he has received research grant support (through his academic institutions) from Alkermes, AstraZeneca, Brainsway, LiteCure, NeoSync, Roche, and Shire. Murrough: In the past 5 years, Dr. Murrough has served as a consultant to Allergan, Boehreinger Ingelheim, Clexio Biosciences, Global Medical Education (GME), Otsuka, Sage Therapeutics, and Engrail Therapeutics. Dr. Murrough is named on a patent pending for neuropeptide Y as a treatment for mood and anxiety disorders and on a patent pending for the use of KCNQ channel openers to treat depression and related conditions. The Icahn School of Medicine (employer of Dr. Murrough) is named on a patent and has entered into a licensing agreement and will receive payments related to the use of ketamine or esketamine for the treatment of depression. The Icahn School of Medicine is also named on a patent related to the use of ketamine for the treatment of PTSD. Dr. Murrough is not named on these patents and will not receive any payments. Yang: reports no financial relationship with commercial interests. Weiner: reports no financial relationship with commercial interests. Sanacora: has consulted for Allergan, Alkermes, AstraZeneca, Avanier Pharmaceuticals, Axsome Therapeutics, Biogen, Biohaven Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Clexio Biosciences, Denovo Biopharma, EMA- Wellness, Engrail, Freedom, Gilgamesh, Hoffman La-Roche, Intra-Cellular Therapies, Janssen, Levo, Lundbeck, Merck, Naurex, Navitor Pharmaceuticals, Neurocrine Biosciences, Novartis, Noven Pharmaceuticals, Otsuka, Praxis Therapeutics, Perception Neuroscience, Praxis Therapeutics, Sage Pharmaceuticals, Seelos Pharmaceuticals, Taisho Pharmaceuticals, Teva, Valeant, Vistagen Therapeutics, and XW Labs. GS also received research funding from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Hoffman La-Roche, Merck, Naurex, Servier and Usona Institute. G.S. holds equity in BioHaven Pharmaceuticals and is a co-inventor on a US patent (#8,778,979) held by Yale University and a co-inventor on US Provisional Patent Application No. 047162-7177P1 (00754) filed on August 20, 2018, by Yale University Office of Cooperative Research. Yale University (Employer of Dr. Sanacora) has a financial relationship with Janssen Pharmaceuticals and may in the future receive financial benefits from this relationship. Keefe: During the period that work was conducted on this study, R.S.E.K. was the owner of VeraSci, a for-profit company that provides clinical trial support and other services for over 100 pharmaceutical companies and other institutions. Song: has received research support from the NIH and GE Healthcare. Goodman: W.G. has consulted for Biohaven Pharmaceuticals, received research funding from the NIH, the McNair Foundation, and Biohaven Pharmaceuticals, and received donated devices from Medtronic. Whitton: Dr. Whitton was partially supported by a grant from the National Health and Medical Research Council of Australia (GNT: 1110773). Potter: Is on a DSMB for Agene-Bio and Regenacy, has stock ownership in Merck, and has received consulting fees from Karuna, Eliem, Neurocrine, Emerald Lake Safety, Boston Pharmaceuticals, and Otsuka and receives research funding from the NIH as a co-PI on a small business grant to praxis Bioresearch. Krystal: Dr. Krystal has received research grants from Janssen Pharmaceuticals, Axsome Pharmaceutics, Reveal Biosensors, The Ray and Dagmar Dolby Family Fund, and the National Institutes of Health. He has received consulting fees from Adare, Axsome Therapeutics, Big Health, Eisai, Evecxia, Ferring Pharmaceuticals, Galderma, Harmony Biosciences, Idorsia, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Millenium Pharmaceuticals, Merck, Neurocrine Biosciences, Neurawell, Pernix, Otsuka Pharmaceuticals, Sage, Takeda, and Angelini. He owns options of Big Health., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Treatment-resistant depression (TRD) is common and associated with multiple serious public health implications. A consensus definition of TRD with demonstrated predictive utility in terms of clinical decision-making and health outcomes does not currently exist. Instead, a plethora of definitions have been proposed, which vary significantly in their conceptual framework. The absence of a consensus definition hampers precise estimates of the prevalence of TRD, and also belies efforts to identify risk factors, prevention opportunities, and effective interventions. In addition, it results in heterogeneity in clinical practice decision-making, adversely affecting quality of care. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adopted the most used definition of TRD (i.e., inadequate response to a minimum of two antidepressants despite adequacy of the treatment trial and adherence to treatment). It is currently estimated that at least 30% of persons with depression meet this definition. A significant percentage of persons with TRD are actually pseudo-resistant (e.g., due to inadequacy of treatment trials or non-adherence to treatment). Although multiple sociodemographic, clinical, treatment and contextual factors are known to negatively moderate response in persons with depression, very few factors are regarded as predictive of non-response across multiple modalities of treatment. Intravenous ketamine and intranasal esketamine (co-administered with an antidepressant) are established as efficacious in the management of TRD. Some second-generation antipsychotics (e.g., aripiprazole, brexpiprazole, cariprazine, quetiapine XR) are proven effective as adjunctive treatments to antidepressants in partial responders, but only the olanzapine-fluoxetine combination has been studied in FDA-defined TRD. Repetitive transcranial magnetic stimulation (TMS) is established as effective and FDA-approved for individuals with TRD, with accelerated theta-burst TMS also recently showing efficacy. Electroconvulsive therapy is regarded as an effective acute and maintenance intervention in TRD, with preliminary evidence suggesting non-inferiority to acute intravenous ketamine. Evidence for extending antidepressant trial, medication switching and combining antidepressants is mixed. Manual-based psychotherapies are not established as efficacious on their own in TRD, but offer significant symptomatic relief when added to conventional antidepressants. Digital therapeutics are under study and represent a potential future clinical vista in this population., (© 2023 World Psychiatric Association.)

