j. john mann

Psychiatric diagnosis rates in suicide decedents appear higher in European ancestry populations compared with East Asians. Shared genetic components exist between major depressive disorder (MDD)/schizophrenia (SCZ) and suicide, but no study has compared these shared polygenic architectures between Europeans and East Asians. We compared polygenic risk scores (PRSs) for MDD/SCZ determined from large data sets specific to each ancestry in European and East Asian suicide decedent samples. MDD/SCZ PRSs appeared more prominent in European suicides compared with Japanese suicides. A greater coexistence of psychiatric disorders in European suicide decedents than in East Asian suicide decedents may be partly explained by genetics. Our results are limited by the smaller sample size of our suicide decedents and sample size disparities between the European discovery data set and the …

BackgroundSuicidal ideation (SI) is associated with higher binding of the translocator protein 18k Da (TSPO), a putative marker of neuroinflammation. However, whether TSPO binding is related to acute emergence of SI and mood symptoms remains unclear. We compared brain TSPO binding in currently depressed subjects with and without history of suicide attempt; and assessed the relationship of TSPO binding to real-time reporting of stressors, suicidal ideation, and negative affect.MethodsFifty-three depressed subjects (n= 15 with prior suicidal behavior) underwent in vivo dynamic PET imaging with 11C-ER176 and concurrent arterial sampling. We quantified a weighted average of TSPO tracer distribution volume (VT) across 11 a priori regions. A subset of n= 21 subjects completed seven consecutive days of ecological momentary assessment (EMA) of their daily stressors, affective responses, and suicidal …

ImportanceSuicide rates in the US increased by 35.6% from 2001 to 2021. Given that most individuals die on their first attempt, earlier detection and intervention are crucial. Understanding modifiable risk factors is key to effective prevention strategies.ObjectiveTo identify distinct suicide profiles or classes, associated signs of suicidal intent, and patterns of modifiable risks for targeted prevention efforts.Design, Setting, and ParticipantsThis cross-sectional study used data from the 2003-2020 National Violent Death Reporting System Restricted Access Database for 306 800 suicide decedents. Statistical analysis was performed from July 2022 to June 2023.ExposuresSuicide decedent profiles were determined using latent class analyses of available data on suicide circumstances, toxicology, and methods.Main Outcomes and MeasuresDisclosure of recent intent, suicide note presence, and known psychotropic usage …

Human genetic studies indicate that suicidal ideation and behavior are both heritable. Most studies have examined associations between aberrant gene expression and suicide behavior, but behavior risk is linked to the severity of suicidal ideation. Through a gene network approach, this study investigates how gene co-expression patterns are associated with suicidal ideation and severity using RNA-seq data in peripheral blood from 46 live participants with elevated suicidal ideation and 46 with no ideation. Associations with the presence of suicidal ideation were found within 18 co-expressed modules (p < 0.05), as well as in 3 co-expressed modules associated with suicidal ideation severity (p < 0.05, not explained by severity of depression). Suicidal ideation presence and severity-related gene modules with enrichment of genes involved in defense against microbial infection, inflammation, and adaptive …

BackgroundInflammation is associated with major depressive disorder (MDD) and suicidal behavior. Pro-inflammatory cytokines may function by altering hypothalamic-pituitary-adrenal (HPA) axis activity in MDD and suicidal behavior.MethodsMethods: We administered the Trier Social Stress Test (TSST), a well-established paradigm for inducing acute psychosocial stress, in patients with MDD (n= 57) and healthy volunteers (n= 41; HV). Patients in the MDD group were further characterized as suicide attempters (n= 26; SA) or non-attempters (n= 31; NA). Salivary cortisol and serum cytokines were collected at baseline and at additional timepoints during and after stressor in the TSST.ResultsBaseline interferon-gamma (IFN-γ) levels in the MDD SA group were lower (F= 4.036, df= 2, 98, p= 0.02) than in the MDD NA (p= 0.026) and HV (p= 0.049) groups. We did not detect group differences in baseline levels or in the …

Objective Explore relationships of acute dissociative effects of intravenous ketamine with change in depression and suicidal ideation and with plasma metabolite levels in a randomized, midazolam-controlled trial. Method Data from a completed trial in suicidal, depressed participants (N=40) randomized to ketamine was used to examine relationships between ketamine treatment-emergent dissociative and psychotomimetic symptoms with pre/post-infusion changes in suicidal ideation and depression severity. Non-parametric correlational statistics were used. These methods were also used to explore associations between dissociative or psychotomimetic symptoms and blood levels of ketamine and metabolites in a subset (N=28) who provided blood samples immediately post-infusion. Results Neither acute dissociative nor psychotomimetic effects of …

In this work we report a -24dB LP11 mode suppression in a 7+1 to 1 Backward Pump-Signal Combiner. The mode content is measured using the S2 -Measurement technique. The high signal beam quality is attributed to a low overlap splice loss between the Tapered Fiber Bundle and the output fiber. The combiner output fiber is large mode area with a LP01 mode effective area of 584 um2.

ImportanceQuestions have emerged as to whether standard intranasal naloxone dosing recommendations (ie, 1 dose with readministration every 2-3 minutes if needed) are adequate in the era of illicitly manufactured fentanyl and its derivatives (hereinafter, fentanyl).ObjectiveTo compare naloxone plasma concentrations between different intranasal naloxone repeat dosing strategies and to estimate their effect on fentanyl overdose.Design, Setting, and ParticipantsThis unblinded crossover randomized clinical trial was conducted with healthy participants in a clinical pharmacology unit (Spaulding Clinical Research, West Bend, Wisconsin) in March 2021. Inclusion criteria included age 18 to 55 years, nonsmoking status, and negative test results for the presence of alcohol or drugs of abuse. Data analysis was performed from October 2021 to May 2023.InterventionNaloxone administered as 1 dose (4 mg/0.1 mL) at 0 …

BackgroundAntidepressant treatment response is limited in patients with Major Depression (MDD) and comorbid Borderline Personality Disorder (BPD). However, recent studies suggest that intravenous ketamine may be an effective antidepressant treatment in this population. It is unknown if this treatment would be effective in MDD and comorbid BPD if suicidal ideation was elevated.MethodsIntravenous, single infusion ketamine treated patients (. 5 mg/kg) in a recent clinical trial (Grunebaum et al., 2018) examining blinded ketamine’s effects on suicidal thinking in depression included 11 participants with comorbid BPD and a minimum Beck Scale for Suicidal Ideation (SSI) score of 9. Treatment response on the Hamilton Depression Scale (HDRS), Beck Depression Inventory (BDI), Profile of Mood States (POMS), and SSI were compared to 24 MDD non-BPD ketamine-treated participants with comparable SSI scores …

Despite a rapid increase in pediatric mortality rate from prescription and illicit opioids, there is limited research on the dose‐dependent impact of opioids on respiratory depression in children, the leading cause of opioid‐associated death. In this article, we extend a previously developed translational model to cover pediatric populations by incorporating age‐dependent pharmacokinetic, pharmacodynamic, and physiological changes compared to adults. Our model reproduced previous perioperative clinical findings that adults and children have similar risk of respiratory depression at the same plasma fentanyl concentration when specific endpoints (minute ventilation, CO2 tension in the blood) were used. However, our model points to a potential caveat that, in a perioperative setting, routine use of mechanical ventilation and supplemental oxygen maintained the blood and tissue oxygen partial pressures in patients …

Identification to Biological Mechanisms Underlying Mood Disorders.’In the face of escalating global rates of mood disorders and their associated morbidity and mortality, improved treatment has never been more critical. Seeking treatment targets for medications identified by the molecular psychopathology of mood disorders is a huge advance over serendipity, which is how most antidepressant medications have been discovered to date. Encouragingly, progress in medical science is gradually illuminating the pathophysiology of mood disorders. For example, the microbiota-brain axis and its role in mediating immune imbalances present a promising frontier.This Research Topic journal issue focuses on neuro-immune regulatory dysfunction related to mood disorders, treatments targeting the gut microbiota, new clinical research on therapeutic mechanisms, and anti-inflammatory treatment studies. These avenues hold the promise of transforming our approach to mood disorder treatments. The Research Topic showcases four papers that delve into the relationship between treatment targets and the biological mechanisms underlying mood disorders. Li et al. dissect olfactory function in patients with bipolar disorder, offering a potential biomarker for early identification and providing nuanced insights into mood disorder subtypes and episodes. In another study, the interplay between inflammation, cytokines, and adolescent Major Depressive Disorder (MDD) was investigated; Maresin-1 was identified as a potential therapeutic target (Qiu et al.). Further, a review examines histamine’s role in

