Emilie Olié

Increased methylation of glucocorticoid receptor gene ( NR3C1 ) in adults with a history of childhood maltreatment: a link with the severity and type of trauma

Childhood maltreatment, through epigenetic modification of the glucocorticoid receptor gene (NR3C1), influences the hypothalamic–pituitary–adrenal axis (HPA axis). We investigated whether childhood maltreatment and its severity were associated with increased methylation of the exon 1F NR3C1 promoter, in 101 borderline personality disorder (BPD) and 99 major depressive disorder (MDD) subjects with, respectively, a high and low rate of childhood maltreatment, and 15 MDD subjects with comorbid post-traumatic stress disorder (PTSD). Childhood sexual abuse, its severity and the number of type of maltreatments positively correlated with NR3C1 methylation (P=6.16 × 10−8, 5.18 × 10−7 and 1.25 × 10−9, respectively). In BPD, repetition of abuses and sexual abuse with penetration correlated with a higher methylation percentage. Peripheral blood might therefore serve as a proxy for environmental effects on epigenetic processes. These findings suggest that early life events may permanently impact on the HPA axis though epigenetic modifications of the NR3C1. This is a mechanism by which childhood maltreatment may lead to adulthood psychopathology.

The suicidal mind and brain: A review of neuropsychological and neuroimaging studies

Abstract Objectives. We aimed at reviewing studies exploring dysfunctional cognitive processes, and their neuroanatomical basis, in suicidal behaviour, and to develop a neurocognitive working model. Methods. A literature search was conducted. Results. Several limitations were found. The main reported neuropsychological findings are a higher attention to specific negative emotional stimuli, impaired decision-making, lower problem-solving abilities, reduced verbal fluency, and possible reduced non-specific attention and reversal learning in suicide attempters. Neuroimaging studies mainly showed the involvement of ventrolateral orbital, dorsomedial and dorsolateral prefrontal cortices, the anterior cingulate gyrus, and, to a lesser extent, the amygdala. In addition, alterations in white matter connections are suggested. Conclusions. These studies support the concept of alterations in suicidal behaviour distinct from those of comorbid disorders. We propose that a series of neurocognitive dysfunctions, some with trait-like characteristics, may facilitate the development of a suicidal crisis during stressful circumstances: (1) an altered modulation of value attribution, (2) an inadequate regulation of emotional and cognitive responses, and (3) a facilitation of acts in an emotional context. This preliminary model may represent a framework for the design of future studies on the pathophysiology, prediction and prevention of these complex human behaviours.

Decreased activation of lateral orbitofrontal cortex during risky choices under uncertainty is associated with disadvantageous decision-making and suicidal behavior

Decision-making impairment has been linked to orbitofrontal cortex lesions and to different disorders including substance abuse, aggression and suicidal behavior. Understanding the neurocognitive mechanisms of these impairments could facilitate the development of effective treatments. In the current study, we aimed to explore the neural and cognitive basis of poor decision-making ability associated with the vulnerability to suicidal behavior, a public health issue in most western countries. Twenty-five not currently depressed male patients, 13 of whom had a history of suicidal acts (suicide attempters) and 12 of whom had none (affective controls), performed an adapted version of the Iowa Gambling Task during functional Magnetic Resonance Imaging. Task-related functional Regions-of-Interest were independently defined in 15 male healthy controls performing the same task (Lawrence et al., 2009). In comparison to affective controls, suicide attempters showed 1) poorer performance on the gambling task 2) decreased activation during risky relative to safe choices in left lateral orbitofrontal and occipital cortices 3) no difference for the contrast between wins and losses. Altered processing of risk under conditions of uncertainty, associated with left lateral orbitofrontal cortex dysfunction, could explain the decision-making deficits observed in suicide attempters. These impaired cognitive and neural processes may represent future predictive markers and therapeutic targets in a field where identification of those at risk is poor and specific treatments are lacking. These results also add to our growing understanding of the role of the orbitofrontal cortex in decision-making and psychopathology.

Temperament personality profiles in suicidal behaviour: An investigation of associated demographic, clinical and genetic factors

BACKGROUND Personality traits have been suggested as possible risk factors for suicidal behaviours. Cloningers model of personality (TCI), given its neurobiological background, might provide an ideal tool for the identification of dimensions associated with suicide attempt. METHODS A number of 1333 suicide attempters and 589 non-suicide attempters suffering from different DSM-IV Axis I disorders were assessed using either the temperament and character inventory (TCI) or the tridimensional personality questionnaire (TPQ), as well as other self-report questionnaires evaluating dimensions associated with suicidal behaviour, such as impulsivity and anger traits. The severity of suicide attempts and the methods used were also assessed. Subjects were genotyped for polymorphisms within the key genes involved in monoaminergic pathways and the HPA axis. RESULTS Compared with non-suicide attempters, suicide attempters scored higher for harm avoidance (HA) and novelty seeking (NS), and lower for self-directedness (SD). The difference was independent of Axis I disorders. Higher HA and NS scores were associated with a greater severity of suicidal behaviour. A multivariate model showed that HA was the single temperamental dimension independently related to suicide attempt history, beside impulsivity and anger-related traits. The genetic factors investigated did not play a significant role in modulating these temperamental dimensions. LIMITATIONS The TCI was available for only half of the sample. CONCLUSIONS Early detection of subjects displaying high HA and low SD, associated with high impulsivity and poor anger control, may help to prevent suicidal behaviours. Physicians should therefore be aware of these risk factors so that they can offer the best primary care intervention.

