Gustavo Turecki

Maternal care influences hypothalamic-pituitary-adrenal (HPA) function in the rat through epigenetic programming of glucocorticoid receptor expression. In humans, childhood abuse alters HPA stress responses and increases the risk of suicide. We examined epigenetic differences in a neuron-specific glucocorticoid receptor (NR3C1) promoter between postmortem hippocampus obtained from suicide victims with a history of childhood abuse and those from either suicide victims with no childhood abuse or controls. We found decreased levels of glucocorticoid receptor mRNA, as well as mRNA transcripts bearing the glucocorticoid receptor 1F splice variant and increased cytosine methylation of an NR3C1 promoter. Patch-methylated NR3C1 promoter constructs that mimicked the methylation state in samples from abused suicide victims showed decreased NGFI-A transcription factor binding and NGFI-A-inducible gene transcription. These findings translate previous results from rat to humans and suggest a common effect of parental care on the epigenetic regulation of hippocampal glucocorticoid receptor expression.

Although it is known that the methylation of DNA in 5' promoters suppresses gene expression, the role of DNA methylation in gene bodies is unclear. In mammals, tissue- and cell type-specific methylation is present in a small percentage of 5' CpG island (CGI) promoters, whereas a far greater proportion occurs across gene bodies, coinciding with highly conserved sequences. Tissue-specific intragenic methylation might reduce, or, paradoxically, enhance transcription elongation efficiency. Capped analysis of gene expression (CAGE) experiments also indicate that transcription commonly initiates within and between genes. To investigate the role of intragenic methylation, we generated a map of DNA methylation from the human brain encompassing 24.7 million of the 28 million CpG sites. From the dense, high-resolution coverage of CpG islands, the majority of methylated CpG islands were shown to be in intragenic and intergenic regions, whereas less than 3% of CpG islands in 5' promoters were methylated. The CpG islands in all three locations overlapped with RNA markers of transcription initiation, and unmethylated CpG islands also overlapped significantly with trimethylation of H3K4, a histone modification enriched at promoters. The general and CpG-island-specific patterns of methylation are conserved in mouse tissues. An in-depth investigation of the human SHANK3 locus and its mouse homologue demonstrated that this tissue-specific DNA methylation regulates intragenic promoter activity in vitro and in vivo. These methylation-regulated, alternative transcripts are expressed in a tissue- and cell type-specific manner, and are expressed differentially within a single cell type from distinct brain regions. These results support a major role for intragenic methylation in regulating cell context-specific alternative promoters in gene bodies.

Suicide is a complex public health problem of global importance. Suicidal behaviour differs between sexes, age groups, geographic regions, and sociopolitical settings, and variably associates with different risk factors, suggesting aetiological heterogeneity. Although there is no effective algorithm to predict suicide in clinical practice, improved recognition and understanding of clinical, psychological, sociological, and biological factors might help the detection of high-risk individuals and assist in treatment selection. Psychotherapeutic, pharmacological, or neuromodulatory treatments of mental disorders can often prevent suicidal behaviour; additionally, regular follow-up of people who attempt suicide by mental health services is key to prevent future suicidal behaviour.

It is well known that most suicide cases meet criteria for a psychiatric disorder. However, rates of specific disorders vary considerably between studies and little information is known about gender and geographic differences. This study provides overall rates of total and specific psychiatric disorders in suicide completers and presents evidence supporting gender and geographic differences in their relative proportion. We carried out a review of studies in which psychological autopsy studies of suicide completers were performed. Studies were identified by means of MEDLINE database searches and by scanning the reference list of relevant publications. Twenty-three variables were defined, 16 of which evaluating psychiatric disorders. Mantel-Haenszel Weighted Odds Ratios were estimated for these 16 outcome variables. Twenty-seven studies comprising 3275 suicides were included, of which, 87.3% (SD 10.0%) had been diagnosed with a mental disorder prior to their death. There were major gender differences. Diagnoses of substance-related problems (OR = 3.58; 95% CI: 2.78–4.61), personality disorders (OR = 2.01; 95% CI: 1.38–2.95) and childhood disorders (OR = 4.95; 95% CI: 2.69–9.31) were more common among male suicides, whereas affective disorders (OR = 0.66; 95% CI: 0.53–0.83), including depressive disorders (OR = 0.53; 95% CI: 0.42–0.68) were less common among males. Geographical differences are also likely to be present in the relative proportion of psychiatric diagnoses among suicides. Although psychopathology clearly mediates suicide risk, gender and geographical differences seem to exist in the relative proportion of the specific psychiatric disorders found among suicide completers.

