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It would be beneficial to find genetic predictors of antidepressant response to help personalise treatment of major depressive disorder (MDD). Rare copy number variants (CNVs) have been implicated in several psychiatric disorders, including MDD, but their role in antidepressant response has yet to be investigated. CNV data were available for 1565 individuals with MDD from the NEWMEDS (Novel Methods leading to New Medications in Depression and Schizophrenia) consortium with prospective data on treatment outcome with either a serotonergic or noradrenergic antidepressant. No association was seen between the presence of CNV (rare or common), the overall number of CNVs or genomic CNV 'burden' and antidepressant response. Specific CNVs were nominally associated with antidepressant response, including 15q13.3 duplications and exonic NRXN1 deletions. These were associated with poor response to antidepressants. Overall burden of CNVs is unlikely to contribute to personalising antidepressant treatment. Specific CNVs associated with antidepressant treatment require replication and further study to confirm their role in the therapeutic action of antidepressant.

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BACKGROUND: Extremely high rates of suicide localized within subgroups of populations where suicide is rare have been reported. We investigated this intriguing observation in a population of South-East Asia, where local culture should theoretically be preventative of suicide. METHOD: A team including an anthropologist and a psychiatrist surveyed all cases of suicide that had occurred over 10 years in four isolated regions. A psychological autopsy was carried out comparing each suicide case with two matched control cases. RESULTS: In a region of 1192 inhabitants, 16 suicides occurred, leading to an annual suicide rate of 134/1,000,00 which is 10 times the rate in the USA or Canada. By contrast, three ethnically similar distant communities showed low to null rates. The gender ratio was three males to one female and two-thirds of cases were aged below 35 years. Methods of suicide were poisoning and hanging and motives mainly included interpersonal discord. The pattern of developmental and clinical risk factors was somewhat different from Western countries, showing no childhood maltreatment, only one case of alcohol/substance abuse and impulsive-aggressive personality but elevated rates of social anxiety. Suicide cases had very high frequencies of second-degree biological relatives who committed suicide. CONCLUSIONS: Our study confirms a persistent phenomenon of high suicide rates restricted to a subgroup of a pre-industrialized population. We hypothesized this might be explained by isolation and endogamy, which may have promoted the selection/amplification of genetic vulnerability factors, or a contagion effect. These findings shed light on suicide from both a singular and a universal perspective, suggesting that particular local conditions may significantly modulate the rate of this complex behavior.

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Focal epilepsy (FE) is one of the most common forms of adult epilepsy and is usually regarded as a multifactorial disorder. Febrile seizures (FS) often appear during childhood in a subtype of FE patients, i.e. with temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS). FS are the most common human convulsive event associated with fever. Genetic evidences for FS have suggested a complex mode of inheritance. Until now, to investigate genes at the genomic level, linkage analysis of familial forms and association studies have been performed, but nothing conclusive has been clearly related to FE and FS. As complex disorders, environmental factors might play a crucial role through epigenetic modification of key candidate genes such as CPA6, which encodes Carboxypeptidase A6, an extracellular protein. Therefore, we assessed DNA methylation in promoter of CPA6. In 186 FE patients and 92 FS patients compared to 93 healthy controls and 42 treated controls with antiepileptic drugs (AEDs), we found significant higher levels of methylation for epileptic patients. Methylation status were 3.4% (±3.2%) for FE cases and 4.3% (±3.5%) for FS cases, whereas healthy individuals and treated controls with AEDs showed a level of 0.8% (±2.9%) and 1.5% (±3.9%), respectively (p≤0.001 for all comparisons). These results let growing evidence for DNA methylation involvment in FE and FS.

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Functional imaging studies have revealed differential brain activation patterns in attention deficit hyperactivity disorder (ADHD) adult patients performing working memory (WM) tasks. The existence of alterations in WM-related cortical circuits during childhood may precede executive dysfunctions in this disorder in adults. To date, there is no study exploring the electrophysiological activation of WM-related neural networks in ADHD. To address this issue, we carried out an electroencephalographic (EEG) activation study associated with time-frequency (TF) analysis in 15 adults with ADHD and 15 controls performing two visual N-back WM tasks, as well as oddball detection and passive fixation tasks. Frontal transient (phasic) theta event-related synchronization (ERS, 0-500 msec) was significantly reduced in ADHD as compared to control subjects. Such reduction was equally present in a task-independent manner. In contrast, the power of the later sustained (∼500-1200 msec) theta ERS for all tasks was comparable in ADHD and control groups. In active WM tasks, ADHD patients displayed lower alpha event-related desynchronization (ERD, ∼200-900 msec) and higher subsequent alpha ERS (∼900-2400 msec) compared to controls. The time course of alpha ERD/ERS cycle was modified in ADHD patients compared to controls, suggesting that they are able to use late compensatory mechanisms in order to perform this WM task. These findings support the idea of an ADHD-related dysfunction of neural generators sub-serving attention directed to the incoming visual information. ADHD cases may successfully face WM needs depending on the preservation of sustained theta ERS and prolonged increase of alpha ERS at later post-stimulus time points.

