Philippe Courtet

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.

ALGOS: the development of a randomized controlled trial testing a case management algorithm designed to reduce suicide risk among suicide attempters.

BackgroundSuicide attempts (SA) constitute a serious clinical problem. People who attempt suicide are at high risk of further repetition. However, no interventions have been shown to be effective in reducing repetition in this group of patients.Methods/DesignMulticentre randomized controlled trial.We examine the effectiveness of «ALGOS algorithm»: an intervention based in a decisional tree of contact type which aims at reducing the incidence of repeated suicide attempt during 6 months. This algorithm of case management comprises the two strategies of intervention that showed a significant reduction in the number of SA repeaters: systematic telephone contact (ineffective in first-attempters) and «Crisis card» (effective only in first-attempters). Participants who are lost from contact and those refusing healthcare, can then benefit from «short letters» or «postcards».DiscussionALGOS algorithm is easily reproducible and inexpensive intervention that will supply the guidelines for assessment and management of a population sometimes in difficulties with healthcare compliance. Furthermore, it will target some of these subgroups of patients by providing specific interventions for optimizing the benefits of case management strategy.Trial RegistrationThe study was registered with the ClinicalTrials.gov Registry; number: NCT01123174.

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.

A genome-wide association study of anorexia nervosa

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge–purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10−7) in SOX2OT and rs17030795 (P=5.84 × 10−6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10−6) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10−6) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10−6), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.

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.

The neuroscience of suicidal behaviors: what can we expect from endophenotype strategies?

Vulnerability to suicidal behavior (SB) is likely mediated by an underlying genetic predisposition interacting with environmental and probable epigenetic factors throughout the lifespan to modify the function of neuronal circuits, thus rendering an individual more likely to engage in a suicidal act. Improving our understanding of the neuroscience underlying SBs, both attempts and completions, at all developmental stages is crucial for more effective preventive treatments and for better identification of vulnerable individuals. Recent studies have characterized SB using an endophenotype strategy, which aims to identify quantitative measures that reflect genetically influenced stable changes in brain function. In addition to aiding in the functional characterization of susceptibility genes, endophenotypic research strategies may have a wider impact in determining vulnerability to SB, as well as the translation of human findings to animal models, and vice versa. Endophenotypes associated with vulnerability to SB include impulsive/aggressive personality traits and disadvantageous decision making. Deficits in realistic risk evaluation represent key processes in vulnerability to SB. Serotonin dysfunction, indicated by neuroendocrine responses and neuroimaging, is also strongly implicated as a potential endophenotype and is linked with impulsive aggression and disadvantageous decision making. Specific endophenotypes may represent heritable markers for the identification of vulnerable patients and may be relevant targets for successful suicide prevention and treatments.

Impulsivity, aggression and suicidal behavior in unipolar and bipolar disorders

BACKGROUND Predictors of suicidal behaviors (SB) in bipolar (BD) and major depressive disorder (MDD) patients are poorly understood. It has been recognized that behavioral dysregulation characterizes SB with traits of impulsivity and aggression being particularly salient. However, little is known about how these traits are segregated among mood disorder patients with and without a history of suicide attempt (SA). METHODS This article aims to compare impulsivity and aggression between 143 controls, 138 BD and 186 MDD subjects with or without a history of SA. RESULTS BD and MDD patients showed higher impulsivity scores (BIS-10 = 57.9 vs. 44.7, p < 0.0001) and more severe lifetime aggression than controls (Lifetime History of Aggression = 7.3 vs. 3.9, p < 0.0001). Whereas impulsivity helped to distinguish MDD subjects without a history of SA from those with such a history, this was not the case in BD subjects where no difference in impulsive traits was observed between BD without and with history of SA (57.2 vs. 63.2 for BIS-10; p = 0.259). Impulsive and aggressive traits were strongly correlated in suicide attempters (independently of the diagnosis) but not in non-suicide attempters. LIMITATIONS Dimensional traits were not characterized at different stages of illness. CONCLUSIONS Impulsivity, as a single trait, may be a reliable suicide risk marker in MDD but not in BD patients, and its strong correlation with aggressive traits seems specifically related to SB. Our study therefore suggests that the specific dimension of impulsive aggression should be systematically assessed in mood disorder patients to address properly their suicidal risk.