Objective: Posttraumatic stress disorder (PTSD) is a chronic and disabling disorder, for which available pharmacotherapies have limited efficacy. The authors' previous proof-of-concept randomized controlled trial of single-dose intravenous ketamine infusion in individuals with PTSD showed significant and rapid PTSD symptom reduction 24 hours postinfusion. The present study is the first randomized controlled trial to test the efficacy and safety of repeated intravenous ketamine infusions for the treatment of chronic PTSD., Methods: Individuals with chronic PTSD (N=30) were randomly assigned (1:1) to receive six infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) (psychoactive placebo control) over 2 consecutive weeks. Clinician-rated and self-report assessments were administered 24 hours after the first infusion and at weekly visits. The primary outcome measure was change in PTSD symptom severity, as assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), from baseline to 2 weeks (after completion of all infusions). Secondary outcome measures included the Impact of Event Scale-Revised, the Montgomery-Åsberg Depression Rating Scale (MADRS), and side effect measures., Results: The ketamine group showed a significantly greater improvement in CAPS-5 and MADRS total scores than the midazolam group from baseline to week 2. At week 2, the mean CAPS-5 total score was 11.88 points (SE=3.96) lower in the ketamine group than in the midazolam group (d=1.13, 95% CI=0.36, 1.91). Sixty-seven percent of participants in the ketamine group were treatment responders, compared with 20% in the midazolam group. Among ketamine responders, the median time to loss of response was 27.5 days following the 2-week course of infusions. Ketamine infusions were well tolerated overall, without serious adverse events., Conclusions: This randomized controlled trial provides the first evidence of efficacy of repeated ketamine infusions in reducing symptom severity in individuals with chronic PTSD. Further studies are warranted to understand ketamine's full potential as a treatment for chronic PTSD.Reprinted from Am J Psychiatry 2021; 178:193-202 , with permission from American Psychiatric Association Publishing. Copyright © 2021., (Copyright © 2023 by the American Psychiatric Association.)

Background: Electroconvulsive therapy (ECT) and subanesthetic intravenous ketamine are both currently used for treatment-resistant major depression, but the comparative effectiveness of the two treatments remains uncertain., Methods: We conducted an open-label, randomized, noninferiority trial involving patients referred to ECT clinics for treatment-resistant major depression. Patients with treatment-resistant major depression without psychosis were recruited and assigned in a 1:1 ratio to receive ketamine or ECT. During an initial 3-week treatment phase, patients received either ECT three times per week or ketamine (0.5 mg per kilogram of body weight over 40 minutes) twice per week. The primary outcome was a response to treatment (i.e., a decrease of ≥50% from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report; scores range from 0 to 27, with higher scores indicating greater depression). The noninferiority margin was -10 percentage points. Secondary outcomes included scores on memory tests and patient-reported quality of life. After the initial treatment phase, the patients who had a response were followed over a 6-month period., Results: A total of 403 patients underwent randomization at five clinical sites; 200 patients were assigned to the ketamine group and 203 to the ECT group. After 38 patients had withdrawn before initiation of the assigned treatment, ketamine was administered to 195 patients and ECT to 170 patients. A total of 55.4% of the patients in the ketamine group and 41.2% of those in the ECT group had a response (difference, 14.2 percentage points; 95% confidence interval, 3.9 to 24.2; P<0.001 for the noninferiority of ketamine to ECT). ECT appeared to be associated with a decrease in memory recall after 3 weeks of treatment (mean [±SE] decrease in the T-score for delayed recall on the Hopkins Verbal Learning Test-Revised, -0.9±1.1 in the ketamine group vs. -9.7±1.2 in the ECT group; scores range from -300 to 200, with higher scores indicating better function) with gradual recovery during follow-up. Improvement in patient-reported quality-of-life was similar in the two trial groups. ECT was associated with musculoskeletal adverse effects, whereas ketamine was associated with dissociation., Conclusions: Ketamine was noninferior to ECT as therapy for treatment-resistant major depression without psychosis. (Funded by the Patient-Centered Outcomes Research Institute; ELEKT-D ClinicalTrials.gov number, NCT03113968.)., (Copyright © 2023 Massachusetts Medical Society.)

Increased awareness of the growing disease burden of treatment resistant depression (TRD), in combination with technological advances in MRI, affords the unique opportunity to research biomarkers that characterize TRD. We provide a narrative review of MRI studies investigating brain features associated with treatment-resistance and treatment outcome in those with TRD. Despite heterogeneity in methods and outcomes, relatively consistent findings include reduced gray matter volume in cortical regions and reduced white matter structural integrity in those with TRD. Alterations in resting state functional connectivity of the default mode network were also found. Larger studies with prospective designs are warranted., (Copyright © 2023 Elsevier Inc. All rights reserved.)

(1) Background: This study examined the prevalence and correlates of factors associated with self-reported mental health service use in a longitudinal cohort of frontline health care workers (FHCWs) providing care to patients with COVID-19 throughout 2020. (2) Methods: The study comprised a two-wave survey ( n = 780) administered in April-May 2020 (T1) and November 2020-January 2021 (T2) to faculty, staff, and trainees in a large urban medical center. Factors associated with initiation, cessation, or continuation of mental health care over time were examined. (3) Results: A total of 19.1% of FHCWs endorsed currently utilizing mental health services, with 11.4% continuing, 4.2% initiating, and 3.5% ceasing services between T1 and T2. Predisposing and need-related factors, most notably a history of a mental health diagnosis and distress related to systemic racism, predicted service initiation and continuation. Among FHCWs with a prior mental health history, those with greater perceived resilience were less likely to initiate treatment at T2. Descriptive data highlighted the importance of services around basic and safety needs (e.g., reliable access to personal protective equipment) relative to mental health support in the acute phase of the pandemic. (4) Conclusions: Results may be helpful in identifying FHCWs who may benefit from mental health services.