<h2>Abstract</h2> The early-life social environment can induce stable changes that influence neurodevelopment and mental health. Research focused on early-life adversity revealed that early-life experiences have a persistent impact on gene expression and behavior through epigenetic mechanisms. The hypothalamus-pituitary-adrenal axis is sensitive to changes in the early-life environment that associate with DNA methylation of a neuron-specific exon 1₇ promoter of the glucocorticoid receptor (GR) (<i>Nr3c1</i>). Since initial findings were published in 2004, numerous reports have investigated GR gene methylation in relationship to early-life experience, parental stress, and psychopathology. We conducted a systematic review of this growing literature, which identified 40 articles (13 animal and 27 human studies) published since 2004. The majority of these examined the GR exon variant 1_F in humans or the GR1₇ in rats, and 89% of human studies and 70% of animal studies of early-life adversity reported increased methylation at this exon variant. All the studies investigating exon 1_F/1₇ methylation in conditions of parental stress (one animal study and seven human studies) also reported increased methylation. Studies examining psychosocial stress and psychopathology had less consistent results, with 67% of animal studies reporting increased exon 1₇ methylation and 17% of human studies reporting increased exon 1_F methylation. We found great consistency among studies investigating early-life adversity and the effect of parental stress, even if the precise phenotype and measures of social environment adversity varied among studies. These results are encouraging and warrant further investigation to better understand correlates and characteristics of these associations.

Studies suggest that heightened peripheral inflammation contributes to the pathogenesis of major depressive disorder. We investigated the effect of chronic social defeat stress, a mouse model of depression, on blood-brain barrier (BBB) permeability and infiltration of peripheral immune signals. We found reduced expression of the endothelial cell tight junction protein claudin-5 (Cldn5) and abnormal blood vessel morphology in nucleus accumbens (NAc) of stress-susceptible but not resilient mice. CLDN5 expression was also decreased in NAc of depressed patients. Cldn5 downregulation was sufficient to induce depression-like behaviors following subthreshold social stress whereas chronic antidepressant treatment rescued Cldn5 loss and promoted resilience. Reduced BBB integrity in NAc of stress-susceptible or mice injected with adeno-associated virus expressing shRNA against Cldn5 caused infiltration of the peripheral cytokine interleukin-6 (IL-6) into brain parenchyma and subsequent expression of depression-like behaviors. These findings suggest that chronic social stress alters BBB integrity through loss of tight junction protein Cldn5, promoting peripheral IL-6 passage across the BBB and depression.

Brain-region-specific RNA-seq from humans with major depressive disorder reveals unique transcriptomic profiles in males and females, with little overlap. Major depressive disorder (MDD) is a leading cause of disease burden worldwide. While the incidence, symptoms and treatment of MDD all point toward major sex differences, the molecular mechanisms underlying this sexual dimorphism remain largely unknown. Here, combining differential expression and gene coexpression network analyses, we provide a comprehensive characterization of male and female transcriptional profiles associated with MDD across six brain regions. We overlap our human profiles with those from a mouse model, chronic variable stress, and capitalize on converging pathways to define molecular and physiological mechanisms underlying the expression of stress susceptibility in males and females. Our results show a major rearrangement of transcriptional patterns in MDD, with limited overlap between males and females, an effect seen in both depressed humans and stressed mice. We identify key regulators of sex-specific gene networks underlying MDD and confirm their sex-specific impact as mediators of stress susceptibility. For example, downregulation of the female-specific hub gene Dusp6 in mouse prefrontal cortex mimicked stress susceptibility in females, but not males, by increasing ERK signaling and pyramidal neuron excitability. Such Dusp6 downregulation also recapitulated the transcriptional remodeling that occurs in prefrontal cortex of depressed females. Together our findings reveal marked sexual dimorphism at the transcriptional level in MDD and highlight the importance of studying sex-specific treatments for this disorder.