Is it valid to measure suicidal ideation by depression rating scales

OBJECTIVE To date, most researchers rely on suicidal items of scales primarily designed to measure depression severity to capture suicidal ideation (SI). This study aims at investigating how well the suicide item of the clinician rated Hamilton Scale for Depression (HAM-D) and principal factors derived from this scale correlate with SI scores derived from a well validated measure of SI: the Becks scale for SI (SSI). METHOD 281 suicide attempters consecutively hospitalized between 2007 and 2009 were assessed by using the SSI, the HAM-D and the self-report Beck Depression Inventory (BDI). Principal Component Analysis (PCA) was computed to extract main factors. Correlations between these factors, BDIs and HAM-Ds suicide items and the SSI scores were then computed. RESULTS Three components were derived from the PCA. Factor 2 showed a major loading for the HAM-D suicide item. Both the HAM-D suicide item and Factor 2 positively correlated with the SSI total score (both p<0.00001). Moreover, the BDI suicide item highly correlated with the Factor 2 (p<0.001) and the SSI total score (p<0.00001). Finally, the HAM-D suicide item correlated significantly with the number of suicide attempts (p=0.0001) and the age at the first attempt (p=0.002). LIMITATIONS Our sample was heterogeneous and future studies should refine the taxonomy of the suicidal behavior in specific sub-populations. The study design was cross-sectional and replication in a prospective study is needed. CONCLUSION These findings suggest that the use of a single suicide item or a dimensional factor derived from a depression scale might be a valid approach to assess the suicidal ideations. Moreover, the results suggest that clinician rated scales as well as self-report questionnaires are equally valid to do so.

Interaction between BDNF Val66Met and childhood trauma on adult's violent suicide attempt.

Genetic factors, specially those related to serotoninergic activities, and childhood maltreatment have both been implicated in suicidal behaviour (SB). However, little attention has been paid to the possible interaction between genes and childhood maltreatment in the comprehension of SB. Brain‐derived neurotrophic factor (BDNF) plays an important role in the growth of serotoninergic neurons during childhood and therefore is a good candidate for studies on SB. Moreover, decreased levels of BDNF have been found in the prefrontal cortex of suicide victims. In our study we wanted to see if Val66Met (a BDNF functional single‐nucleotide polymorphism) could moderate the effect of childhood maltreatment on the onset, number and violence of SB in a sample of 813 Caucasian suicide attempters. Childhood maltreatment was evaluated using the Childhood Trauma Questionnaire. We used a regression framework to test the interaction between Val66Met and childhood maltreatment. Childhood sexual abuse was associated with violent suicide attempts (SA) in adulthood only among Val/Val individuals and not among Val/Met or Met/Met individuals (P = 0.05). The severity of childhood maltreatment was significantly associated with a higher number of SA and with a younger age at onset of suicide attempt. This result suggests that Val66Met modulates the effect of childhood sexual abuse on the violence of SB. It is proposed that childhood sexual abuse elicits brain structural modifications through BDNF dysfunction and enhances the risk of violent SB in adulthood.

Prefrontal cortex dysfunction in patients with suicidal behavior

BACKGROUND Abnormal serotonergic neurotransmission has long been demonstrated in suicidal behavior. The dorsal and median raphe nuclei housing the main serotonergic cell bodies and the prefrontal cortex (PFC), particularly the ventral part innervated by the serotonergic system, have therefore been studied extensively in suicidal behavior research. However, only a few studies have described neuropsychological function impairment in suicidal patients. We investigated PFC-related neuropsychological function in patients with suicidal behavior, separating dorsolateral PFC (DLPFC)- and orbitofrontal cortex (OFC)-related functions. METHOD We compared 30 euthymic patients with suicidal behavior aged 18-65 years with 39 control subjects, for the following neuropsychological domains: global intellectual functioning, reward sensitivity, initiation, inhibition, and working memory. Patients and controls were compared by means of univariate and multivariate analyses, adjusting for age at interview, level of education and mood state at the time of evaluation. Trait impulsivity, measured with the Barratt Impulsivity Scale version 10 (BIS-10), was also included as a covariate in a subset of analyses. RESULTS Multivariate comparisons demonstrated significant executive function deficits in patients with suicidal behavior. In particular, we observed impairment in visuospatial conceptualization (p<0.0001), spatial working memory (p=0.001), inhibition (Hayling B-A, p=0.04; go anticipations, p=0.01) and visual attention (or reading fluency) (p=0.002). Similar results were obtained following adjustment for motor impulsivity as a covariate, except for spatial working memory. CONCLUSIONS These deficits are consistent with prefrontal dysfunction in patients with suicidal behavior. Differentiation between DLPFC- and OFC-related neuropsychological functions showed no specific dysfunction of the orbitofrontal region in patients with suicidal behavior in our sample.