Pathophysiology Of Suicidal Behavior Research Articles

Association of Α-Klotho with regulation of Keap1/Nrf2/Interleukin-1 pathway and AMPA receptor trafficking in the brain of suicide victims.

Suicide is a significant public health challenge worldwide. Statistical data confirm a strong relationship between suicidal behavior and depressive disorders (DDs), but the molecular mechanisms of these diseases are still poorly understood. A growing body of research suggests that the Klotho-mediated pathway may be a novel intracellular target for the development of suicide-related disorders (including DDs). To verify this hypothesis, the link between α-Klotho levels, Nrf2-related inflammatory status (IL-1α, IL-1β, Keap1, NFκB p65), AMPA (GluA1, GluA2, p-S831-GluA1, p-S845-GluA1) receptor subunit trafficking and AMPK (AMPKα1/2; pT172-AMPKα1) signalling pathways in the brain of suicide victims as compared to controls were investigated. Commercially available enzyme-linked immunoassay (ELISA) and Western blot analysis were performed in the hippocampus (HP) and frontal cortex (FCx) of suicide victims and matched controls. Group differences were assessed using an unpaired Student's t-test. A statistically significant decrease in the level of α-Klotho (HP: p=0.001; FCx: p=0.012) with an increase in IL-1β (HP: p=0.0108) and IL-1α (FCx: p=0.009) concentrations were shown. These alterations were associated with increased Keap1 (FCx: p=0.023) and NF-κB-p65 (HP: p=0.039; FCx: p=0.013 nuclear fraction) protein levels. Furthermore, a significant reduction in p-S831-GluA1 (HP: p=0.029; FCx=0.002) and p-S845-GluA1 (HP: p=0.0012) proteins was observed. Similarly, the level of GluA2 (HP: p=0.011; FCx: p=0.002) and in p-T172-AMPKα1 (HP: p=0.0288; FCx: p=0.0338) protein were statistically decreased. Our findings demonstrate that a reduction in α-Klotho levels in brain structures related to mood disorders (HP, FCx) correlates with suicidal behavior. Moreover, our study provides novel insights into the molecular mechanisms underlying suicide-related disorders, highlighting the role of α-Klotho, Nrf2-related inflammatory status, AMPA receptor trafficking, and AMPK signaling pathways in the pathophysiology of suicidal behavior. These results may have implications for the development of targeted interventions for individuals at risk of suicide.

Evaluation of peripheral inflammatory parameters of cases with suicide attempts

PurposeThe purpose of the present study was to examine the inflammation markers of patients who have attempted suicide by comparing them with those of healthy controls. The leukocyte cell levels, Neutrophil/Lymphocyte Ratios (NLR), Basophil/Lymphocyte Ratios (BLR), Platelet/Lymphocyte Ratios (PLR), Monocyte/Lymphocyte Ratios (MLR), Systemic Inflammation Index (SII), Neutrophil/Albumin Ratios (NAR) values were compared with those of healthy controls. MethodA total of 376 people were included in the study (276 patients who attempted suicide, and 100 healthy people (the control group)). The demographic data and laboratory parameters of the participants were analyzed from the hospital automation system. ResultsThe participants’ female/male ratio was 158/118 (42.8%/57.1%) in the group of patients who attempted suicide and 41/59 (41/59%) in the control group. When the distribution of laboratory parameters was evaluated, although the NLR, BLR, NAR, SII, and MLR values, which are indicators of peripheral inflammation, were high in patients who attempted suicide (p = 0.049 for MLR, p = 0.000 for other values), the PLR (p = 0.586) value did not differ significantly between the groups. Patients who had attempted more than one suicide had elevated BLR (p = 0.007), SII (p = 0.003), and NAR (p = 0.003) values. DiscussionBased on the results obtained, it was considered that paying attention to inflammation parameters in patient follow-ups, and monitoring of SII, NLR, BLR, and NAR values of patients who had attempted suicide once would be beneficial in preventing future suicide attempts. These results strengthen the idea that inflammatory processes play roles in the pathophysiology of suicidal behavior. However, further studies are needed to elucidate the complex pathophysiological mechanisms of immune pathways underlying suicidal behavior.

Oxidative stress responses and their alterations in the Nrf2-NMDA receptor pathway in the brain of suicide victims.

