Revisiting Associations Among Parent and Adolescent Religiosity and Early Adolescent Suicide Risk in the United States.

The contributions of religion to reduced suicide risk have been studied in adults and adolescents, though to our knowledge no comprehensive investigation has been conducted in early adolescents, at a time coinciding with emergence of suicide risk trajectories. In this largest study to date on this topic, we aimed to characterise the contributions of various measures of "private" and "public" religiosity to early adolescent suicide ideation (SI) and suicide attempt (SA) histories using information from a large, epidemiologically informed U.S. sample of adolescents (N = 7068; mean age = 12.89 years, 47% female) and their parents. In all youth, parent-reported adolescent religious importance was associated with reduced odds of SA (OR = 0.75, CI = 0.61-0.92, P = .005). Muslim youth were more likely (OR = 1.52, CI = 1.02-2.22, P = .033), and Catholic youth were less likely (OR = 0.80, CI = 0.67-0.95, P = .014), to report SI. A variety of sex differences were noted, with significant protective associations of adolescent self-reported religiosity on SI and SA, religious service attendance on SI, and religious importance on SI, in female-but not male-youth; and significant protective associations of religious importance on SA in male-but not female-youth. Against expectations, there was no evidence that parent religiosity moderated the link between youth religiosity and SI or SA. These results shed light on the roles of cultural and familial context in youth suicide risk, which may ultimately be targeted in screening and interventional approaches.

Chronic loss of muscarinic M5 receptor function manifests disparate impairments in exploratory behavior in male and female mice despite common dopamine regulation.

There are five cloned muscarinic acetylcholine receptors (M1-M5). Of these, the muscarinic type 5 receptor (M5) is the only one localized to dopamine neurons in the ventral tegmental area and substantia nigra. Unlike M1-M4, the M5 receptor has relatively restricted expression in the brain, making it an attractive therapeutic target. Here we performed an in-depth characterization of M5-dependent potentiation of dopamine transmission in the nucleus accumbens and accompanying exploratory behaviors in male and female mice. We show that M5 receptors potentiate dopamine transmission by acting directly on the terminals within the nucleus accumbens. Using the muscarinic agonist oxotremorine, we revealed a unique concentration-response curve and a sensitivity to repeated forced swim stress or restraint stress exposure. We found that constitutive deletion of M5 receptors reduced exploration of the center of an open field while at the same time impairing normal habituation only in male mice. In addition, M5 deletion reduced exploration of salient stimuli, especially under conditions of high novelty, yet had no effect on hedonia assayed using the sucrose preference test or on stress coping strategy assayed using the forced swim test. We conclude that M5 receptors are critical for both engaging with the environment and updating behavioral output in response to environment cues, specifically in male mice. A cardinal feature of mood and anxiety disorders is withdrawal from the environment. These data indicate that boosting M5 receptor activity may be a useful therapeutic target for ameliorating these symptoms of depression and anxiety.Significance Statement:The basic physiological and behavioral functions of the muscarinic M5 receptor remain understudied. Furthermore, its presence on dopamine neurons, relatively restricted expression in the brain, and recent crystallization make it an attractive target for therapeutic development. Yet, most preclinical studies of M5 receptor function have primarily focused on substance use disorders in male rodents. Here we characterized the role of M5 receptors in potentiating dopamine transmission in the nucleus accumbens, finding impaired functioning after stress exposure. Furthermore, we show that M5 receptors can modulate exploratory behavior in a sex-specific manner, without impacting hedonic behavior. These findings further illustrate the therapeutic potential of the M5 receptor, warranting further research in the context of treating mood disorders.

Patterns of experience, expression, and physiology of stress relate to depressive symptoms and self-injurious thoughts and behaviors in adolescents: a person-centered approach.