Background: The sense of agency, or the belief in action causality, is an elusive construct that impacts day-to-day experience and decision-making. Despite its relevance in a range of neuropsychiatric disorders, it is widely under-studied and remains difficult to measure objectively in patient populations. We developed and tested a novel cognitive measure of reward-dependent agency perception in an in-person and online cohort., Methods: The in-person cohort consisted of 52 healthy control subjects and 20 subjects with depression and anxiety disorders (DA), including major depressive disorder and generalized anxiety disorder. The online sample consisted of 254 participants. The task consisted of an effort implementation for monetary rewards with computerized visual feedback interference and trial-by-trial ratings of self versus other agency., Results: All subjects across both cohorts demonstrated higher self-agency after receiving positive-win feedback, compared to negative-loss feedback when the level of computer inference was kept constant. Patients with DA showed reduced positive feedback-dependent agency compared to healthy controls. Finally, in our online sample, we found that higher self-agency following negative-loss feedback was associated with worse anhedonia symptoms., Conclusion: Together this work suggests how positive and negative environmental information impacts the sense of self-agency in healthy subjects, and how it is perturbed in patients with depression and anxiety., Competing Interests: The authors have no conflicts of interest to declare., (Copyright: © 2023 Mehta et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Major depressive disorder (MDD) is a prevalent health problem with complex pathophysiology that is not clearly understood. Prior work has implicated the hippocampus in MDD, but how hippocampal subfields influence or are affected by MDD requires further characterization with high-resolution data. This will help ascertain the accuracy and reproducibility of previous subfield findings in depression as well as correlate subfield volumes with MDD symptom scores. The objective of this study was to assess volumetric differences in hippocampal subfields between MDD patients globally and healthy controls (HC) as well as between a subset of treatment-resistant depression (TRD) patients and HC using automatic segmentation of hippocampal subfields (ASHS) software and ultra-high field MRI., Methods: Thirty-five MDD patients and 28 HC underwent imaging using 7-Tesla MRI. ASHS software was applied to the imaging data to perform automated hippocampal segmentation and provide volumetrics for analysis. An exploratory analysis was also performed on associations between symptom scores for diagnostic testing and hippocampal subfield volumes., Results: Compared to HC, MDD and TRD patients showed reduced right-hemisphere CA2/3 subfield volume ( p  = 0.01, η 2  = 0.31 and p  = 0.3, η 2  = 0.44, respectively). Additionally, negative associations were found between subfield volumes and life-stressor checklist scores, including left CA1 ( p  = 0.041, f 2  = 0.419), left CA4/DG ( p  = 0.010, f 2  = 0.584), right subiculum total ( p  = 0.038, f 2  = 0.354), left hippocampus total ( p  = 0.015, f 2  = 0.134), and right hippocampus total ( p  = 0.034, f 2  = 0.110). Caution should be exercised in interpreting these results due to the small sample size and low power., Conclusion: Determining biomarkers for MDD and TRD pathophysiology through segmentation on high-resolution MRI data and understanding the effects of stress on these regions can enable better assessment of biological response to treatment selection and may elucidate the underlying mechanisms of depression., Competing Interests: PB is a named inventor on patents relating to magnetic resonance imaging (MRI) and RF pulse design. The patents have been licensed to GE Healthcare, Siemens AG, and Philips international. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Alper, Feng, Verma, Rutter, Huang, Xie, Yushkevich, Jacob, Brown, Kautz, Schneider, Lin, Fleysher, Delman, Hof, Murrough and Balchandani.)

Objective: Rapid-acting treatment options are needed for major depressive disorder (MDD). The objective of this systematic review and meta-analysis was to estimate the magnitude of the treatment effect for intranasal esketamine over placebo at 24 hours after the first dose and at endpoint., Data Sources: PubMed, abstracts of major psychiatric meetings, and ClinicalTrials.gov were searched up to November 2020 with no language constraints, cross-referencing the term intranasal with esketamine and randomized ., Study Selection: Of 27 studies reviewed, 8 articles, with a total of 1,437 patients with MDD, met study criteria and were included in the meta-analysis., Data Extraction: Randomized, double-blind clinical trials comparing adjunctive treatment of standard antidepressants with intranasal esketamine for MDD, using intranasal placebo augmentation as a comparator, were selected., Results: Estimates of the standardized mean difference (SMD) in change scores were pooled after examining for homogeneity using the test statistic proposed by DerSimonian and Laird. Findings of the random effects model were presented. Augmentation of standard antidepressants with intranasal esketamine resulted in greater Montgomery-Asberg Depression Rating Scale (MADRS) score reduction than adjunctive intranasal placebo at 24 hours. Across the trials, the SMD was 0.34 (95% CI = 0.11 to 0.46, P  < .0001) with a 2.9-point greater mean MADRS score reduction following intranasal esketamine versus active control plus intranasal saline. A similar finding was evident at endpoint., Conclusions: This updated systematic review and meta-analysis found that augmentation of antidepressants with intranasal esketamine was statistically and clinically more effective in reducing depression severity than augmentation with placebo, at both 24 hours and study endpoint. Future studies are needed to evaluate dose-response relationship for esketamine., (© Copyright 2022 Physicians Postgraduate Press, Inc.)

Women suffer from depression at twice the rate of men, but the underlying molecular mechanisms are poorly understood. Here, we identify marked baseline sex differences in the expression of long noncoding RNAs (lncRNAs), a class of regulatory transcripts, in human postmortem brain tissue that are profoundly lost in depression. One such human lncRNA, RP11-298D21.1 (which we termed FEDORA), is enriched in oligodendrocytes and neurons and up-regulated in the prefrontal cortex (PFC) of depressed females only. We found that virally expressing FEDORA selectively either in neurons or in oligodendrocytes of PFC promoted depression-like behavioral abnormalities in female mice only, changes associated with cell type-specific regulation of synaptic properties, myelin thickness, and gene expression. We also found that blood FEDORA levels have diagnostic implications for depressed women and are associated with clinical response to ketamine. These findings demonstrate the important role played by lncRNAs, and FEDORA in particular, in shaping the sex-specific landscape of the brain and contributing to sex differences in depression.

The ventral tegmental area (VTA) is one of the major sources of dopamine in the brain and has been associated with reward prediction, error-based reward learning, volitional drive and anhedonia. However, precise anatomical investigations of the VTA have been prevented by the use of standard-resolution MRI, reliance on subjective manual tracings, and lack of quantitative measures of dopamine-related signal. Here, we combine ultra-high field 400 µm 3 quantitative MRI with dopamine-related signal mapping, and a mixture of machine learning and supervised computational techniques to delineate the VTA in a transdiagnostic sample of subjects with and without depression and anxiety disorders. Subjects also underwent cognitive testing to measure intrinsic and extrinsic motivational tone. Fifty-one subjects were scanned in total, including healthy control (HC) and mood/anxiety (MA) disorder subjects. MA subjects had significantly larger VTA volumes compared to HC but significantly lower signal intensity within VTA compared to HC, indicating reduced structural integrity of the dopaminergic VTA. Interestingly, while VTA integrity did not significantly correlate with self-reported depression or anxiety symptoms, it was correlated with an objective cognitive measure of extrinsic motivation, whereby lower VTA integrity was associated with lower motivation. This is the first study to demonstrate a computational pipeline for detecting and delineating the VTA in human subjects with 400 μm 3 resolution. We highlight the use of objective transdiagnostic measures of cognitive function that link neural integrity to behavior across clinical and non-clinical groups., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Depression is disabling and highly prevalent. Intravenous (IV) ketamine displays rapid-onset antidepressant properties, but little is known regarding which patients are most likely to benefit, limiting personalized prescriptions. We identified randomized controlled trials of IV ketamine that recruited individuals with a relevant psychiatric diagnosis (e.g., unipolar or bipolar depression; post-traumatic stress disorder), included one or more control arms, did not provide any other study-administered treatment in conjunction with ketamine (although clinically prescribed concurrent treatments were allowable), and assessed outcome using either the Montgomery-Åsberg Depression Rating Scale or the Hamilton Rating Scale for Depression (HRSD-17). Individual patient-level data for at least one outcome was obtained from 17 of 25 eligible trials [pooled n = 809]. Rates of participant-level data availability across 33 moderators that were solicited from these 17 studies ranged from 10.8% to 100% (median = 55.6%). After data harmonization, moderators available in at least 40% of the dataset were tested sequentially, as well as with a data-driven, combined moderator approach. Robust main effects of ketamine on acute [~24-hours; β*(95% CI) = 0.58 (0.44, 0.72); p < 0.0001] and post-acute [~7 days; β*(95% CI) = 0.38 (0.23, 0.54); p < 0.0001] depression severity were observed. Two study-level moderators emerged as significant: ketamine effects (relative to placebo) were larger in studies that required a higher degree of previous treatment resistance to federal regulatory agency-approved antidepressant medications (≥2 failed trials) for study entry; and in studies that used a crossover design. A comprehensive data-driven search for combined moderators identified statistically significant, but modest and clinically uninformative, effects (effect size r ≤ 0.29, a small-medium effect). Ketamine robustly reduces depressive symptoms in a heterogeneous range of patients, with benefit relative to placebo even greater in patients more resistant to prior medications. In this largest effort to date to apply precision medicine approaches to ketamine treatment, no clinical or demographic patient-level features were detected that could be used to guide ketamine treatment decisions.Review Registration: PROSPERO Identifier: CRD42021235630., (© 2022. The Author(s).)