The serotonin 1A receptor has been linked to both the pathophysiology of major depressive disorder (MDD) and the antidepressant action of serotonin reuptake inhibitors. Most PET studies of the serotonin 1A receptor in MDD used the receptor antagonist radioligand, carbonyl-11CWAY100635 however the interpretation of the combined results has been contentious owing to reports of higher or lower binding in MDD with different outcome measures. The reasons for these divergent results originate from several sources, including properties of the radiotracer itself, which complicate its quantification and interpretation; as well as from previously reported differences between MDD and healthy volunteers in both reference tissue binding and plasma free fraction, which are typically assumed not to differ. Recently, we have developed two novel hierarchical multivariate methods which we validated for the quantification and analysis of 11CWAY100635, which show better accuracy and inferential efficiency compared to standard analysis approaches. Importantly, these new methods should theoretically be more resilient to many of the factors thought to have caused the discrepancies observed in previous studies. We sought to apply these methods in the largest 11CWAY100635 sample to date, consisting of 160 individuals, including 103 MDD patients, of whom 50 were not-recently-medicated and 53 were antidepressant-exposed, as well as 57 healthy volunteers. While the outcome measure discrepancies were substantial using conventional univariate analysis, our multivariate analysis techniques instead yielded highly consistent results across PET …

BackgroundTo decipher hippocampus cellular and molecular changes in major depression (MDD), we sequenced single-nucleus RNA (snRNA-seq) and accessible chromatin (snATAC-seq), spatial RNA (Visium, 10X Genomics) and multiome via deterministic barcoding in intact tissue (DBiT-seq).MethodsLibraries of 293,236 nuclei from 16 males (age 43±13, RIN> 7) were sequenced, data preprocessed and integrated. We used the RNA velocity (scVelo) to compute RNA synthesis, splicing, and degradation, ran Cell2location algorithm to deconvolute the cellular composition in spatial spots. Differentially expressed genes (DEG) were identified by the “FindMarkers” function in Seurat.ResultsWe identified all canonical neurons, oligodendrocytes, microglia, vasculature, epithelial, choroid plexus, Cajal-Retzius, and oligodendrocyte progenitor cells. We discovered a neural progenitor cell cluster (NPC) enriched for …

BackgroundAccumulating evidence points to altered immune response in suicide, which implicates malfunction of blood-brain barrier that we investigate in the present study through transcriptional profiling of the human Neurovascular unit (NVU).MethodsNVU from human prefrontal cortex was mechanically isolated from 119 (age range18-71, 46% females) consisting of 32 depressed and 29 schizophrenia cases who died by suicide, and 30 non psychiatric control and 29 schizophrenia cases who died of accidental causes. NVU RNA was isolated and sequenced, filtered to remove lowly-expressed genes (0.5 count per million (CPM) in fewer than 2% of samples or mean logCPM and lt;= 1.2 in all four groups), and 25% most variable genes were selected for Weighted gene co-expression network analysis (WGCNA). Gene co-expression suicide associated modules were identified using the Wilcoxonrank sum test …

BackgroundIndividuals who have lost a loved one to suicide demonstrate an attentional bias to deceased-related stimuli during early grief. Regulating attention toward reminders of the deceased during acute bereavement may be linked to grief trajectory and pathological grief development. Despite the potential prognostic importance, little is known about underlying neural circuitry correlates of deceased-related grief processing. The current study examines neural substrates of deceased-related attentional processing during acute grief in individuals bereaved by suicide.MethodsThirty-seven participants grieving the loss of a first-degree relative or partner to suicide in the prior six months, underwent functional magnetic resonance imaging (fMRI) while performing an emotional Stroop task using words related to the deceased and a living attachment figure, in order to examine neural correlates of deceased-specific …

Emergency department (ED) visits for suicidal ideation or behavior have been increasing in all age groups, particularly younger adults. A rapid-acting treatment to reduce suicidal thinking, adapted for ED use, is needed. Previous studies have shown a single dose of ketamine can improve depression and suicidal ideation within hours. However, most studies used 40 min intravenous infusions which can be impractical in a psychiatric ED. The ER-Ketamine study we describe here is a randomized midazolam-controlled clinical trial (RCT; NCT04640636) testing intramuscular (IM) ketamine's feasibility, safety, and effectiveness to rapidly reduce suicidal ideation and depression in a psychiatric ED. A pre-injection phase involves screening, informed consent, eligibility confirmation, and baseline assessment of suicidal ideation, depression, and comorbidities. The randomized double-blind IM injection is administered in the …

Background Social support (SS) and social isolation (SI) are social determinants of health (SDOH) associated with psychiatric outcomes. In electronic health records (EHRs), individual-level SS/SI is typically documented as narrative clinical notes rather than structured coded data. Natural language processing (NLP) algorithms can automate the otherwise labor-intensive process of data extraction. Data and Methods Psychiatric encounter notes from Mount Sinai Health System (MSHS, n=300) and Weill Cornell Medicine (WCM, n=225) were annotated and established a gold standard corpus. A rule-based system (RBS) involving lexicons and a large language model (LLM) using FLAN-T5-XL were developed to identify mentions of SS and SI and their subcategories (e.g., social network, instrumental support, and loneliness). Results For extracting SS/SI, the RBS obtained higher macro-averaged f-scores than the LLM at both MSHS (0.89 vs. 0.65) and WCM (0.85 vs. 0.82). For extracting subcategories, the RBS also outperformed the LLM at both MSHS (0.90 vs. 0.62) and WCM (0.82 vs. 0.81). Discussion and Conclusion Unexpectedly, the RBS outperformed the LLMs across all metrics. Intensive review demonstrates that this finding is due to the divergent approach taken by the RBS and LLM. The RBS were designed and refined to follow the same specific rules as the gold standard annotations. Conversely, the LLM were more inclusive with categorization and conformed to common English-language understanding. Both approaches offer advantages and are made available open-source for future testing.

BackgroundFrom 2000–2021, U.S. suicide deaths have risen 36 %. Identification of pharmacological agents associated with increased suicide risk and safer alternatives may help reduce this trend.MethodsAn exposure-only within-subject time-to-event pharmacoepidemiologic study of the dynamic association between alprazolam treatment and suicide attempts over 2-years. Parallel analyses were conducted for diazepam, lorazepam and buspirone. Data for 2,495,520 patients were obtained from U.S. private insurance medical claims MarketScan from 2010 to 2019.FindingsAlprazolam was associated with over a doubling of risk of suicide attempts (HR=2.21, 95 % CI=2.06,2.38). A duration-response analysis for the modal dose (0.5 mg) revealed a 5 % increase in suicidal events per additional month of treatment (HR=1.05, 95 % CI=1.04,1.07). Parallel analyses with long-acting (diazepam) and short-acting …

BackgroundBrain changes related to suicide are determined by a combination of genetic and epigenetic effects. This study investigated blood-brain barrier (BBB) integrity examining the tight junction protein CLAUDIN-5, and blood-borne proteins ALBUMIN and Immunoglobulin-G (IgG), normally excluded by the BBB, in the brains of suicide decedents (SUI), hypothesizing BBB integrity may be disrupted and allow neurotoxic molecules into the brain.MethodsPostmortem homogenates of dorsolateral prefrontal cortex (dlPFC, BA9) from SUI (n= 20) and controls (CNTRL, n= 20) were processed by ELISA quantifying CLAUDIN-5, ALBUMIN and IgG in the P1 pellet (microvessels) and the supernatant (neurons and parenchyma). CLAUDIN-5 anatomical localization was determined using immunohistochemistry. RNA-seq data from BA20 (10 CNTRL and 10 SUI from our BrainQUANT collection) were aligned (STAR …

BackgroundPro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α are elevated in response to psychosocial stress; however, less is known about other inflammatory markers.MethodsWe explored response to the Trier Social Stress Test (TSST) of 16 cytokines and growth factors in patients with major depressive disorder (MDD, n = 12) vs. healthy volunteers (HV, n = 16). Outcomes were baseline and post-stress levels estimated by area under the curve (AUCi) and peak change over 3 timepoints. We also explored correlations between biomarkers and clinical characteristics.ResultsBaseline concentrations were higher in MDD for platelet-derived growth factor (PDGF)-AB/BB (p = 0.037, d = 0.70), granulocyte-macrophage colony-stimulating factor (GM-CSF, p = 0.033, d = 0.52), and IL-8 (p = 0.046, d = 0.74). After TSST, AUCi was higher in MDD for GM-CSF (p = 0.003, d = 1.21), IL-5 (p …

Portable, cost-effective PET cameras can radically expand the applicability of PET. We present here a within-participant comparison of fully quantified [18F]FDG dynamic scans in healthy volunteers using the standard Biograph mCT scanner and portable CerePET scanner. Methods Each of 20 healthy volunteers underwent dynamic [18F]FDG imaging with both scanners (1–154 d apart) and concurrent arterial blood sampling. Tracer SUV, net influx rate (Ki), and the corresponding cerebral metabolic rate of glucose (CMRglu) were quantified at regional and voxel levels. Results At the regional level, CerePET outcome measure estimates within participants robustly correlated with Biograph mCT estimates in the neocortex, wherein the average Pearson correlation coefficients across participants ± SD were 0.83 ± 0.07 (SUV) and 0.85 ± 0.08 (Ki and CMRglu). There was also strong agreement between CerePET …

