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Background: Corpus callosum (CC) size has been associated with cognitive and emotional deficits in a range of neuropsychiatric and mood disorders. As such deficits are also found in suicidal behavior, we investigated specifically the association between CC atrophy and suicidal behavior. Methods: We studied 435 right-handed individuals without dementia from a cohort of community-dwelling persons aged 65 years and over (the ESPRIT study). They were divided in three groups: suicide attempters (n = 21), affective control subjects (AC) (n = 180) without history of suicide attempt but with a history of depression, and healthy control subjects (HC) (n = 234). T1-weighted magnetic resonance images were traced to measure the midsagittal areas of the anterior, mid, and posterior CC. Multivariate analysis of covariance was used to compare CC areas in the three groups. Results: Multivariate analyses adjusted for age, gender, childhood trauma, head trauma, and total brain volume showed that the area of the posterior third of CC was significantly smaller in suicide attempters than in AC (p = .020) and HC (p = .010) individuals. No significant differences were found between AC and HC. No differences were found for the anterior and mid thirds of the CC. Conclusions: Our findings emphasize a reduced size of the posterior third of the CC in subjects with a history of suicide, suggesting a diminished interhemispheric connectivity and a possible role of CC in the pathophysiology of suicidal behavior. Further studies are needed to strengthen these results and clarify the underlying cellular changes leading to these morphometric differences. [Copyright &y& Elsevier]

Abstract: Background: Pre- and perinatal insults increase suicide risk. The main objective of the present study is to investigate if prematurity interacts in an additive fashion with postnatal risk factors of suicidal behavior. Method: Sample and procedure: 857 adult suicide attempters consecutively hospitalized for a suicide attempt were included. Studied characteristics of suicide attempts included use of a violent mean, age at first suicide attempt, and number of suicide attempts. Risk factors of suicidal behavior included indexes of pre- and perinatal adversity, childhood maltreatment as measured with the Childhood Trauma Questionnaire, personality traits as measured with the Tridimensional Personality Questionnaire, and family history of suicidal behavior. Statistical analyses: Comparisons between the different patterns of suicide attempts characteristics were made using logistic regression with crude and adjusted odds ratios and 95% confidence intervals. Results: The risk of violent suicide attempts increased significantly in patients born prematurely (OR [95%] = 2.38[1.12–5.08]). There were additive effects for very preterm birth and 1) emotional abuse (OR [95% CI] = 4.52 [1.75–11.60]), 2) novelty seeking (OR [95% CI] = 8.92[3.09–25.7]), and 3) harm avoidance (OR [95% CI] = 5.81 [2.43–13.90]) on the age at first suicide attempt, after adjustment for potential confounders. Conclusions: Very preterm birth appears to be the first step in a cascade of stressors across lifetime, which affects the risk and the severity of suicidal behavior. Furthermore, very preterm birth, childhood maltreatment and personality traits have additive effects that influence the age at onset of suicide attempt. Our findings may have potential consequences for preventive policies. [Copyright &y& Elsevier]

Abstract: Implication of immune processes in bipolar disorder (BD) has recently gained increasing attention. Tolerogenic molecules, among which HLA-G plays a prominent role, mediate the modulation of such processes. The HLA-G locus is characterized by a high number of polymorphisms including a functionally relevant 14 base pair (bp) insertion/deletion (Ins/Del) allele affecting the HLA-G expression. Here, we analyzed the distribution of this polymorphism in 561 BD patients and 161 healthy and found that the HLA-G 14bp Ins/Ins genotype was significantly more prevalent in healthy controls than in patients (corrected p; pc =0.032) and that the prevalence of such protective genotype is lower among patients born during the winter season as compared to those born in other periods (pc =0.006). Possible mechanisms between low HLA G expression and resistance to infections as well as potential relationships between infections in early life and susceptibility to BD are discussed. [Copyright &y& Elsevier]

