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Background: Impaired emotion regulation (ER) contributes to major depression and suicidal ideation and behavior. ER is typically studied by explicitly directing participants to regulate, but this may not capture spontaneous tendencies of individuals with depression to engage ER in daily life., Methods: In 82 participants with major depressive disorder, we examined the relationship of spontaneous engagement of ER to real-world responses to stress. We used a machine learning-derived neural signature reflecting neural systems that underlie cognitive reappraisal (an ER strategy) to identify reappraisal-related activity while participants recalled negative autobiographical memories under the following conditions: 1) unstructured recall; 2) distanced recall, a form of reappraisal; and 3) immersed recall (comparison condition). Participants also completed a week of ecological momentary assessment measuring daily stressors, suicidal ideation, and negative affect., Results: Higher reappraisal signature output for the unstructured period, a proxy for the spontaneous tendency to engage ER, was associated with greater increases in suicidal ideation following stressors (b = 0.083, p = .041). Higher signature output for distanced recall, a proxy for the capacity to engage ER when directed, was associated with lower negative affect following stressors (b = -0.085, p = .029). Output for the immerse period was not associated with ecological momentary assessment outcomes., Conclusions: Findings suggest that in major depressive disorder, the spontaneous tendency to react to negative memories with attempts to reappraise may indicate greater reactivity to negative cues, while intact capacity to use reappraisal when directed may be associated with more adaptive responses to stress. These data have implications for understanding stress-related increases in suicide risk in depression., (Copyright © 2024. Published by Elsevier Inc.)

Objective: The rate of worldwide mass shootings increased almost 400% over the last 40 years. About 30% are followed by the perpetrator's fatal or nonfatal suicide attempt., Method: We examined the rate of fatal and nonfatal attempts among 528 mass shooters over the last 40 years and their relationship to detected mental illness to better understand this specific context of suicide. We collected information on U.S.-based, personal-cause mass murders that involved one or more firearms, from online sources., Results: A greater proportion of mass shooters from 2000 to 2019 took or attempted to take their own lives (40.5%) compared with those from 1980 to 1999 (23.2%, p  < 0.001). More than double the proportion of perpetrators who made a fatal or nonfatal suicide attempt had a history of non-psychotic psychiatric/neurologic symptoms (38.9%), compared with perpetrators who did not make a fatal or nonfatal suicide attempt (18.1%; p  < 0.001). Among mass shooters who made fatal or nonfatal suicide attempts, 77 of 175 (44%) did not have any recorded psychiatric, neurologic, or substance use condition. Of the 98 mass shooters who made fatal or non-fatal suicide attempts and had a psychiatric, substance use, or neurologic condition, 41 had depressive disorders., Conclusion: It is possible that a lack of information about the perpetrators' mental health or suicidal ideation led to an underestimation of their prevalence. These data suggest that suicide associated with mass shootings may represent a specific context for suicide, and approaches such as psychological autopsy can help to ascertain when psychiatric illness mediates the relationship between mass shootings and suicide.

Importance: Brain translocator protein 18k Da (TSPO) binding, a putative marker of neuroinflammatory processes (eg, gliosis), is associated with stress and elevated in depressed and suicidal populations. However, it is unclear whether neuroinflammation moderates the impact of daily life stress on suicidal ideation and negative affect, thereby increasing risk for suicidal behavior., Objective: To examine the association of TSPO binding in participants with depression with real-world daily experiences of acute stress-related suicidal ideation and negative affect, as well as history of suicidal behavior and clinician-rated suicidal ideation., Design, Setting, and Participants: Data for this cross-sectional study were collected from June 2019 through July 2023. Procedures were conducted at a hospital-based research center in New York, New York. Participants were recruited via clinical referrals, the Columbia University research subject web portal, and from responses to internet advertisements. Of 148 participants who signed informed consent for study protocols, 53 adults aged 18 to 60 years who met DSM-5 diagnostic criteria for current major depressive disorder completed procedures with approved data and were enrolled. Participants were free of schizophrenia spectrum disorders, active physical illness, cognitive impairment, and substance intoxication or withdrawal at the time of scan., Exposures: All participants underwent positron emission tomography imaging of TSPO binding with 11C-ER176 and concurrent arterial blood sampling., Main Outcome and Measures: A weighted average of 11C-ER176 total distribution volume (VT) was computed across 11 a priori brain regions and made up the primary outcome measure. Clinician-rated suicidal ideation was measured via the Beck Scale for Suicidal Ideation (BSS). A subset of participants (n = 21) completed 7 days of ecological momentary assessment (EMA), reporting daily on suicidal ideation, negative affect, and stressors., Results: In the overall sample of 53 participants (mean [SD] age, 29.5 [9.8] years; 37 [69.8%] female and 16 [30.2%] male), 11C-ER176 VT was associated at trend levels with clinician-rated suicidal ideation severity (β, 0.19; 95% CI, -0.03 to 0.39; P = .09) and did not differ by suicide attempt history (n = 15; β, 0.18; 95% CI, -0.04 to 0.37; P = .11). Exploratory analyses indicated that presence of suicidal ideation (on BSS or EMA) was associated with higher 11C-ER176 VT (β, 0.21; 95% CI, 0.01 to 0.98; P = .045). In 21 participants who completed EMA, 11C-ER176 VT was associated with greater suicidal ideation and negative affect during EMA periods with stressors compared with nonstress periods (β, 0.12; SE, 0.06; 95% CI, 0.01 to 0.23; P = .03 and β, 0.19; SE, 0.06; 95% CI, 0.08 to 0.30; P < .001, respectively)., Conclusion and Relevance: TSPO binding in individuals with depression may be a marker of vulnerability to acute stress-related increases in suicidal ideation and negative affect. Continued study is needed to determine the causal direction of TSPO binding and stress-related suicidal ideation or negative affect and whether targeting neuroinflammation may improve resilience to life stress in patients with depression.