Measurement of total serum cholesterol in the evaluation of suicidal risk.

BACKGROUND Many studies have demonstrated an association between suicidal behavior and low levels of total serum cholesterol. To our knowledge, this association has mainly been reported in men. This case-control study was undertaken to assess the association between serum cholesterol level and suicide attempts in both genders. METHODS A total of 3207 subjects was included, divided into three groups: 510 patients with a history of suicidal attempts, 275 patients with no history of suicidal attempts, and 2422 controls. Mean and quartile total cholesterol levels were compared between the three groups according to gender. ROC curves were drawn to determine the biologically relevant threshold. RESULTS After adjustment for age, cholesterol level was significantly lower (p<0.01) in suicide attempters than in non-attempters and controls for both genders. Male non-suicide attempters had similar cholesterol levels to controls (p=0.7), but the levels in female non-attempters were significantly higher (p=0.004). The proportion of suicide attempters in the lowest cholesterol level quartile (51.3% of men, 40.1% of women) was significantly higher than that in the highest quartile (8.1% of men, 12.4% of women). For triglyceride level, no difference was found between the three groups, suggesting that this association was not due to malnutrition linked to depression. LIMITATIONS The effect of acute or chronic administration of medications on serum cholesterol levels was not controlled. Psychiatric history in surgical controls was not recorded. CONCLUSIONS Total serum cholesterol levels measured at admission may be a useful biological marker of suicidal risk.

Feasibility and validity of ecological momentary assessment in the investigation of suicide risk

Ecological Momentary Assessment has been used to investigate a wide range of behaviors and psychiatric conditions. Previous investigations have consistently obtained promising results with high acceptance and compliance rates, and with only minor reactive effects for specific variables. Despite the promise of this methodology for the study of severe psychiatric populations, little is known about its feasibility in samples at risk for suicide. In the present study, four samples at varying risk for suicide completed an Ecological Momentary Assessment study by responding to five electronic assessments per day over a one-week period. Samples included healthy controls (n=13), affective controls (n=21), past suicide attempters (n=20), and recent suicide attempters (n=42). The results demonstrate satisfactory participation rates and high compliance with daily life repeated assessments across all groups. Importantly, negative thoughts or suicidal ideation were not reactive to the duration of the study, indicating that the repeated assessment of such cognitions in daily life have little or no effect on their frequency. The findings provide support for the use of Ecological Momentary Assessment in the study of suicidal ideation and suggest that mobile technologies represent new opportunities for the assessment of high-risk cognitive states experienced by patients in daily life.

Borderline personality disorder and childhood maltreatment: a genome‐wide methylation analysis

Early life adversity plays a critical role in the emergence of borderline personality disorder (BPD) and this could occur through epigenetic programming. In this perspective, we aimed to determine whether childhood maltreatment could durably modify epigenetic processes by the means of a whole‐genome methylation scan of BPD subjects. Using the Illumina Infinium® HumanMethylation450 BeadChip, global methylation status of DNA extracted from peripheral blood leucocytes was correlated to the severity of childhood maltreatment in 96 BPD subjects suffering from a high level of child adversity and 93 subjects suffering from major depressive disorder (MDD) and reporting a low rate of child maltreatment. Several CpGs within or near the following genes (IL17RA, miR124‐3, KCNQ2, EFNB1, OCA2, MFAP2, RPH3AL, WDR60, CST9L, EP400, A2ML1, NT5DC2, FAM163A and SPSB2) were found to be differently methylated, either in BPD compared with MDD or in relation to the severity of childhood maltreatment. A highly relevant biological result was observed for cg04927004 close to miR124‐3 that was significantly associated with BPD and severity of childhood maltreatment. miR124‐3 codes for a microRNA (miRNA) targeting several genes previously found to be associated with BPD such as NR3C1. Our results highlight the potentially important role played by miRNAs in the etiology of neuropsychiatric disorders such as BPD and the usefulness of using methylome‐wide association studies to uncover such candidate genes. Moreover, they offer new understanding of the impact of maltreatments on biological processes leading to diseases and may ultimately result in the identification of relevant biomarkers.