Suicide is a global public health concern. There is evidence of an association between suicidal behavior and depressive disorders (DDs). An increasing number of studies have suggested that nuclear factor erythroid-derived 2-like 2 (Nrf2), a major endogenous regulator of the oxidative stress response, can be a novel target for the neurobiology of suicide-related disorders (including depression). This study aimed to investigate the relationship between oxidative stress progression, Nrf2 regulation, and N-methyl-D-aspartate receptor (NMDA) subunit composition in the hippocampus (Hp) and frontal cortex (FCx) of suicide victims (n=14) and matched controls (n=8). Furthermore, zinc and magnesium concentrations and their potency to inhibit [3H] MK-801 (radioactively labeled form of MK-801 - dizocilpine, a well-characterized NMDAR channel uncompetitive antagonist frequently used in receptor-binding assays) binding to NMDA receptor channels were measured. Our results revealed a statistically significant increase in protein carbonyl levels and thiobarbituric acid-reactive substances (TBARS) concentrations in Hp and FCx of suicide victims. Enhanced superoxide dismutase (SOD) activity (only in FCx) in suicides compared to controls was shown. These alterations were accompanied by an increase in Nrf2 protein levels in whole homogeneous tissue lysates and cytosolic fractions of Hp and FCx. Importantly, suicide victims presented a significant reduction in Nrf2 protein levels in the nuclear fraction of FCx. Finally, the observed decrease in N-methyl-D-aspartate receptor subunit 2B (GluN2B) and postsynaptic density proteins 95 (PSD-95) protein levels was associated with a statistically significant reduction in magnesium levels in the FCx of suicide victims. These results confirm for the first time that increased oxidative stress parameters are related to Nrf2 protein changes and alterations in the NMDA receptor complex in the pathophysiology of suicidal behavior.

Interpretable Estimation of Suicide Risk and Severity from Complete Blood Count Parameters with Explainable Artificial Intelligence Methods.

The peripheral inflammatory markers are important in the pathophysiology of suicidal behavior. However, methods for practical uses haven't been developed enough yet. This study developed predictive models based on explainable artificial intelligence (xAI) that use the relationship between complete blood count (CBC) values and suicide risk and severity of suicide attempt. 544 patients who attempted an incomplete suicide between 2010-2020 and 458 healthy individuals were selected. The data were obtained from the electronic registration systems. To develop prediction models using CBC values, the data were grouped in two different ways as suicidal/healthy and attempted/non-attempted violent suicide. The data sets were balanced for the reliability of the results of the machine learning (ML) models. Then, the data was divided into two; 80% of as the training set and 20% as the test set. For suicide prediction, models were created with Random Forest, Logistic Regression, Support vector machines and XGBoost algorithms. SHAP, was used to explain the optimal model. Of the four ML methods applied to CBC data, the best-performing model for predicting both suicide risk and suicide severity was the XGBoost model. This model predicted suicidal behavior with an accuracy of 0.83 (0.78-0.88) and the severity of suicide attempt with an accuracy of 0.943 (0.91-0.976). Lower levels of NEU, WBC, MO, NLR, MLR and, age higher levels of HCT, PLR, PLT, HGB, RBC, EO, MPV and, BA contributed positively to the predictive created model for suicide risk, while lower PLT, BA, PLR and RBC levels and higher MO, EO, HCT, LY, MLR, NEU, NLR, WBC, HGB and, age levels have a positive contribution to the predictive created model for violent suicide attempt. Our study suggests that the xAI model developed using CBC values may be useful in detecting the risk and severity of suicide in the clinic.

Testosterone and Suicidal Behavior in Bipolar Disorder.

Bipolar disorder is associated with suicidal behavior. The risk of suicide for individuals with bipolar disorder is up to 20-30 times larger than that of the general population. Considerable evidence suggests that testosterone may play a role in the pathophysiology of suicidal behavior in both men and women with bipolar disorder and other psychiatric conditions. Testosterone has complex effects on psychological traits. It affects mood and behavior, including interactions with other people. Testosterone regulates pro-active and re-active aspects of aggression. Probably, both high and low levels of testosterone may contribute to the neurobiology of suicide in various patient populations. The effects of endogenous and exogenous testosterone on suicidality in patients with bipolar disorder need further investigation. The aim of this commentary article is to provide a commentary on the author's work on the topic, summarize the literature on testosterone, bipolar disorder, and suicide, and encourage future research on this poorly studied topic.