Objectives: 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 in narrative clinical notes rather than as structured coded data. Natural language processing (NLP) algorithms can automate the otherwise labor-intensive process of extraction of such information., Materials and Methods: Psychiatric encounter notes from Mount Sinai Health System (MSHS, n = 300) and Weill Cornell Medicine (WCM, n = 225) were annotated to create 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 (eg, social network, instrumental support, and loneliness)., Results: For extracting SS/SI, the RBS obtained higher macroaveraged F1-scores than the LLM at both MSHS (0.89 versus 0.65) and WCM (0.85 versus 0.82). For extracting the subcategories, the RBS also outperformed the LLM at both MSHS (0.90 versus 0.62) and WCM (0.82 versus 0.81)., Discussion and Conclusion: Unexpectedly, the RBS outperformed the LLMs across all metrics. An intensive review demonstrates that this finding is due to the divergent approach taken by the RBS and LLM. The RBS was designed and refined to follow the same specific rules as the gold-standard annotations. Conversely, the LLM was more inclusive with categorization and conformed to common English-language understanding. Both approaches offer advantages, although additional replication studies are warranted., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Importance: Diagnostic codes in the Electronic Health Record (EHR) are known to be limited in reporting patient suicidality, and especially in differentiating the levels of suicide severity., Objective: The authors developed and validated a portable natural language processing (NLP) algorithm for detection of suicidal ideation (SI) and suicide-related behavior and attempts (SB/SA) in EHR data. The algorithm was then deployed, and SI and SB/SA ascertainment was compared to that of International Statistical Classification of Diseases (ICD-9 and 10) diagnostic codes., Design: A group of experts designed the pipeline to detect and distinguish suicide severity based on the Columbia-Suicide Severity Rating Scale (C-SSRS). Notes were manually annotated to create the "Gold Standard" with which the algorithm output was evaluated for accuracy., Setting: The algorithm was developed at two academic medical centers, Weill Cornell Medicine (WCM), the Mount Sinai Health System (MSHS), and tested at these two, plus a third, the University of Utah Healthcare Center (UUHSC)., Participants: Notes were from participants with psychiatric encounters at the three institutions., Main Outcomes: The two main outcomes were the accuracy scores of the NLP pipeline and comparison of ascertainment rates to ICD codes., Results: F1 accuracy scores ranged from 0.86-0.97 at the three sites. The NLP rate of detection of SB/SA was almost 30 times higher, and SI was almost 10 times higher, when compared with that of diagnostic codes. NLP detected almost all cases detected by diagnostic codes. No bias in performance was found for race/ethnicity and performance was comparable in psychiatric and non-psychiatric EHRs., Conclusions and Relevance: EHRs from cohorts with psychiatric diagnoses or encounters at WCM, MSHS, and UUHSC had SI and SB/SA extracted using an NLP algorithm based on parameters defined by the C-SSRS. Validity was determined by comparing the algorithm output to manual annotations of clinical notes by domain experts. NLP-detection of SI and SB/SA was compared with that of ICD codes across a range of demographic groups. Algorithm performance was also examined for bias in minoritized groups and in non-psychiatric notes., Key Points: Question: Can we automate the extraction of data available in clinical notes to accurately detect and distinguish patients with suicidal ideation (SI) and suicidal behavior (SB)? Findings: Our Natural Language Processing (NLP) approach was able to identify and distinguish SI and SB at three different hospital systems with benchmarked accuracy scores (above 0.85). The rate of detecting SI and SB using the algorithm was 10-30 times that of diagnostic codes found in the Electronic Health Record. Meaning: Our algorithm renders the use of International Classification of Disease (ICD) diagnostic codes for SI and SB ascertainment obsolete.

Background: Early life adversity is a risk factor for psychopathology and is associated with epigenetic alterations in the 5-HT 1A receptor gene promoter. The 5-HT 1A receptor mediates neurotrophic effects, which could affect brain structure and function. We examined relationships between self-reported early childhood abuse, 5-HT 1A receptor promoter DNA methylation, and gray matter volume (GMV) in Major Depressive Disorder (MDD)., Methods: Peripheral DNA methylation of 5-HT 1A receptor promoter CpG sites -681 and -1007 was assayed in 50 individuals with MDD, including 18 with a history of childhood abuse. T1-weighted structural magnetic resonance imaging (MRI) was performed. Voxel-based morphometry (VBM) was quantified in amygdala, hippocampus, insula, occipital lobe, orbitofrontal cortex, temporal lobe, parietal lobe, and at the voxel level., Results: No relationship was observed between DNA methylation and history of childhood abuse. We observed regional heterogeneity comparing -681 CpG site methylation and GMV (p = 0.014), with a positive relationship to GMV in orbitofrontal cortex (p = 0.035). Childhood abuse history was associated with higher GMV considering all ROIs simultaneously (p < 0.01). In whole-brain analyses, childhood abuse history was positively correlated with GMV in multiple clusters, including insula and orbitofrontal cortex (p FWE  = 0.005), and negatively in intracalcarine cortex (p FWE  = 0.001)., Limitations: Small sample size, childhood trauma assessment instrument used, and assay of peripheral, rather than CNS, methylation., Conclusions: These cross-sectional findings support hypotheses of 5-HT 1A receptor-related neurotrophic effects, and of increased regional GMV as a potential regulatory mechanism in the setting of childhood abuse. Orbitofrontal cortex was uniquely associated with both childhood abuse history and 5-HT 1A receptor methylation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Oquendo receives royalties from the Research Foundation for Mental Hygiene for the commercial use of the Columbia Suicide Severity Rating Scale. She serves as an advisor to Alkermes, Mind Medicine, Sage Therapeutics, St. George's University and Fundación Jimenez Diaz. Her family owns stock in Bristol Myers Squibb. Dr. Mann receives royalties from the Research Foundation for Mental Hygiene for commercial use of the C-SSRS. Dr. Sullivan is currently an employee of Tonix Pharmaceuticals Holding Corp and owns stock and stock options in the company. All other authors have no disclosures or competing interests to report. Dr. Miller has received research support from Evecxia and AbbVie Pharmaceuticals., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Suicide is the second leading cause of death in U.S. adolescents and young adults and is generally associated with a psychiatric disorder. Suicidal behavior has a complex etiology and pathogenesis. Moderate heritability suggests genetic causes. Associations between childhood and recent life adversity indicate contributions from epigenetic factors. Genomic contributions to suicide pathogenesis remain largely unknown. This article is based on a workshop held to design strategies to identify molecular drivers of suicide neurobiology that would be putative new treatment targets. The panel determined that while bulk tissue studies provide comprehensive information, single-nucleus approaches that identify cell type-specific changes are needed. While single-nuclei techniques lack information on cytoplasm, processes, spines, and synapses, spatial multiomic technologies on intact tissue detect cell alterations specific to brain tissue layers and subregions. Because suicide has genetic and environmental drivers, multiomic approaches that combine cell type-specific epigenome, transcriptome, and proteome provide a more complete picture of pathogenesis. To determine the direction of effect of suicide risk gene variants on RNA and protein expression and how these interact with epigenetic marks, single-nuclei and spatial multiomics quantitative trait loci maps should be integrated with whole-genome sequencing and genome-wide association databases. The workshop concluded with a recommendation for the formation of an international suicide biology consortium that will bring together brain banks and investigators with expertise in cutting-edge omics technologies to delineate the biology of suicide and identify novel potential treatment targets to be tested in cellular and animal models for drug and biomarker discovery to guide suicide prevention., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Treatment resistance is common in major depressive disorder (MDD), yet clinical risk factors are not well understood. Using a discovery-replication design, we conducted phenome-wide association studies (PheWASs) of MDD treatment resistance in two electronic health record (EHR)-linked biobanks. The PheWAS included participants with an MDD diagnosis in the EHR and at least one antidepressant (AD) prescription. Participant lifetime diagnoses were mapped to phecodes. PheWASs were conducted for three treatment resistance outcomes based on AD prescription data: number of unique ADs prescribed, ≥1 and ≥2 CE switches. Of the 180 phecodes significantly associated with these outcomes in the discovery cohort (n = 12,558), 71 replicated (n = 8,206). In addition to identifying known clinical factors for treatment resistance in MDD, the total unique AD prescriptions was associated with additional clinical variables including irritable bowel syndrome, gastroesophageal reflux disease, symptomatic menopause, and spondylosis. We calculated polygenic risk of specific-associated conditions and tested their association with AD outcomes revealing that genetic risk for many of these conditions is also associated with the total unique AD prescriptions. The number of unique ADs prescribed, which is easily assessed in EHRs, provides a more nuanced measure of treatment resistance, and may facilitate future research and clinical application in this area., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Mann receives royalties for commercial use of the C-SSRS from the Research Foundation for Mental Hygiene and from Columbia University from sales of the Columbia Pathways app. Dr. Weissman has received funding from NIMH and Columbia University Institute for Developmental Sciences and receives book royalties from Perseus Press and Oxford Press. None of these represent a conflict of interest. If there are other authors, they 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. Published by Elsevier B.V.)