Background: Stress exposure is a key risk factor for the development of major depressive disorder and posttraumatic stress disorder. Enhancing stress resilience in at-risk populations could potentially protect against stress-induced disorders. The administration of ketamine one week prior to an acute stressor prevents the development of stress-induced depressive-like behavior in rodents. This study aimed to test if the prophylactic effect of ketamine against stress also applies to humans., Methods: We conducted a double-blind, placebo-controlled study wherein 24 healthy subjects (n = 11 males) were randomized to receive either ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) intravenously one week prior to an acute stress [Trier Social Stress Test (TSST)]. The primary endpoint was the anxious-composed subscale of the Profile of Mood States Bipolar Scale (POMS-Bi) administered immediately after the TSST. Salivary and plasma cortisol and salivary alpha amylase were also measured at 15-min intervals for 60 min following the stressor, as proxies of hypothalamic pituitary adrenal (HPA) and sympathetic-adrenal-medullary (SAM) axis activity, respectively., Results: Compared to the midazolam group (n = 12), the ketamine group (n = 12) showed a moderate to large (Cohen's d = 0.7) reduction in levels of anxiety immediately following stress, although this was not significant (p = 0.06). There was no effect of group on change in salivary cortisol or salivary alpha amylase following stress. We conducted a secondary analysis excluding one participant who did not show an expected correlation between plasma and salivary cortisol (n = 23, ketamine n = 11). In this subgroup, we observed a significant reduction in the level of salivary alpha amylase in the ketamine group compared to midazolam (Cohen's d = 0.7, p = 0.03). No formal adjustment for multiple testing was made as this is a pilot study and all secondary analyses are considered hypothesis-generating., Conclusions: Ketamine was associated with a numeric reduction in TSST-induced anxiety, equivalent to a medium-to-large effect size. However, this did not reach statistical significance . In a subset of subjects, ketamine appeared to blunt SAM reactivity following an acute stressor. Future studies with larger sample size are required to further investigate the pro-resilient effect of ketamine., Competing Interests: Dr. Dennis Charney (Dean of Icahn School of Medicine at Mount Sinai) is a named co-inventor on several issued U.S. patents, and several pending U.S. patent applications filed by the Icahn School of Medicine at Mount Sinai (ISMMS) related to pharmacologic therapy for treatment-resistant depression, suicidal ideation and other disorders. ISMMS has entered into a licensing agreement with Janssen Pharmaceuticals, Inc. and it has and will receive payments from Janssen under the license agreement related to these patents. As a co-inventor, Dr. Charney is entitled to a portion of the payments received by the ISMMS. Since SPRAVATO (esketamine) has received regulatory approval for treatment-resistant depression, ISMMS and Dr. Charney as its employee and a co-inventor, will be entitled to additional payments, under the license agreement. Drs. Charney and Feder are named co-inventors on an issued patent in the United States and several issued patents outside of the United States, filed by the Icahn School of Medicine at Mount Sinai for the use of ketamine as therapy for posttraumatic stress disorder; this intellectual property has not been licensed. Dr. Costi has provided consultation services for Guidepoint and TCG Crossover. Dr. Jha has received contract research grants from 10.13039/100014387Acadia Pharmaceuticals, 10.13039/100014593Neurocrine Bioscience, Navitor/Supernus and 10.13039/100005205Janssen Research & Development, educational grant to serve as Section Editor of the Psychiatry & Behavioral Health Learning Network, consultant fees from Eleusis Therapeutics US, Inc, Janssen Global Services, Janssen Scientific Affairs, Worldwide Clinical Trials/Eliem, and Guidepoint Global, and honoraria from North American Center for Continuing Medical Education, Medscape/WebMD, Clinical Care Options, and Global Medical Education. Dr. Matthew Klein is currently a full-time employee of Janssen Research & Development. Dr. Klein conducted all work related to this manuscript during his previous position as a full-time employee of the ISMMS. In the past 5 years, Dr. Murrough has provided consultation services and/or served on advisory boards for Boehreinger Ingelheim, Clexio Biosciences, FSV7, Global Medical Education (GME), Otsuka, and Sage Therapeutics. Dr. Murrough is named on a patent pending for neuropeptide Y as a treatment for mood and anxiety disorders and on a patent pending for the use of ezogabine and other KCNQ channel openers to treat depression and related conditions. All the other authors report no conflict of interest., (© 2022 Published by Elsevier Inc.)