Brain-derived neurotrophic factor in war veterans with or without a history of suicide attempt

BackgroundBrain-derived neurotrophic factor (BDNF) plays a central role in brain development and plasticity and has been demonstrated to be altered in neuropsychiatric diseases and suicidal behavior. We examined whether there is a difference with regard to plasma BDNF levels between veterans who made or did not make a suicide attempt post-deployment. MethodsCombat veterans who made or did not make post-deployment suicide attempts were interviewed using Mini-International Neuropsychiatric Interview, the Montgomery-Åsberg Depression Rating Scale, the Barratt Impulsivity Scale (BIS) and the Scale for Suicidal Ideation (SSI). Reaction to the most recent suicide attempt was evaluated using item 16 of the Suicide Intent Scale. Plasma BDNF levels were determined by the BDNF ELISA kit. ResultsControlling for age and body-mass index (BMI), BDNF levels were higher among suicide attempters than non-attempters. We observed a positive correlation between BDNF levels and SSI scores among non-attempters but not among attempters. BDNF levels positively correlated with BIS scores among suicide attempters but not among non-attempters. Suicide attempters who regretted that they made a suicide attempt had significantly higher BDNF levels in comparison to attempters who did not regret their attempts, controlling or not controlling for age and BMI. LimitationsA modest sample size is a shortcoming of our study. ConclusionsOur study demonstrates that BDNF may be involved in the pathophysiology of suicidal behavior in combat veterans. Given the relative ease of measuring plasma BDNF levels, it may be appropriate to consider adding such assessments to studies of suicidal behavior.

Associations of three major physiological stress systems with suicidal ideation and suicide attempts in patients with a depressive and/or anxiety disorder

BackgroundPeople with depressive and/or anxiety disorders are at increased risk of suicidal ideation and suicide attempts, but biological correlates signaling such risk remain unclear. Independent and cumulative dysregulations in physiological stress systems, in particular the hypothalamic–pituitaryadrenal axis (HPA-axis), immune-inflammatory system, and autonomous nervous system (ANS), may contribute to this risk. However, findings have either been heterogeneous or absent thus far. MethodsAssociations between individual markers and cumulative indices of the HPA-axis (cortisol awakening response and evening cortisol), immune-inflammatory system (C-reactive protein, interleukin-6 (IL-6), and tumor necrosis factor-α), and the ANS (heart rate, respiratory sinus arrhythmia, and pre-ejection period) and the outcomes no suicide ideation with suicide attempt (SI-SA+), suicide ideation without suicide attempt (SI+SA-) and suicide ideation with suicide attempt (SI+SA+) were investigated in 1749 persons with depressive and/or anxiety disorders from the Netherlands Study of Depression and Anxiety (NESDA). ResultsHigh levels of CRP and IL-6 were associated with SI-SA+ and SI+SA+ respectively when compared to non-suicidal patients after adjusting for confounders and multiple testing. Also, cumulative immune-inflammatory dysregulations were positively associated with SI+SA+, suggesting a dose–response effect. No significant associations were found between HPA-axis or ANS indicators and suicide-outcomes and between immune-inflammatory system markers or cumulative stress system dysregulations and SI+SA-. ConclusionAlthough stress system markers could not differentiate between SI+SA- and non-suicidal patients, findings indicate that dysregulations of individual and cumulative immune-inflammatory markers are associated with suicide attempts in depressive and/or anxiety patients. Thus, immune-inflammatory system dysregulation may be involved in the pathophysiology of suicidal behavior, supporting further examination of the effects of anti-inflammatory interventions on suicidality.