HPA axis genes may modulate the effect of childhood adversities on decision-making in suicide attempters

Decision-making impairment is found in several neuropsychiatric disorders, including suicidal behavior, and has been shown to be modulated by genes. On the other hand, early trauma have/has been associated with poor mental health outcome in adulthood, in interaction with genetic factors, possibly through sustained alterations in the hypothalamic-pituitary-adrenal axis (HPA axis). Here, we aimed to investigate the effect of childhood trauma and its interaction with HPA-axis related genes on decision-making abilities in adulthood among a sample of suicide attempters. The Iowa Gambling Task (IGT) was used to assess decision-making in 218 patients with a history of suicide attempt. Participant fulfilled the Childhood Trauma Questionnaire to report traumatic childhood experiences. Patients were genotyped for single-nucleotide polymorphisms within CRHR1 and CRHR2 genes. Patients with a history of sexual abuse had significantly lower IGT scores than non-sexually abused individuals. Polymorphisms within CRHR1 and CRHR2 genes interacted with both childhood sexual abuse and emotional neglect to influence IGT performance. In conclusion, childhood sexual abuse and emotional neglect may have long-term effects on decision-making through an interaction with key HPA axis genes. Even if these results need to be replicated in other sample, impaired decision-making may thus be the dimension through which child maltreatment, in interaction with HPA axis related genes, may have a sustained negative impact on adult mental health.

Acceptance and Commitment Therapy for Management of Suicidal Patients: A Pilot Study

(6) pharmacological treatment and number of visits for psychiatric emergencies in the previous 3 months. Self-assessments included: (1) suicidal ideation on a visual analogue scale from 0 (none) to 10 (maximum), currently and during the last 15 days; (2) depressive intensity using Beck Depression Inventory-II (BDI); (3) psycho-logical pain on a visual analogue scale from 0 (none) to 10 (maxi-mum); (4) anxiety state using the State-Trait Anxiety Inventory (STAI); (5) hopelessness during the last month using the Beck Hopelessness Scale; (6) quality of life using the World Health Or-ganization Quality of Life measure, and (7) acceptance using the Acceptance and Action Questionnaire (AAQ) [10] . Considering the small sample size and skewed distribution of most continuous variables, median (min–max) and non-paramet-ric tests were used. Friedman’s tests for quantitative variables and Cochran’s Q test for categorical variables were used to globally compare the three time points. If the global p value was p < 0.05, two-by-two comparisons were run (signed rank, McNemar’s and kappa tests) and corrected for multiple comparisons (Bonferroni correction). Spearman’s rank order correlations were applied to measure associations between continuous variables. Statistical analyses were performed using SAS software, version 9.2 (SAS In-stitute, Cary, N.C., USA). Two patients did not start the programme; 78.8% attended all sessions. ACT was reported to be helpful by 96.9% patients. One patient (suffering from borderline personality disorder) commit-ted suicide during the first month of the study, without any clear association with intervention. Sociodemographic characteristics were as follows: 57.1% males, median age 38.4 years (min–max: 18–60), 48.6% single, 60% fully employed. The majority of patients were currently depressed (94.3%), having attempted suicide the month preceding the inclu-sion (93.9%). Psychiatric disorders were unipolar (37.1%), bipolar (57.1%), anxiety (97.1%), addictive (28.6%), eating (17.1%), and/or borderline personality (20%) disorders. All participants were on psychotropic medications. There were significant differences for all scores between the three visits (p < 0.001). Between inclusion and the 1-week follow-up, there was a significant reduction of the C-SSRS ‘suicidal ide-ation’ subscore [20 (0–30) vs. 0 (0–20), respectively; p < 0.001], SSI score [7 (0–22) vs. 0 (0–10); p < 0.001] as well as intensity of current and previous suicidal ideations during the last 15 days [1 (0–10) vs. 0 (0–3), 2 (0–9) vs. 0 (0–5), respectively; both p < 0.001]. Of note, reduction in the C-SSRS ‘suicidal ideation’ subscore was cor-related to the AAQ score (p = 0.04, r = –0.37), but not to BDI and STAI scores. Between inclusion and 3-month follow-up, the re-duction of all suicidal ideation scores remained significant. There were no suicide reattempts during the follow-up period. With one million deaths every year, suicide is a major health problem worldwide. Recently, suicidal behaviour disorder (SBD) has been included in DSM-5 as an independent clinical entity [1] . It highlights the need to address the suicidal process as a primary target of concern and to identify corresponding transnosographic preventive strategies, including psychotherapy. Acceptance and Commitment Therapy (ACT), a ‘third-wave’ behavioural therapy, targets experiential avoidance (tendency to avoid unwanted thoughts or emotions) at the core of psychiatric disorders. Of note, suicidal subjects report intrusive mental images of suicide that they try to suppress, increasing in their intensity and frequency, inde-pendently from depressive symptoms [2] . Indeed, experiential avoidance would predict suicidal behaviours [3] . Moreover, two case reports have suggested the preventive role of ACT on suicidal reattempts at 1 year [4] . Thus, we aimed at examining the useful-ness of an add-on ACT group programme to decrease suicidal ide-ation in high-risk patients. The study was conducted in the Department of Psychiatric Emergency and Acute Crisis, Academic Hospital of Montpellier, France. Thirty-five outpatients suffering from a current SBD ac-cording to DSM-5 [1] (history of suicidal attempt in the past year) were included in an ACT programme ( table 1 ) [5–7] . Exclusion criteria were current mania or depressive episode with mixed fea-tures, and schizophrenia. Patients were assessed at inclusion (1 week before the pro-gramme, T0) and 1 week (T1) and 3 months (T2) after programme completion. Psychiatrists assessed: (1) suicidal ideation using the Columbia-Suicide Severity Rating Scale (C-SSRS) [8] (suicidal ide- ation subscore = severity and intensity items) and the Scale for Suicidal Ideation (SSI score) [9]; (2) psychiatric disorders using the French version of the Mini International Neuropsychiatric Inter-view; (3) borderline personality disorder using the Screening In-terview for Axis II Disorder; (4) depressive symptomatology using the Inventory of Depressive Symptomatology (IDS-C30); (5) glob-al functioning using the Functioning Assessment Short Test, and