Major depressive disorder (MDD) is the leading cause of disability worldwide. There is an urgent need for objective biomarkers to diagnose this highly heterogeneous syndrome, assign treatment, and evaluate treatment response and prognosis. MicroRNAs (miRNAs) are short non-coding RNAs, which are detected in body fluids that have emerged as potential biomarkers of many disease conditions. The present study explored the potential use of miRNAs as biomarkers for MDD and its treatment. We profiled the expression levels of circulating blood miRNAs from mice that were collected before and after exposure to chronic social defeat stress (CSDS), an extensively validated mouse model used to study depression, as well as after either repeated imipramine or single-dose ketamine treatment. We observed robust differences in blood miRNA signatures between stress-resilient and stress-susceptible mice after an incubation period, but not immediately after exposure to the stress. Furthermore, ketamine treatment was more effective than imipramine at re-establishing baseline miRNA expression levels, but only in mice that responded behaviorally to the drug. We identified the red blood cell-specific miR-144-3p as a candidate biomarker to aid depression diagnosis and predict ketamine treatment response in stress-susceptible mice and MDD patients. Lastly, we demonstrate that systemic knockdown of miR-144-3p, via subcutaneous administration of a specific antagomir, is sufficient to reduce the depression-related phenotype in stress-susceptible mice. RNA-sequencing analysis of blood after such miR-144-3p knockdown revealed a blunted transcriptional stress signature as well. These findings identify miR-144-3p as a novel target for diagnosis of MDD as well as for antidepressant treatment, and enhance our understanding of epigenetic processes associated with depression., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Clinical trials of intravenous (IV) racemic (R,S)-ketamine (hereafter referred to as IV ketamine) have consistently reported rapid and substantial reductions in overall depressive symptoms compared with saline (inactive placebo) or midazolam (active placebo). The evidence for IV ketamine's specific effects on suicidal ideation is less clear, however. This study sought to examine whether differential placebo (saline or midazolam) response to overall depressive symptoms vs suicidal ideation may help explain these divergent findings., Methods: Data for this participant-level integrative data analysis were drawn from 151 participants across 10 studies, and linear regression was used to examine the relationship between placebo response for suicidal ideation vs other depressive symptoms indexed from standard rating scales-specifically, depressed mood, anhedonia, anxiety, and guilt-over time., Results: For participants receiving saline placebo (n = 46), greater placebo response was observed for suicidal ideation compared with other symptoms indexed from standard depression rating scales, except for anxiety. For those receiving midazolam placebo (n = 105), greater placebo response was observed for suicidal ideation compared with depressed mood or anhedonia, and no significant differences were observed when comparing suicidal ideation with anxiety or guilt., Conclusions: Taken together, the results provide preliminary evidence of a differential placebo response for suicidal ideation vs other depressive symptoms, while anxiety and suicidal ideation appear to produce similar placebo response profiles. These findings may help explain the more modest findings in clinical IV ketamine trials for suicidal ideation than overall depression., (Published by Oxford University Press on behalf of CINP 2022.)

Objectives: We sought to describe the course and correlates of psychological distress in frontline healthcare workers (FHCWs) during the COVID-19 pandemic in New York City (NYC)., Methods: A prospective cohort study of FHCWs at the Mount Sinai Hospital was conducted during the initial 2020 surge (T1) and 7 months later (T2). Psychological distress [i.e., positive screen for pandemic-related post-traumatic stress disorder (PTSD), major depressive disorder (MDD), and/or generalized anxiety disorder (GAD)], occupational and personal exposures to COVID-19, coping strategies, and psychosocial characteristics were assessed. Four courses of psychological distress response were identified: no/minimal, remitted, persistent, and new-onset. Multinomial logistic regression and relative importance analyses were conducted to identify factors associated with courses of distress., Results: Of 786 FHCWs, 126 (16.0%) FHCWs had persistent distress; 150 (19.1%) remitted distress; 35 (4.5%) new-onset distress; and 475 (60.4%) no/minimal distress. Relative to FHCWs with no/minimal distress, those with persistent distress reported greater relationship worries [19.8% relative variance explained (RVE)], pre-pandemic burnout (18.7% RVE), lower dispositional optimism (9.8% RVE), less emotional support (8.6% RVE), and feeling less valued by hospital leadership (8.4% RVE). Relative to FHCWs with remitted symptoms, those with persistent distress reported less emotional support (29.7% RVE), fewer years in practice (28.3% RVE), and psychiatric history (23.6% RVE)., Conclusions: One-fifth of FHCWs in our study experienced psychological distress 7 months following the COVID-19 surge in NYC. Pandemic-related worries, pre-pandemic burnout, emotional support, and feeling valued by leaders were linked to persistent distress. Implications for prevention, treatment, and organizational efforts to mitigate distress in FHCWs are discussed., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Depression is characterized by altered neurobiological responses to threat and inflammation may be involved in the development and maintenance of symptoms. However, the mechanistic pathways underlying the relationship between the neural underpinnings of threat, inflammation and depressive symptoms remain unknown., Methods: Twenty participants with major depressive disorder (MDD) and 17 healthy controls (HCs) completed this study. Peripheral blood mononuclear cells (PBMCs) were collected and stimulated ex vivo with lipopolysaccharide (LPS). We then measured a broad array of secreted proteins and performed principal component analysis to compute an aggregated immune reactivity score. Subjects completed a well-validated emotional face processing task during functional magnetic resonance imaging (fMRI). Amygdala activation was measured during perception of threat for the main contrast of interest: fear > happy face. Participants completed the Mood and Anxiety Symptom Questionnaire (MASQ) and the Perceived Stress Scale (PSS). Correlation analyses between amygdala activation, the aggregate immune score, and symptom were computed across groups. A mediation analysis was also performed across groups to further explore the relationship between these three variables., Results: In line with our hypotheses and with prior work, the MDD group showed greater amygdala activation in response to threat compared to the HC group [t 35  = -2.038, p = 0.049]. Internal consistency of amygdala activation to threat was found to be moderate. Response to an ex vivo immune challenge was greater in MDD than HC based on the computed immune reactivity score (PC1; t 35  = 2.674, p = 0.011). Amygdala activation was positively correlated with the immune score (r = 0.331, p = 0.045). Moreover, higher amygdala activation was associated with greater anxious arousal measured by the MASQ (r = 0.390, p = 0.017). Exploring the role of stress, we found that higher perceived stress was positively associated with both inflammatory response (r = 0.367, p = 0.026) and amygdala response to threat (r = 0.325, p = 0.050). Mediation analyses showed that perceived stress predicted anxious arousal, but neither inflammation nor amygdala activation fully accounted for the effect of perceived stress on anxious arousal., Conclusion: These data highlight the potential importance of threat circuitry hyperactivation in MDD, consistent with prior reports. We found that higher levels of inflammatory biomarkers were associated with higher amygdala activation, which in turn was associated with anxious arousal. Future research utilizing larger sample sizes are needed to replicate these preliminary results., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Stress exposure is one of the greatest risk factors for psychiatric illnesses, including major depressive disorder (MDD) and posttraumatic stress disorder (PTSD). Enhancing stress resilience could potentially protect against the development of stress-induced psychiatric disorders, yet no resilience-enhancing pharmaceuticals have been developed to date. This review serves to consider the existing evidence for a potential pro-resilience effect of ketamine in rodents as well as the preliminary evidence of ketamine as a prophylactic treatment for postpartum depression (PPD) in humans. Several animal studies have demonstrated that ketamine administered 1 week prior to a stressor (e.g., chronic social defeat and learned helplessness) may protect against depressive-like behavior. A similar protective effect has been demonstrated against PTSD-like behavior following Contextual Fear Conditioning (CFC). Recent work has sought to explore if the administration of ketamine prevented the development of postpartum depression (PPD) in humans. Researchers administered ketamine immediately following caesarian-section and found a significantly reduced prevalence of PPD in the ketamine-treated groups compared to the control groups. Utilizing ketamine as a resilience-enhancing treatment may have unique applications, including leading to a deeper understanding of the neurobiological mechanism underlying resilience. Future trials aiming to translate and replicate these findings with humans are warranted., Competing Interests: DC (Dean of Icahn School of Medicine at Mount Sinai) is a named co-inventor on several issued U.S. patents and several pending U.S. patent applications filed by the Icahn School of Medicine at Mount Sinai (ISMMS) related to ketamine and esketamine for treatment-resistant depression, suicidal ideation, and other disorders. ISMMS has entered into a licensing agreement with Janssen Pharmaceuticals, Inc. and it has and will receive payments from Janssen under the license agreement related to these patents. As a co-inventor, DC is entitled to a portion of the payments received by the ISMMS. Since SPRAVATO (esketamine) has received regulatory approval for treatment-resistant depression, ISMMS and DC as its employee and a co-inventor, will be entitled to additional payments, under the license agreement. SC has provided consultation services for Guidepoint and TCG Crossover. In the past 5 years, JM has provided consultation services and/or served on advisory boards for Allergan, Boehreinger Ingelheim, Clexio Biosciences, Fortress Biotech, FSV7, Global Medical Education (GME), Otsuka, and Sage Therapeutics. JM is named on a patent pending for neuropeptide Y as a treatment for mood and anxiety disorders and on a patent pending for the use of ezogabine and other KCNQ channel openers to treat depression and related conditions., (Copyright © 2022 Evers, Murrough, Charney and Costi.)