Serum endocannabinoid levels in suicide attempters: A pilot study

The search for a biomarker for suicide risk is a longstanding pursuit in clinical psychiatry. Literature addressing the role of endocannabinoids in suicide attempters (SA) is sparse. This cross-sectional study is aimed at comparing 8 AM serum concentrations of 4 endogenous cannabinoids (anandamide, AEA; 2-arachidonoylglycerol, 2-AG; N-palmitoiletanolamida, PEA; and oleoylethanolamide, OEA) in 30 suicide attempters (SA) and 12 psychiatric controls (PC). 8 AM AEA and PEA serum levels were higher in SA compared to PC without controlling for cannabis use (n = 42) (3.58 ± 5.77 vs. 1.62 ± 2.49, F = 3.04, P = 0.089; and 3.31 ± 4.82 vs. 1.21 ± 1.20, F = 6.22, p = 0.017, respectively). Serum ACTH was higher in PC compared to SA (32.11 ± 21.60 vs. 20.05 ± 9.96, F = 9.031, p = 0.0.005). After controlling for cannabis use in the urine test (n = 28), 8 AM AEA and PEA serum levels remained higher in SA compared to PC (4.57 ± 6.38 vs. 0.64 ± 1.11, F = 4.852, P = 0.037; and 4.35 ± 5.46 vs. 1.21 ± 1.25, F = 4.125, p = 0.053, respectively). The present study offers preliminary evidence about the role of AEA and PEA in suicidal behavior (SB). Furthermore, in the context of the mental pain model of SB, our findings suggest that some endocannabinoids may play a role in the pathophysiology of SB. Our pilot study deserves replication by other studies with bigger sample sizes.

Neutrophil-to-lymphocyte ratio: A potential new peripheral biomarker of suicidal behavior.

Neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) have emerged as important peripheral inflammatory biomarkers. Recent data suggest a possible role of the immune system in the pathophysiology of suicidal behavior (SB). The aim of this study is to evaluate the association among NLR, MLR, and PLR and SB in patients with major depressive disorder (MDD), and to test its validity as a biomarker for suicidality. We evaluated 538 patients with MDD (mean age [standard deviation]=43.87 [14.36] years; females: 68.8%). A logistic regression model was estimated to determine the independent factors associated with suicide risk in patients with and without a history of suicide attempt (SA). Three hundred ninety-three patients (74.7%) had a personal history of SA. Patients with a previous SA were more frequently female (71.9% vs. 59.6%; p=0.007), significantly younger (41.20 vs. 51.77years; p<0.001), had lower depression severity at enrolment (15.58 vs. 18.42; p<0.000), and significantly higher mean NLR and PLR ratios (2.27 vs. 1.68, p=0.001; 127.90 vs. 109.97, p=0.007, respectively). In the final logistic regression model, after controlling for age, sex, and depression severity, NLR was significantly associated with SB (β=0.489, p=0.000; odds ratio [95% confidence intervals]=1.631 [1.266-2.102]). We propose a cut-off value of NLR=1.30 (sensitivity=75% and specificity=35%). Our data suggest that NLR may be a valuable, reproducible, easily accessible, and cost-effective strategy to determine suicide risk in MDD.

Evaluation of the Effectiveness of Auricular Acupuncture in Suicidal Ideation and Cortisol Level in Dysthymic Patients with Comorbid Opiate Use Disorders Enrolled in Methadone Maintenance Treatment: A Randomized, Double-Blind, Sham-Controlled Trial

Background: Suicide is one of the leading causes of death around the world. The hypothalamic-pituitary-adrenal (HPA) axis disorder is involved in the pathophysiology of suicidal behavior. Acupuncture by regulating the activity of the HPA axis could regulate the secretion of cortisol. Objectives: This study aimed to evaluate the effectiveness of auricular acupuncture in the reduction of cortisol level and suicidal ideation in dysthymic patients with comorbid opiate use disorders enrolled in methadone maintenance treatment (MMT). Methods: In a randomized, double-blind, sham-controlled trial (TCTR20180328001), from December 2015 to June 2016, 24 patients (mean age = 24 years) with persistent depressive disorder (dysthymia) under methadone maintenance treatment who referred to Bijan Center for Substance Abuse Treatment in Tehran were selected through respondent-driven sampling (RDS). After 28 days of evaluation, the participants were randomized into two active or sham continuous groups. Auricular acupuncture was performed twice a week for four weeks for the experimental group while the control group received the sham acupuncture. Assessments were carried out before treatment (baseline) and every week for four weeks. Salivary cortisol was considered the primary outcome and the suicide ideation was the secondary outcome. The data were analyzed by the generalized estimation equation (GEE) model and the chi-square test. The qualitative data were analyzed using ATLAS/TI 5 software. Results: Acupuncture had a significant effect on the cortisol level, as the primary outcome, during the four weeks of treatment. Moreover, there was a significant reduction in suicidal ideation as the secondary outcome (all P values < 0.01). Conclusions: Acupuncture as an alternative method could reduce the cortisol level and significantly decrease suicidal ideation.