Mitochondrial oxidative phosphorylation (OxPhos) powers brain activity 1, 2, and mitochondrial defects are linked to neurodegenerative and neuropsychiatric disorders 3, 4, underscoring the need to define the brain’s molecular energetic landscape 5–10. To bridge the cognitive neuroscience and cell biology scale gap, we developed a physical voxelization approach to partition a frozen human coronal hemisphere section into 703 voxels comparable to neuroimaging resolution (3x3x3 mm). In each cortical and subcortical brain voxel, we profiled mitochondrial phenotypes including OxPhos enzyme activities, mitochondrial DNA and volume density, and mitochondria-specific respiratory capacity. We show that the human brain contains a diversity of mitochondrial phenotypes driven by both topology and cell types. Compared to white matter, grey matter contains> 50% more mitochondria. We show that the more abundant grey matter mitochondria also are biochemically optimized for energy transformation, particularly among recently evolved cortical brain regions. Scaling these data to the whole brain, we created a backward linear regression model integrating several neuroimaging modalities11, thereby generating a brain-wide map of mitochondrial distribution and specialization that predicts mitochondrial characteristics in an independent brain region of the same donor brain. This new approach and the resulting MitoBrainMap of mitochondrial phenotypes provide a foundation for exploring the molecular energetic landscape that enables normal brain functions, relating it to neuroimaging data, and defining the subcellular basis for regionalized brain …

ObjectiveSuicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.MethodsThis study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression …

Major depressive disorder (MDD) is a chronic, generally episodic and debilitating disease that affects an estimated 300 million people worldwide, but its pathogenesis is poorly understood. The heritability estimate of MDD is 30–40%, suggesting that genetics alone do not account for most of the risk of major depression. Another factor known to associate with MDD involves environmental stressors such as childhood adversity and recent life stress. Recent studies have emerged to show that the biological impact of environmental factors in MDD and other stress-related disorders is mediated by a variety of epigenetic modifications. These epigenetic modification alterations contribute to abnormal neuroendocrine responses, neuroplasticity impairment, neurotransmission and neuroglia dysfunction, which are involved in the pathophysiology of MDD. Furthermore, epigenetic marks have been associated with the diagnosis …

We report BDFA with >20 dB gain over 1255-1355 nm bandwidth (17.6 THz) with maximum gain of 29.3 dB and corresponding NF of 4.6 dB (λ=1300 nm, Pin=-20 dBm). The BDFA has electrical power consumption of 8.1-9.6 W over 20-70 °C.

Human genetic studies indicate that suicidal ideation and behavior are both heritable. Most studies have examined associations between aberrant gene expression and suicide behavior, but behavior risk is linked to severity of suicidal ideation. Through a gene network approach, this study investigates how gene co-expression patterns are associated with suicidal ideation and severity using RNA-seq data in peripheral blood from 46 live participants with elevated suicidal ideation and 46 with no ideation. Associations with presence and severity of suicidal ideation were found within 18 and 3 co-expressed modules respectively (p< 0.05), not explained by severity of depression. Suicidal ideation presence and severity-related gene modules with enrichment of genes involved in defense against microbial infection, inflammation, and adaptive immune response were identified, and tested using RNA-seq data from …

ImportanceSocial determinants of health (SDOH) influence child health. However, most previous studies have used individual, small-set, or cherry-picked SDOH variables without examining unbiased computed SDOH patterns from high-dimensional SDOH factors to investigate associations with child mental health, cognition, and physical health.ObjectiveTo identify SDOH patterns and estimate their associations with children’s mental, cognitive, and physical developmental outcomes.Design, Setting, and ParticipantsThis population-based cohort study included children aged 9 to 10 years at baseline and their caregivers enrolled in the Adolescent Brain Cognitive Development (ABCD) Study between 2016 and 2021. The ABCD Study includes 21 sites across 17 states.ExposuresEighty-four neighborhood-level, geocoded variables spanning 7 domains of SDOH, including bias, education, physical and health …

BackgroundReported childhood adversity (CA) is associated with development of depression in adulthood and predicts a more severe course of illness. Although elevated serotonin 1A receptor (5-HT1AR) binding potential, especially in the raphe nuclei, has been shown to be a trait associated with major depression, we did not replicate this finding in an independent sample using the partial agonist positron emission tomography tracer [11C]CUMI-101. Evidence suggests that CA can induce long-lasting changes in expression of 5-HT1AR, and thus, a history of CA may explain the disparate findings.MethodsFollowing up on our initial report, 28 unmedicated participants in a current depressive episode (bipolar n = 16, unipolar n = 12) and 19 non-depressed healthy volunteers (HVs) underwent [11C]CUMI-101 imaging to quantify 5-HT1AR binding potential. Participants in a depressive episode were stratified into mild …

BackgroundDepression and anxiety are common and highly comorbid, and their comorbidity is associated with poorer outcomes posing clinical and public health concerns. We evaluated the polygenic contribution to comorbid depression and anxiety, and to each in isolation.MethodsDiagnostic codes were extracted from electronic health records for four biobanks [N = 177 865 including 138 632 European (77.9%), 25 612 African (14.4%), and 13 621 Hispanic (7.7%) ancestry participants]. The outcome was a four-level variable representing the depression/anxiety diagnosis group: neither, depression-only, anxiety-only, and comorbid. Multinomial regression was used to test for association of depression and anxiety polygenic risk scores (PRSs) with the outcome while adjusting for principal components of ancestry.ResultsIn total, 132 960 patients had neither diagnosis (74.8%), 16 092 depression-only (9.0%), 13 098 …

BackgroundConverging Evidence Shows Associations between Inflammation in suicide, which We Will Investigate Using Omics Approaches.MethodsParticipants with diagnosis of Major Depressive Disorder (MDD) with/out suicide attempt history and non-psychiatric non-attempter controls were followed longitudinally, where data on depression and suicide ideation and blood were collected at baseline, 3/6months (N= 112), and blood plasma processed using Luminex assay. Blood RNA-seq gene expression network analysis was performed on an independent cohort (N= 100) to identify coordinated gene expression patterns associated with suicidal ideation/severity.ResultsCytokines IL-6, TNF-α, IFN-γ, and IL-4 levels in participants’ blood were monitored longitudinally. Significant decrease in IL-6 (p= 0.0182) and TNF-α (p= 0.0304) levels was observed in depressed attempters vs. controls over time. IL-6 levels …

Objective The authors sought to identify scalable evidence-based suicide prevention strategies. Methods A search of PubMed and Google Scholar identified 20,234 articles published between September 2005 and December 2019, of which 97 were randomized controlled trials with suicidal behavior or ideation as primary outcomes or epidemiological studies of limiting access to lethal means, using educational approaches, and the impact of antidepressant treatment. Results Training primary care physicians in depression recognition and treatment prevents suicide. Educating youths on depression and suicidal behavior, as well as active outreach to psychiatric patients after discharge or a suicidal crisis, prevents suicidal behavior. Meta-analyses find that antidepressants prevent suicide attempts, but individual randomized controlled trials appear to be underpowered. Ketamine reduces suicidal ideation in hours …

ImportanceSuicide is a leading cause of death; however, the molecular genetic basis of suicidal thoughts and behaviors (SITB) remains unknown.ObjectiveTo identify novel, replicable genomic risk loci for SITB.Design, Setting, and ParticipantsThis genome-wide association study included 633 778 US military veterans with and without SITB, as identified through electronic health records. GWAS was performed separately by ancestry, controlling for sex, age, and genetic substructure. Cross-ancestry risk loci were identified through meta-analysis. Study enrollment began in 2011 and is ongoing. Data were analyzed from November 2021 to August 2022.Main Outcome and MeasuresSITB.ResultsA total of 633 778 US military veterans were included in the analysis (57 152 [9%] female; 121 118 [19.1%] African ancestry, 8285 [1.3%] Asian ancestry, 452 767 [71.4%] European ancestry, and 51 608 [8.1%] Hispanic …

I was introduced to Barbara Stanley in 1978 by her husband Michael Stanley when I joined NYU as a research fellow in Psychiatry. Michael was studying the pharmacology of antipsychotics and offered me a desk in his office. I was studying the pathogenesis of mood disorders and the action of antidepressants. This act of kindness was only the beginning of many that led to a close collaboration until Michael died unexpectedly in his sleep in 1993, leaving Barbara to raise their two children and keep their joint research program running. Michael was the person who suggested to me that, in order to study the pathogenesis of mood disorders, I should collect brain specimens from suicide decedents at the New York City Chief Medical Examiner’s Office, which was located next to the NYU Medical Center. He was an expert in measuring monoamine metabolites using HPLC, and I had done assays of monoamine oxidase …