Objectives: On a background of the rapidly expanding clinical use of ketamine and esketamine for treatment of depression and other conditions, we examined safety monitoring, seeking to identify knowledge gaps relevant to clinical practice., Methods: An international group of psychiatrists discussed the issue of safety of ketamine and esketamine and came to a consensus on key safety gaps., Results: There is no standard safety monitoring for off-label generic ketamine. For intranasal esketamine, each jurisdiction providing regulatory approval may specify monitoring. Treatment is often provided beyond the period for which safety has been demonstrated, with no agreed framework for monitoring of longer term side effects for either generic ketamine or intranasal esketamine., Limitations: The KSET has established face and content validity, however it has not been validated against other measures of safety., Conclusions: We recommend the Ketamine Side Effect Tool (KSET) as a comprehensive safety monitoring tool for acute and longer term side effects., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: Emerging evidence in depression suggests that blood-brain barrier (BBB) breakdown and elevated inflammatory cytokines in states of persistent stress or trauma may contribute to the development of symptoms. Signal-to-noise ratio afforded by ultra-high field MRI may aid in the detection of maladaptations of the glymphatic system related to BBB integrity that may not be visualized at lower field strengths., Methods: We investigated the link between glymphatic neuroanatomy via perivascular spaces (PVS) and trauma experience in patients with major depressive disorder (MDD) and in healthy controls using 7-Tesla MRI and a semi-automated segmentation algorithm., Results: After controlling for age and gender, the number of traumatic events was correlated with total PVS volume in MDD patients (r = 0.50, p = .028) and the overall population (r = 0.34, p = .024). The number of traumatic events eliciting horror was positively correlated with total PVS volume in MDD patients (r = 0.50, p = .030) and the overall population (r = 0.32, p = .023). Age correlated positively with PVS count, PVS total volume, and PVS density in all participants (r > 0.35, p < .01)., Conclusions: These results suggest a relationship between glymphatic dysfunction related to BBB integrity and psychological trauma, and that glymphatic impairment may play a role in trauma-related symptomatology., (© 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

The hippocampus and amygdala limbic structures are critical to the etiology of major depressive disorder (MDD). However, there are no high-resolution characterizations of the role of their subregions in the whole brain network (connectome). Connectomic examination of these subregions can uncover disorder-related patterns that are otherwise missed when treated as single structures. 38 MDD patients and 40 healthy controls (HC) underwent anatomical and diffusion imaging using 7-Tesla MRI. Whole-brain segmentation was performed along with hippocampus and amygdala subregion segmentation, each representing a node in the connectome. Graph theory analysis was applied to examine the importance of the limbic subregions within the brain network using centrality features measured by node strength (sum of weights of the node's connections), Betweenness (number of shortest paths that traverse the node), and clustering coefficient (how connected the node's neighbors are to one another and forming a cluster). Compared to HC, MDD patients showed decreased node strength of the right hippocampus cornu ammonis (CA) 3/4, indicating decreased connectivity to the rest of the brain, and decreased clustering coefficient of the right dentate gyrus, implying it is less embedded in a cluster. Additionally, within the MDD group, the greater the embedding of the right amygdala central nucleus (CeA) in a cluster, the greater the severity of depressive symptoms. The altered role of these limbic subregions in the whole-brain connectome is related to diagnosis and depression severity, contributing to our understanding of the limbic system involvement in MDD and may elucidate the underlying mechanisms of depression., (© 2022. The Author(s).)

Objective: To evaluate the direct and interacting effects of personal and systemic factors that contribute to psychological distress among frontline healthcare workers (FHCWs) during the COVID-19 pandemic., Methods: Data were collected using a hospital-wide, cross-sectional survey. A multivariable binary logistic regression and relative importance analysis was conducted to identify factors associated with screening positive for C19-distress., Results: A total of 1005 (39.0%, 95%CI - 37.1-40.9%) out of 2579 FHCWs met the prespecified cutoff values for significant symptoms of C19-distress. Fewer sleep hours and lower perceptions of leadership support explained the majority of variance (19.4% relative variance explained [RVE]) in C19-distress, followed by team camaraderie (6.4% RVE), physical exercise (4.9% RVE), and engagement in hobbies (3.2% RVE)., Conclusion: These results underscore the importance of restorative behaviors as potential targets to help decrease distress and promote resilience in FHCWs., (Copyright © 2022 American College of Occupational and Environmental Medicine.)