Oxidative stress biomarkers in bipolar disorder with suicidal behavior: A systematic review

Oxidative stress has been implicated in suicidal behavior and bipolar disorder (BD), respectively. However, the role of oxidative stress as a biomarker of suicidal behavior in BD remains inconclusive. This systematic review aims to determine the association between oxidative stress biomarkers and suicidal behavior among BD patients. All human studies from Scopus and Ovid Medline up until August 2017 on suicidal behavior, BD, and oxidative stress biomarkers were included according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of five studies met the eligibility criteria, of which 4 were case–control studies. Three studies identified at least one biomarker with significant association between suicidal acts and oxidative stress biomarkers (i.e., increased lipid peroxidation and NOS3 rs 1799983 TT genotype) in previous suicide attempt and increased deoxyribonucleic acid damage in suicide among sample populations with BD patients. No study reported conclusive associations between Ala-9 Val manganese superoxide dismutase or Pro 197 Leu glutathione peroxidase gene polymorphisms; or levels of nitric oxide metabolites, plasma total antioxidant potential, and malondialdehyde with suicidal acts among BD patients. Based on this systematic review, there is limited evidence of any association of the association between oxidative stress biomarkers and suicidal acts in BD patients. Definitive conclusions could not be ascertained due to lack of homogenous properly controlled and adequately powered studies. Future systematically well-designed and larger, prospective studies are warranted to clarify the role of oxidative stress pathways in the pathophysiology of suicidal behavior in BD.

Suicide attempt, clinical correlates, and BDNF Val66Met polymorphism in chronic patients with schizophrenia.

Recent evidence suggests the role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of suicidal behavior. Because schizophrenia patients usually have high suicide rates and numerous studies have suggested that BDNF may contribute to the psychopathology of schizophrenia, we hypothesized that the functional polymorphism of BDNF (Val66Met) was associated with suicide attempts in patients with schizophrenia in a Chinese Han population. This polymorphism was genotyped in 825 chronic schizophrenia patients with (n = 123) and without (n = 702) suicide attempts and 445 healthy controls without a history of suicide attempts using a case-control design. The schizophrenia symptoms were assessed by the Positive and Negative Syndrome Scale. There were no significant differences in BDNF Val66Met genotype and allele distributions between the patients and healthy controls. However, we found the Val allele (p = .023) and the Val/Val genotypes (p = .058) to be associated with a history of suicide attempts. Moreover, some clinical characteristics, including age and cigarettes smoked each day, interacted with the BDNF gene variant and appeared to play an important role in suicide attempts among schizophrenia patients. The BDNF Val66Met polymorphism itself and its interaction with some clinical variables may influence suicide attempts among schizophrenia patients. (PsycINFO Database Record

The connections among suicidal behavior, lipid profile and low-grade inflammation in patients with major depressive disorder: a specific relationship with the neutrophil-to-lymphocyte ratio

Objectives: The role of inflammation and lipid metabolism in the pathophysiology of suicidal behavior has received particular attention in recent years. The neutrophil-to-lymphocyte ratio (NLR) has been suggested as a new and more reliable indicator of low-grade inflammation. NLR has been found to be altered in major depressive disorder (MDD) and has been related to various factors, including chronic stress and impulsivity that were previously reported to be related to suicidal behavior. We aimed to explore the roles of NLR, C-reactive protein (CRP) and serum lipid levels on suicidal behavior in patients with MDD.Methods: The study group consisted of 139 inpatients diagnosed with MDD [37 suicide attempters (SA); 102 suicide non-attempters (NSA)], 50 healthy controls and matched according to age, gender and education. NLR, PLR, CRP and lipid values were obtained from digital inpatient records.Results: CRP levels and NLR were substantially higher in patients with SA than in subjects with NSA and healthy comparison subjects after adjusting the confounding factors. The logistic regression included two predictive variables for suicide status in patients with depressive disorder (A) previous suicidal history; (B) NLR.Conclusions: This is the first study suggesting that NLR may be a trait marker for suicidal vulnerability via a relationship between NLR and a recent suicide attempt in depressed inpatients. Future prospective studies are needed to determine the exact roles of NLR, and other inflammatory markers on suicidality in MDD.