Although recent years have seen large decreases in the overall global rate of suicide fatalities, this trend is not reflected everywhere. Suicide and suicidal behaviour continue to present key challenges for public policy and health services, with increasing suicide deaths in some countries such as the USA. The development of suicide risk is complex, involving contributions from biological (including genetics), psychological (such as certain personality traits), clinical (such as comorbid psychiatric illness), social and environmental factors. The involvement of multiple risk factors in conveying risk of suicide means that determining an individual's risk of suicide is challenging. Improving risk assessment, for example, by using computer testing and genetic screening, is an area of ongoing research. Prevention is key to reduce the number of suicide deaths and prevention efforts include universal, selective and indicated interventions, although these interventions are often delivered in combination. These interventions, combined with psychological (such as cognitive behavioural therapy, caring contacts and safety planning) and pharmacological treatments (for example, clozapine and ketamine) along with coordinated social and public health initiatives, should continue to improve the management of individuals who are suicidal and decrease suicide-associated morbidity.

Objective: Involvement of personality traits in susceptibility to suicidality has been the subject of research since the 1950s. Because of the diversity of conceptual and methodological approaches, the extent of their independent contribution has been difficult to establish. Here, we review conceptual background and empirical evidence investigating roles of traits in suicidal behaviors. Method: We selected original studies published in English in MEDLINE and PsycINFO databases, focusing on suicidal ideation, suicide attempts, or suicide completions, and using standardized personality measures. Results: Most studies focused on investigating risk for suicide attempts. Hopelessness, neuroticism, and extroversion hold the most promise in relation to risk screening across all three suicidal behaviors. More research is needed regarding aggression, impulsivity, anger, irritability, hostility, and anxiety. Conclusion: Selected personality traits may be useful markers of suicide risk. Future research needs to establish their contributions in relation to environmental and genetic variation in different gender, age, and ethnocultural groups.

Major depression is a major risk factor for suicide. However, not all individuals with major depression commit suicide. Impulsive and aggressive behaviors have been proposed as risk factors for suicide, but it remains unclear whether their effect on the risk of suicide is at least partly explained by axis I disorders commonly associated with suicide, such as major depression. With a case-control design, a comparison of the level of impulsive and aggressive behaviors and the prevalence of associated psychopathology was carried out with control for the presence of primary psychopathology.One hundred and four male suicide completers who died during an episode of major depression and 74 living depressed male comparison subjects were investigated with proxy-based interviews by using structured diagnostic instruments and personality trait assessments.The authors found that current (6-month prevalence) alcohol abuse/dependence, current drug abuse/dependence, and cluster B personality disorders increased the risk of suicide in individuals with major depression. Also, higher levels of impulsivity and aggression were associated with suicide. An analysis by age showed that these risk factors were more specific to younger suicide victims (ages 18-40). A multivariate analysis indicated that current alcohol abuse/dependence and cluster B personality disorder were two independent predictors of suicide.Impulsive-aggressive personality disorders and alcohol abuse/dependence were two independent predictors of suicide in major depression, and impulsive and aggressive behaviors seem to underlie these risk factors. A developmental hypothesis of suicidal behavior, with impulsive and aggressive behaviors as the starting point, is discussed.

<h3>Context</h3>Our genome adapts to environmental influences, in part through epigenetic mechanisms, including DNA methylation. Variations in the quality of the early environment are associated with alterations in DNA methylation in rodents, and recent data suggest similar processes in humans in response to early-life adversity.<h3>Objective</h3>To determine genome-wide DNA methylation alterations induced by early-life trauma.<h3>Design</h3>Genome-wide study of promoter methylation in individuals with severe abuse during childhood.<h3>Patients, Setting, and Main Outcome Measures</h3>Promoter DNA methylation levels were profiled using methylated DNA immunoprecipitation followed by microarray hybridization in hippocampal tissue from 41 French-Canadian men (25 with a history of severe childhood abuse and 16 control subjects). Methylation profiles were compared with corresponding genome-wide gene expression profiles obtained by messenger RNA microarrays. Methylation differences between groups were validated on neuronal and nonneuronal DNA fractions isolated by fluorescence-assisted cell sorting. Functional consequences of site-specific promoter methylation were assessed by luciferase assays.<h3>Results</h3>We identified 362 differentially methylated promoters in individuals with a history of abuse compared with controls. Among these promoters, 248 showed hypermethylation and 114 demonstrated hypomethylation. Validation and site-specific quantification of DNA methylation in the 5 most hypermethylated gene promoters indicated that methylation differences occurred mainly in the neuronal cellular fraction. Genes involved in cellular/neuronal plasticity were among the most significantly differentially methylated, and, among these, Alsin (ALS2) was the most significant finding. Methylated ALS2 constructs mimicking the methylation state in samples from abused suicide completers showed decreased promoter transcriptional activity associated with decreased hippocampal expression of ALS2 variants.<h3>Conclusion</h3>Childhood adversity is associated with epigenetic alterations in the promoters of several genes in hippocampal neurons.