Stress disorders are leading causes of disease burden in the U.S. and worldwide, yet available therapies are fully effective in less than half of all individuals with these disorders. Although to date, much of the focus has been on neuron-intrinsic mechanisms, emerging evidence suggests that chronic stress can affect a wide range of cell types in the brain and periphery, which are linked to maladaptive behavioral outcomes. Here, we synthesize emerging literature and discuss mechanisms of how non-neuronal cells in limbic regions of brain interface at synapses, the neurovascular unit, and other sites of intercellular communication to mediate the deleterious, or adaptive (i.e., pro-resilient), effects of chronic stress in rodent models and in human stress-related disorders. We believe that such an approach may one day allow us to adopt a holistic "whole body" approach to stress disorder research, which could lead to more precise diagnostic tests and personalized treatment strategies. Stress is a major risk factor for many psychiatric disorders. Cathomas et al. review new insight into how non-neuronal cells mediate the deleterious effects, as well as the adaptive, protective effects, of stress in rodent models and human stress-related disorders., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Major depressive disorder (MDD) is a leading cause of disability worldwide and less than one-third of patients with MDD achieve stable remission of symptoms, despite currently available treatments. Although MDD represents a serious health problem, a complete understanding of the neurobiological mechanisms underlying this condition continues to be elusive. Accumulating evidence from preclinical and animal studies provides support for the antidepressant potential of modulators of KCNQ voltage-gated potassium (K + ) channels. KCNQ K +  channels, through regulation of neuronal excitability and activity, contribute to neurophysiological mechanisms underlying stress resilience, and represent potential targets of drug discovery for depression. The present article focuses on the pharmacology and efficacy of KCNQ2/3 K + channel openers as novel therapeutic agents for depressive disorders from initial studies conducted on animal models showing depressive-like behaviors to recent work in humans that examines the potential for KCNQ2/3 channel modulators as novel antidepressants. Data from preclinical work suggest that KCNQ-type K +  channels are an active mediator of stress resilience and KCNQ2/3 K + channel openers show antidepressant efficacy. Similarly, evidence from clinical trials conducted in patients with MDD using the KCNQ2/3 channel opener ezogabine (retigabine) showed significant improvements in depressive symptoms and anhedonia. Overall, KCNQ channel openers appear a promising target for the development of novel therapeutics for the treatment of psychiatric disorders and specifically for MDD., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Ketamine has rapid and sustained antidepressant effects in patients with treatment-resistant depression (TRD). However, the underlying mechanisms of action are not well understood. There is increasing evidence that TRD is associated with a pro-inflammatory state and that ketamine may inhibit inflammatory processes. We thus investigated whole blood transcriptional profiles related to TRD and gene expression changes associated with treatment response to ketamine. Whole blood was collected at baseline (21 healthy controls [HC], 26 patients with TRD) and then again in patients with TRD 24 hours following a single intravenous infusion of ketamine (0.5 mg/kg). We performed RNA-sequencing and analyzed (a) baseline transcriptional profiles between patients with TRD and HC, (b) responders vs. non-responders before ketamine treatment, and (c) gene expression signatures associated with clinical improvement. At baseline, patients with TRD compared to HC showed a gene expression signature indicative of interferon signaling pathway activation. Prior to ketamine administration, the metabotropic glutamate receptor gene GRM2 and the ionotropic glutamate receptor gene GRIN2D were upregulated in responders compared to non-responders. Response to ketamine was associated with a distinct transcriptional signature, however, we did not observe gene expression changes indicative of an anti-inflammatory effect. Future studies are needed to determine the role of the peripheral immune system in the antidepressant effect of ketamine., (© 2021. The Author(s).)

Anhedonia - the reduced ability to experience or respond to pleasure - is an important symptom domain for many psychiatric disorders. It is particularly relevant to depression and other mood disorders and it is a diagnostic criterion of a major depressive episode. Developing safe and effective pharmacological interventions for anhedonia is a critical public health need. The current chapter will review the state of the field with respect to both the efficacy of currently available pharmacotherapies for anhedonia and the recent clinical research focusing on new brain targets, including the kappa-opioid receptor and the KCNQ2/3 receptors. The evidence for anti-anhedonic effects of ketamine and psychedelic agents will be reviewed, as well., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Bioactive dietary polyphenols in grape ( Vitis vinifera ) have been used in Dietary Supplements (DSs) with the aim to prevent numerous diseases, including cardiovascular and neurodegenerative diseases, and to reduce depression and anxiety. Given prior recognition that DSs can be quality challenged from the purity, authentication, adulteration, and actual concentration of targeted bioactives, to ensure consumer health protection as well as the quality and safety of grape polyphenol-based DSs, the present investigation was aimed at establishing a comprehensive quality control (QC) approach for grape polyphenol-based DSs in support of a human clinical study. In this study, the manufactured grape seed polyphenol extract (GSPE) and trans -resveratrol (RSV) capsules and Concord Grape Juice (CGJ) along with the corresponding original drug materials were analyzed using the developed different liquid chromatography/UV-visible spectroscopy/mass spectrometry (LC/UV-Vis/MS) methods. The weight variation of GSPE and RSV capsules was also evaluated according to the US Pharmacopeia (USP) tests. The results indicate that the total identified polyphenol content in each grape seed extract (GSE) capsule/CGJ is very similar and all GSE/RSV capsules pass the content/weight uniformity test. Given the complexity of these and many botanical products from the issues of purity, quality, adulteration, consistency, and their coupling to the complex chemistry in each grape-derived botanical, quality assurance and the steps needed to ensure grape-derived DSs being well homogeneous and stable and containing the known and expected bioactives at specific concentration ranges are fundamental to any research study and in particular to a clinical trial. Each of these issues is essential to provide a solid foundation upon which clinical trials with botanicals can be conducted with the goal of realizing measurable mental health outcomes such as reducing depression and anxiety as well as understanding of their underlying biological mechanisms., Competing Interests: DR was employed by company Eagle Nutritionals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lyu, Rodriguez, Ferruzzi, Pasinetti, Murrough, Simon and Wu.)