Commentary: CSF and Plasma Testosterone in Attempted Suicide.

Commentary: CSF and Plasma Testosterone in Attempted Suicide.

Hypothalamic–pituitary–adrenal axis hyperactivity is associated with decreased brain-derived neurotrophic factor in female suicide attempters

Introduction: Both decreased levels of brain-derived neurotrophic factor (BDNF) and hypothalamic–pituitary–adrenal (HPA) axis dysregulation may be involved in the pathophysiology of suicidal behaviour, as well as cognitive symptoms of depression. Pre-clinical and clinical studies have shown interactions between HPA-axis activity and BDNF, but this has not been studied in a clinical cohort of suicidal subjects. The purpose of this study was, therefore, to investigate associations between HPA-axis activity and BDNF in suicide attempters. Furthermore, this study examined the relationship between the HPA-axis, BDNF, and cognitive symptoms in suicidal patients. Since previous data indicate gender-related differences in BDNF and the HPA axis, males and females were examined separately.Method: Seventy-five recent suicide attempters (n = 41 females; n = 34 males) were enrolled in the study. The Dexamethasone Suppression Test (DST) was performed and BDNF in plasma were analysed. Patients were evaluated with the Comprehensive Psychopathological Rating Scale (CPRS) from which items ‘Concentration difficulties’ and ‘Failing memory’ were extracted.Results: Only among females, DST non-suppressors had significantly lower BDNF compared to DST suppressors (p = 0.022), and there was a significant correlation between post-DST serum cortisol at 8 a.m. and BDNF (rs = −0.437, p = 0.003). Concentration difficulties correlated significantly with post-DST cortisol in all patients (rs = 0.256, p = 0.035), in females (rs = 0.396, p = 0.015), and with BDNF in females (rs = −0.372, p = 0.020).Conclusion: The findings suggest an inverse relationship between the HPA-axis and BDNF in female suicide attempters. Moreover, concentration difficulties may be associated with low BDNF and DST non-suppression in female suicide attempters.

Assessment of serum cortisol, thoughts of death, and loss of pleasure in patients with schizophrenia: a correlative study

Context The hypothalamic–pituitary–adrenal (HPA) axis seems dysregulated in schizophrenic patients, but the underlying mechanisms are unknown; yet recent evidence indicates that systemic cortisol metabolism influences blood cortisol levels and HPA axis functioning. There has been a recent increase in interest in anhedonia research. Linkages to schizophrenia and the underlying neurobiology are still not well understood. There is clear evidence that the activity of certain neurobiological systems has a role in the pathophysiology of suicidal behavior and this includes hyperactivity of the HPA axis. Objectives The objectives of this work were to examine whether there is an increased activity of HPA axis in schizophrenic patients, and to detect the presence of an association between the level of plasma cortisol and thoughts of death and anhedonia in the disorder. Setting and design Twenty patients diagnosed with schizophrenia were studied in comparison with 20 controls. Patients and methods All patients were assessed through Present State Examination, 10th revision. The Snaith Hamilton Pleasure Scale was used to assess anhedonia, and Beck’s Suicidal Ideation Scale was used to quantify suicidal intention. In addition, The Positive and Negative Syndrome Scale was also used. Blood samples were collected from all patients to assess plasma cortisol level in the morning and evening. Statistical analysis Collected data in this study were analyzed using the statistical package for the social sciences (version 15). Results There were increased levels of morning and evening cortisol in schizophrenic patients. Thoughts of death were positively associated with elevated morning cortisol. Conclusion Schizophrenic patients have higher cortisol levels in comparison with controls, suggesting hyperactivity of the HPA axis in the disorder. Anhedonia predicts suicidal tendencies in schizophrenia; the higher the anhedonia, the higher the suicidal ideations.

Glucocorticoid regulates TrkB protein levels via c-Cbl dependent ubiquitination: a decrease in c-Cbl mRNA in the prefrontal cortex of suicide subjects.