BACKGROUND: Preliminary evidence shows that discordance in stress experience, expression, and physiology (EEP) in adolescents is linked to depression, suicidal ideation (SI), non-suicidal self-injury (NSSI), and brain functioning. This study employs person-centered analysis to probe the relationship between stress responses, psychopathology, and neural patterns in female adolescents who are oversampled for engagement in NSSI. METHODS: Adolescent females (N = 109, ages 12-17) underwent a social stress test from which self-report measures of stress experience, observer ratings of stress expression, and physiological metrics of stress (via salivary cortisol) were obtained. Multi-trajectory modeling was employed to identify concordant and discordant stress EEP groups. Depressive symptoms, SI and attempt, NSSI engagement, frontal and limbic activation to emotional stimuli, and resting state fronto-limbic connectivity were examined in the EEP groups derived from the multi-trajectory models. RESULTS: Four groups were identified, three of which demonstrated relatively concordant EEP and one which demonstrated discordant EEP (High Experience-High Expression-Low Physiology). Further, replicating past research, the High Experience-High Expression-Low Physiology discordant group exhibited higher depressive symptoms, SI, suicide attempt, and NSSI episodes (only for sensitivity analyses based on past year) relative to other EEP groups. No significant group differences in brain functioning emerged. CONCLUSION: Results indicate that within-person, multi-level patterns in stress responding capture risk for dysfunction including depression and self-injurious thoughts and behaviors. Further interrogating of system-level stress functioning may better inform assessment and intervention efforts.

Understanding heterogeneity in suicidal thoughts and behaviours and the implications for genetic studies - a commentary on Lannoy et al. (2022).

Preventing suicidal thoughts and behaviours (STB) among youth is a global public health priority. STB are known to have a heritable basis, and the development of risk for STB likely arises from complex gene-environment interactions across the life course. Lannoy et al. (Journal of Child Psychology and Psychiatry, 63, 2022 and 1164) describe a study in which polygenic risk for suicide attempt, as well as recent negative life events, were related to recent suicidal ideation in adolescents of about 17 years old. Building on this important work, we highlight several critical areas of focus for research in suicide genetics, including problems of measurement, as well as priorities for better uncovering the specific aetiological pathways to STB.

Stress system concordance as a predictor of longitudinal patterns of resilience in adolescence.

Resilience promotes positive adaptation to challenges and may facilitate recovery for adolescents experiencing psychopathology. This work examined concordance across the experience, expression, and physiological response to stress as a protective factor that may predict longitudinal patterns of psychopathology and well-being that mark resilience. Adolescents aged 14-17 at recruitment (oversampled for histories of non-suicidal self-injury; NSSI) were part of a three-wave (T1, T2, T3) longitudinal study. Multi-trajectory modeling produced four distinct profiles of stress experience, expression, and physiology at T1 (High-High-High, Low-Low-Low, High-Low-Moderate, and High-High-Low, respectively). Linear mixed-effect regressions modeled whether the profiles predicted depressive symptoms, suicide ideation, NSSI engagement, positive affect, satisfaction with life, and self-worth over time. Broadly, concordant stress response profiles (Low-Low-Low, High-High-High) were associated with resilient-like patterns of psychopathology and well-being over time. Adolescents with a concordant High-High-High stress response profile showed a trend of greater reduction in depressive symptoms (B = 0.71, p = 0.052), as well as increased global self-worth (B = -0.88, p = 0.055), from T2 to T3 compared to the discordant High-High-Low profile. Concordance across multi-level stress responses may be protective and promote future resilience, whereas blunted physiological responses in the presence of high perceived and expressed stress may indicate poorer outcomes over time.

Genetics and epigenetics of self-injurious thoughts and behaviors: Systematic review of the suicide literature and methodological considerations.

Suicide is a multifaceted and poorly understood clinical outcome, and there is an urgent need to advance research on its phenomenology and etiology. Epidemiological studies have demonstrated that suicidal behavior is heritable, suggesting that genetic and epigenetic information may serve as biomarkers for suicide risk. Here we systematically review the literature on genetic and epigenetic alterations observed in phenotypes across the full range of self-injurious thoughts and behaviors (SITB). We included 577 studies focused on genome-wide and epigenome-wide associations, candidate genes (SNP and methylation), noncoding RNAs, and histones. Convergence of specific genes is limited across units of analysis, although pathway-based analyses do indicate nervous system development and function and immunity/inflammation as potential underlying mechanisms of SITB. We provide suggestions for future work on the genetic and epigenetic correlates of SITB with a specific focus on measurement issues.

Multimodal assessment of sustained threat in adolescents with nonsuicidal self-injury.