Background: Borderline personality disorder (BPD) is a severe mental illness, with high rates of co-morbid depression and suicidality. Despite the importance of optimizing treatment in BPD, little is known about how neural processes relate to individual treatment response. This 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 six-month randomized clinical trial of Dialectical Behavior Therapy (DBT) or Selective Serotonin Reuptake Inhibitor (SSRI) treatment., Methods: Unmedicated females with BPD (N = 37), with recent suicidal behavior or self-injury, underwent an fMRI task in which negative personal memories were presented and they were asked to distance (i.e., downregulate their emotional response) or immerse (i.e., experience emotions freely). Patients were then randomized to DBT (N = 16) or SSRI (N = 21) treatment, with baseline and post-treatment depression and BPD severity assessed., Results: BOLD activity in prefrontal cortex, anterior cingulate, and insula was associated with distancing. Baseline BOLD during distancing in dorsolateral, ventrolateral, and orbital prefrontal cortex (dlPFC, vlPFC, OFC) differentially predicted depression response across treatment groups, with higher activity predicting better response in the SSRI group, and lower activity predicting better response in the DBT group., Limitations: All female samples., Discussion: Findings indicate that greater prefrontal engagement during emotion regulation may predict more antidepressant benefit from SSRIs, whereas lower engagement may predict better response to DBT. These results suggest different mechanisms of action for SSRI and DBT treatment, and this may allow fMRI to guide individualized treatment selection., Competing Interests: Declaration of competing interest JJM and BHS receive royalties from the Research Foundation for Mental Hygiene for commercial use of the C-SSRS. CAM, NS, BSB, and KNO have no conflicts to report. The design, preparation, review, and approval of the manuscript as well as the decision to submit the manuscript for publication was entirely done by the authors CAM, NS, BSB, KNO, JJM, and BHS., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Decedents with no known mental disorder comprise 5-40% of suicides, suggesting that suicide ideation (SI) and behavior may occur in the psychiatrically healthy with important implications for suicide risk screening. Healthy Volunteers (HV) and patients with Major Depressive Disorder (MDD) provided 7 days of Ecological Momentary Assessment (EMA) data about SI and stressors. Longitudinal mixed effects logistic regression models compared HV and patient SI and stressors. Mixed effects linear regression models compared HVs' and patients' SI score change from the previous epoch's SI score when each stressor occurred. HVs (n = 42) reported less frequent (p < 0.001) and less intense SI (p < 0.003) than patients (n = 80), yet did endorse SI and/or SI-related items in 44% of EMA epochs, endorsing SI items in 25% of epochs with non-zero SI scores. For 7 of 8 stressors, patients reported stressors more often than HVs (all p < 0.001) responding to them with increased SI (0.0001 < p < 0.0472). HVs were relatively resilient to stressors, reporting SI increases only in response to neglect (p < 0.0147). Although SI and SAs are documented among psychiatrically healthy individuals, scientific attention to these observations has been scant. Real-time SI measurement showed that HVs' SI was less pronounced than MDD patients', but was endorsed, nonetheless. Patients were more likely to report stressors than HVs, perhaps due to greater sensitivity to the environment, and reported SI in response to stressors, which was less common in HVs. Both MDD patients and HVs most often manifested passive SI (viz, "decreased wish to live"). However, passive SI (viz, "desire for death"), may predict suicide, even absent SI per se (thinking about killing yourself). This study validates the utility of real-time SI assessment, showing that HVs endorse SI items in 11% of epochs, which implies that suicide risk screening focused on those with mental disorders may be too narrow an approach., (© 2024. The Author(s).)

Some have challenged the validity of labelling suicidal thoughts and behaviours (STB) as pathological. In this paper, we argue that STB is indeed pathological, thereby, situating suicide prevention within the realm of medicine, complicating calls for the legalisation of medical assistance in dying for individuals whose sole condition is psychiatric (psychiatric medical assistance in dying (MAID)). Evidence shows STB predicts the risk of suicide; moreover, several mental illnesses are associated with STB, and 70%-90% of suicide deaths are linked to psychiatric illness. Treating psychiatric illnesses can prevent suicide. We contend that this clinical evidence not only warrants the classification of STB as pathological but also necessitates its treatment and prevention. This perspective poses a challenge to legislation that would legalise psychiatric MAID., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Veterans with PTSD are at higher risk for suicide. This study examined the specific associations of PTSD symptom clusters with suicidal ideation (SI) and death ideation (DI), independently from depressive symptom clusters. Participants included 695 Israeli male outpatient military veterans (M = 25.35 years, SD = 5.65), divided into subsamples of probable PTSD (PTSD Checklist for DSM-5 [PCL-5] ≥ 33) and subthreshold PTSD scores (PCL-5 < 33). Data were extracted from medical chartsand self-report questionnaires. The main analyses included logistic regression to evaluate the associations between SI and DI (Brief Symptom Inventory, items 9 and 39) and PTSD symptom clusters (PCL-5), controlling for depressive symptom clusters (Beck Depression Inventory; cognitive-affective and somatization) in each subsample. The results showed that, for veterans with probable PTSD, the negative alterations in cognition and mood symptom cluster was positively correlated with SI and DI, while avoidance was negatively correlated with SI, independently from depressive symptoms clusters. In those with sub-syndromal PTSD, the re-experiencing cluster was positively correlated with DI, independently from the depressive symptom clusters. These findings highlight the importance of targeting PTSD components, such as negative alterations in cognition and mood symptoms experienced by veterans with PTSD, as part of suicide prevention efforts., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Ecological Momentary Assessment (EMA) holds promise for providing insights into daily life experiences when studying mental health phenomena. However, commonly used mixed-effects linear statistical models do not fully utilize the richness of the ultidimensional time-varying data that EMA yields. Recurrent Neural Networks (RNNs) provide an alternative data analytic method to leverage more information and potentially improve prediction, particularly for non-normally distributed outcomes., Methods: As part of a broader research study of suicidal thoughts and behavior in people with borderline personality disorder (BPD), eighty-four participants engaged in EMA data collection over one week, answering questions multiple times each day about suicidal ideation (SI), stressful events, coping strategy use, and affect. RNNs and mixed-effects linear regression models (MEMs) were trained and used to predict SI. Root mean squared error (RMSE), mean absolute percent error (MAPE), and a pseudo-R 2 accuracy metric were used to compare SI prediction accuracy between the two modeling methods., Results: RNNs had superior accuracy metrics (full model: RMSE = 3.41, MAPE = 42 %, pseudo-R 2  = 26 %) compared with MEMs (full model: RMSE = 3.84, MAPE = 56 %, pseudo-R 2  = 16 %). Importantly, RNNs showed significantly more accurate prediction at higher values of SI. Additionally, RNNs predicted, with significantly higher accuracy, the SI scores of participants with depression diagnoses and of participants with higher depression scores at baseline., Conclusion: In this EMA study with a moderately sized sample, RNNs were better able to learn and predict daily SI compared with mixed-effects models. RNNs should be considered as an option for EMA analysis., Competing Interests: Declaration of competing interest Dr. Herzog, Dr. Brodsky, and Mr. Choo report no conflicts of interest. Dr. Galfalvy discloses that she and her family own stock in IBM Inc. Dr. Mann has received grant support from the National Institute of Mental Health, and royalties from the New York State Research Foundation for Mental Hygiene for commercial use of the Colombia Suicide Severity Rating Scale. Dr. Wall also reports grants from the National Institute of Health. Dr. Stanley is being included as an author posthumously., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Light-sheet fluorescence microscopy (LSFM) is a widely used technique for imaging cleared tissue and living samples. However, high-performance LSFM systems are typically expensive and not easily scalable. Here we introduce a low-cost, scalable and versatile LSFM framework, which we named 'projected light-sheet microscopy' (pLSM), with high imaging performance and small device and computational footprints. We characterized the capabilities of pLSM, which repurposes readily available consumer-grade components, optimized optics, over-network control architecture and software-driven light-sheet modulation, by performing high-resolution mapping of cleared mouse brains and of post-mortem pathological human brain samples, and via the molecular phenotyping of brain and blood-vessel organoids derived from human induced pluripotent stem cells. We also report a method that leverages pLSM for the live imaging of the dynamics of sparsely labelled multi-layered bacterial pellicle biofilms at an air-liquid interface. pLSM can make high-resolution LSFM for biomedical applications more accessible, affordable and scalable., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Standardized definitions of suicidality phenotypes, including suicidal ideation (SI), attempt (SA), and death (SD) are a critical step towards improving understanding and comparison of results in suicide research. The complexity of suicidality contributes to heterogeneity in phenotype definitions, impeding evaluation of clinical and genetic risk factors across studies and efforts to combine samples within consortia. Here, we present expert and data-supported recommendations for defining suicidality and control phenotypes to facilitate merging current/legacy samples with definition variability and aid future sample creation., Methods: A subgroup of clinician researchers and experts from the Suicide Workgroup of the Psychiatric Genomics Consortium (PGC) reviewed existing PGC definitions for SI, SA, SD, and control groups and generated preliminary consensus guidelines for instrument-derived and international classification of disease (ICD) data. ICD lists were validated in two independent datasets (N = 9,151 and 12,394)., Results: Recommendations are provided for evaluated instruments for SA and SI, emphasizing selection of lifetime measures phenotype-specific wording. Recommendations are also provided for defining SI and SD from ICD data. As the SA ICD definition is complex, SA code list recommendations were validated against instrument results with sensitivity (range = 15.4% to 80.6%), specificity (range = 67.6% to 97.4%), and positive predictive values (range = 0.59-0.93) reported., Conclusions: Best-practice guidelines are presented for the use of existing information to define SI/SA/SD in consortia research. These proposed definitions are expected to facilitate more homogeneous data aggregation for genetic and multisite studies. Future research should involve refinement, improved generalizability, and validation in diverse populations., Competing Interests: Disclosures Ole Andreassen: Consultant to Cortechs.ai and Precision-Health.ai, and received speaker’s honorarium from Lundbeck, Sunovion, Janssen and Otsuka. Murray Stein: MBS has in the past 3 years received consulting income from Aptinyx, atai Life Sciences, BigHealth, Biogen, Bionomics, Boehringer Ingelheim, Delix Therapeutics, EmpowerPharm, Engrail Therapeutics, Janssen, Jazz Pharmaceuticals, Karuna Therapeutics, Lykos Therapeutics, NeuroTrauma Sciences, Otsuka US, PureTech Health, Sage Therapeutics, Seaport Therapeutics, and Roche/Genentech. Dr. Stein has stock options in Oxeia Biopharmaceuticals and EpiVario. He has been paid for his editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor), and UpToDate (Co-Editor-in-Chief for Psychiatry). He is on the scientific advisory board of the Brain and Behavior Research Foundation and the Anxiety and Depression Association of America. Philip Harvey: Dr. Harvey consults for a variety of pharmaceutical and device manufacturers on phase 2 and 3 studies of cognition and negative symptoms in SMI. These activities have been reviewed and determined not to be related to the content of this paper. John Mann: Dr. Mann receives royalties for commercial use of the C-SSR S from the Research Foundation of Mental Hygiene and from Columbia University for the Columbia Pathways App. All other listed authors declare no conflicts of interest.