Prefrontal cortex markers of suicidal vulnerability in mood disorders: a model-based structural neuroimaging study with a translational perspective.

The vulnerability to suicidal behavior has been modeled in deficits in both valuation and cognitive control processes, mediated by ventral and dorsal prefrontal cortices. To uncover potential markers of suicidality based on this model, we measured several brain morphometric parameters using 1.5T magnetic resonance imaging in a large sample and in a specifically designed study. We then tested their classificatory properties. Three groups were compared: euthymic suicide attempters with a past history of mood disorders and suicidal behavior (N=67); patient controls with a past history of mood disorders but not suicidal behavior (N=82); healthy controls without any history of mental disorder (N=82). A hypothesis-driven region-of-interest approach was applied targeting the orbitofrontal cortex (OFC), ventrolateral (VLPFC), dorsal (DPFC) and medial (including anterior cingulate cortex; MPFC) prefrontal cortices. Both voxel-based (SPM8) and surface-based morphometry (Freesurfer) analyses were used to comprehensively evaluate cortical gray matter measure, volume, surface area and thickness. Reduced left VLPFC volume in attempters vs both patient groups was found (P=0.001, surviving multiple comparison correction, Cohen’s d=0.65 95% (0.33–0.99) between attempters and healthy controls). In addition, reduced measures in OFC and DPFC, but not MPFC, were found with moderate effect sizes in suicide attempters vs healthy controls (Cohen’s d between 0.34 and 0.52). Several of these measures were correlated with suicidal variables. When added to mood disorder history, left VLPFC volume increased within-sample specificity in identifying attempters in a significant but limited way. Our study, therefore, confirms structural prefrontal alterations in individuals with histories of suicide attempts. A future clinical application of these markers will, however, necessitate further research.The vulnerability to suicidal behavior has been modeled in deficits in both valuation and cognitive control processes, mediated by ventral and dorsal prefrontal cortices. To uncover potential markers of suicidality based on this model, we measured several brain morphometric parameters using 1.5T magnetic resonance imaging in a large sample and in a specifically designed study. We then tested their classificatory properties. Three groups were compared: euthymic suicide attempters with a past history of mood disorders and suicidal behavior (N=67); patient controls with a past history of mood disorders but not suicidal behavior (N=82); healthy controls without any history of mental disorder (N=82). A hypothesis-driven region-of-interest approach was applied targeting the orbitofrontal cortex (OFC), ventrolateral (VLPFC), dorsal (DPFC) and medial (including anterior cingulate cortex; MPFC) prefrontal cortices. Both voxel-based (SPM8) and surface-based morphometry (Freesurfer) analyses were used to comprehensively evaluate cortical gray matter measure, volume, surface area and thickness. Reduced left VLPFC volume in attempters vs both patient groups was found (P=0.001, surviving multiple comparison correction, Cohens d=0.65 95% (0.33–0.99) between attempters and healthy controls). In addition, reduced measures in OFC and DPFC, but not MPFC, were found with moderate effect sizes in suicide attempters vs healthy controls (Cohens d between 0.34 and 0.52). Several of these measures were correlated with suicidal variables. When added to mood disorder history, left VLPFC volume increased within-sample specificity in identifying attempters in a significant but limited way. Our study, therefore, confirms structural prefrontal alterations in individuals with histories of suicide attempts. A future clinical application of these markers will, however, necessitate further research.