Nonsuicidal self-injury (NSSI) is a common but poorly understood phenomenon in adolescents. This study examined the Sustained Threat domain in female adolescents with a continuum of NSSI severity (N = 142). Across NSSI lifetime frequency and NSSI severity groups (No + Mild NSSI, Moderate NSSI, Severe NSSI), we examined physiological, self-reported and observed stress during the Trier Social Stress Test; amygdala volume; amygdala responses to threat stimuli; and resting-state functional connectivity (RSFC) between amygdala and medial prefrontal cortex (mPFC). Severe NSSI showed a blunted pattern of cortisol response, despite elevated reported and observed stress during TSST. Severe NSSI showed lower amygdala-mPFC RSFC; follow-up analyses suggested that this was more pronounced in those with a history of suicide attempt for both moderate and severe NSSI. Moderate NSSI showed elevated right amygdala activation to threat; multiple regressions showed that, when considered together with low amygdala-mPFC RSFC, higher right but lower left amygdala activation predicted NSSI severity. Patterns of interrelationships among Sustained Threat measures varied substantially across NSSI severity groups, and further by suicide attempt history. Study limitations include the cross-sectional design, missing data, and sampling biases. Our findings highlight the value of multilevel approaches in understanding the complexity of neurobiological mechanisms in adolescent NSSI.

Editorial: Temporally Dynamic Perspectives on Risk in the Development of Psychopathology: Moving Toward the Identification of Risk Trajectories.

Internalizing problems contribute to significant distress and despair across the lifespan,1 as well as risk for suicide death. Understanding their associated patterns of development, especially in early life, could be key to identifying novel, upstream preventive and interventional strategies. Stressors and early seeds of dysfunction in the first phases of life, particularly during sensitive periods of developmental organization, can have powerful, lasting consequences across multiple levels of functioning.2 These cascade-inducing effectors are dynamic, and they are attuned to their particular contexts. For example, risk confined to a circumscribed period of development may differ from more extended, chronic disturbances.3 When early patterns of functioning are considered, their variability across development may likewise provide insight into their embedding into models, relationships, and circuits that will be carried forward and possibly eventuate to negative outcomes. Therefore, modeling risk as a dynamic process, particularly in the language of trajectories, may best capture the effects on patterns of ontogenesis.

Perceptions of Suicide among Pakistanis: Results of an Online Survey.

OBJECTIVE: In Pakistan, a predominantly Muslim country, information on the patterning of suicidal thoughts and behaviors, as well as associated public perceptions and opinions, is limited. We sought to advance knowledge on suicide and self-harm in Pakistan with a large, online survey. METHOD: Leveraging results from a twelve-item online survey (N = 5,157) circulated by the largest English language newspaper in Pakistan, we assessed personal experiences, opinions, and attitudes toward help-seeking in the context of suicide. We calculated proportions with 95% confidence intervals for endorsed responses and implemented binomial generalized linear models with odds ratios to assess differing response tendencies by age, gender, and urban/rural residence. RESULTS: Personal experiences related to suicide and self-harm as well as encounters in social circles were common. Mental illness tended to be recognized as a high likelihood contributor to suicide death over and above nonviolent interpersonal problems. Most considered suicide a way to escape pain, and few considered suicide to be immoral. Barriers to help-seeking included social deterrents, inaccessibility, and unaffordability. Women and youth emerged as higher risk groups, though the status of rural Pakistanis remained unclear. CONCLUSION: The survey provides a preliminary basis for considering the unique experiences and perspectives of the public in shaping suicide prevention and intervention efforts in Pakistan.

A voluntary online survey about suicide with over 5,000 responses from a cross-section of Pakistani populationResults illuminate popular opinions on suicide risk and mental health treatmentWomen and youth appear to be especially vulnerable warranting targeted intervention.

Blood epigenome-wide association studies of suicide attempt in adults with bipolar disorder.

Suicide attempt (SA) risk is elevated in individuals with bipolar disorder (BD), and DNA methylation patterns may serve as possible biomarkers of SA. We conducted epigenome-wide association studies (EWAS) of blood DNA methylation associated with BD and SA. DNA methylation was measured at >700,000 positions in a discovery cohort of n = 84 adults with BD with a history of SA (BD/SA), n = 79 adults with BD without history of SA (BD/non-SA), and n = 76 non-psychiatric controls (CON). EWAS revealed six differentially methylated positions (DMPs) and seven differentially methylated regions (DMRs) between BD/SA and BD/non-SA, with multiple immune-related genes implicated. There were no epigenome-wide significant differences when BD/SA and BD/non-SA were each compared to CON, and patterns suggested that epigenetics differentiating BD/SA from BD/non-SA do not differentiate BD/non-SA from CON. Weighted gene co-methylation network analysis and trait enrichment analysis of the BD/SA vs. BD/non-SA contrast further corroborated immune system involvement, while gene ontology analysis implicated calcium signalling. In an independent replication cohort of n = 48 BD/SA and n = 47 BD/non-SA, fold changes at the discovery cohort's significant sites showed moderate correlation across cohorts and agreement on direction. In both cohorts, classification accuracy for SA history among individuals with BD was highest when methylation at the significant CpG sites as well as information from clinical interviews were combined, with an AUC of 88.8% (CI = 83.8-93.8%) and 82.1% (CI = 73.6-90.5%) for the combined epigenetic-clinical classifier in the discovery and replication cohorts, respectively. Our results provide novel insight to the role of immune system functioning in SA and BD and also suggest that integrating information from multiple levels of analysis holds promise to improve risk assessment for SA in adults with BD.