Importance: Increasing evidence suggests a potential role of immune-modulatory drugs for treatment-resistant depression. This scoping review explores the emerging evidence regarding the antidepressant effects of monoclonal antibodies (mAbs), a relatively newer class of immune therapeutics with favorable safety profile., Observations: PubMed was searched up to November 2023 for English publications addressing the antidepressant effects of mAbs, including meta-analyses, randomized controlled trials, open-label, single-arm studies, and case series. Several mAbs have shown potential antidepressant effects, but most studies in primary inflammatory disorders included patients with mild depression. Only infliximab and sirukumab were directly examined in individuals with primary depression. mAbs that do not require laboratory monitoring, such as ixekizumab and dupilumab, could hold potential promise if future studies establish their safety profile regarding suicide risk., Conclusions and Relevance: The use of several mAbs for the treatment of primary inflammatory disorders has been associated with improvement of comorbid depressive symptoms. Given their unique mechanisms of action, mAbs may offer a new hope for depressed patients who do not respond to currently available antidepressants. Further research addressing individuals with more severe depressive symptoms is essential. Direct examination of antidepressant effects of mAbs in people with primary depressive disorders is also crucial to refine their clinical use in the treatment of depression., (© Copyright 2024 Physicians Postgraduate Press, Inc.)

Importance: Suicide 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., Objective: To identify distinct suicide profiles or classes, associated signs of suicidal intent, and patterns of modifiable risks for targeted prevention efforts., Design, Setting, and Participants: This 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., Exposures: Suicide decedent profiles were determined using latent class analyses of available data on suicide circumstances, toxicology, and methods., Main Outcomes and Measures: Disclosure of recent intent, suicide note presence, and known psychotropic usage., Results: Among 306 800 suicide decedents (mean [SD] age, 46.3 [18.4] years; 239 627 males [78.1%] and 67 108 females [21.9%]), 5 profiles or classes were identified. The largest class, class 4 (97 175 [31.7%]), predominantly faced physical health challenges, followed by polysubstance problems in class 5 (58 803 [19.2%]), and crisis, alcohol-related, and intimate partner problems in class 3 (55 367 [18.0%]), mental health problems (class 2, 53 928 [17.6%]), and comorbid mental health and substance use disorders (class 1, 41 527 [13.5%]). Class 4 had the lowest rates of disclosing suicidal intent (13 952 [14.4%]) and leaving a suicide note (24 351 [25.1%]). Adjusting for covariates, compared with class 1, class 4 had the highest odds of not disclosing suicide intent (odds ratio [OR], 2.58; 95% CI, 2.51-2.66) and not leaving a suicide note (OR, 1.45; 95% CI, 1.41-1.49). Class 4 also had the lowest rates of all known psychiatric illnesses and psychotropic medications among all suicide profiles. Class 4 had more older adults (23 794 were aged 55-70 years [24.5%]; 20 100 aged ≥71 years [20.7%]), veterans (22 220 [22.9%]), widows (8633 [8.9%]), individuals with less than high school education (15 690 [16.1%]), and rural residents (23 966 [24.7%])., Conclusions and Relevance: This study identified 5 distinct suicide profiles, highlighting a need for tailored prevention strategies. Improving the detection and treatment of coexisting mental health conditions, substance and alcohol use disorders, and physical illnesses is paramount. The implementation of means restriction strategies plays a vital role in reducing suicide risks across most of the profiles, reinforcing the need for a multifaceted approach to suicide prevention.