Brain derived neurotrophic factor (BDNF) signaling through its receptor TrkB plays a crucial role in neurodevelopment and plasticity. Stress and glucocorticoids have been shown to alter TrkB signaling in neurons, and defects in TrkB expression have been reported in the prefrontal cortex of suicide subjects. Glucocorticoid treatment has been shown to induce deleterious effects on the neuronal maturation. However, the mechanisms involved in the regulation of TrkB by glucocorticoid during neurodevelopment are not clear. Here we show that acute corticosterone exposure induced posttranslational upregulation of TrkB in primary cortical neurons (days in vitro 4, DIV4), which was blocked by the proteasome inhibitors. Acute corticosterone-induced increase in TrkB protein levels was dependent on glucocorticoid receptor (GR). At the cellular level, ubiquitin E3 ligase c-Cbl mediates TrkB stabilization and corticosterone-induced TrkB levels. Moreover, the tyrosine kinase binding domain in c-Cbl plays a critical role in corticosterone-induced TrkB levels. Chronic treatment of neurons with corticosterone induced significant decreases in both TrkB and c-Cbl protein levels. Acute corticosterone treatment failed to induce any significant change in TrkB and c-Cbl protein levels in mature neurons (DIV 12), where as chronic corticosterone exposure reduced TrkB levels. Under an in vivo condition, chronic corticosterone exposure induced down-regulation of c-Cbl in mouse frontal cortex and hippocampus. Importantly, we demonstrate for the first time a significant decrease in c-Cbl mRNA levels in the prefrontal cortex of suicide subjects indicating the possible role of c-Cbl in the pathophysiology of suicidal behavior. Thus, ubiquitin-proteasome-mediated TrkB regulation may be an important mechanism for improving BDNF signaling and maintaining neuroplasticity in stress-related neuropsychiatric disorders.

EPA-0413 – The role of inflammatory cytokines in suicidal behavior

Evidence suggests that inflammatory mediators may play a critical role in the pathophysiology of major depression and suicidal behavior. Immunological differences have been found in patients with affective disorders and suicidal behavior. Especially, increased levels of pro-inflammatory cytokines have been reported to correlate with the severity of depression and various cytokines have been identified as potentially relevant in understanding the pathophysiology of affective disorders/suicidality. We aimed to review the current literature to investigate the association between inflammatory cytokines and suicidal behavior. A systematic review of the current literature was conducted to investigate the association between inflammatory cytokines and suicidal behavior. Only articles from peer-reviewed journals were selected for inclusion. Most studies reported the association between suicidality and IL2, IL-6, IL-8, TNF-α and VEGF levels that have been found altered in suicidal behavior. The presence of major depressive disorder (MDD) with suicidal ideation/attempts was associated with differences in inflammatory cytokine profile when compared to that without suicidal ideation/attempts. Most suicide attempters or subjects with suicidal ideation showed an imbalance of the immune system but this does not imply the existence of a causal link. Also, not all studies showed a positive correlation between inflammatory cytokines and suicidal behavior. Inflammatory cytokines play a key role in the pathophysiology of suicidal behavior. However, further additional studies should elucidate the molecular mechanisms of the immune activation pathways underlying suicidality.

Do testosterone and brain-derived neurotrophic factor interactions play a role in the pathophysiology of suicidal behavior?

Do testosterone and brain-derived neurotrophic factor interactions play a role in the pathophysiology of suicidal behavior?

The role of neuropeptides in suicidal behavior: a systematic review.

There is a growing evidence that neuropeptides may be involved in the pathophysiology of suicidal behavior. A critical review of the literature was conducted to investigate the association between neuropeptides and suicidal behavior. Only articles from peer-reviewed journals were selected for the inclusion in the present review. Twenty-six articles were assessed for eligibility but only 22 studies were included. Most studies have documented an association between suicidality and some neuropeptides such as corticotropin-releasing factor (CRF), VGF, cholecystokinin, substance P, and neuropeptide Y (NPY), which have been demonstrated to act as key neuromodulators of emotional processing. Significant differences in neuropeptides levels have been found in those who have attempted or completed suicide compared with healthy controls or those dying from other causes. Despite cross-sectional associations between neuropeptides levels and suicidal behavior, causality may not be inferred. The implications of the mentioned studies were discussed in this review paper.