BackgroundSoluble epoxide hydrolase (sEH, encoded by EPHX2) and P2X2 (a subtype of ATP receptors) may mediate the antidepressant-like effects of ATP. We sought to determine whether polymorphisms and mRNA expression of EPHX2 and P2X2 are associated with depression and suicidal behavior and how cognition may mediate such associations.MethodWe examined 83 single nucleotide polymorphisms (SNPs) of EPHX2 and P2X2. Subjects were MDD suicide attempters (N = 143), MDD non-suicide attempters (N = 248), and healthy volunteers (HV, N = 110). Data on demographics, depression severity, and suicide attempts were collected. Participants completed a set of cognitive tasks. Polymorphisms were genotyped using MALDI-TOF MS within the MassARRAY system. The expression of mRNA was measured using real-time polymerase chain reaction (RT-PCR).ResultsCognitive function was a …

Biomarkers that can differentiate between psychiatric disorders with and without suicidal behavior history from each other and from healthy volunteers may explain part of the pathogenesis of suicidal behavior. We conducted the hitherto largest meta-analysis comparing immune biomarkers between subjects with and without suicide attempt history or death by suicide. The study protocol was registered with PROSPERO, CRD42020212841. Standardized mean differences (SMD) were pooled with random-effects models. Heterogeneity between studies was assessed with the I2-statistic and publication bias was evaluated by the Egger test and funnel plots. Data were based on 36 studies including 2679 persons with suicidal behaviors and 6839 comparison subjects, and four immune-related biomarkers (CRP, IL-6, TNF-α and IL-1β). Suicidal behavior was associated with higher CRP blood levels compared with …

Time from first DSM4 major depressive episode (MDE) until treatment in the community was compared across racial/ethnic groups. This secondary analysis used structured baseline data from a depression research clinic (N = 260). Chi-square and survival analyses compared rates and delays to antidepressant medication and psychotherapy. Non-Hispanic Black and Hispanic (any race) participants had lower rates of both antidepressant medication and psychotherapy and longer delays to antidepressant medication compared with non-Hispanic White participants. The results underscore the need to reduce these disparities.

BackgroundBorderline personality disorder (BPD) is characterized by an elevated distress response to social exclusion (i.e., rejection distress), the neural mechanisms of which remain unclear. Functional magnetic resonance imaging studies of social exclusion have relied on the classic version of the Cyberball task, which is not optimized for functional magnetic resonance imaging. Our goal was to clarify the neural substrates of rejection distress in BPD using a modified version of Cyberball, which allowed us to dissociate the neural response to exclusion events from its modulation by exclusionary context.MethodsTwenty-three women with BPD and 22 healthy control participants completed a novel functional magnetic resonance imaging modification of Cyberball with 5 runs of varying exclusion probability and rated their rejection distress after each run. We tested group differences in the whole-brain response to …

ObjectiveOur group reported previously a comparable overall antisuicidal effect of lithium and valproate in bipolar patients. We investigated factors associated with higher antisuicidal efficacy of lithium in older individuals.MethodsThe age-related antisuicidal effect of lithium and valproate was compared in ninety-four (n = 94) high-risk bipolar suicide attempters who participated in a 2.5-year randomized, double-blind trial.ResultsAge significantly moderated the effect of lithium vs. valproate on the risk of suicide event during the study (z = −1.98, p = 0.049). We found that those who were 42 years or older (above the 75th percentile), and on lithium had significantly lower risk of suicidal behavior than older patients on valproate (>42y) or younger (<42 y) patients on either medication (interaction HR = 0.09, 95%CI: 0.01–0.89, z = −2.07, p = 0.039). This difference in risk differences was not explained away by age-related …

Depression and suicide CNRS Inist Pascal-Francis CNRS Pascal and Francis Bibliographic Databases Simple search Advanced search Search by classification Search by vocabulary My Account Home > Search results Help Export Export Selection : Selected items (1) Format : Permanent link CopyPermanent link Copy http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=7315553 Depression and suicide Author STIFFMAN, Arlene R 1 ; FELDMAN, Ronald A [1] Washington univ., George Warren Brown school social work, United States Source Advances in adolescent mental health. 1988, Vol 3 ; XVIII-304 [322 p.] ; ref : dissem Document type Serial Issue Language English Keyword (fr) Adolescent Délinquance juvénile Echec scolaire Environnement social Epidémiologie Etat dépressif Psychométrie Psychothérapie Suicide Toxicomanie Traitement Trouble affectivité Homme Keyword (en) …

Background Suicidal behavior is moderately heritable and a consequence of a combination of the diathesis traits for suicidal behavior and suicide-related major psychiatric disorders. Here, we sought to examine shared polygenic effects between various psychiatric disorders/traits and suicidal behavior and to compare the shared polygenic effects of various psychiatric disorders/traits on non-fatal suicide attempt and suicide death. Methods We used our genotyped European ancestry sample of 260 non-fatal suicide attempters, 317 suicide decedents and 874 non-psychiatric controls to test whether polygenic risk scores (PRSs) obtained from large GWASs for 22 suicide-related psychiatric disorders/traits were associated with suicidal behavior. Results were compared between non-fatal suicide attempt and suicide death in a sensitivity analysis. Results PRSs for major depressive disorder, bipolar disorder …

Neurocognitive deficits are implicated in major depressive disorder (MDD) and suicidal behavior, and cognitive function may be affected by blood levels of polyunsaturated fatty acids (PUFAs). Neuroprotective functions have been described for omega-3 (n-3) PUFAs, while omega-6 (n-6) PUFAs exhibit broadly opposing activities. Both classes of PUFAs are linked to MDD and suicidal behavior. However, few studies have investigated the relationships between PUFAs and neurocognitive function with respect to MDD or suicidal behavior. Among participants with MDD (n = 45) and healthy volunteers (HV, n = 30) we assessed performance on tasks of attentional capacity and executive function and its relationship to plasma phospholipid PUFA levels, expressed as a percentage of total plasma phospholipids, for eicosapentaenoic acid (EPA%), docosahexaenoic acid (DHA%), and arachidonic acid (AA%). Regression models tested the correlations between PUFA levels and task performance in three groups: MDD with a history of suicide attempt (SA, n = 20), MDD with no attempts (NA, n = 25), and HV. Interaction testing indicated a significant positive correlation of EPA% with continuous performance test scores in the NA group (F = 4.883, df = 2,72, p = 0.01), a measure of sustained attention. The AA% correlated negatively with performance on two executive function tasks, object alternation (beta = −3.97, z-score = −2.67, p = 0.008) and the Wisconsin card sort (beta = 0.80, t-score = −2.16, df = 69, p = 0.035), after adjustment for group and age, with no group effects. Our findings suggest a role for PUFA imbalance in attentional functioning and executive …

BackgroundThe hippocampus is implicated in the pathogenesis of major depressive disorder (MDD). The hippocampus differs functionally along its longitudinal axis, the anterior being involved with stress processing and mood, and posterior with visuo-spatial navigation. Neurogenesis is impaired in anterior hippocampus in primate and rodent models of depression and in postmortem studies of unmedicated MDD compared with healthy volunteers (HV) and medicated MDD. Functioning along the anterior-posterior axis has not been examined in MDD in vivo. In this study, we examine anterior hippocampal functioning using functional magnetic resonance imaging (fMRI) with an emotional pattern separation task (E-MST).MethodsUnmedicated MDD (N= 16) and HV (N= 12) completed the fMRI E-MST. The E-MST consists of an encoding and retrieval phase. During retrieval, individuals view a series of images, some of …

BackgroundEmotion regulation (ER) processes help support well-being, but ineffective ER is implicated in several psychiatric disorders. Engaging ER flexibly by going online and offline as needs and capacities shift may be more effective than engaging ER rigidly across time. Here, we sought to observe the neural temporal dynamics of an ER process, reappraisal, during regulation of responses to negative memories in healthy control subjects (n = 33) and subjects with major depressive disorder (n = 36).MethodsTo track the temporal dynamics of reappraisal neural systems, we used a functional magnetic resonance imaging neural decoding approach. In task 1, subjects explicitly engaged reappraisal on instruction in response to aversive images, and we used this task to develop the decoder for detecting reappraisal. In task 2, subjects experienced negative autobiographical memories from a distant (third person …

We examined relationships between the serotonin system and stress in major depression and suicidal behavior. Twenty-five medication-free depressed participants (13 suicide attempters) underwent same-day [11C]DASB and [11C]CUMI-101 positron emission tomography (PET) imaging. Binding potential (BPND) to the serotonin transporter (5-HTT) and serotonin 1A (5-HT1A) receptor, respectively, was quantified using the NRU 5-HT atlas, reflecting distinct spatial distributions of multiple serotonin targets. Ecological momentary assessment (EMA) measured current stress over one week proximal to imaging. EMA stress did not differ between attempters and non-attempters. In all depressed participants, 5-HTT and 5-HT1A BPND were unrelated to EMA stress. There were region-specific effects of 5-HTT (p=0.002) and 5-HT1A BPND (p=0.03) in attempters vs. nonattempters. In attempters, region-specific associations …