Dysfunction in emotion regulation (ER) and autobiographical memory are components of major depressive disorder (MDD). However, little is known about how they mechanistically interact with mood disturbances in real time. Using machine learning-based neural signatures, we can quantify negative affect (NA), ER, and memory continuously to evaluate how these processes dynamically interact in MDD. Unmedicated individuals with MDD ( N =45) and healthy volunteers (HV; N =38) completed a negative autobiographical memory functional magnetic resonance imaging task wherein they recalled, distanced from (an ER strategy), and immersed into memories. We used a negative affect signature (PINES) and an emotion regulation signature (ERS) to quantify moment-to-moment NA and ER. We then examined whether memory engagement, indexed by hippocampal activity, predicted subsequent change in PINES and ERS over time. During memory recall and immersion, greater hippocampal activity predicted increased PINES across groups. During distancing, greater hippocampal activity in HVs predicted increased ERS but not PINES. In MDD, greater hippocampal activity predicted increased PINES but not ERS. Findings suggest abnormalities in the real-time relationship between memory, NA, and ER in MDD. During distancing, as predicted, HVs showed an attenuation of the linkage between memory engagement and NA, and they had subsequent increases in ER following memory reactivation. In contrast, MDD was characterized by continued linkage between memory engagement and NA, without subsequent increases in ER. Deficits in engagement of ER and ineffective modulation of NA following negative memory recall may contribute to the mood disturbances in MDD and are potential targets for clinical intervention., Competing Interests: JJM receives royalties from the Research Foundation for Mental Hygiene for commercial use of the C-SSRS. CAM, MS, SH, KO, LD, and NS have no Conflicts to report.

Background: From 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., Methods: An 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., Findings: Alprazolam 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 (lorazepam), found similar associations (diazepam HR=2.87, 95 % CI=2.56,3.21; lorazepam HR=1.83, 95 % CI=1.69,2.00), whereas the non-benzodiazepine anxiolytic, buspirone, showed significantly less risk (HR=1.25, 95 % CI=1.13,1.38), and no increased risk in patients with an attempt history (HR=1.05, 95 % CI=0.70,1.59)., Interpretation: This study confirmed an earlier signal linking alprazolam to increased suicide attempt risk. The increased risk extends to benzodiazepines in general, regardless of half-life and risk of withdrawal seizure. Buspirone appears to be a safer treatment than benzodiazepines, particularly in patients at increased risk for suicide., Competing Interests: Declaration of competing interest Dr. Gibbons has served as an expert witness in cases related to suicide for the US Department of Justice, and Pfizer, Wyeth, and GSK pharmaceutical companies and founded the company Adaptive Testing Technologies that distributes computerized adaptive mental health tests. These activities have been reviewed and approved by the University of Chicago in accordance with its conflict-of-interest policies. This study was reviewed and deemed exempt from review by the University of Chicago institutional review board. Dr. Mann receives royalties from the Research Foundation for Mental Hygiene for commercial use of the C-SSRS., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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 immune response were identified and investigated using RNA-seq data from postmortem brain that revealed gene expression differences with moderate effect sizes in suicide decedents vs. non-suicides in white matter, but not gray matter. Findings support a role of brain and peripheral blood inflammation in suicide risk, showing that suicidal ideation presence and severity are associated with an inflammatory signature detectable in blood and brain, indicating a biological continuity between ideation and suicidal behavior that may underlie a common heritability., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: We sought to 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., Methods: Data from a completed trial in suicidal, depressed participants (n = 40) randomly assigned 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. Nonparametric 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 of participants (n = 28) who provided blood samples immediately post-infusion., Results: Neither acute dissociative nor psychotomimetic effects of ketamine were associated with changes in suicidal ideation or depressive symptoms from pre- to post-infusion. Norketamine had a trend-level, moderate inverse correlation with dissociative symptoms on Day 1 post-injection (P  = .064; P =.013 removing 1 outlier). Dehydronorketamine correlated with Clinician-Administered Dissociative States Scale scores at 40 minutes (P = .034), 230 minutes (P = .014), and Day 1 (P = .012)., Conclusion: We did not find evidence that ketamine's acute, transient dissociative, or psychotomimetic effects are associated with its antidepressant or anti-suicidal ideation actions. The correlation of higher plasma norketamine with lower dissociative symptoms on Day 1 post-treatment suggests dissociation may be more an effect of the parent drug., (© The Author(s) 2024. Published by Oxford University Press on behalf of CINP.)

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 (3×3×3 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 modalities 11 , 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 processes relevant to neuropsychiatric and neurodegenerative disorders., Competing Interests: Financial competing interests The authors have no competing interests to declare.

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- 11 C]WAY100635; 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 [ 11 C]WAY100635, 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 [ 11 C]WAY100635 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 outcome measures and across pharmacokinetic models, with all approaches showing higher serotonin 1A autoreceptor binding potential in the raphe nuclei of not-recently-medicated MDD patients relative to both healthy volunteers and antidepressant-exposed MDD patients. Moreover, with the additional precision of estimates afforded by this approach, we can show that while binding is also higher in projection areas in this group, these group differences are approximately half of those in the raphe nuclei, which are statistically distinguishable from one another. These results are consistent with the biological role of the serotonin 1A autoreceptor in the raphe nuclei in regulating serotonin neuron firing and release, and with preclinical and clinical evidence of deficient serotonin activity in MDD due to over expression of autoreceptors resulting from genetic and/or epigenetic effects. These results are also consistent with downregulation of autoreceptors as a mechanism of action of selective serotonin reuptake inhibitors. In summary, the results using multivariate analysis approaches therefore demonstrate both face and convergent validity, and may serve to provide a resolution and consensus interpretation for the disparate results of previous studies examining the serotonin 1A receptor in MDD., Competing Interests: 8DECLARATION OF COMPETING INTERESTS The authors declare no conflicts of interest.

Background: Individuals 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., Methods: Thirty-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 attentional processing. Clinical interviews were conducted at baseline., Results: Deceased-related attentional bias was associated with blood oxygen level-dependent (BOLD) activation in a brain network, including dorsolateral prefrontal cortex (dlPFC), ventrolateral prefrontal cortex (vlPFC), orbitofrontal cortex (OFC), and insula. Greater activation of a bilateral prefrontal cluster during deceased-specific attention was negatively correlated with self-reported grief avoidance behaviors., Limitations: Lack of non-suicide grief control and small sample size., Conclusions: These data, if confirmed, indicate a neural network specific to deceased-related attention, and that cognitive control regions within this network appear to be related to grief avoidance behaviors during acute bereavement., Competing Interests: Declaration of competing interest JJM receives royalties from the Research Foundation for Mental Hygiene for commercial use of the C-SSRS. CAM and NS have no conflicts to report. The design, preparation, review, and approval of the manuscript as well as the decision to submit the manuscript for publication was entirely done by the authors CAM, NS, and JJM., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Portable, cost-effective PET cameras can radically expand the applicability of PET. We present here a within-participant comparison of fully quantified [ 18 F]FDG dynamic scans in healthy volunteers using the standard Biograph mCT scanner and portable CerePET scanner. Methods: Each of 20 healthy volunteers underwent dynamic [ 18 F]FDG imaging with both scanners (1-154 d apart) and concurrent arterial blood sampling. Tracer SUV, net influx rate (K i ), and the corresponding cerebral metabolic rate of glucose (CMR glu ) 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 (K i and CMR glu ). There was also strong agreement between CerePET and Biograph mCT estimates, wherein the average regression slopes across participants were 0.84 ± 0.17 (SUV), 0.83 ± 0.17 (K i ), and 0.85 ± 0.18 (CMR glu ). There was similar bias across participants but higher correlation and less variability in subcortical regions than in cortical regions. Pearson correlation coefficients for subcortical regions equaled 0.97 ± 0.02 (SUV) and 0.97 ± 0.03 (K i and CMR glu ), and average regression slopes equaled 0.79 ± 0.14 (SUV), 0.83 ± 0.11 (K i ), and 0.86 ± 0.11 (CMR glu ). In voxelwise assessment, CerePET and Biograph mCT estimates across outcome measures were significantly different only in a cluster of left frontal white matter. Conclusion: Our results indicate robust correlation and agreement between semi- and fully quantitative brain glucose metabolism measurements from portable CerePET and standard Biograph mCT scanners. The results obtained with a portable PET scanner in this comparison in humans require follow-up but lend confidence to the feasibility of more flexible and portable brain imaging with PET., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

