Diligent for better or worse: Conscientiousness is associated with higher likelihood of suicidal behavior and more severe suicidal intent in later life.

BACKGROUND: Contradictory findings link trait conscientiousness in mid- and late life to increased healthspan and lifespan, as well as to death by suicide. It remains unclear whether conscientiousness is associated with higher odds of attempting suicide or with more severe suicidal behavior among attempters, and whether its relationship to suicide risk varies with aging-related stressors, such as declining health. METHODS: In this cross-sectional study comprising 313 depressed adults aged ≥40 years and participating in the Longitudinal Research Program in Late-Life Suicide (Pittsburgh, USA), we employed logistic and linear regression to test whether conscientiousness was associated with the presence of recent suicidal behavior (≤2 years) and with intent severity in recent attempters (n = 84). We further tested whether the above relationships varied based on mental, cognitive, and physical health status, measured as depression severity, cognitive functioning, and the presence/absence of severe physical illness. RESULTS: Participants were 62.1 years old on average (SD = 7.6), 85% White, and 53% female. Recent attempters had a mean age of 61.8 years at their most recent attempt (SD = 8.5), had lower cognitive functioning and were more likely severely physically ill than comparisons. Conscientiousness was positively associated with a higher likelihood of recent suicidal behavior overall (adjusted OR = 1.44, 95% CI = 1.09, 1.90, p = .010), but not in case of co-occurring severe physical illness (interaction OR = 0.54, 95% CI = 0.30, 0.97, p = .039). Conscientiousness was also positively associated with suicidal intent at the most recent attempt (adjusted ß = 1.60, SE = 0.62, p = .012), explaining 7% of its variance, although this association lost significance after adjusting for other personality dimensions. CONCLUSIONS: Highly conscientious middle-aged and older adults may be at increased risk of resolute suicidal behavior, although conscientiousness may not confer additional suicide risk among those severely physically ill.

A Neural Signature for Reappraisal as an Emotion Regulation Strategy: Relationship to Stress-Related Suicidal Ideation and Negative Affect in Major Depression.

BACKGROUND: Impaired emotion regulation (ER) contributes to major depression, and suicidal ideation (SI) and behavior. ER is typically studied by explicitly directing participants to regulate, but this may not capture depressed individuals' spontaneous tendencies to engage ER in daily life. METHODS: In N=82 participants with major depressive disorder (MDD), 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 underlying 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 (EMA) measuring daily stressors, suicidal ideation (SI), 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 SI following stressors (b=0.083, p=0.041). 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=0.029). Output for the immerse period was not associated with EMA outcomes. CONCLUSIONS: Findings suggest that, in MDD, 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.

Pilot study of telehealth delivery of horticultural therapy (TeleHT) as an acceptable intervention and in reducing suicide risk factors in veterans.

OBJECTIVES: Converging evidence indicates that Horticultural Therapy (HT) contributes to significant reductions in stress, loneliness, and depression, notable risk factors for suicidality. This pilot study aimed to assess the initial feasibility and acceptability of HT when virtually administered. INTERVENTION: Telehealth-delivered horticultural therapy (TeleHT) was administered to groups of Veterans, including those with elevated suicide risk over the course of four weeks. Participants were each sent a package through the mail of at-home gardening supplies that were used to facilitate multisensory, nature experiences during weekly HT sessions administered via Zoom. OUTCOME MEASURES: Participants completed thermometer-based scales for the suicide risk factors of stress, loneliness, depression, and pain before and after each TeleHT session. Post-intervention qualitative assessments were completed upon the conclusion of the four-week intervention. RESULTS: Significant reductions in stress, depression, and loneliness risk were observed from weekly pre- to post-session measures (p < 0.05), with 89.1 % HT completion rate. Stress, pain, depression, and loneliness indices also showed small to medium sized symptom reduction amongst Veterans with no history of suicidality (Cohen's d=-0.70, d=-0.49, d=-0.62, d=-0.71), while those with elevated suicide risk at baseline also showed reduction in these risk factors with small to medium effect sizes (d=-0.58, d=-.018, d=-0.46, d=-0.41). Qualitative post-intervention assessments indicated a high degree of acceptability and pointed to the inclusion of mailed gardening packages as particularly relevant to positive experiences. CONCLUSIONS: While future work is needed to fully assess efficacy, findings from this pilot study demonstrate an initial feasibility and acceptability through a high retention rate and positive qualitative assessments for TeleHT that mirror that of the in-person intervention.

Identifying factors impacting missingness within smartphone-based research: Implications for intensive longitudinal studies of adolescent suicidal thoughts and behaviors.