Adolescent non-suicidal self-injury during the COVID-19 pandemic: A prospective longitudinal study of biological predictors of maladaptive emotion regulation.

BACKGROUND: Non-suicidal self-injury (NSSI) in adolescence is thought to stem from interactions between vulnerability in developing biological systems and experience of stressors. The current study assesses whether multiple levels of the stress system's response to threat could prospectively predict NSSI engagement during the COVID-19 pandemic, a shared, time-locked stressor. METHODS: Participants were 64 female adolescents (ages 12-16) from community and clinical settings who were oversampled for NSSI histories. Prior to the onset of the COVID-19 pandemic, adolescents completed a protocol that measured hypothalamic-pituitary-adrenal axis response to a social stressor (via salivary cortisol), amygdala volume, amygdala emotion-evoked activation, and frontolimbic resting-state functional connectivity. During early months of the pandemic (Summer 2020), measures of NSSI behavior (Inventory of Statements About Self-Injury), emotion regulation difficulties (Difficulties in Emotion Regulation Scale), perceived stress (Perceived Stress Scale), and pandemic-related stressors (Epidemic Pandemic Impacts Inventory) were collected. Multinomial logistic regression was used to assess if pre-pandemic biomarkers predicted mid-pandemic NSSI engagement: persistence of NSSI (Persist; N = 21), cessation of NSSI (Desist; N = 26), and no history of NSSI (Never; N = 17). Linear regressions explored if pre-pandemic biomarkers predicted mid-pandemic difficulties in emotion regulation and perceived stress. RESULTS: Higher pre-pandemic overall cortisol response to stress and amygdala emotion-evoked activation characterized adolescents who persisted in NSSI, compared to those who desisted. These findings remained significant when controlling for pandemic related stressors. Lower prepandemic cortisol reactivity predicted more difficulties in emotion regulation during the pandemic. This finding did not remain significant after controlling for pandemic related stressors. CONCLUSIONS: Findings suggest that patterns in key biological threat response systems may confer vulnerability for risk outcomes including NSSI engagement in adolescent females in the context of a shared, novel, naturally-occurring stressor. The results point to the importance of multi-level, longitudinal approaches for understanding the interface between developing neurobiological systems and experiential stress in at-risk adolescents. Identified patterns give insight into potential risk assessment strategies based on an understanding of the multi-level threat response.

Association between the epigenetic lifespan predictor GrimAge and history of suicide attempt in bipolar disorder.

Bipolar disorder (BD) has been previously associated with premature mortality and aging, including acceleration of epigenetic aging. Suicide attempts (SA) are greatly elevated in BD and are associated with decreased lifespan, biological aging, and poorer clinical outcomes. We investigated the relationship between GrimAge, an epigenetic clock trained on time-to-death and associated with mortality and lifespan, and SA in two independent cohorts of BD individuals (discovery cohort - controls (n = 50), BD individuals with (n = 77, BD/SA) and without (n = 67, BD/non-SA) lifetime history of SA; replication cohort - BD/SA (n = 48) and BD/non-SA (n = 47)). An acceleration index for the GrimAge clock (GrimAgeAccel) was computed from blood DNA methylation (DNAm) and compared between groups with multiple general linear models. Differences in epigenetic aging from the discovery cohort were validated in the independent replication cohort. In the discovery cohort, controls, BD/non-SA, and BD/SA significantly differed on GrimAgeAccel (F = 5.424, p = 0.005), with the highest GrimAgeAccel in BD/SA (p = 0.004, BD/SA vs. controls). Within the BD individuals, BD/non-SA and BD/SA differed on GrimAgeAccel in both cohorts (p = 0.008) after covariate adjustment. Finally, DNAm-based surrogates revealed possible involvement of plasminogen activator inhibitor 1, leptin, and smoking pack-years in driving accelerated epigenetic aging. These findings pair with existing evidence that not only BD, but also SA, may be associated with an accelerated biological aging and provide putative biological mechanisms for morbidity and premature mortality in this population.