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, we identified a total of 40 differentially methylated regions in the suicide decedent group, mapping to seven genes with inflammatory function. There was a significant association between NPAS4 DNA methylation and NPAS4 expression in the control group that was absent in the suicide decedent group, confirming its dysregulation. NPAS4 expression was significantly associated with the expression of multiple inflammatory factors in the brain tissue. Overall, gene sets and pathways closely linked to inflammation were significantly upregulated, while specific pathways linked to neuronal development were suppressed in the suicide decedent group. Excitotoxicity as well as suppressed oligodendrocyte function were also implicated in the suicide decedents. In summary, we have identified central nervous system inflammatory mechanisms that may be active during suicidal behavior, along with oligodendrocyte dysfunction and altered glutamate neurotransmission. In these processes, NPAS4 might be a master regulator, warranting further studies to validate its role as a potential biomarker or therapeutic target in suicidality., (© 2023. The Author(s).)

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 ED under research staff supervision, vital sign monitoring, pharmacokinetic blood sampling, and clinical assessments. The post-injection phase occurs on a psychiatric inpatient unit with follow-up research assessments through four weeks post-discharge. Outcome measures are feasibility, safety, and effects on suicidal ideation and depression at 24 h post-injection, and through follow-up. The target sample is N = 90 adults in a major depressive episode, assessed by ED clinicians as warranting hospitalization for suicide risk. Here we report design, rationale, and preliminary feasibility and safety for this ongoing study. Demographics of the 53 participants (ages 18 to 65 years) randomized to date suggest a diverse sample tending towards younger adults., Competing Interests: Declaration of Competing Interest This work was supported by federal grant R01 MH125155 (PI: Grunebaum). Dr. Mann receives royalties from the Research Foundation for Mental Hygiene for commercial use of the C-SSRS. The other authors report no conflicts of interest.

Background: Pro-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., Methods: We 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 (AUC i ) and peak change over 3 timepoints. We also explored correlations between biomarkers and clinical characteristics., Results: Baseline 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, AUC i was higher in MDD for GM-CSF (p = 0.003, d = 1.21), IL-5 (p = 0.014, d = 1.62), and IL-27 (p = 0.041, d = 0.74). In MDD, depression severity correlated positively with soluble CD40L (sCD40L) for AUC i (Spearman's ρ = 0.76, p = 0.004) and with baseline vascular endothelial growth factor A (VEGFA, r = 0.85, p < 0.001), but negatively with baseline monokine induced by gamma interferon (MIG, aka CXCL9; r = -0.77, p = 0.003)., Conclusions: Effect sizes were robust in this exploratory study, although interpretation of the results must be cautious, given small sample size and multiple comparisons. Differential study of stress-induced biomarkers may have important ramifications for MDD treatment., Competing Interests: Declaration of competing interest JJM receives royalties for commercial use of the C-SSRS from the Research Foundation for Mental Hygiene. HG and spouse own stocks in Illumina, Inc. and IBM, Inc. JGK and spouse own stock in Pfizer and Zoetis. All other authors have no conflicts to report., (Copyright © 2023. Published by Elsevier Ltd.)

Importance: Social 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., Objective: To identify SDOH patterns and estimate their associations with children's mental, cognitive, and physical developmental outcomes., Design, Setting, and Participants: This 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., Exposures: Eighty-four neighborhood-level, geocoded variables spanning 7 domains of SDOH, including bias, education, physical and health infrastructure, natural environment, socioeconomic status, social context, and crime and drugs, were studied. Hierarchical agglomerative clustering was used to identify SDOH patterns., Main Outcomes and Measures: Associations of SDOH and child mental health (internalizing and externalizing behaviors) and suicidal behaviors, cognitive function (performance, reading skills), and physical health (body mass index, exercise, sleep disorder) were estimated using mixed-effects linear and logistic regression models., Results: Among 10 504 children (baseline median [SD] age, 9.9 [0.6] years; 5510 boys [52.5%] and 4994 girls [47.5%]; 229 Asian [2.2%], 1468 Black [14.0%], 2128 Hispanic [20.3%], 5565 White [53.0%], and 1108 multiracial [10.5%]), 4 SDOH patterns were identified: pattern 1, affluence (4078 children [38.8%]); pattern 2, high-stigma environment (2661 children [25.3%]); pattern 3, high socioeconomic deprivation (2653 children [25.3%]); and pattern 4, high crime and drug sales, low education, and high population density (1112 children [10.6%]). The SDOH patterns were distinctly associated with child health outcomes. Children exposed to socioeconomic deprivation (SDOH pattern 3) showed the worst health profiles, manifesting more internalizing (β = 0.75; 95% CI, 0.14-1.37) and externalizing (β = 1.43; 95% CI, 0.83-2.02) mental health problems, lower cognitive performance, and adverse physical health., Conclusions: This study shows that an unbiased quantitative analysis of multidimensional SDOH can permit the determination of how SDOH patterns are associated with child developmental outcomes. Children exposed to socioeconomic deprivation showed the worst outcomes relative to other SDOH categories. These findings suggest the need to determine whether improvement in socioeconomic conditions can enhance child developmental outcomes.

Objective: Our 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., Methods: The 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., Results: Age 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 differences in the proportion of participants with bipolar II disorder (Fisher's test p = 0.020) or higher lethality of past suicide attempts in younger participants (Wilcoxon test p = 0.024); neither was there any correlation with age in the longitudinally measured blood lithium levels (t = 1.04, df = 36, p = 0.307) or valproate levels (t = -0.50, df = 41, p = 0.621)., Limitations: Besides the fact that this is a secondary analysis, a limitation is that the study is not powered to detect suicide deaths or suicide attempts., Conclusion: Bipolar patients randomized to lithium and older than 42 years had less suicidal behavior compared to same aged patients on valproate or younger patients (<42 y) on either medication. This effect was independent of clinical and sociodemographic characteristics., Competing Interests: Declaration of competing interest Drs. Oquendo and Mann receive royalties from the Research Foundation for Mental Hygiene for the commercial use of the Columbia Suicide Severity Rating Scale. Dr. Oquendo owns shares in Mantra, Inc. and serves as an advisor to Alkermes, Mind Med, Sage Therapeutics, St. George's University and Fundacion Jimenez Diaz. Her family owns stock in Bristol Myers Squibb. Dr. Sullivan is a member of the scientific advisory board for TONIX Pharmaceuticals. Dr. Mann has received grant support from GlaxoSmithKline and Novartis. Dr. Dervic and Dr. Sher report no conflict of interest., (Published by Elsevier B.V.)

Background: Depression 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., Methods: Diagnostic 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., Results: In total, 132 960 patients had neither diagnosis (74.8%), 16 092 depression-only (9.0%), 13 098 anxiety-only (7.4%), and 16 584 comorbid (9.3%). In the European meta-analysis across biobanks, both PRSs were higher in each diagnosis group compared to controls. Notably, depression-PRS (OR 1.20 per s.d. increase in PRS; 95% CI 1.18-1.23) and anxiety-PRS (OR 1.07; 95% CI 1.05-1.09) had the largest effect when the comorbid group was compared with controls. Furthermore, the depression-PRS was significantly higher in the comorbid group than the depression-only group (OR 1.09; 95% CI 1.06-1.12) and the anxiety-only group (OR 1.15; 95% CI 1.11-1.19) and was significantly higher in the depression-only group than the anxiety-only group (OR 1.06; 95% CI 1.02-1.09), showing a genetic risk gradient across the conditions and the comorbidity., Conclusions: This study suggests that depression and anxiety have partially independent genetic liabilities and the genetic vulnerabilities to depression and anxiety make distinct contributions to comorbid depression and anxiety.