Despite increasing evidence supporting the neuroinflammatory theory of depression, little is known about cerebral macrophages in individuals suffering from major depression. In the present study, we investigated the morphology and distribution of cells immunostained for the macrophage-specific marker ionized calcium binding adaptor molecule 1 (IBA1) in the dorsal anterior cingulate cortex (dACC) white matter of middle-aged depressed suicides and matched non-psychiatric controls. This region is known for its implication in mood disorders, and its white matter compartment was previously found to display hypertrophic astrocytes in depressed suicides. Distributions of IBA1-immunoreactive (IBA-IR) microglial phenotypes were assessed using stereology and cell morphometry, and blood vessels were characterized as being intimately associated with either a high or a low density of IBA1-IR amoeboid-like cells. Total densities of IBA1-IR microglia did not differ between depressed suicides and controls. However, a finer analysis examining relative proportions of microglial phenotypes revealed that the ratio of primed over ramified ("resting") microglia was significantly increased in depressed suicides. Strikingly, the proportion of blood vessels surrounded by a high density of macrophages was more than twice higher in depressed suicides than in controls, and this difference was strongly significant. Consistent with these observations, gene expression of IBA1 and MCP-1, a chemokine involved in the recruitment of circulating monocytes, was significantly upregulated in depressed suicides. Furthermore, mRNA for CD45, a marker enriched in perivascular macrophages, was also significantly increased in samples from depressed suicides. An increase compared to controls was also observed in the proportion of blood vessels surrounded by a high density of CD45-IR cells, but this difference did not reach significance. These histological and molecular data suggest the recruitment of monocytes in dACC white matter of depressed suicides, although it cannot be excluded that other types of macrophages (including microglia) account for the observed accumulation of macrophages closely associated with blood vessels. Altogether, these findings suggest that the previously reported depression- and suicide-associated increases in circulating pro-inflammatory cytokines may be associated with low-grade cerebral neuroinflammation involving the recruitment of circulating monocytes.

Genome scans of bipolar disorder (BPD) have not produced consistent evidence for linkage. The rank-based genome scan meta-analysis (GSMA) method was applied to 18 BPD genome scan data sets in an effort to identify regions with significant support for linkage in the combined data. The two primary analyses considered available linkage data for "very narrow" (i.e., BP-I and schizoaffective disorder-BP) and "narrow" (i.e., adding BP-II disorder) disease models, with the ranks weighted for sample size. A "broad" model (i.e., adding recurrent major depression) and unweighted analyses were also performed. No region achieved genomewide statistical significance by several simulation-based criteria. The most significant P values (<.01) were observed on chromosomes 9p22.3-21.1 (very narrow), 10q11.21-22.1 (very narrow), and 14q24.1-32.12 (narrow). Nominally significant P values were observed in adjacent bins on chromosomes 9p and 18p-q, across all three disease models on chromosomes 14q and 18p-q, and across two models on chromosome 8q. Relatively few BPD pedigrees have been studied under narrow disease models relative to the schizophrenia GSMA data set, which produced more significant results. There was no overlap of the highest-ranked regions for the two disorders. The present results for the very narrow model are promising but suggest that more and larger data sets are needed. Alternatively, linkage might be detected in certain populations or subsets of pedigrees. The narrow and broad data sets had considerable power, according to simulation studies, but did not produce more highly significant evidence for linkage. We note that meta-analysis can sometimes provide support for linkage but cannot disprove linkage in any candidate region.