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Downregulation of brain-derived neurotrophic factor (BDNF) gene expression with corresponding increased methylation at specific promoters has been associated with stressful experiences in early life and may explain later adulthood psychopathology. We measured the percentage of methylation at BDNF CpG exons I and IV as well as plasma BDNF protein levels in 115 subjects with borderline personality disorder (BPD) and 52 controls. BPD subjects then underwent a 4-week course of intensive dialectical behavior therapy (I-DBT). BDNF methylation status and protein levels were re-assessed at the end of treatment. BPD subjects had significantly higher methylation status in both CpG regions than controls. In addition, the higher the number of childhood trauma, the higher was the methylation status. In BPD subjects, BDNF methylation significantly increased after I-DBT. Nonresponders accounted for the majority of this increase, whereas responders showed a decrease in methylation status over time. Accordingly, the changes in methylation status over time were significantly associated with changes in depression scores, hopelessness scores and impulsivity. No association was found between protein levels and BDNF methylation status. We here found a relationship between child maltreatment and higher DNA methylation of BDNF. These results moreover support the idea that these epigenetic marks may be changed through psychotherapeutic approaches and that these changes underline changes in cognitive functions.

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BACKGROUND: Family history of suicidal behavior and personal history of childhood trauma are risk factors for suicidal behaviors. We hypothesize that subjects with any of these risk factors will show differential features and that subjects with both of them will display more severe phenotypes. METHODS: This study compares three groups of suicide attempters (n=878): subjects with a family history of suicidal behavior and a personal history of early traumatic experiences, subjects with a family history of suicidal behavior or a personal history of early traumatic experiences, and subjects with neither of these two risk factors, with regards to psychopathology, personality traits and suicidal behavior. RESULTS: Subjects with a family history of suicidal behavior and childhood trauma were younger at their first suicide attempt and made more frequent, severe and violent attempts when compared with the other groups. Differences in number and precocity of attempts remained after adjustments in a multinomial regression model. Finally, personality profiles were also substantially different in the group with higher impulsiveness, novelty seeking, affective lability and hopelessness. LIMITATIONS: The information provided by subjects regarding childhood abuse and family history of suicidal behavior was not confirmed by other sources. CONCLUSIONS: Suicide attempters with a family history of suicidal behavior and childhood trauma show specific characteristics that might be used to prevent future suicidal behaviors in this population. Both risk factors should be routinely investigated when assessing the suicidal risk of a patient.

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Childhood maltreatment and genes underlie vulnerability to suicidal behaviours (SB), possibly by affecting the constitution of endophenotypes such as anger traits. The CREB protein has been implicated in antidepressant response, suicide and mood disorders in general. The aim of this study was to investigate if CREB1 gene is associated with SB and/or anger-related traits and if these associations are modulated by childhood maltreatment. Five hundred and thirty-four male suicide attempters and 357 male non-suicide attempters were genotyped for several polymorphisms within CREB1 gene. Four hundred and thirty-seven (156 non-suicide attempters and 281 suicide attempters) completed the State-Trait Anger Expression Inventory (STAXI) and 288 (265 suicide attempters and 23 controls) fulfilled the Childhood Trauma Questionnaire (CTQ). In total, 72 males had experienced childhood sexual abuse. Our results did not show any significant association between CREB1 and suicide behaviour. We found a significant interaction showing that CREB1 rs4675690 polymorphism modulated the effect of childhood sexual abuse on adulthood anger-out levels (P = 0.003). Sexually abused subjects carrying the CC genotype showed higher anger-out scores than T allele carriers, whereas no difference was observed in non-sexually abused subjects. CREB1 rs4675690 polymorphism modulates the association between childhood sexual abuse and adulthood anger-trait level. This is, to our knowledge, the first study to show such an interaction and to highlight the main effect of this gene on modulating the effect of child abuse on psychopathologies and warrant further investigation on this topic.

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We report a Tunisian patient born from consanguineous marriage affected with progressive myoclonus epilepsy and cognitive decline, consistent with the diagnosis of Lafora disease. Genetic analysis showed a novel c.659 T>A mutation on exon 3 of the EPM2A gene, converting a leucine to a glutamine residue at amino acid position 220 (p.Leu220Gln), in the dual-specificity phosphatase domain.

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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 1(F) 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.