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 performance; however, no MDD-specific effect was observed.

Background: Childhood 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., Aims: To determine whether, and how, mood disorders and aggressive traits mediate the effects of reported physical and sexual abuse on future suicidal behavior., Methods: Five 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: Aggressive trait severity and mood disorder onset each mediated the relationship between CA and future suicide attempts. Greater aggression severity also raised the hazard of the development of a mood disorder. If aggressive trait severity was clearly elevated, then onset of mood disorder did not increase further the hazard of the suicide attempt. Including family as a random effect had a much bigger effect on attempt outcome for physical abuse compared with sexual abuse., Conclusions: Amelioration of aggressive traits and treatment of mood disorders in CA-exposed offspring of a parent with a mood disorder may prevent future suicide attempts and may reduce the risk of mood disorder. Familial factors influence the impact of childhood physical abuse but not sexual abuse. HIGHLIGHTSChildhood Adversity (CA) predicted future mood disorder and aggression severity.Depression and aggression mediate the relationship between CA and suicide attempts.When one mediator is present, the presence of the other does not increase the hazard.Between family variation contributed much more to suicidal behavior outcomes relative to the effect of physical abuse, but sexual abuse contributed to suicidal outcomes more than family variation.

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 I 2 -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: healthy controls (SMD [95%CI] = 1.42[0.85-1.98]); patients with depression alone (SMD [95%CI] = 1.23[0.20-2.26]); and patients with any psychiatric disorders (SMD [95%CI] = 0.39[0.22-0.55]). IL-6 blood level was higher in patients with suicidal behaviors compared with healthy controls (SMD [95%CI] = 1.13[0.45-1.82]) and when compared with psychiatric patients without suicidal behaviors (SMD [95%CI] = 0.22 [0.11-0.33]). Meta-regression and subgroup analyses revealed that increased CRP in suicidal behavior is primarily driven by recent suicidal behavior. These results implicate the immune system and inflammatory response in suicidal behavior independent of a relationship to major psychiatric disorders, and that these biological measures are predominantly state-dependent markers. Future studies are needed to determine the cause-and-effect relationship of these immune system biomarkers with suicidal behavior, and their potential predictive properties., Competing Interests: Conflict of interest Dr. Mann receives royalties from the Research Foundation for Mental Hygiene for commercial use of the Columbia-Suicide Severity Rating Scale. The remaining authors have nothing to disclose., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Childhood and lifetime adversity may reduce brain serotonergic (5-HT) neurotransmission by epigenetic mechanisms., Aims: We tested the relationships of childhood adversity and recent stress to serotonin 1A (5-HT 1A ) receptor genotype, DNA methylation of this gene in peripheral blood monocytes and in vivo 5-HT 1A receptor binding potential (BP F ) determined by positron emission tomography (PET) in 13 a priori brain regions, in participants with major depressive disorder (MDD) and healthy volunteers (controls)., Method: Medication-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-HT 1A receptor gene. A subgroup ( n = 119) had regional brain 5-HT 1A receptor BP F quantified by PET. Multi-predictor models were used to test associations between diagnosis, recent stress, childhood adversity, genotype, methylation and BP F ., Results: Recent stress correlated positively with blood monocyte methylation at the -681 CpG site, adjusted for diagnosis, and had positive and region-specific correlations with 5-HT 1A BP F in participants with MDD, but not in controls. In participants with MDD, but not in controls, methylation at the -1007 CpG site had positive and region-specific correlations with binding potential. Childhood adversity was not associated with methylation or BP F in participants with MDD., Conclusions: These findings support a model in which recent stress increases 5-HT 1A receptor binding, via methylation of promoter sites, thus affecting MDD psychopathology.

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 (AUC g ), F(1,60)=10.04, SE=5.095, p=.003, and lower HPA-axis stress responsivity to the TSST (AUC i ), 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 (F[1,61]=6.413, SE=10.55, p=.014) both at baseline (mean diff =22.32, p=.038) and in response to the stressor task (mean diff =37.62, p=.003). Vulnerability to suicidal behavior in high-intent individuals may be related to the combined profile of impaired physiological responses to stress and greater negative affectivity. This clinical and biologic subgroup may benefit from targeted suicide prevention interventions., Competing Interests: Declaration of Competing Interest Drs. Mann, Oquendo and Stanley receive royalties for commercial use of the Columbia Suicide Severity Rating Scale from the Research Foundation for Mental Hygiene. Dr. Oquendo serves as an advisor to Alkermes, Mind Medicine, Sage Therapeutics, St. George's University and Fundacion Jimenez Diaz. Her family owns stock in Bristol Myers Squibb., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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 and treatment of MDD. The evaluation of epigenetic modifications holds promise for further understanding of the heterogeneous etiology and complex phenotypes of MDD, and may identify new therapeutic targets. Here, we review preclinical and clinical epigenetic findings, including DNA methylation, histone modification, noncoding RNA, RNA modification, and chromatin remodeling factor in MDD. In addition, we elaborate on the contribution of these epigenetic mechanisms to the pathological trait variability in depression and discuss how such mechanisms can be exploited for therapeutic purposes., (© 2023. West China Hospital, Sichuan University.)

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.

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., Competing Interests: Declaration of Competing Interest This work was supported by federal grant P50 MH062185 (Conte Center for the Neuroscience of Mental Disorders: The Neurobiology of Suicidal Behavior (PI: Mann)., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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: There were no suicide- or ELA-related differences in CRH, CRH binding protein, GR, or FKBP5 in BA9 or BA24 and no interaction between suicide and ELA (P > .05). For BDNF, there was an interaction between suicide and ELA in BA24; suicides without ELA had less BDNF than controls without ELA, and controls with ELA had less BDNF than controls without ELA. CRH in BA9 and FKBP5 in anterior cingulate cortex correlated negatively with RLS. Least Absolute Shrinkage and Selection Operator logistic regression with cross-validation found combining BDNF, GR, and FKBP5 BA24 levels predicted suicide, but ELA did not contribute. A calculated "suicide risk score" using these measures had 71% sensitivity and 71% specificity., Conclusion: A dysregulated HPA axis is related to suicide but not with ELA. RLS was related to select HPA axis proteins in specific brain regions. BDNF appears to be dysregulated in a region-specific way with ELA and suicide., (© The Author(s) 2023. Published by Oxford University Press on behalf of CINP.)