Most studies investigating the neurobiology of depression and suicide have focused on the serotonergic system. While it seems clear that serotonergic alterations play a role in the pathogenesis of these major public health problems, dysfunction in additional neurotransmitter systems and other molecular alterations may also be implicated. Microarray expression studies are excellent screening tools to generate hypotheses about additional molecular processes that may be at play. In this study we investigated brain regions that are known to be implicated in the neurobiology of suicide and major depression are likely to represent valid global molecular alterations.We performed gene expression analysis using the HG-U133AB chipset in 17 cortical and subcortical brain regions from suicides with and without major depression and controls. Total mRNA for microarray analysis was obtained from 663 brain samples isolated from 39 male subjects, including 26 suicide cases and 13 controls diagnosed by means of psychological autopsies. Independent brain samples from 34 subjects and animal studies were used to control for the potential confounding effects of comorbidity with alcohol. Using a Gene Ontology analysis as our starting point, we identified molecular pathways that may be involved in depression and suicide, and performed follow-up analyses on these possible targets. Methodology included gene expression measures from microarrays, Gene Score Resampling for global ontological profiling, and semi-quantitative RT-PCR. We observed the highest number of suicide specific alterations in prefrontal cortical areas and hippocampus. Our results revealed alterations of synaptic neurotransmission and intracellular signaling. Among these, Glutamatergic (GLU) and GABAergic related genes were globally altered. Semi-quantitative RT-PCR results investigating expression of GLU and GABA receptor subunit genes were consistent with microarray data.The observed results represent the first overview of global expression changes in brains of suicide victims with and without major depression and suggest a global brain alteration of GLU and GABA receptor subunit genes in these conditions.

Background Alterations in gene expression in the suicide brain have been reported and for several genes DNA methylation as an epigenetic regulator is thought to play a role. rRNA genes, that encode ribosomal RNA, are the backbone of the protein synthesis machinery and levels of rRNA gene promoter methylation determine rRNA transcription.Methodology/Principal FindingsWe test here by sodium bisulfite mapping of the rRNA promoter and quantitative real-time PCR of rRNA expression the hypothesis that epigenetic differences in critical loci in the brain are involved in the pathophysiology of suicide. Suicide subjects in this study were selected for a history of early childhood neglect/abuse, which is associated with decreased hippocampal volume and cognitive impairments. rRNA was significantly hypermethylated throughout the promoter and 5′ regulatory region in the brain of suicide subjects, consistent with reduced rRNA expression in the hippocampus. This difference in rRNA methylation was not evident in the cerebellum and occurred in the absence of genome-wide changes in methylation, as assessed by nearest neighbor.Conclusions/SignificanceThis is the first study to show aberrant regulation of the protein synthesis machinery in the suicide brain. The data implicate the epigenetic modulation of rRNA in the pathophysiology of suicide.

Up to 15% of depression patients eventually present with treatment-resistant or refractory depression (TRD), a condition that causes significant social and economic burdens. Our paper aims to summarize the current medical literature on the conceptual and methodologic issues involved in the definition, assessment, and staging of TRD.We reviewed the recently published medical literature to identify papers that specifically discuss TRD. For this, we searched MEDLINE, EMBASE, and PsycINFO for potentially relevant English-language articles published between January 1996 and June 2006.Recent methodologic and conceptual advances have contributed to the achievement of an acceptable level of theoretical consensus on the general meaning of TRD. Accordingly, depression is usually considered resistant or refractory when at least 2 trials with antidepressants from different pharmacologic classes (adequate in terms of dosage, duration, and compliance) fail to produce a significant clinical improvement. Regarding diagnostic assessments, an accurate and systematic evaluation should be made to elicit the potential role of several contributing factors, such as medical and psychiatric comorbidity.Recently, 3 staging methods for TRD have been described, but they currently require extensive empirical support. Future research on TRD should include prospective studies addressing the validity of the proposed criteria, the impact of depression comorbid with other psychiatric disorders and (or) physical conditions, and the possible predictors o treatment outcome. There is an important and clear need for studies that empirically test current definitions, assessment strategies, and staging methods of TRD.