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OBJECTIVE: A better understanding of the pathophysiology of suicidal behaviour (SB) may enable the discovery of more specific treatments and a better identification of vulnerable patients. The vulnerability to SB appears to be underlied by genetic factors coding for traits rendering the individual less able to cope with stressing situations, and more likely to be engaged in a suicidal process. METHOD: During the recent years, neuroscientific studies begun to identify potential endophenotypes. RESULTS: We have shown that disadvantageous decision making (DM) was involved in the vulnerability to SB. DM impairment appears to be independent of comorbid psychiatric disorders, associated with emotional dysregulation (i.e. affective lability trait and skin conductance responses), and modulated by serotonergic genotypes associated with SB. In recent fMRI studies, the region that is likely involved in DM, is overactivited in response to angry faces, suggesting a higher sensitivity to specific negative social stimuli. Deficit in risk evaluation and excessive response to specific emotional stimuli may represent key processes in the vulnerability to SB. CONCLUSIONS: These potential endophenotypes may represent future relevant markers of vulnerability for the identification of vulnerable patients, and relevant targets for the development of new treatments.

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The AKT1 gene has been associated with the genetic aetiology of schizophrenia. Following the overlap model of bipolar disorder and schizophrenia, we aimed to investigate AKT1 genetic variants and protein expression in both diseases. A total of 679 subjects with European ancestry were included: 384 with schizophrenia, 130 with bipolar disorder and 165 controls. Six single nucleotide polymorphisms (SNPs) were investigated for association with the diseases using single- and multi-locus analyses. AKT1 and AKT2 protein levels were measured in post-mortem brain tissues from ante-mortem diagnosed schizophrenia (n = 30) and bipolar disorder subjects (n = 12) and matched controls. The analysis identified a significant global distortion in schizophrenia (P = 0.0026) and a weak association in bipolar disorder (P = 0.046). A sliding window procedure showed a five-SNP haplotype (TCGAG) to be associated with schizophrenia (P = 1.22 x 10(-4)) and bipolar disorder (P = 0.0041) and a four-SNP haplotype (TCGA) with the combined sample (1.73 x 10(-5)). On the basis of selected genotypes, a significant difference in protein expression emerged between subjects (P < 0.02). In conclusion, our findings, by showing the involvement of the AKT1 gene in both schizophrenia and bipolar disorder, support the role of AKT1 in the genetics of both disorders and add support to the view that there is some genetic overlap between them.

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Juvenile myoclonic epilepsy (JME) is the most common form of idiopathic generalized epilepsies (IGE) that account for about 5-10% of all types of epilepsies. The first putative locus termed EJM1 is on the human leucocyte antigen (HLA-II) region of chromosome 6p21.3. Interestingly, the EJM1 region includes the Transporter associated with antigen processing 1 (TAP-1) gene encoding the TAP-1, and previous studies have reported associations between HLA-II polymorphisms and different types of epilepsy. In this study, we report an association between two TAP-1 functional polymorphisms the I333V and the D637G and most common IGE in Tunisian population, but we fail to find significant results in Caucasian with JME.

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Anger-related traits are regulated by genes as well as early environmental factors. Both childhood maltreatment and genes underlie vulnerability to suicidal behaviors, possibly by affecting the constitution of intermediate phenotypes such as anger traits. The aim of this study was to test the interaction between nine candidate genes and childhood maltreatment in modulating anger-related traits in 875 adult suicide attempters. The State-Trait Anger Expression Inventory and the Childhood Trauma Questionnaire were used to examine anger traits and traumatic childhood experiences, respectively. The functional polymorphism of the catecholamine-O-methyl-transferase (COMT) gene Val158Met significantly modulated the association between sexual abuse and anger-trait level (P = 0.001). In the presence of sexual abuse, individuals carrying the Val high-activity allele displayed greater disposition toward anger than individuals homozygous for the Met allele (P = 0.0003). Notably, none of the serotonin-related genes influenced the effect of childhood abuse on anger traits. The results of the present study suggest that anger-trait level is influenced by the interaction between childhood abuse and functional polymorphism in the COMT gene. This study was carried out in a population with a high frequency of childhood abuse and a high disposition toward anger, and replication in healthy subjects is needed.

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A genetic association between the tryptophan hydroxylase gene (TPH)-1 A218C polymorphism and suicidal behaviour is supported by numerous case-control studies as well as recent meta-analyses. Some data suggest that this polymorphism could also influence individual differences in anger-related personality traits, a phenotype partially under genetic control and known to increase the risk of suicide ideation and attempt. The aim of the present study was to investigate whether the TPH-1 A218C polymorphism affected anger-related personality traits in suicide attempters (n = 544). We hypothesized that suicide attempters carrying the AA genotype would display different scores on a scale measuring anger-related traits compared with suicide attempters carrying the CC genotype. Indeed, the dimension of Anger Control was significantly affected by the TPH-1 A218C polymorphism: suicide attempters carrying the AA genotype scored significantly lower on the Anger Control subscale than suicide attempters carrying the AC and CC genotypes. This polymorphism did not display any influence on the other State-Trait Anger Expression Inventory subscales. This result confirms our working hypothesis and suggests that the TPH-1 genotype could confer a vulnerability to suicidal behaviour through a reduced capacity to control anger, which in turn may represent a common psychopathological and behavioural pathway to suicidal behaviour in an important subgroup of clinical subjects.