BackgroundResilience represents coping abilities to overcome exposure to psychopathological risk. In the context of risk factors for suicidal behavior, it is unknown if this attribute is deficient in suicide attempters, how it relates to other measures of risk, and where it may overlap with other risk factors associated with suicidal behavior.MethodsThe present study examined the performance on the Connor-Davidson Resilience Scale (CD-RISC) in three groups of individuals with familial risk for both mood disorder and suicidal behavior, as well as a healthy comparison group. Other risk factors for suicidal behavior, such as depression severity, hopelessness, and lifetime impulsiveness were examined as well to determine if these mediated group differences in CD-RISC scores.ResultsCD-RISC scores differed between groups, with lowest scores in the past attempter group. However, CD-RISC scores were strongly …

In our recent review [1], we discussed how pharmacological therapies share some common mechanisms in modulating neuroplasticity and reverse some of the neuropathology observed in untreated major depressive disorder (MDD). We reviewed the utility of a rapid-acting agent like ketamine, that delivers an antidepressant response (decrease in depression severity) within 24 h after a single dose and whose effects can be sustained for at least one week post treatment [1]. This contrasts with selective serotonin reuptake inhibitor (SSRI) treatment, which typically requires four weeks to achieve an antidepressant response. In their letter [2], our colleagues appropriately highlight how electroconvulsive therapy (ECT) is a treatment for MDD that utilizes neuroplasticity mechanisms and may exert its effects more rapidly than SSRIs. A standard course of ECT involves 6–12 treatments, with two to three treatments per week …

We previously showed that folic acid prescriptions for any indication were associated with lower rates of suicidal behaviour. Given that future randomised clinical trials are likely to focus on psychiatric disorders carrying elevated risk for suicide, we now report on the moderating effects of prior suicidal behaviour, psychiatric diagnoses and psychotropic medications on potential antisuicidal effects of folic acid. Data were obtained from the MarketScan Commercial Claims and Encounters databases that cover 164 million insured persons from 2005–2017, from which a cohort of 866 586 patients was derived. Analysis revealed no significant moderation effects on the antisuicidal effect of folic acid. These findings indicate that the potential benefit of folic acid for preventing suicidal behaviour is comparable in psychiatric populations at higher risk of suicide and that it may be additive to any benefit from psychotropic medications.

Background The hypothalamic-pituitary-adrenal (HPA) axis is a major stress response system, and excessive HPA responses can impact major depressive disorder and suicide. We examined relationships between reported early-life adversity (ELA), recent-life stress (RLS), suicide, and corticotropin-releasing hormone (CRH), CRH binding protein, FK506-binding protein (FKBP5), glucocorticoid receptor (GR), and brain-derived neurotrophic factor (BDNF) in postmortem human prefrontal cortex (BA9), and anterior cingulate cortex (BA24). Methods Thirteen quadruplets, matched for sex, age, and postmortem interval and consisting of suicide decedents and healthy controls, were divided equally into those with and without ELA. ELA, RLS, and psychiatric diagnoses were determined by psychological autopsy. Protein levels were determined by western blots. Results …

BackgroundNeuroinflammation is hypothesized to contribute to suicide risk and Major Depressive Disorder (MDD). Early life adversity (ELA) and recent life stress (RLS) can each increase the risk of both MDD and suicide by causing inflammation and compromising brain function in regions involved in mood regulation, such as the dorsolateral prefrontal cortex (dlPFC). In particular, the proinflammatory molecule Cyclooxygenase 2 (Cox-2), the prostaglandin synthesizing enzyme, is elevated in MDD patients and may represent a risk factor for suicide. We sought to examine Cox-2 expression in neurons and glia in the dlPFC in depressed suicide decedents and assess the effect of reported ELA and RLS.MethodsThe dlPFC (Brodmann area 9 (BA9)) from 9 quadruplets of nonsuicides with and without ELA and suicide decedents with and without ELA were processed for immunohistochemistry of Cox-2 and neuronal …

Background Borderline personality disorder (BPD) is a severe mental illness, with high rates of co-morbid major depression and suicidality. Despite the importance of optimizing treatment in BPD, little is known about how neural processes relate to individual treatment response. The present study examines how baseline regional brain blood oxygen level dependent (BOLD) activation during a functional magnetic resonance imaging (fMRI) task of emotion regulation is related to treatment response following a randomized clinical trial of six months of Dialectical Behavior Therapy (DBT) or Selective Serotonin Reuptake Inhibitor (SSRI) treatment. Methods Unmedicated individuals with BPD (N= 35), reporting suicidal behavior or self-injury in the prior six months, underwent an fMRI task in which negative personal memories were presented and they were asked to either distance (ie, experience the memory from a third-person perspective, a regulation strategy) or immerse (ie, experience the memory from a first-person perspective). Patients were then randomized to six months of either DBT (N= 16) or SSRI (N= 19) treatment. Baseline and post-treatment depression severity was scored. Results BOLD activity in prefrontal cortex, anterior cingulate, insula, and dorsal striatum was associated with distancing compared with immerse. Baseline activation during distancing in dorsolateral and ventrolateral prefrontal cortex (dlPFC, vlPFC) differentially predicted antidepressant treatment response across the SSRI and DBT groups, with higher activity predicting better response in the SSRI group, and lower activity predicting better response in the DBT group …

Suicide rates have increased steadily world-wide over the past two decades, constituting a serious public health crisis that creates a significant burden to affected families and the society as a whole. Suicidal behavior involves a multi-factorial etiology, including psychological, social and biological factors. Since the molecular neural mechanisms of suicide remain vastly uncharacterized, we examined transcriptional- and methylation profiles of postmortem brain tissue from subjects who died from suicide as well as their neurotypical healthy controls. We analyzed temporal pole tissue from 61 subjects, largely free from antidepressant and antipsychotic medication, using RNA-sequencing and DNA-methylation profiling using an array that targets over 850,000 CpG sites. Expression of NPAS4, a key regulator of inflammation and neuroprotection, was significantly downregulated in the suicide decedent group. Moreover …

Background Several social determinants of health (SDoH) have been associated with the onset of major depressive disorder (MDD). However, prior studies largely focused on individual SDoH and thus less is known about the relative importance (RI) of SDoH variables, especially in older adults. Given that risk factors for MDD may differ across the lifespan, we aimed to identify the SDoH that was most strongly related to newly diagnosed MDD in a cohort of older adults. Methods We used self-reported health-related survey data from 41 174 older adults (50–89 years, median age = 67 years) who participated in the Mayo Clinic Biobank, and linked ICD codes for MDD in the participants' electronic health records. Participants with a history of clinically documented or self-reported MDD prior to survey completion were excluded from analysis (N = 10 938, 27%). We used Cox proportional hazards models with a …

2020-05-19 Assigned to JOHNSON CONTROLS TECHNOLOGY COMPANY reassignment JOHNSON CONTROLS TECHNOLOGY COMPANY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MERKL, CHRISTOPHER, DUENKEL, GERALD A., TRIKHA, Dinesh, Van Buren, Rick A., DOLL, HERBERT J., PASSONI, MARCELLO, PRATO, NICHOLAS P., WEISS, KEVIN A., HOBGOOD, Hunter, MANN, JOSEPH F., ROMANOWICH, GARY A., DREES, KIRK H., KHAN, Abu Bakr

BackgroundStress-induced neuroinflammatory processes may underly depressive symptomatology, and stressor timing and severity may play a role. We investigated relationships of childhood and recent stressors with translocator protein (TSPO) binding, a putative biomarker of neuroinflammation, using [11C] ER176 positron emission tomography (PET).MethodsDynamic scans with concurrent arterial sampling were obtained in currently-depressed, medication-free participants with major depressive disorder (MDD; n= 40) and healthy volunteers (HV; n= 18). Tracer volume of distribution was quantified using a metabolite-corrected arterial input function in seven a priori regions (rostral anterior cingulate (rACC), caudal ACC, rostral middle frontal (RMF), putamen, hippocampus, thalamus, and nucleus accumbens). Stressor categories were:(1)“childhood”(Childhood Trauma Questionnaire summed across subscales …

BackgroundIndividuals who have lost a loved one to suicide are at increased risk for developing complicated grief (CG). It is unclear why only a subgroup of bereaved develops pathological forms of grief. Vulnerability may be related to the ability to regulate attention toward reminders of the deceased during the acute phase of grief. Using a longitudinal design, we determined whether loss-related attentional bias during acute grief predicts grief severity one year later.MethodsThirty-seven participants grieving a first-degree relative or partner to suicide in the prior 6 months performed an emotional Stroop task using words related to the deceased, a living attachment figure, living non-attachment figure, and color congruent Stroop to quantify related attentional bias during the acute grief period. Clinical interviews were conducted at baseline (N = 37) and one year later (N = 35).ResultsParticipants showed greater …

Painful conditions are probably among the most frequent reasons for seeking medical advice and assistance. Although pain is a common complaint among psychiatric patients, clinicians generally separate its presence from the background mental disorder and downplay its importance, trying primarily to control the psychiatric symptomatology. As a sensory modality, the presence of pain and its importance account for an impressive body of scholarly research. Cartesian methodology considered sensations of all modalities in a mechanistic form, which actually sounds obsolete. However, authors have continuously been faced with the same dilemmas plaguing scholars for centuries. We assume that a large portion of the sensory inputs might be generators of distorted perceptions, which subsequently lead to psychopathology. Auditory and visual hallucinations are incontestable examples. Somaesthetic hallucinations also exist, but pain hardly deserves such a denomination. Nevertheless, chronic pain and psychiatric comorbidity is a reality that needs explanation. Painkillers are not effective in treating psychiatric disorders, and antipsychotics do very little, perhaps nothing, to relieve pain. The pharmacological approach opens one door on the horizon and closes many others, while clinicians continue to face a high prevalence of comorbid pain and mental health issues. However, attempts to correlate altered body schemata (as distorted as it may be, for example, in phantom limb pain) with somatic delusions can simplify all these dilemmas, and the basket of psychophysiology, in fact, might be bigger than presumed.