Intensive longitudinal research-including experience sampling and smartphone sensor monitoring-has potential for identifying proximal risk factors for psychopathology, including suicidal thoughts and behaviors (STB). Yet, missing data can complicate analysis and interpretation. This study aimed to address whether clinical and study design factors are associated with missing data and whether missingness predicts changes in symptom severity or STB. Adolescents ages 13- to 18 years old (N = 179) reporting depressive, anxiety, and/or substance use disorders were enrolled; 65% reported current suicidal ideation and 29% indicated a past-year attempt. Passively acquired smartphone sensor data (e.g., global positioning system, accelerometer, and keyboard inputs), daily mood surveys, and weekly suicidal ideation surveys were collected during the 6-month study period using the effortless assessment research system smartphone app. First, acquisition of passive smartphone sensor data (with data on ∼80% of days across the whole sample) was strongly associated with survey data acquisition on the same day (∼44% of days). Second, STB and psychiatric symptoms were largely not associated with missing data. Rather, temporal features (e.g., length of time in study, weekends, and summer) explained more missingness of survey and passive smartphone sensor data. Last, within-participant changes in missing data over time neither followed nor predicted subsequent change in suicidal ideation and psychiatric symptoms. Findings indicate that considering technical and study design factors impacting missingness is critical and highlight several factors that should be addressed to maximize the validity of clinical interpretations in intensive longitudinal research. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Impact of an internet-based insomnia intervention on suicidal ideation and associated correlates in veterans at elevated suicide risk.

Improving public health approaches to suicide prevention requires scalable evidence-based interventions that can be easily disseminated. Given empirical data supporting the association between insomnia and suicide risk, internet-delivered insomnia interventions are promising candidates to meet this need. The purpose of this study was to examine whether an unguided internet-delivered cognitive-behavioral therapy for insomnia (iCBT-I) improved insomnia severity, suicidal ideation (SI), and suicide risk correlates (depression, post-traumatic stress disorder, anxiety, hostility, belongingness, hopelessness, agitation, irritability, concentration) in a sample of veterans. Secondary data analysis of Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn veterans (n = 50) with clinically significant insomnia and elevated SI drawn from a larger randomized controlled trial (RCT) of an iCBT-I, Sleep Healthy Using the Internet (SHUTi). Two-sample t-tests or Wilcoxon rank sum tests were used to evaluate between-group differences (SHUTi vs. Insomnia Education Website control) in symptom improvement from baseline to post-intervention. SHUTi participants experienced a significant improvement in insomnia severity (P < .001; d = -1.08) and a non-significant with small (subthreshold medium) effect size reduction of SI (P = .17, d = 0.40), compared to control participants. Significant improvement in hopelessness was observed (medium effect size), with non-significant small to medium effect size reductions in most remaining suicide risk correlates. Self-administered iCBT-I was associated with improvements in insomnia severity in veterans at elevated risk for suicide. These preliminary findings suggest that SI and suicide risk correlates may improve following an iCBT-I intervention, demonstrating the need for future well-powered iCBT-I RCTs targeted for populations at elevated suicide risk.

In this secondary data analysis, we examined improvements in insomnia severity, suicidal ideation (SI), and suicide risk correlates in veterans with clinically significant insomnia and elevated SI drawn from a larger randomized controlled trial (RCT) examining an unguided internet-delivered cognitive-behavioral therapy for insomnia (iCBT-I). Veterans in the iCBT-I group experienced greater improvements in insomnia severity and hopelessness than veterans in the Insomnia Education Website control. Although between-group differences in SI and other suicide risk correlates were not statistically significant, effect sizes suggest that SI and symptoms of depression, irritability, concentration, post-traumatic stress disorder, and hostility may improve following iCBT-I intervention. These results suggest that digital and iCBT-I interventions may be especially powerful tools for use in suicide prevention among veterans but highlight the critical need for additional large-scale studies to examine suicide-specific mechanisms and outcomes to guide implementation efforts.

Temporal prediction of suicidal ideation in an ecological momentary assessment study with recurrent neural networks.

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-R2 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-R2 = 26 %) compared with MEMs (full model: RMSE = 3.84, MAPE = 56 %, pseudo-R2 = 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.

Occurrence and characteristics of suicidal ideation in psychiatrically healthy individuals based on ecological momentary assessment.

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.

Acute Dissociation and Ketamine's Antidepressant and Anti-Suicidal Ideation Effects in a Midazolam-Controlled Trial.

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.

Relationship of Major Depressive Disorder and Schizophrenia Polygenic Risk Scores to Suicide: A Comparison Between European and Asian Ancestry Populations.

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

Psychiatric diagnosis in suicides appears more common in Europeans than in East Asians.This is the first comparison of suicide genome-wide association studies between Europeans and East Asians.Major depressive disorder/schizophrenia polygenic risk scores for suicide were more significant for Europeans than for East Asians.

Study protocol: Identifying transcriptional regulatory alterations of chronic effects of blast and disturbed sleep in United States Veterans.