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BACKGROUND AND OBJECTIVE: Childhood trauma and aggressive traits are considered risk factors for suicidal behavior. The hypothesis we aimed to test in this study was the existence of an association between childhood trauma and aggression in two distinct samples of Italian and French suicide attempters. METHOD: Study participants comprise 587 subjects with different psychiatric diagnoses according to DSM-IV-TR criteria. Three different samples were analyzed and compared: a group of French suicide attempters (N=396; mean age 40.47 SD=13.52; M/F: 110/286); a group of Italian suicide attempters (N=103; mean age 38.60 SD=12.04; M/F 27/76) and an Italian psychiatric comparison group (N=88; mean age: 41.49 SD=12.05; M/F; 37/51). Patients were interviewed with the Brown-Goodwin Assessment for Lifetime History of Aggression (BGLHA) and the Childhood Trauma Questionnaire (CTQ) 34-items for Italian data and 28-items for French data. RESULTS: When compared with the comparison group, Italian suicide attempters had significantly higher scores on the BGLHA scale and reported higher scores on the CTQ scores for physical abuse, sexual abuse and emotional abuse. Significant correlations between childhood trauma and aggression were found in both groups, Italian and French, of suicide attempters. CONCLUSION: The hypothesis tested was supported as psychiatric patients who had attempted suicide reported significantly more childhood trauma and aggression. Significant correlations were found between aggressive behavior, and childhood trauma in suicidal patients. This finding was replicated in two independently recruited samples in two countries with different prevalence of suicidal behavior.

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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.

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OBJECTIVE: Decision-making impairment is an important feature of psychiatric disorders. In a large comorbid psychiatric population, we explored the link between decision-making deficit and clinical variables. METHOD: We used the Iowa Gambling Task to measure decision-making in 317 patients. Psychiatric diagnoses were made according to the DSM-IV criteria. Self-questionnaires were used to assess several personality traits. The last and most severe suicidal acts were characterized. RESULTS: (1) After controlling for age and medication intake, a past history of suicide attempt (OR=2.0 [1.1-3.8]) and normothymic bipolar disorders (OR=3.4 [1.1-10.5]) were significantly and independently associated with impaired decision-making. (2) Decision-making performance was significantly correlated with affective lability. (3) No association was found between decision-making skills and suicidal characteristics. DISCUSSION: A lack of statistical power may have masked associations with obsessive-compulsive disorder and anorexia nervosa. We did not control for other cognitive functions except attention. CONCLUSION: This study supports the independent association of decision-making impairment with vulnerability to suicidal behaviour but not with substance abuse. Normothymic bipolar disorders, but not unipolar disorders, were also linked to low performance. At the dimensional level, impulsivity and decision-making abilities may be distinct processes. Affective regulation skills appear to be a major influence on decision-making performance and following a relevant therapeutic target.

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Preliminary studies suggested that age at onset (AAO) may help to define homogeneous bipolar affective disorder (BPAD) subtypes. This candidate symptom approach might be useful to identify vulnerability genes. Thus, the probability of detecting major disease-causing genes might be increased by focusing on families with early-onset BPAD type I probands. This study was conducted as part of the European Collaborative Study of Early Onset BPAD (France, Germany, Ireland, Scotland, Switzerland, England, Slovenia). We performed a genome-wide search with 384 microsatellite markers using non-parametric linkage analysis in 87 sib-pairs ascertained through an early-onset BPAD type I proband (AAO of 21 years or below). Non-parametric multipoint analysis suggested eight regions of linkage with P-values<0.01 (2p21, 2q14.3, 3p14, 5q33, 7q36, 10q23, 16q23 and 20p12). The 3p14 region showed the most significant linkage (genome-wide P-value estimated over 10 000 simulated replicates of 0.015 [0.01-0.02]). After genome-wide search analysis, we performed additional linkage analyses with increased marker density using markers in four regions suggestive for linkage and having an information contents lower than 75% (3p14, 10q23, 16q23 and 20p12). For these regions, the information content improved by about 10%. In chromosome 3, the non-parametric linkage score increased from 3.51 to 3.83. This study is the first to use early-onset bipolar type I probands in an attempt to increase sample homogeneity. These preliminary findings require confirmation in independent panels of families.

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