Depression and anxiety disorders are more prevalent in females, but the majority of research in animal models, the first step in finding new treatments, has focused predominantly on males. Here we report that exposure to subchronic variable stress (SCVS) induces depression-associated behaviors in female mice, whereas males are resilient as they do not develop these behavioral abnormalities. In concert with these different behavioral responses, transcriptional analysis of nucleus accumbens (NAc), a major brain reward region, by use of RNA sequencing (RNA-seq) revealed markedly different patterns of stress regulation of gene expression between the sexes. Among the genes displaying sex differences was DNA methyltransferase 3a ( Dnmt3a ), which shows a greater induction in females after SCVS. Interestingly, Dnmt3a expression levels were increased in the NAc of depressed humans, an effect seen in both males and females. Local overexpression of Dnmt3a in NAc rendered male mice more susceptible to SCVS, whereas Dnmt3a knock-out in this region rendered females more resilient, directly implicating this gene in stress responses. Associated with this enhanced resilience of female mice upon NAc knock-out of Dnmt3a was a partial shift of the NAc female transcriptome toward the male pattern after SCVS. These data indicate that males and females undergo different patterns of transcriptional regulation in response to stress and that a DNA methyltransferase in NAc contributes to sex differences in stress vulnerability. SIGNIFICANCE STATEMENT Women have a higher incidence of depression than men. However, preclinical models, the first step in developing new diagnostics and therapeutics, have been performed mainly on male subjects. Using a stress-based animal model of depression that causes behavioral effects in females but not males, we demonstrate a sex-specific transcriptional profile in brain reward circuitry. This transcriptional profile can be altered by removal of an epigenetic mechanism, which normally suppresses DNA transcription, creating a hybrid male/female transcriptional pattern. Removal of this epigenetic mechanism also induces behavioral resilience to stress in females. These findings shed new light onto molecular factors controlling sex differences in stress response.

Childhood abuse alters hypothalamic-pituitary-adrenal (HPA) function and increases the risk of suicide. Hippocampal glucocorticoid receptor (GR) activation regulates HPA activity, and human GR expression (hGR) is reduced in the hippocampus of suicide completers with a history of childhood abuse compared with controls. The abuse-related decrease in hGR expression associates with increased DNA methylation of the promoter of the hGR(1F) variant in the hippocampus.In this study, we investigated the expression and methylation levels of other hGR splice variants in the hippocampus and anterior cingulate gyrus in suicide completers with and without a history of childhood abuse and in controls. Expression levels were quantified using quantitative reverse-transcriptase polymerase chain reaction and promoter methylation was assessed by pyrosequencing.In the hippocampus, the expression of total hGR and variants 1(B), 1(C), and 1(H) was decreased in suicide completers with histories of abuse compared with suicides with no histories of abuse and with control subjects. In the anterior cingulate gyrus, however, no group differences in hGR total or variant expression were found. Site-specific methylation in hGR1(B) and 1(C) promoter sequences were negatively correlated with total hGR messenger RNA, as well as with hGR1(B) and 1(C) expression. Luciferase assay showed that methylation in hGR promoter decreases transcriptional activity. In contrast, total and site-specific methylation in the hGR1(H) promoter was positively correlated with total hGR messenger RNA and hGR1(H) expression.These findings suggest that early-life events alter the expression of several hGR variants in the hippocampus of suicide completers through effects on promoter DNA methylation.

Parental care influences development across mammals. In humans such influences include effects on phenotypes, such as stress reactivity, which determine individual differences in the vulnerability for affective disorders. Thus, the adult offspring of rat mothers that show an increased frequency of pup licking/grooming (ie, high LG mothers) show increased hippocampal glucocorticoid receptor (GR) expression and more modest hypothalamic–pituitary–adrenal responses to stress compared with the offspring of low LG mothers. In humans, childhood maltreatment associates decreased hippocampal GR expression and increased stress responses in adulthood. We review the evidence suggesting that such effects are mediated by epigenetic mechanisms, including DNA methylation and hydroxymethylation across GR promoter regions. We also present new findings revealing associated histone post-translational modifications of a critical GR promoter in rat hippocampus. Taken together these existing evidences are consistent with the idea that parental influences establish stable phenotypic variation in the offspring through effects on intracellular signaling pathways that regulate the epigenetic state and function of specific regions of the genome.

Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified.Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis.A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37 × 10(-8); rs78015114, p=1·31 × 10(-8); rs74795342, p=3·31 × 10(-9); and rs75222709, p=3·50 × 10(-9)). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0).The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings.Deutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.