Blood epigenome-wide association studies of suicide attempt in adults with bipolar disorder.

Suicide attempt (SA) risk is elevated in individuals with bipolar disorder (BD), and DNA methylation patterns may serve as possible biomarkers of SA. We conducted epigenome-wide association studies (EWAS) of blood DNA methylation associated with BD and SA. DNA methylation was measured at > 700,000 positions in a discovery cohort of n = 84 adults with BD with a history of SA (BD/SA), n = 79 adults with BD without history of SA (BD/non-SA), and n = 76 non-psychiatric controls (CON). EWAS revealed six differentially methylated positions (DMPs) and seven differentially methylated regions (DMRs) between BD/SA and BD/non-SA, with multiple immune-related genes implicated. There were no epigenome-wide significant differences when BD/SA and BD/non-SA were each compared to CON, and patterns suggested that epigenetics differentiating BD/SA from BD/non-SA do not differentiate BD/non-SA from CON. Weighted gene co-methylation network analysis and trait enrichment analysis of the BD/SA vs. BD/non-SA contrast further corroborated immune system involvement, while gene ontology analysis implicated calcium signalling. In an independent replication cohort of n = 48 BD/SA and n = 47 BD/non-SA, fold-changes at the discovery cohort's significant sites showed moderate correlation across cohorts and agreement on direction. In both cohorts, classification accuracy for SA history among individuals with BD was highest when methylation at the significant CpG sites as well as information from clinical interviews were combined, with an AUC of 88.8% (CI = 83.8-93.8%) and 82.1% (CI = 73.6-90.5%) for the combined epigenetic-clinical predictor in the discovery and replication cohorts, respectively. Our results provide novel insight to the role of immune system functioning in SA and BD and also suggest that integrating information from multiple levels of analysis holds promise to improve risk assessment for SA in adults with BD.

Biased reporting of past self-injurious thoughts and behaviors: A literature review.

BACKGROUND: Accurate assessment of suicide risk is critical for clinical practice, empirical advances, and informing public policy. In this narrative review of the literature, we compiled evidence from longitudinal studies that identify reporting bias of past self-injurious thoughts and behaviors (SITB) and examined possible correlates of inconsistent reporting. METHOD: We conducted an extensive literature search, including 19 longitudinal samples or subsamples who reported the presence of current or past SITB at an initial but not at a subsequent assessment (yes/no inconsistent reports). RESULTS: The median was 33%, and the weighted mean was 39% (95% CI, 37%-41%) for the prevalence of inconsistent reporting of SITB across the longitudinal samples. Importantly, inconsistent reports were linked with less internalizing psychopathology and more adaptive functioning. The type of sample recruited and assessment interval may also be relevant factors to consider. LIMITATIONS: Variability of sample characteristics and methodology made it challenging to draw firm conclusions across studies but provide information about critical sources of bias. CONCLUSIONS: Results suggest considerable caution for clinical, empirical, and policy decision-making based on lifetime reports of suicide and encourage a continued consideration for identifying potential reporting biases for SITB.

Basal and reactive cortisol: A systematic literature review of offspring of parents with depressive and bipolar disorders.

One of the most consistent biological findings in the study of affective disorders is that those with depression commonly show abnormal cortisol response, which suggests dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. Children of parents with mood disorders offer the opportunity to explore the biological pathways that may confer risk for psychopathology. This review explores basal and reactive cortisol in the offspring of parents who are currently depressed or have had a history of a depressive or bipolar disorder. Using PRISMA guidelines, search terms yielded 2002 manuscripts. After screening, 87 of these manuscripts were included. Results from the literature suggest that while the degree and direction of dysregulation varies, offspring of a parent with depression tend to show elevations in both basal (particularly morning and evening) and reactive (tentatively for social stressors) cortisol levels. There were few studies focused on offspring of parents with bipolar disorder. This review also discusses implications and recommendations for future research regarding the HPA axis in the intergenerational transmission of depressive disorders.