Résumé: La consanguinité est une relation entre deux personnes qui partagent un ancêtre commun. Elle est habituellement définie comme le résultat d’une reproduction sexuée entre deux individus apparentés. En d’autres termes, les mariages consanguins se réfèrent à des unions contractées entre des individus biologiquement liés. Ces unions sont encore fréquentes et constituent des pratiques très répandues dans certaines régions du monde. La région la plus concernée s’étend de la rive sud de la mer méditerranée à travers le Moyen-Orient, la Mésopotamie, le Golfe persique et l’Inde subcontinentale jusqu’au sud-est de l’Asie. Sur la base des données disponibles, il apparaît que les couples apparentés au second degré ou plus et leur progéniture représentent 10,4 % de la population mondiale actuelle. Leurs conséquences sur la fréquence des maladies à déterminisme génétique sont importantes et notamment en ce qui concerne les maladies autosomales récessives. Les études de jumeaux et d’adoption et les estimations du risque de survenue de troubles mentaux chez les apparentés de sujets atteints dans les études familiales ont confirmé l’existence d’une composante génétique dans la vulnérabilité à de nombreuses affections psychiatriques. Les techniques récentes d’examen du génome entier ou étude d’association pangénomique, en anglais genome-wide association study (GWAS), permettent d’identifier de plus en plus de gènes impliqués dans les troubles mentaux majeurs tels que la schizophrénie, l’autisme et le trouble bipolaire. Les études d’épidémiologie génétique auprès de populations consanguines et/ou constituant un isolat géographique mettent en évidence une augmentation des taux de mortalité et de morbidité infantiles, de la fréquence des maladies monogéniques récessives et une concentration accrue de maladies communes multifactorielles comme les troubles psychotiques. Elles confirmeraient l’existence d’un lien significatif entre consanguinité et troubles mentaux et l’augmentation du risque au sein de la descendance des couples consanguins. Ces études sur les liens entre consanguinité et troubles psychotiques sont peu nombreuses. Les rares données dont nous disposons semblent pourtant en faveur d’une augmentation de la fréquence de la schizophrénie et des troubles bipolaires dans la descendance de parents consanguins. La découverte récente des variants génétiques rares et leurs implications dans les troubles psychotiques constituent un argument en faveur de l’hypothèse « maladie commune-variants rares ». Dans ce cadre, l’étude de familles consanguines pourrait contribuer à tester les liens entre ces variants rares et quelques phénotypes et à établir des descriptions d’associations génotype/phénotype. Le développement de techniques nouvelles en génétique moléculaire devrait favoriser de telles études. L’ensemble de ces aspects mettent en évidence l’importance de l’étude des populations consanguines dans la compréhension du rôle des déterminants génétiques dans les pathologies psychiatriques et soulignent l’intérêt du conseil génétique pour ces communautés à hauts risques de troubles mentaux. Ils peuvent permettre également la mise en place de politiques de prévention et de sensibilisation sur les risques liés aux unions consanguines. [ABSTRACT FROM AUTHOR]

Background: Pharmacogenetic studies aiming to personalize the treatment of depression are based on the assumption that response to antidepressants is a heritable trait, but there is no compelling evidence to support this. Methods: We estimate the contribution of common genetic variation to antidepressant response with Genome-Wide Complex Trait Analysis in a combined sample of 2799 antidepressant-treated subjects with major depressive disorder and genome-wide genotype data. Results: We find that common genetic variants explain 42% (SE = .180, p = .009) of individual differences in antidepressant response. Conclusions: These results suggest that response to antidepressants is a complex trait with substantial contribution from a large number of common genetic variants of small effect. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Carboxypeptidase A6 (CPA6) is a member of the A/B subfamily of M14 metallocarboxypeptidases that is expressed in brain and many other tissues during development. Recently, two mutations in human CPA6 were associated with febrile seizures and/or temporal lobe epilepsy. In this study we screened for additional CPA6 mutations in patients with febrile seizures and focal epilepsy, which encompasses the temporal lobe epilepsy subtype. Mutations found from this analysis as well as CPA6 mutations reported in databases of single nucleotide polymorphisms were further screened by analysis of the modeled proCPA6 protein structure and the functional role of the mutated amino acid. The point mutations predicted to affect activity and/or protein folding were tested by expression of the mutant inHEK293cellsandanalysis of the resultingCPA6protein. Common polymorphisms in CPA6 were also included in this analysis. Several mutations resulted in reduced enzyme activity or CPA6 protein levels in the extracellular matrix. The mutants with reduced extracellular CPA6 protein levels showed normal levels of 50-kDa proCPA6 in the cell, and this could be converted into 37-kDa CPA6 by trypsin, suggesting that protein folding was not greatly affected by the mutations. Interestingly, three of the mutations that reduced extracellular CPA6 protein levels were found in patients with epilepsy. Taken together, these results provide further evidence for the involvement of CPA6 mutations in human epilepsy and reveal additional rare mutations that inactivate CPA6 and could, therefore, also be associated with epileptic phenotypes [ABSTRACT FROM AUTHOR]