ImportanceThe adverse effects of COVID-19 containment policies disrupting child mental health and sleep have been debated. However, few current estimates correct biases of these potential effects.ObjectivesTo determine whether financial and school disruptions related to COVID-19 containment policies and unemployment rates were separately associated with perceived stress, sadness, positive affect, COVID-19–related worry, and sleep.Design, Setting, and ParticipantsThis cohort study was based on the Adolescent Brain Cognitive Development Study COVID-19 Rapid Response Release and used data collected 5 times between May and December 2020. Indexes of state-level COVID-19 policies (restrictive, supportive) and county-level unemployment rates were used to plausibly address confounding biases through 2-stage limited information maximum likelihood instrumental variables analyses. Data from …

BackgroundChildhood and lifetime adversity may reduce brain serotonergic (5-HT) neurotransmission by epigenetic mechanisms.AimsWe tested the relationships of childhood adversity and recent stress to serotonin 1A (5-HT1A) receptor genotype, DNA methylation of this gene in peripheral blood monocytes and in vivo 5-HT1A receptor binding potential (BPF) determined by positron emission tomography (PET) in 13 a priori brain regions, in participants with major depressive disorder (MDD) and healthy volunteers (controls).MethodMedication-free participants with MDD (n = 192: 110 female, 81 male, 1 other) and controls (n = 88: 48 female, 40 male) were interviewed about childhood adversity and recent stressors and genotyped for rs6295. DNA methylation was assayed at three upstream promoter sites (−1019, −1007, −681) of the 5-HT1A receptor gene. A subgroup (n = 119) had regional brain 5-HT1A receptor …

Mood disorders and suicidal behavior have moderate heritability and familial transmission, and are associated with smaller hippocampal volumes. However, it is unclear whether hippocampal alterations reflect heritable risk or epigenetic effects of childhood adversity, compensatory mechanisms, illness-related changes, or treatment effects. We sought to separate the relationships of hippocampal substructure volumes to mood disorder, suicidal behavior, and risk and resilience to both by examining high familial risk individuals (HR) who have passed the age of greatest risk for psychopathology onset. Structural brain imaging and hippocampal substructure segmentation quantified Cornu Ammonis (CA1-4), dentate gyrus, and subiculum gray matter volumes in healthy volunteers (HV, N = 25) and three groups with one or more relatives reporting early-onset mood disorder and suicide attempt: 1. Unaffected HR (N = 20 …

BackgroundChildhood adversity (CA) is linked to suicidal behavior as well as to mood disorders and aggressive traits. This raises the possibility that depression and aggressive traits mediate the relationship of childhood adversity to suicide risk. Moreover, it is not known if they operate independently or interactively.AimsTo determine whether, and how, mood disorders and aggressive traits mediate the effects of reported physical and sexual abuse on future suicidal behavior.MethodsFive hundred and forty-eight subjects, offspring of parents with mood disorders, were interviewed at baseline and at yearly follow-ups with questionnaires assessing aggression, mood disorders, and suicidal behavior. The mediation analysis involved a three-step process, testing the relationships between (1) CA and attempt; (2) CA and putative mediators; and (3) putative mediators and suicide attempt, adjusting for CA.Results …

BackgroundKetamine improves depressive symptoms rapidly but appears to affect subsets of symptoms selectively. Multiple ketamine infusions are now common clinical practice, but the time course of their effects on specific depressive symptoms remains understudied and may provide information crucial to understanding the behavioral and neurobiological effects of ketamine.MethodsKetamine improves depressive symptoms rapidly but appears to affect subsets of symptoms selectively. Multiple ketamine infusions are now common clinical practice, but the time course of their effects on specific depressive symptoms remains understudied and may provide information crucial to understanding the behavioral and neurobiological effects of ketamine.ResultsTotal depression severity scores (HDRS:(F [8, 40]= 6.23, p<. 001); BDI:(F [8, 40]= 3.83, p<. 002) fell significantly after the first infusion and remained below baseline …

Background: This project proposed to systematically review and perform meta-analyses of existing findings regarding association of specific immune and inflammation related genetic and epigenetic variants to SB and/or mood disorders. Thereby, we aim to establish if these variants profile are associated with SB independently of mood disorder diagnoses.Methods: Design and methods used for this systematic review comply with the PRISMA Guidelines and follows the Meta-analyses of Observational Studies in Epidemiology (MOOSE) checklist, and is reported in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). MEDLINE, PsycINFO, Scopus, and Embase databases were searched for studies reporting gene variant (s) related to immune or inflammatory processes and compared those variants between individuals with a history of suicide attempt/suicide decedents with at …

We report 6 kW pump limited power handling in a 7+1 to 1 Pump-Signal Combiner. The high pump transmission efficiency of 98% and optimal thermal management of the combiner package enables a low thermal slope of 0.0037 C/W measured up to 6 kW of pump power. The low thermal slope allows for a potential 9 kW pump power handling capacity of the 7+1 to 1 combiner.

Goodwin et al.1 report a single 25 mg dose of psilocybin has an antidepressant effect short-term in medication-resistant depression. Unanswered questions include drug blood level as a guide to dose, psychedelic effects relationship to antidepressant benefit, and potential suicide risk of psilocybin.

Emerging spatial technologies, including spatial transcriptomics and spatial epigenomics, are becoming powerful tools for profiling of cellular states in the tissue context, , , –. However, current methods capture only one layer of omics information at a time, precluding the possibility of examining the mechanistic relationship across the central dogma of molecular biology. Here, we present two technologies for spatially resolved, genome-wide, joint profiling of the epigenome and transcriptome by cosequencing chromatin accessibility and gene expression, or histone modifications (H3K27me3, H3K27ac or H3K4me3) and gene expression on the same tissue section at near-single-cell resolution. These were applied to embryonic and juvenile mouse brain, as well as adult human brain, to map how epigenetic mechanisms control transcriptional phenotype and cell dynamics in tissue. Although highly concordant tissue …

BackgroundSuicide remains a leading cause of death in youth. In recent years, suicide rates have risen disproportionately in Black youth, yet we know very little about risk factors specific to this group or the reasons behind this trend. We sought to identify the role of parental history of suicidal behavior in predicting suicide-related behaviors (SRB) in a sample of Black youth at high risk for suicidal behavior.MethodsThe sample includes 156 offspring of parents with mood disorders (mean age: 12.63 years, standard deviation: 2.66). Youth underwent baseline and yearly study assessments during this longitudinal study (mean years of follow-up: 3.84). Observations were censored at the time point closest to the first episode of SRB for youth with SRB and at the time of last observation for youth without suicidal behavior. ANOVA, Chi-square, Fisher’s exact test and Firth logistic regression were used to test the hypotheses …

BACKGROUNDThe Coronavirus disease 19 (COVID-19)-related psychiatric burden partly results from prolonged social stress world-wide. Studies have examined the psychiatric impact of COVID-19 on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM 5) and International Classification of Diseases 11 th Revision (ICD-11) categories, implicating multiple diagnoses, complicating clinical management.AIMTo verify whether COVID-19-related psychopathology spans multiple DSM-5 and ICD-11 diagnoses, but not in a random pattern. Consequently, empirical analysis of the multiple associated symptoms will better describe COVID-19-related psychopathology.METHODSWe conducted a bi-national study during the first surge of the pandemic: an Italian sample (n= 21217, studied March-April 2020); and three representative longitudinal samples from Israel (n= 1276, 1189, and 1432 respectively …

BackgroundMedical comorbidity and healthcare utilization in patients with treatment resistant depression (TRD) is usually reported in convenience samples, making estimates unreliable. There is only limited large-scale clinical research on comorbidities and healthcare utilization in TRD patients.MethodsElectronic Health Record data from over 3.3 million patients from the INSIGHT Clinical Research Network in New York City was used to define TRD as initiation of a third antidepressant regimen in a 12-month period among patients diagnosed with major depressive disorder (MDD). Age and sex matched TRD and non-TRD MDD patients were compared for anxiety disorder, 27 comorbid medical conditions, and healthcare utilization.ResultsOut of 30,218 individuals diagnosed with MDD, 15.2 % of patients met the criteria for TRD (n = 4605). Compared to MDD patients without TRD, the TRD patients had higher rates …