Promising initial data indicate that the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine may be beneficial in post-traumatic stress disorder (PTSD). Here, we explore the neural correlates of ketamine-related changes in PTSD symptoms, using a rich battery of functional imaging data (two emotion-processing tasks and one task-free scan), collected from a subset of participants of a randomized clinical trial of repeated-dose intravenous ketamine vs midazolam (total N = 21). In a pre-registered analysis, we tested whether changes in an a priori set of imaging measures from a target neural circuit were predictive of improvement in PTSD symptoms, using leave-one-out cross-validated elastic-net regression models (regions of interest in the target circuit consisted of the dorsal and rostral anterior cingulate cortex, ventromedial prefrontal cortex, anterior hippocampus, anterior insula, and amygdala). Improvements in PTSD severity were associated with increased functional connectivity between the ventromedial prefrontal cortex (vmPFC) and amygdala during emotional face-viewing (change score retained in model with minimum predictive error in left-out subjects, standardized regression coefficient [β] = 2.90). This effect was stronger in participants who received ketamine compared to midazolam (interaction β = 0.86), and persisted following inclusion of concomitant change in depressive symptoms in the analysis model (β = 0.69). Improvement following ketamine was also predicted by decreased dorsal anterior cingulate activity during emotional conflict regulation, and increased task-free connectivity between the vmPFC and anterior insula (βs = -2.82, 0.60). Exploratory follow-up analysis via dynamic causal modelling revealed that whilst improvement in PTSD symptoms following either drug was associated with decreased excitatory modulation of amygdala→vmPFC connectivity during emotional face-viewing, increased top-down inhibition of the amygdala by the vmPFC was only observed in participants who improved under ketamine. Individuals with low prefrontal inhibition of amygdala responses to faces at baseline also showed greater improvements following ketamine treatment. These preliminary findings suggest that, specifically under ketamine, improvements in PTSD symptoms are accompanied by normalization of hypofrontal control over amygdala responses to social signals of threat., (© 2021. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Methods for a dissolution study by ultra-high performance liquid chromatography/triple quadrupole mass spectrometry (UHPLC-QqQ/MS) analysis of grape polyphenol dietary supplements, namely, grape seed extract (GSE) and resveratrol (RSV) capsules, were developed following the guidance of United States Pharmacopeia (USP) <2040>. Two dissolution media, 0.1 N hydrochloric acid (pH 1.2) and 0.05 M acetate buffer (pH 4.6), were evaluated with dissolution apparatus (USP 1), 100 rpm rotation speed, and 900 ml dissolution medium volume. Dissolution profiling was performed over 120 min. Major phenolic compounds of gallic acid, catechin, epicatechin, and procyanidin B2 were quantitated to obtain the dissolution profile of GSE capsules, and trans-RSV was used for RSV capsules. Results indicated that the released trans-RSV for RSV capsules in both of the dissolution media meets the USP standards, and that for the GSE capsules, all the four marker compounds passed the dissolution test in the HCl medium but did not reach a 75% release within 60 min in the acetate buffer. These promising results suggest that the general USP dissolution protocols are adequate for the successful release of RSV capsules in HCl medium and acetate buffer and GSE capsules (in HCl medium), but may be inadequate for GSE capsules in acetate buffer. These results showed that under a low pH of 1.2 (simulated stomach environment), bioactive compounds were released on time from the GSE capsules and met the USP guidelines; however, under a higher pH of 4.6 (simulated duodenum environment), the same biomarkers failed, suggesting the need to further improve the dissolution of GSE over a wider range of pH environments to enhance bioavailability and efficacy., Competing Interests: DR was employed by company Eagle Nutritionals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lyu, Omar, Patel, Rodriguez, Ferruzzi, Pasinetti, Murrough, Muzzio, Simon and Wu.)

Increased levels of peripheral cytokines have been previously associated with depression in preclinical and clinical research. Although the precise nature of peripheral immune dysfunction in depression remains unclear, evidence from animal studies points towards a dysregulated response of peripheral leukocytes as a risk factor for stress susceptibility. This study examined dynamic release of inflammatory blood factors from peripheral blood mononuclear cells (PBMC) in depressed patients and associations with neural and behavioral measures of reward processing. Thirty unmedicated patients meeting criteria for unipolar depressive disorder and 21 healthy control volunteers were enrolled. PBMCs were isolated from whole blood and stimulated ex vivo with lipopolysaccharide (LPS). Olink multiplex assay was used to analyze a large panel of inflammatory proteins. Participants completed functional magnetic resonance imaging with an incentive flanker task to probe neural responses to reward anticipation, as well as clinical measures of anhedonia and pleasure including the Temporal Experience of Pleasure Scale (TEPS) and the Snaith-Hamilton Pleasure Scale (SHAPS). LPS stimulation revealed larger increases in immune factors in depressed compared to healthy subjects using an aggregate immune score (t 49  = 2.83, p = 0.007). Higher peripheral immune score was associated with reduced neural responses to reward anticipation within the ventral striatum (VS) (r = -0.39, p = 0.01), and with reduced anticipation of pleasure as measured with the TEPS anticipatory sub-score (r = -0.318, p = 0.023). Our study provides new evidence suggesting that dynamic hyper-reactivity of peripheral leukocytes in depressed patients is associated with blunted activation of the brain reward system and lower subjective anticipation of pleasure., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Background: Posttraumatic stress disorder (PTSD) is associated with hyperarousal and stress reactivity, features consistent with behavioral sensitization. In this Phase 1b, parallel-arm, randomized, double-blind, placebo-controlled trial, we tested whether the selective low-trapping N-methyl-D-aspartate receptor (NMDAR) antagonist [Lanicemine (BHV-5500)] blocks expression of behavioral sensitization., Methods: Twenty-four participants with elevated anxiety potentiated startle (APS) and moderate-to-severe PTSD symptoms received three infusions of lanicemine 1.0 mg/ml (100 mg) or matching placebo (0.9% saline) (1:1 ratio), over a 5-day period. The primary outcome was change in APS from baseline to end of third infusion. We also examined changes in EEG gamma-band oscillatory activity as measures of NMDAR target engagement and explored Clinician-Administered PTSD Scale (CAPS-5) hyperarousal scores., Results: Lanicemine was safe and well-tolerated with no serious adverse events. Using Bayesian statistical inference, the posterior probability that lanicemine outperformed placebo on APS T-score after three infusions was 38%. However, after the first infusion, there was a 90% chance that lanicemine outperformed placebo in attenuating APS T-score by a standardized effect size more than 0.4., Conclusion: We demonstrated successful occupancy of lanicemine on NMDAR using gamma-band EEG and effects on hyperarousal symptoms (Cohen's d = 0.75). While lanicemine strongly attenuated APS following a single infusion, differential changes from placebo after three infusions was likely obscured by habituation effects. To our knowledge, this is the first use of APS in the context of an experimental medicine trial of a NMDAR antagonist in PTSD. These findings support selective NMDAR antagonism as a viable pharmacological strategy for salient aspects of PTSD., (© 2021 Wiley Periodicals LLC.)