Abstract: Background: In spite of the high prevalence of suicide behaviours and the magnitude of the resultant burden, little is known about why individuals reattempt. We aim to investigate the relationships between clinical risk factors and the repetition of suicidal attempts. Methods: 1349 suicide attempters were consecutively recruited in the Emergency Room (ER) of two academic hospitals in France and Spain. Patients were extensively assessed and demographic and clinical data obtained. Data mining was used to determine the minimal number of variables that blinded the rest in relation to the number of suicide attempts. Using this set, a probabilistic graph ranking relationships with the target variable was constructed. Results: The most common diagnoses among suicide attempters were affective disorders, followed by anxiety disorders. Risk of frequent suicide attempt was highest among middle-aged subjects, and diminished progressively with advancing age of onset at first attempt. Anxiety disorders significantly increased the risk of presenting frequent suicide attempts. Pathway analysis also indicated that frequent suicide attempts were linked to greater odds for alcohol and substance abuse disorders and more intensive treatment. Conclusions: Novel statistical methods found several clinical features that were associated with a history of frequent suicide attempts. The identified pathways may promote new hypothesis-driven studies of suicide attempts and preventive strategies. [Copyright &y& Elsevier]

Background: Lipids appear to mediate depressive vulnerability in the elderly; however, sex differences and genetic vulnerability have not been taken into account in previous prospective studies. Methods: Depression was assessed in a population of 1040 women and 752 men aged 65 years and older at baseline and after 7-year follow-up. Clinical level of depression (DEP) was defined as having either a score of 16 or higher on the Centre for Epidemiology Studies Depression scale or a diagnosis of current major depression on the Mini-International Neuropsychiatric Interview. Lipid levels, apolipoprotein E, and serotonin transporter linked promoter region (5-serotonin transporter gene linked promoter region) genotypes were evaluated at baseline. Results: Multivariate analyses adjusted by sociodemographic and behavioral variables, measures of physical health including ischemic pathologies, and genetic vulnerability indicated gender-specific associations between dyslipidemia and DEP, independent of the use of lipid-lowering agents or apolipoprotein E status. Men with low low-density lipoprotein cholesterol levels had twice the risk of prevalent and incident DEP, whereas in women low high-density lipoprotein cholesterol levels were found to be significantly associated with increased prevalent DEP (odds ratio = 1.5) only. A significant interaction was observed between low low-density lipoprotein-cholesterol and 5-serotonin transporter gene linked promoter region genotype, men with s/s or s/l genotype being at increased risk of DEP (odds ratio = 6.0 and 2.7, respectively). No significant gene–environment interaction was observed for women. Conclusions: DEP is associated with higher atherogenic risk in women (low high-density lipoprotein cholesterol), whereas the reverse is observed in men (low low-density lipoprotein cholesterol). Late-life depression may have a complex gender-specific etiology involving genetic vulnerability in men. [Copyright &y& Elsevier]

Abstract: Background: Identification of patients with a bipolar disorder (BPD) among those presenting a major depressive episode is often difficult, resulting in common misdiagnosis and mistreatment. Our aim was to identify clinical variables unrelated to current depressive episode and relevant to suicidal behavior that may help to improve the detection of BPD in suicide attempters presenting with recurrent major depressive disorder. Method: 211 patients suffering from recurrent major depressive disorder or BPD, hospitalized after a suicide attempt (SA), were interviewed by semi-structured interview and validated questionnaires about DSM-IV axis I disorders, SA characteristics and a wide range of personality traits relevant to suicidal vulnerability. Multivariate logistic regression analysis was performed to determine differences between RMDD and BPD attempters. Results: Logistic regression analysis showed that serious SA and family history of suicide are closely associated with a diagnosis of BPD [respectively OR=2.28, p =0.0195; OR=2.98, p =0.0081]. The presence of both characteristics increase the association with BDP [OR=4.78, p =0.005]. Conversely, when looking for the features associated with a serious SA, BPD was the only associated diagnosis [OR=2.03, p =0.004]. Lastly, affect intensity was higher in BPD samples [OR=2.08, p =0.041]. Limitations: Retrospective nature of the study, lack of the separate analysis of bipolar subtypes. Conclusion: Serious suicide attempt and a familial history of completed suicide in patients with major depression seem to be a clinical marker of bipolarity. Facing suicide attempters with recurrent depression, clinician should be awareness to these characteristics to detect BPD. [Copyright &y& Elsevier]