Higher intent suicide attempts carry elevated risk of future suicidal behavior. Abnormal functioning of the hypothalamic-pituitary-adrenal (HPA) axis is both linked to nonfatal suicidal behavior and suicide deaths in major depressive disorder. Few studies, however, have identified biological markers of a high-intent suicidal subgroup. We examined HPA axis output and reactivity to the Trier Social Stress Test (TSST) via salivary cortisol in depressed individuals (N=68) with a suicide attempt (SA) history. A median split of higher and lower suicidal intent scores was used to define groups. Individuals with high intent SA had attenuated total cortisol output (AUCg), F(1,60)=10.04, SE=5.095, p=.003, and lower HPA-axis stress responsivity to the TSST (AUCi), F(1,60)=4.50, SE=4.604, p=.039, compared with the low intent SA group. The high intent group also reported more pronounced negative affect than the low intent group …

Suicide rates have increased steadily world-wide over the past two decades, constituting a serious public health crisis that creates a significant burden to affected families and the society as a whole. Suicidal behavior involves a multi-factorial etiology, including psychological, social and biological factors. Since the molecular neural mechanisms of suicide remain largely uncharacterized, we examined transcriptional-and methylation profiles of postmortem brain tissue from subjects who died from suicide as well as their neurotypical healthy controls. We analyzed temporal pole tissue from 61 subjects, free from antidepressant and antipsychotic medication, using whole genome RNA-sequencing and DNA-methylation profiling using an array that targets over 850,000 CpG sites. Expression of

We compared BDFAs directly pumped with 1195 nm single-mode semiconductor laser(s) to 915 nm multimode laser via YDF mode/wavelength conversion stage. We demonstrated that 915/1150 nm pumping have superior performance and lower power consumption compared to 1195 nm.

BackgroundInsecure attachment is associated with mental health morbidity. We explored associations between parent and offspring attachment style in a longitudinal study of families with a depressed parent.MethodsParents (N = 169) with a DSM-IV mood disorder and their adult offspring (N = 267), completed the Adult Attachment Questionnaire at one or more time points during up to 9.7 years of follow-up. Linear mixed effects models explored associations between parent and offspring anxious and avoidant attachment scores. Residualized models accounted for parent and offspring depression severity.ResultsAvoidant attachment scores were associated between parents and offspring with (p = .034) and without (p = .012) adjustment for baseline age and sex of parent and offspring. Depressed father-offspring relationships showed more avoidant attachment in offspring compared to depressed mother-offspring …

BackgroundDuring drug development, it is essential to gather information about the change of clinical exposure of a drug (object) due to the pharmacokinetic (PK) drug-drug interactions (DDIs) with another drug (precipitant). While many natural language processing (NLP) methods for DDI have been published, most were designed to evaluate if (and what kind of) DDI relationships exist in the text, without identifying the direction of DDI (object vs. precipitant drug). Here we present a method for the automatic identification of the directionality of a PK DDI from literature or drug labels.MethodsWe reannotated the Text Analysis Conference (TAC) DDI track 2019 corpus for identifying the direction of a PK DDI and evaluated the performance of a fine-tuned BioBERT model on this task by following the training and validation steps prespecified by TAC.ResultsThis initial attempt showed the model achieved an F-score of 0.82 …

BackgroundInterleukin (IL)-6 and tumor necrosis factor (TNF) α are reportedly elevated in major depressive disorder (MDD) and in response to acute psychosocial stress, suggesting a role of inflammation in MDD. Less is known about other potentially implicated cytokines/chemokines in the inflammatory response.MethodsThe Trier Social Stress Test (TSST) was administered to adults with MDD (N= 12) and healthy volunteers (HV, N= 16). Blood was collected prior to starting the TSST, and 60 and 90 minutes after the procedure. Serum levels of 48 cytokines were quantified, using fluorescent bead technology. Sixteen cytokines had detection rates> 95% and were included in subsequent analyses. Outcome measures were levels at baseline and change over time using area under curve with respect to baseline (AUCi). Effect sizes for MDD vs. HV group contrast were calculated using Glass’s delta (d). Results with …

Trends in Suicide Deaths With and Without Warning From 2003-2019: Identifying the Missing Link for Effective Suicide Prevention

IntroductionCurrent treatment of major depressive disorder (MDD) warrants critical reexamination. Initial treatment response rates are modest and drop dramatically after 3 months. Meanwhile, MDD is emerging as the leading cause of disease burden worldwide.Areas coveredWe searched PubMed (up to June 2021) for randomized controlled trials comparing antidepressant combinations versus monotherapy. We discuss findings from these studies in light of current treatment guidelines for MDD. These recommend a sequence of single, six-week-long, medication trials, before trying antidepressant combinations. The result leaves one third of patients still depressed after six months of treatment.Expert opinionOptimizing the first three months of MDD treatment is crucial because response rates during this period are five times better than in the second three months. We propose a new, evidence-based algorithm of …

BackgroundTranslocator protein (TSPO), a putative biomarker of neuroinflammation, and monoamine oxidase A (MAO-A), a catabolic enzyme for monoamine neurotransmitters, are both reported to be elevated in major depressive disorder and with stress. MAO-A is implicated in oxidative stress, which is related to inflammation. Higher MAO-A levels would mean higher levels of free oxygen radicals and the potential cellular injury could stimulate an inflammatory response. TSPO is induced during inflammatory responses. We therefore used positron emission tomography (PET) to compare TSPO with MAO-A binding in healthy volunteers (HV).Methods[11C] ER176 (targeting TSPO) and [11C] Harmine (targeting MAO-A) PET scans both with concurrent arterial sampling were obtained in 12 HV. Tracer volumes of distribution (VT) were quantified at the regional level. Pearson’s correlations between [11C] ER176 and …

BackgroundThis large-scale pharmacoepidemiologic study was conducted to confirm a previous signal for decreased risk of suicide attempt following prescription fills for benztropine.MethodsWe used a within-person exposure-only cohort design to study the dynamic association between benztropine prescription fills over a 12-month period and suicidal events (suicide attempts and intentional self-harm) in 62,493 patients with private health insurance (MarketScan - MS) who filled a new benztropine prescription between 2011 and 2019. A discrete-time survival analysis was used to analyze the data, adjusting for age, sex, diagnoses related to suicidal behavior, Parkinson's disease, medical comorbidities, history of suicide attempts, concomitant CNS medications, and time-varying antipsychotic use.ResultsOverall, there were 486 suicidal events (0.8%) following the index end-date of the one-year baseline period …

Suicidal behavior is associated with deficits in cognitive control; however, suicidal ideation (SI), a key precursor to suicidal behavior, has been less consistently linked to neuropsychological functioning. Additionally, no study to date has examined attentional control capacities in relation to variability in suicidal ideation, defined as fluctuation in SI intensity and duration across short periods of time. Prior research suggests that suicidal individuals with highly variable SI experience greater stress-responsive increases in SI and cortisol, potentially raising risk for suicidal behavior. Here, we examined attentional control capacities associated with SI variability and severity in ninety-five subjects with major depressive disorder. Variability and severity of SI and depressive affect were quantified using Ecological Momentary Assessment (EMA) over a 7-day period. Participants completed the Continuous Performance Task (CPT …

Mood disorders and suicidal behavior have moderate heritability and are associated with altered corticolimbic serotonin 1A receptor (5-HT1A) brain binding. However, it is unclear whether this reflects genetic effects or epigenetic effects of childhood adversity, compensatory mechanisms, or illness stress-related changes. We sought to separate such effects on 5-HT1A binding by examining high familial risk individuals (HR) who have passed through the age of greatest risk for psychopathology onset with and without developing mood disorder or suicidal behavior. PET imaging quantified 5-HT1A binding potential BPND using [11C]CUMI-101 in healthy volunteers (HV, N = 23) and three groups with one or more relatives manifesting early-onset mood disorder and suicide attempt: 1. unaffected HR (N = 23); 2. HR with lifetime mood disorder and no suicide attempt (HR-MOOD, N = 26); and 3. HR-MOOD with …

ImportanceSuicide is a leading cause of death in the United States, having increased more than 30% from 2000 to 2018. An inexpensive, safe, widely available treatment for preventing suicidal behavior could reverse this trend.ObjectiveTo confirm a previous signal for decreased risk of suicide attempt following prescription fills for folic acid in a national pharmacoepidemiologic study of patients treated with folic acid.Design, Setting, and ParticipantsA within-person exposure-only cohort design was used to study the dynamic association between folic acid (vitamin B9) prescription fills over a 24-month period and suicide attempts and intentional self-harm. Data were collected from a pharmacoepidemiologic database of US medical claims (MarketScan) for patients with private health insurance who filled a folic acid prescription between 2012 and 2017. The same analysis was repeated with a control supplement …