There are widespread genetic effects on DNA methylation in the developing brain. Fetal brain mQTLs are enriched in regulatory domains, overlapping with variants influencing gene expression. Most are developmentally stable, but some are fetal specific. These mQTLs are enriched in genomic regions associated with schizophrenia, a neuropsychiatric disorder with neurodevelopmental origins. We characterized DNA methylation quantitative trait loci (mQTLs) in a large collection (n = 166) of human fetal brain samples spanning 56–166 d post-conception, identifying >16,000 fetal brain mQTLs. Fetal brain mQTLs were primarily cis-acting, enriched in regulatory chromatin domains and transcription factor binding sites, and showed substantial overlap with genetic variants that were also associated with gene expression in the brain. Using tissue from three distinct regions of the adult brain (prefrontal cortex, striatum and cerebellum), we found that most fetal brain mQTLs were developmentally stable, although a subset was characterized by fetal-specific effects. Fetal brain mQTLs were enriched amongst risk loci identified in a recent large-scale genome-wide association study (GWAS) of schizophrenia, a severe psychiatric disorder with a hypothesized neurodevelopmental component. Finally, we found that mQTLs can be used to refine GWAS loci through the identification of discrete sites of variable fetal brain methylation associated with schizophrenia risk variants.

Bipolar disorder (BD) is a common and highly heritable mental illness and genome-wide association studies (GWAS) have robustly identified the first common genetic variants involved in disease aetiology. The data also provide strong evidence for the presence of multiple additional risk loci, each contributing a relatively small effect to BD susceptibility. Large samples are necessary to detect these risk loci. Here we present results from the largest BD GWAS to date by investigating 2.3 million single-nucleotide polymorphisms (SNPs) in a sample of 24,025 patients and controls. We detect 56 genome-wide significant SNPs in five chromosomal regions including previously reported risk loci ANK3, ODZ4 and TRANK1, as well as the risk locus ADCY2 (5p15.31) and a region between MIR2113 and POU3F2 (6q16.1). ADCY2 is a key enzyme in cAMP signalling and our finding provides new insights into the biological mechanisms involved in the development of BD. Bipolar disorder (BD) is a severe mood disorder, which has been shown to have a large genetic component. Here the authors identify two previously unreported BD risk loci and provide further insights into the biological mechanisms underlying BD development.

Early life experience is associated with long-term effects on behavior and epigenetic programming of the NR3C1 ( GLUCOCORTICOID RECEPTOR ) gene in the hippocampus of both rats and humans. However, it is unlikely that such effects completely capture the evolutionarily conserved epigenetic mechanisms of early adaptation to environment. Here we present DNA methylation profiles spanning 6.5 million base pairs centered at the NR3C1 gene in the hippocampus of humans who experienced abuse as children and nonabused controls. We compare these profiles to corresponding DNA methylation profiles in rats that received differential levels of maternal care. The profiles of both species reveal hundreds of DNA methylation differences associated with early life experience distributed across the entire region in nonrandom patterns. For instance, methylation differences tend to cluster by genomic location, forming clusters covering as many as 1 million bases. Even more surprisingly, these differences seem to specifically target regulatory regions such as gene promoters, particularly those of the protocadherin α, β, and γ gene families. Beyond these high-level similarities, more detailed analyses reveal methylation differences likely stemming from the significant biological and environmental differences between species. These results provide support for an analogous cross-species epigenetic regulatory response at the level of the genomic region to early life experience.

Recent studies suggest that alterations in expression of genes, including those which regulate neural and structural plasticity, may be crucial in the pathogenesis of depression. MicroRNAs (miRNAs) are newly discovered regulators of gene expression that have recently been implicated in a variety of human diseases, including neuropsychiatric diseases.The present study was undertaken to examine whether the miRNA network is altered in the brain of depressed suicide subjects. Expression of miRNAs was measured in prefrontal cortex (Brodmann Area 9) of antidepressant-free depressed suicide (n = 18) and well-matched non-psychiatric control subjects (n = 17) using multiplex RT-PCR plates. We found that overall miRNA expression was significantly and globally down-regulated in prefrontal cortex of depressed suicide subjects. Using individual tests of statistical significance, 21 miRNAs were significantly decreased at p = 0.05 or better. Many of the down-regulated miRNAs were encoded at nearby chromosomal loci, shared motifs within the 5'-seeds, and shared putative mRNA targets, several of which have been implicated in depression. In addition, a set of 29 miRNAs, whose expression was not pairwise correlated in the normal controls, showed a high degree of co-regulation across individuals in the depressed suicide group.The findings show widespread changes in miRNA expression that are likely to participate in pathogenesis of major depression and/or suicide. Further studies are needed to identify whether the miRNA changes lead to altered expression of prefrontal cortex mRNAs, either directly (by acting as miRNA targets) or indirectly (e.g., by affecting transcription factors).