Abstract: We assessed whether smoking behavior was associated with nine polymorphisms in genes coding for the nicotinic receptor subunits α-4 (rs1044394, rs1044396, rs2236196 and rs2273504), α-5 (rs16969968), β-2 (rs2072661 and rs4845378) and β-3 (rs4953 and rs6474413). We conducted an Internet survey and collected saliva by mail for DNA and cotinine analyses, in Switzerland in 2003. We conducted DNA analyses for 277 participants and cotinine analyses for 141 current daily smokers. Cotinine levels were higher in carriers of the CC genotype of CHRNA4 rs1044396 (371 ng/ml) than in those with the CT or TT genotypes (275 ng/ml, p =0.049), a difference of 0.53 standard deviation units. However, this difference was not robust to correction for multiple testing using Bonferroni adjustment. These 9 polymorphisms were not otherwise associated with smoking behavior and nicotine dependence. There were possible associations between the temperament trait novelty seeking and CHRNA4 rs1044396, CHRNA5 rs16969968 and CHRNB2 rs4845378, but these associations were not robust to correction for multiple testing. We conclude that the analysis of polymorphisms in genes coding for four nicotinic acetylcholine receptor subunits (CHRNA4, CHRNA5, CHRNB2 and CHRNB3) and several smoking-related phenotypes revealed no statistically significant association. [Copyright &y& Elsevier]

Abstract: In 1994, it was proposed that decision-making requires emotion-related signals, known as somatic markers. In contrast, some authors argued that conscious knowledge of contingencies is sufficient for advantageous decision-making. We aimed to investigate the respective roles of somatic markers and explicit knowledge in decision-making. Thirty healthy volunteers performed the Iowa Gambling Task (IGT). Conscious knowledge was assessed using a sensitive questionnaire and skin conductance responses (SCRs) were recorded. Most participants acquired a preference for advantageous choices during the task and generated larger anticipatory SCRs before disadvantageous relative to advantageous choices. Performance on the IGT and the autonomic response were positively correlated (r =0.38, p =0.045). Moreover, there was a statistically significant difference in performance according to conscious awareness (p =0.009). There was no significant association between level of explicit knowledge and SCR (p =0.1). Finally, we did not find any interaction between explicit knowledge and performance although a lack of statistical power is not to be excluded. Advantageous decision-making therefore seems to be associated with two distinct, namely implicit and explicit, systems. [Copyright &y& Elsevier]

Abstract: Background: Decision-making has been found to be altered in suicide attempters and may represent a neuropsychological trait of vulnerability to suicidal behaviour. Environmental stressors such as adverse life events and interpersonal problems have been demonstrated to precipitate suicidal acts in vulnerable people. However, the link between vulnerability and stressors is complex and may even be circular. In the present study, we hypothesized that impaired decision-making may be associated with an increased risk of negative life events in suicide attempters. Methods: Forty-eight patients with a history of attempted suicide were assessed with the Iowa Gambling Task and interviewed regarding life events experienced over the past 12 months. Results: Decision-making performance was negatively correlated with interpersonal difficulties in the affective – namely marital and family – domain (rs=−0.39, p =0.006) but not with interpersonal difficulties in other social contexts, stressful life events or somatic health problems. Limitations: The relatively small sample size and the use of non-parametric methods may lead to a risk of type II errors. Furthermore, data on life events were retrospectively collected. Conclusions: Altered decision-making may increase the risk of problematic affective relationships. These results underline the complex and possibly reciprocal link between environmental stress factors and cognitive vulnerability traits. This could be useful for the design of intervention strategies for suicidal behaviour. [Copyright &y& Elsevier]