Depression is the leading cause of disability globally (1, 2). One-third to one-half of patients suffering from major depressive disorder (MDD) do not achieve remission even after multiple antidepressant trials (3). Ketamine is a commonly-used FDA-approved anesthetic medication that at subanesthetic doses leads to rapid antidepressant and anti-suicidal ideation effects in hours, rather than weeks, following administration. Despite these promising findings, a key limitation of ketamine treatment is that it only yields an antidepressant response in approximately 50% of those treated. The goal of this project is to A) elucidate ketamine’s mechanism of action and B) identify biomarkers predicting treatment outcome to ketamine which could be used to match patients to treatment based on the likelihood of effectiveness at the individual level. Data from animal models suggests that ketamine acts by enhancing the connections between neurons through a process known as synaptic plasticity (4-7), and that these biological changes are responsible for the sustained behavioral effects of ketamine (8). A newly available tool allows us to image the density of these synaptic connections in the living brain using PET imaging with a radiotracer called [ 11 C] UCB-J, which is a marker of synaptic density. We propose to directly quantify synaptic density in depressed patients before and after a course of ketamine, to examine changes in density following treatment. In exploratory analyses, we will examine synaptic density as a mediator of the sustained antidepressant effects of ketamine and as a predictor of treatment

In response to a surge of deaths from synthetic opioid overdoses, there have been increased efforts to distribute naloxone products in community settings. Prior research has assessed the effectiveness of naloxone in the hospital setting; however, it is challenging to assess naloxone dosing regimens in the community/first‐responder setting, including reversal of respiratory depression effects of fentanyl and its derivatives (fentanyls). Here, we describe the development and validation of a mechanistic model that combines opioid mu receptor binding kinetics, opioid agonist and antagonist pharmacokinetics, and human respiratory and circulatory physiology, to evaluate naloxone dosing to reverse respiratory depression. Validation supports our model, which can quantitatively predict displacement of opioids by naloxone from opioid mu receptors in vitro, hypoxia‐induced cardiac arrest in vivo, and opioid‐induced …

The various functions of the skeleton are influenced by extracellular cues, hormones, and neurotransmitters. One type of neuronal regulation favors bone mass accrual by inhibiting sympathetic nervous system (SNS) activity. This observation raises questions about the transcriptional mechanisms regulating catecholamine synthesis. Using a combination of genetic and pharmacological studies, we found that the histone deacetylase sirtuin 1 (SIRT1) is a transcriptional modulator of the neuronal control of bone mass. Neuronal SIRT1 reduced bone mass by increasing SNS signaling. SIRT1 did so by increasing expression of monoamine oxidase A (MAO-A), a SIRT1 target that reduces brain serotonin levels by inducing its catabolism and by suppressing tryptophan hydroxylase 2 (Tph2) expression and serotonin synthesis in the brain stem. SIRT1 upregulated brain catecholamine synthesis indirectly through serotonin …

Cellular function in tissue is dependent on the local environment, requiring new methods for spatial mapping of biomolecules and cells in the tissue context. The emergence of spatial transcriptomics has enabled genome-scale gene expression mapping, , –, but the ability to capture spatial epigenetic information of tissue at the cellular level and genome scale is lacking. Here we describe a method for spatially resolved chromatin accessibility profiling of tissue sections using next-generation sequencing (spatial-ATAC-seq) by combining in situ Tn5 transposition chemistry and microfluidic deterministic barcoding. Profiling mouse embryos using spatial-ATAC-seq delineated tissue-region-specific epigenetic landscapes and identified gene regulators involved in the development of the central nervous system. Mapping the accessible genome in the mouse and human brain revealed the intricate arealization of brain …

Public health and epidemiologic research have established that social connectedness promotes overall health. Yet there have been no recent reviews of findings from research examining social connectedness as a determinant of mental health. The goal of this review was to evaluate recent longitudinal research probing the effects of social connectedness on depression and anxiety symptoms and diagnoses in the general population. A scoping review was performed of PubMed and PsychInfo databases from January 2015 to December 2021 following PRISMA-ScR guidelines using a defined search strategy. The search yielded 66 unique studies. In research with other than pregnant women, 83% (19 of 23) studies reported that social support benefited symptoms of depression with the remaining 17% (5 of 23) reporting minimal or no evidence that lower levels of social support predict depression at follow-up. In research with pregnant women, 83% (24 of 29 studies) found that low social support increased postpartum depressive symptoms. Among 8 of 9 studies that focused on loneliness, feeling lonely at baseline was related to adverse outcomes at follow-up including higher risks of major depressive disorder, depressive symptom severity, generalized anxiety disorder, and lower levels of physical activity. In 5 of 8 reports, smaller social network size predicted depressive symptoms or disorder at follow-up. In summary, most recent relevant longitudinal studies have demonstrated that social connectedness protects adults in the general population from depressive symptoms and disorders. The results, which were largely consistent across settings …

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 …

In proton magnetic resonance spectroscopy (1H MRS)‐based thermometry of brain, averaging temperatures measured from more than one reference peak offers several advantages, including improving the reproducibility (i.e., precision) of the measurement. This paper proposes theoretically and empirically optimal weighting factors to improve the weighted average of temperatures measured from three references. We first proposed concepts of equivalent noise and equivalent signal‐to‐noise ratio in terms of frequency measurement and a concept of relative frequency that allows the combination of different peaks in a spectrum for improving the precision of frequency measurement. Based on these, we then derived a theoretically optimal weighting factor and proposed an empirical weighting factor, both involving equivalent noise levels, for a weighted average of temperatures measured from three references (i.e …

Background: A significant limitation in our understanding of the genetic and clinical mediating factors of clinical remission of major depressive disorder (MDD) is that there is currently no standard definition of what is known as treatment-resistant depression (TRD). Multiple criteria have been proposed to standardize TRD as a qualitative trait. Most criteria set a threshold of 1-2 “standard” treatment trials after which the patient would be classified as having TRD. Yet, such a categorical definition might not be representative of the heterogeneous nature of MDD or its treatment failure. Defining TRD as a continuum instead of a dichotomous cut-point may enable further individualization of care by providing a more sensitive measure of each patient's degree of resistance to treatment. In two different biobanks with linked electronic health record (EHR) data, we compared multiple qualitative measures of TRD to a quantitative …

ObjectiveTreatment-resistant depression (TRD), defined as inadequate response to at least one or at least two antidepressant (AD) trials, is common in major depressive disorder (MDD). In this study, electronic health records (EHR) were used to identify clinical associations with TRD.MethodsUsing two biobanks, phenomes of patients with at least one MDD-related diagnostic code and one AD prescription (N=17,049) were generated using aggregated diagnostic codes (phecodes) from EHRs. Phenotype-by-phenome-wide association analyses were performed for two binary definitions of TRD, based on either one or more, or two or more, AD switches after at least 30 days but within 14 weeks, and a quantitative measure defined as the number of unique ADs prescribed for at least 30 days.ResultsOf the 17,049 patients with MDD, 1624 (9.5%) had at least one switch, 422 (2.5%) had at least two switches, and the number of unique antidepressant prescriptions ranged from one to twelve. After accounting for multiple testing, 142, 18, and 7 phecodes were significantly associated with the quantitative definition and the two binary definitions (≥1 AD switch or ≥2 AD switches), respectively. All three outcomes were significantly associated with known TRD risk factors including anxiety disorders, insomnia, and suicidal ideation. The quantitative measure was uniquely associated with other conditions including irritable bowel syndrome and decreased white blood cell count.ConclusionsIn addition to identifying known clinical associations, the quantitative measure of treatment resistance uncovered new factors potentially associated with TRD. This measure …

With the ongoing global pandemic of coronavirus disease 2019 (COVID‐19), there is an urgent need to accelerate the traditional drug development process. Many studies identified potential COVID‐19 therapies based on promising nonclinical data. However, the poor translatability from nonclinical to clinical settings has led to failures of many of these drug candidates in the clinical phase. In this study, we propose a mechanism‐based, quantitative framework to translate nonclinical findings to clinical outcome. Adopting a modularized approach, this framework includes an in silico disease model for COVID‐19 (virus infection and human immune responses) and a pharmacological component for COVID‐19 therapies. The disease model was able to reproduce important longitudinal clinical data for patients with mild and severe COVID‐19, including viral titer, key immunological cytokines, antibody responses, and time …

Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with acute and postacute cognitive and neuropsychiatric symptoms including impaired memory, concentration, attention, sleep and affect. Mechanisms underlying these brain symptoms remain understudied. Here we report that SARS-CoV-2-infected hamsters exhibit a lack of viral neuroinvasion despite aberrant blood–brain barrier permeability. Hamsters and patients deceased from coronavirus disease 2019 (COVID-19) also exhibit microglial activation and expression of interleukin (IL)-1β and IL-6, especially within the hippocampus and the medulla oblongata, when compared with non-COVID control hamsters and humans who died from other infections, cardiovascular disease, uraemia or trauma. In the hippocampal dentate gyrus of both COVID-19 hamsters and humans, we observed fewer neuroblasts and …