Injury related to blast exposure dramatically rose during post-911 era military conflicts in Iraq and Afghanistan. Mild traumatic brain injury (mTBI) is among the most common injuries following blast, an exposure that may not result in a definitive physiologic marker (e.g., loss of consciousness). Recent research suggests that exposure to low level blasts and, more specifically repetitive blast exposure (RBE), which may be subconcussive in nature, may also impact long term physiologic and psychological outcomes, though findings have been mixed. For military personnel, blast-related injuries often occur in chaotic settings (e.g., combat), which create challenges in the immediate assessment of related-injuries, as well as acute and post-acute sequelae. As such, alternate means of identifying blast-related injuries are needed. Results from previous work suggest that epigenetic markers, such as DNA methylation, may provide a potential stable biomarker of cumulative blast exposure that can persist over time. However, more research regarding blast exposure and associations with short- and long-term sequelae is needed. Here we present the protocol for an observational study that will be completed in two phases: Phase 1 will address blast exposure among Active Duty Personnel and Phase 2 will focus on long term sequelae and biological signatures among Veterans who served in the recent conflicts and were exposed to repeated blast events as part of their military occupation. Phase 2 will be the focus of this paper. We hypothesize that Veterans will exhibit similar differentially methylated regions (DMRs) associated with changes in sleep and other psychological and physical metrics, as observed with Active Duty Personnel. Additional analyses will be conducted to compare DMRs between Phase 1 and 2 cohorts, as well as self-reported psychological and physical symptoms. This comparison between Service Members and Veterans will allow for exploration regarding the natural history of blast exposure in a quasi-longitudinal manner. Findings from this study are expected to provide additional evidence for repetitive blast-related physiologic changes associated with long-term neurobehavioral symptoms. It is expected that findings will provide foundational data for the development of effective interventions following RBE that could lead to improved long-term physical and psychological health.

Is Late-Onset Suicidal Behavior a Distinct Subtype?

This clinical viewpoint article aims to draw attention to a yet unexplored factor influencing suicidal behavior: age of onset of suicidal behavior. To tackle the substantial heterogeneity among depressed older attempters, we suggest consideration of at least two distinct pathways to suicidal behavior in late life based on when the first suicidal crisis occurred. Specifically, we discuss the current state of research and the rationale behind the suggested early-late-onset categorization of late-life suicidal behavior. We summarize available evidence so far on early-onset and late-onset attempters, and the potential heterogeneity in the interplay of risk/precipitating factors. Certain risk factors for suicide, such as impulsivity and borderline traits, decrease with age, while memory and broader cognitive impairments increase with age. Research indicates that familial/social exposure to suicidal behavior, childhood trauma, impulsivity, maladaptive personality traits, longstanding interpersonal difficulties, and legal problems are found predominantly in attempters experiencing their first suicidal crisis between youth and early midlife. In contrast, dementia prodrome is one of the most promising but understudied candidates for late-onset suicide risk, especially in the context of other risk factors. Moreover, personality traits conferring increased vulnerability to late-onset suicidal behavior (such as high conscientiousness) are not the same as ones classically identified in younger attempters and in older suicide attempters who have early-onset suicidal behavior (such as neuroticism and Cluster B traits). We discuss methodological points about studying age of onset of suicidal behavior, outline clinical implications, share ideas for future directions, and call for research on this understudied topic.

Brain and blood transcriptome profiles delineate common genetic pathways across suicidal ideation and suicide.

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.

Intramuscular ketamine vs. midazolam for rapid risk-reduction in suicidal, depressed emergency patients: Clinical trial design and rationale.

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.

Plasma cytokine and growth factor response to acute psychosocial stress in major depressive disorder.

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 (AUCi) 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, AUCi 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 AUCi (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.

Life is precious: A quasi-experimental study of a community-based program to prevent suicide among Latina adolescents in New York City.

INTRODUCTION: Rising rates of suicidal thoughts and behaviors (STBs) among U.S. Latina adolescents urgently need attention. Life is Precious (LIP) is a culturally responsive, community-based, afterschool-model program offering wellness-support services to supplement outpatient mental health treatment for Latina adolescents experiencing STB's. This 12-month quasi-experimental pilot study explored LIP's impact on clinical outcomes. METHODS: Latina adolescents newly enrolled in LIP and receiving outpatient treatment (n = 31) and those newly starting outpatient treatment only (n = 12; Usual Care) were assessed for Suicidal Ideation (Suicidal Ideation Questionnaire; SIQ) and depressive symptoms (Patient Health Questionnaire-9). We estimated differences in mean scores using longitudinal linear mixed models and adjusted risk ratios (ARRs) of SIQ-25%, SIQ-50%, and PHQ-9-5-point improvements using exact logistic models. RESULTS: The direction of the estimated impact of LIP was positive [differences (95% CIs): -15.5 (-34.16, 3.15) for SIQ; -1.16 (-4.39, 2.07) for PHQ-9], with small-to-moderate nonsignificant effect sizes (0.19-0.34). LIP participants saw two to three times higher prevalence than controls of SIQ-25%, SIQ-50%, and PHQ-9-5-point improvements; ARRs (95% CIs) were 1.91 (0.61, 3.45), 3.04 (0.43, 11.33), and 1.97 (0.44, 5.07), respectively. Suicidal behaviors also decreased in LIP. CONCLUSION: The effects of LIP were in positive directions across clinical outcomes, warranting further research on its effectiveness in decreasing STBs.