Background: Past studies in the neurobiology of suicide have reported alterations in serotonin and downstream effectors, such as Akt/protein kinase B. In this study, we aimed to examine possible abnormality in the Akt/glycogen synthase kinase-3β (GSK-3β) axis of depressed suicide victims’ brains. Methods: Twenty suicide victims and 20 drug-free non-suicide subjects were included for a postmortem study. The ventral prefrontal cortex area (BA’11) was used, and antemortem diagnoses of major depression disorder (MDD) (DSM-IV) were made from Institution’s records. The protein levels of GSK-3α/β and Akt-1 were assayed with the Western blot method, and the kinase activity of Akt and GSK-3α/β were determined by phosphorylation of specific substrates. Results: There was no change either in GSK-3α/β and Akt-1 protein levels or in lithium-inhibitable total GSK-3α/β enzyme activity of the ventral prefrontal cortex. The enzyme activity of Akt decreased significantly [analysis of variance (ANOVA): F(3,36) = 5.372; p = .003], whereas GSK-3β activity increased significantly [ANOVA: F(3,36) = 8.567; p = .002] in depressed suicide victims and non-suicide subjects but not in non-depressed suicide victims. Conclusions: This study indicated that the activity rather than the protein levels of Akt and GSK-3β was altered. The alteration was associated with MDD rather than with suicide per se. [Copyright &y& Elsevier]

: BackgroundIn the first year following a suicide attempt, patients are at high risk for reattempt and for completed suicide. We aim to determine the predictive value of two serotonin-related genes, the tryptophan hydroxylase (TPH) and serotonin transporter (5-HTTLPR) genes that have been involved in the susceptibility to suicidal behavior.: MethodsAfter a one-year follow-up study of 103 patients hospitalized after a suicide attempt, patients have been genotyped for both the A218C TPH and the functional S/L 5-HTTLPR polymorphisms.: ResultsPatients who reattempted suicide during the follow-up period had significantly higher frequencies of the S allele and the SS genotype. The odds ratio for the SS genotype vs. the LL genotype was 6.5 (95% CI [1.18–35.84]). No difference was observed for TPH gene. Patients carrying the SS genotype were more impulsive. However, multivariate analysis suggested an independent effect of both the SS genotype and impulsivity on the risk of repeated suicide attempts.: ConclusionsThese results suggest that the 5-HTTLPR SS genotype is associated with further suicide attempts among patients who have previously attempted suicide. [Copyright &y& Elsevier]

Abstract: Modification of the effect of life events on risk of depression by a polymorphism in the serotonin transporter gene promoter (5-HTTLPR) has been reported in child, adolescent, adult and elderly populations. Replication attempted on data collected from 1421 individuals aged 65 and over from a French community study provided no evidence of a similar modifying effect. In the only analysis known to the authors to be carried out in an exclusively elderly, European population, this null finding remained consistent after restriction of analysis to prevalent or incident cases. [Copyright &y& Elsevier]

Background: It was recently reported that a rare functional variant, R441H, in the human tryptophan hydroxylase-2 gene (hTPH2) could represent an important risk factor for unipolar major depression (UP) since it was originally found in 10% of UP patients (vs. 1.4% in control subjects). Methods: We explored the occurrence of this variation in patients with affective disorders (n = 646), autism spectrum disorders (n = 224), and obsessive-compulsive disorder (OCD) (n = 201); in healthy volunteers with no psychiatric disorders (n = 246); and in an ethnic panel of control individuals from North Africa, Sub-Saharan Africa, India, China, and Sweden (n = 277). Results: Surprisingly, we did not observe the R441H variant in any of the individuals screened (3188 independent chromosomes). Conclusions: Our results do not confirm the role of the R441H mutation of the hTPH2 gene in the susceptibility to UP. The absence of the variant from a large cohort of psychiatric patients and control subjects suggests that the findings reported in the original study could be due to a genotyping error or to stratification of the initial population reported. Additional data by other groups should contribute to the clarification of the discrepancy between our results and those previous published. [Copyright &y& Elsevier]