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); 2. HR with lifetime mood disorder and no suicide attempt (HR-MOOD, N = 25); and 3. HR with lifetime mood disorder and a previous suicide attempt (HR-MOOD + SA, N = 18). Findings were tested in an independent cohort not selected for family history (HV, N = 47; MOOD, N = 44; and MOOD + SA, N = 21). Lower CA3 volume was found in HR (vs. HV), consistent with the direction of previously published findings in MOOD+SA (vs. HV and MOOD), suggesting the finding reflects a familial biological risk marker, not illness or treatment-related sequelae, of suicidal behavior and mood disorder. Familial suicide risk may be mediated in part by smaller CA3 volume. The structure may serve as a risk indicator and therapeutic target for suicide prevention strategies in high-risk families., Competing Interests: Declaration of competing interest Authors SPP NMM ML JMM JGK have no conflicts of interest to report. JJM and AB receive royalties for commercial use of the C-SSRS from the Research Foundation for Mental Hygiene. DAB receives research support from NIMH, AFSP, the Once Upon a Time Foundation, and the Beckwith Foundation, receives royalties from Guilford Press, from the electronic self-rated version of the C-SSRS from eRT, Inc., and from performing duties as an UptoDate Psychiatry Section Editor, receives consulting fees from Healthwise, receives Honoraria from the Klingenstein Third Generation Foundation for scientific board membership and grant reviews, and is a scientific board member for AFSP. Intellectual Property, currently with no financial interest: Funding from the National Institute of Mental Health supported the development of intellectual property for BRITE, the As Safe As Possible intervention, the Computerized Adaptive Screen for Suicidal Youth (CASSY) measure, a suicide risk machine learning algorithm, and the Screening Wizard screening tool., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Borderline 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., Methods: Twenty-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 exclusion events and in the parametric modulation of that response by rejection distress using mass univariate analysis., Results: Although rejection distress was higher in participants with BPD (F 1,40  = 5.25, p = .027, η 2  = 0.12), both groups showed similar neural responses to exclusion events. However, as rejection distress increased, the rostromedial prefrontal cortex response to exclusion events decreased in the BPD group but not in control participants. Stronger modulation of the rostromedial prefrontal cortex response by rejection distress was associated with higher trait rejection expectation, r = -0.30, p = .050., Conclusions: Heightened rejection distress in BPD might stem from a failure to maintain or upregulate the activity of the rostromedial prefrontal cortex, a key node of the mentalization network. Inverse coupling between rejection distress and mentalization-related brain activity might contribute to heightened rejection expectation in BPD., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

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 postmortem brain that revealed gene expression differences in suicide decedents vs. non-suicides in white matter, but not gray matter. Findings support a role of brain and peripheral blood inflammation in suicide risk, showing that suicidal ideation presence and severity is associated with an inflammatory signature detectable in blood and brain, indicating a biological continuity between ideation and suicidal behavior that may underlie a common heritability., Competing Interests: Conflict of Interest: The authors declare no conflict of interest.

Background: Individuals 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., Methods: Thirty-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)., Results: Participants showed greater attentional bias to deceased-related word trials compared with living attachment, non-attachment, and congruent trials, controlling for age, time since loss, depression, and psychiatric medication. A greater reduction in grief severity over time was associated with more deceased-related attentional bias at baseline. Self-reported grief avoidance was related to deceased-related attentional bias, with lower avoidance scores associated with greater bias., Limitations: Lack of non-suicide grief control and small sample size., Conclusions: Less deceased-related bias following the loss may hinder the transition from acute to integrated grief and result in poorer grief trajectories., Competing Interests: Conflict of interest JJM receives royalties from the Research Foundation for Mental Hygiene for commercial use of the C-SSRS. CAM, HG, and NS have no conflicts to report. The design, preparation, review, and approval of the manuscript as well as the decision to submit the manuscript for publication was entirely done by the authors CAM, HCG, NS, and JJM., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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 [ 11 C]DASB and [ 11 C]CUMI-101 positron emission tomography (PET) imaging. Binding potential (BP ND ) to the serotonin transporter (5-HTT) and serotonin 1A (5-HT 1A ) 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-HT 1A BP ND were unrelated to EMA stress. There were region-specific effects of 5-HTT (p=0.002) and 5-HT 1A BP ND (p=0.03) in attempters vs. nonattempters. In attempters, region-specific associations between 5-HTT (p=0.03) and 5-HT 1A (p=0.005) BP ND and EMA stress emerged. While no post-hoc 5-HTT BP ND correlations were significant, 5-HT 1A BP ND correlated positively with EMA stress in attempters in 9/10 regions (p-values<0.007), including the entire cortex except the largely occipital region 5. Brodmann-based regional analyses found diminished effects for 5-HTT and subcortically localized positive corrrelations between 5-HT 1A and EMA stress, in attempters only. Given comparable depression severity and childhood and current stress between attempters and nonattempters, lower 5-HTT binding in attempters vs. nonattempters may suggest a biological risk marker. Localized lower 5-HTT and widespread higher 5-HT 1A binding with stress among attempters specifically may suggest that a serotonergic phenotype might be a key determinant of risk or resiliency for suicidal behavior., Competing Interests: Declaration of Competing Interest Drs. Bartlett, Zanderigo, Stanley, Choo, Galfalvy, Pantazatos, Sublette, and Miller declares that they have no conflict of interest. Drs. Oquendo and Mann receive royalties from the Research Foundation for Mental Hygiene for the commercial use of the Columbia Suicide Severity Rating Scale. Dr. Oquendo serves as an advisor to Alkermes, Otsuka, Mind Medicine, St. George's University and Fundacion Jimenez Diaz. Her family owns stock in Bristol Myers Squibb., (Copyright © 2023 Elsevier B.V. and ECNP. All rights reserved.)

Objective: The authors sought to identify scalable evidence-based suicide prevention strategies., Methods: A search of PubMed and Google Scholar identi- fied 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 rec- ognition and treatment prevents suicide. Educating youths on depression and suicidal behavior, as well as active out- reach 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 but is untested for suicidal behavior prevention. Cognitive-behavioral therapy and dialectical behavior therapy prevent suicidal behavior. Active screening for suicidal ideation or behavior is not proven to be better than just screening for depression. Education of gatekeepers about youth suicidal behavior lacks effectiveness. No randomized trials have been reported for gatekeeper training for prevention of adult suicidal behavior. Algorithm-driven electronic health record screening, Internet-based screening, and smartphone passive monitoring to identify high-risk patients are under-studied. Means restriction, including of firearms, prevents suicide but is sporadically employed in the United States, even though firearms are used in half of all U.S. suicides., Conclusions: Training general practitioners warrants wider implementation and testing in other nonpsychiatrist physi- cian settings. Active follow-up of patients after discharge or a suicide-related crisis should be routine, and restricting firearm access by at-risk individuals warrants wider use. Combination approaches in health care systems show promise in reducing suicide in several countries, but evaluating the benefit attributable to each component is essential. Further suicide rate reduction requires evaluating newer approaches, such as electronic health record-derived algorithms, Internet-based screening methods, ketamine's potential benefit for preventing attempts, and passive monitoring of acute suicide risk change.Reprinted from Am J Psychiatry 2021; 178:611-624 , with permission from American Psychiatric Association Publishing. Copyright © 2021., (Copyright © 2023 by the American Psychiatric Association.)

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, schizophrenia, ADHD, alcohol dependence, sensitivity to environmental stress and adversity, educational attainment, cognitive performance, and IQ were associated with suicidal behavior (Bonferroni-corrected p < 2.5 × 10 -4 ). The polygenic effects of all 22 psychiatric disorders/traits had the same direction ( p for binomial tests = 4.8 × 10 -7 ) and were correlated (Spearman's ρ = 0.85) between non-fatal suicide attempters and suicide decedents., Conclusions: We found that polygenic effects for major psychiatric disorders and diathesis-related traits including stress responsiveness and intellect/cognitive function contributed to suicidal behavior. While we found comparable polygenic architecture between non-fatal suicide attempters and suicide decedents based on correlations with PRSs of suicide-related psychiatric disorders/traits, our analyses are limited by small sample size resulting in low statistical power to detect difference between non-fatal suicide attempt and suicide death.