Integrative transcriptome- and DNA methylation analysis of brain tissue from the temporal pole in suicide decedents and their controls.

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.

Plasma Phospholipid Polyunsaturated Fatty Acid Associations with Neurocognition.

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.

Association of interleukin-6 with suicidal ideation in veterans: a longitudinal perspective.

Introduction: Studies showing associations between inflammation in suicide are typically cross-sectional. Present study investigated how cytokine levels track with suicidal ideation and severity longitudinally. Methods: Veterans with a diagnosis of major depressive disorder (MDD) with or without suicide attempt history (MDD/SA n = 38, MDD/NS n = 41) and non-psychiatric non-attempter controls (HC n = 33) were recruited, MDD/SA and HC groups were followed longitudinally at 3 months and 6 months. Blood plasma was collected and processed using Luminex Immunology Multiplex technology. Results: Significant differences in depression severity (BDI) and suicidal ideation severity (SSI) were observed across all groups at study entry, wherein MDD/SA group had the highest scores followed by MDD/NS and HC, respectively. Cytokines IL-1ß, IL-4, TNF-α, IFN-γ, and IL-6 were examined at study entry and longitudinally, with IL6 levels differing significantly across the groups (p = 0.0123) at study entry. Significant differences in changes in cytokine levels between depressed attempters and the control group were detected for IL-6 (interaction F1,91.77 = 5.58, p = 0.0203) and TNF-α (F1,101.73 = 4.69, p = 0.0327). However, only depressed attempters showed a significant change, in IL-6 and TNF-α levels, decreasing over time [IL-6: b = -0.04, 95% CI = (-0.08, -0.01), p = 0.0245 and TNF-α: b = -0.02, 95% CI = (-0.04, -0.01), p = 0.0196]. Although IL-6 levels were not predictive of suicidal ideation presence [OR = 1.34, 95% CI = (0.77, 2.33), p = 0.3067], IL-6 levels were significantly associated with suicidal ideation severity (b = 0.19, p = 0.0422). Discussion: IL-6 was not associated with presence of suicidal ideation. IL-6 however, was associated with severity of ideation, suggesting that IL-6 may be useful in clinical practice, as an objective marker of heightened suicide risk.

Mindfulness-based real-time fMRI neurofeedback: a randomized controlled trial to optimize dosing for depressed adolescents.

BACKGROUND: Adolescence is characterized by a heightened vulnerability for Major Depressive Disorder (MDD) onset, and currently, treatments are only effective for roughly half of adolescents with MDD. Accordingly, novel interventions are urgently needed. This study aims to establish mindfulness-based real-time fMRI neurofeedback (mbNF) as a non-invasive approach to downregulate the default mode network (DMN) in order to decrease ruminatory processes and depressive symptoms. METHODS: Adolescents (N = 90) with a current diagnosis of MDD ages 13-18-years-old will be randomized in a parallel group, two-arm, superiority trial to receive either 15 or 30 min of mbNF with a 1:1 allocation ratio. Real-time neurofeedback based on activation of the frontoparietal network (FPN) relative to the DMN will be displayed to participants via the movement of a ball on a computer screen while participants practice mindfulness in the scanner. We hypothesize that within-DMN (medial prefrontal cortex [mPFC] with posterior cingulate cortex [PCC]) functional connectivity will be reduced following mbNF (Aim 1: Target Engagement). Additionally, we hypothesize that participants in the 30-min mbNF condition will show greater reductions in within-DMN functional connectivity (Aim 2: Dosing Impact on Target Engagement). Aim 1 will analyze data from all participants as a single-group, and Aim 2 will leverage the randomized assignment to analyze data as a parallel-group trial. Secondary analyses will probe changes in depressive symptoms and rumination. DISCUSSION: Results of this study will determine whether mbNF reduces functional connectivity within the DMN among adolescents with MDD, and critically, will identify the optimal dosing with respect to DMN modulation as well as reduction in depressive symptoms and rumination. TRIAL REGISTRATION: This study has been registered with clinicaltrials.gov, most recently updated on July 6, 2023 (trial identifier: NCT05617495).

Antisuicidal effect of lithum in bipolar disorder: is there an age-specific effect?

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.