It is unclear whether the association between impulsive-aggressive behaviours and suicide exists across different ages.Via psychological autopsy, we examined a total of 645 subjects aged 11-87 years who died by suicide. Proxy-based interviews were conducted using the SCID-I & SCID-II or K-SADS interviews and a series of behavioural and personality-trait assessments. Secondarily, 246 living controls were similarly assessed.Higher levels of impulsivity, lifetime history of aggression, and novelty seeking were associated with younger age of death by suicide, while increasing levels of harm avoidance were associated with increasing age of suicide. This effect was observed after accounting for age-related psychopathology (current and lifetime depressive disorders, lifetime anxiety disorders, current and lifetime substance abuse disorders, psychotic disorders and cluster B personality disorders). Age effects were not due to the characteristics of informants, and such effects were not observed among living controls. When directly controlling for major psychopathology, the interaction between age, levels of impulsivity, aggression and novelty seeking predicted suicide status while controlling for the independent contributions of age and these traits.Higher levels of impulsive-aggressive traits play a greater role in suicide occurring among younger individuals, with decreasing importance with increasing age.

Abstract Exosomes are a class of extracellular vesicles of endocytic origin, which are released by cells and are accessible in biofluids, such as saliva, urine, and plasma. These vesicles are enriched with small RNA, and they play a role in many physiological processes. In the brain, they are involved in processes including synaptic plasticity, neuronal stress response, cell-to-cell communication and neurogenesis. While exosomes have been implicated previously in cancer and neurodegenerative diseases, research regarding their role in mental disorders remains scarce. Given their functional significance in the brain, investigation in this field is warranted. Additionally, because exosomes can cross the blood–brain barrier, they may serve as accessible biomarkers of neural dysfunction. Studying exosomes may provide information towards diagnosis and therapeutic intervention, and specifically those derived from the brain may provide a mechanistic view of the disease phenotype. This review will discuss the roles of exosomes in the brain, and relate novel findings to current insights into mental disorders.

Chronic stress and depression induce structural and functional plasticity; however, the mechanisms responsible for these alterations remain incompletely characterized. Here Scott J Russo and colleagues demonstrate that the Rac1 promoter is epigenetically modified, and its expression is reduced in the nucleus accumbens of mice after chronic defeat stress and in subjects with major depressive disorders. Reduced Rac1 expression is sufficient to induce depression-related behavior and stubby spine formation in mice. Depression induces structural and functional synaptic plasticity in brain reward circuits, although the mechanisms promoting these changes and their relevance to behavioral outcomes are unknown. Transcriptional profiling of the nucleus accumbens (NAc) for Rho GTPase–related genes, which are known regulators of synaptic structure, revealed a sustained reduction in RAS-related C3 botulinum toxin substrate 1 (Rac1) expression after chronic social defeat stress. This was associated with a repressive chromatin state surrounding the proximal promoter of Rac1. Inhibition of class 1 histone deacetylases (HDACs) with MS-275 rescued both the decrease in Rac1 transcription after social defeat stress and depression-related behavior, such as social avoidance. We found a similar repressive chromatin state surrounding the RAC1 promoter in the NAc of subjects with depression, which corresponded with reduced RAC1 transcription. Viral-mediated reduction of Rac1 expression or inhibition of Rac1 activity in the NAc increases social defeat–induced social avoidance and anhedonia in mice. Chronic social defeat stress induces the formation of stubby excitatory spines through a Rac1-dependent mechanism involving the redistribution of synaptic cofilin, an actin-severing protein downstream of Rac1. Overexpression of constitutively active Rac1 in the NAc of mice after chronic social defeat stress reverses depression-related behaviors and prunes stubby spines. Taken together, our data identify epigenetic regulation of RAC1 in the NAc as a disease mechanism in depression and reveal a functional role for Rac1 in rodents in regulating stress-related behaviors.

Objectives Bipolar disorder is associated with a high risk of suicide attempts and suicide death. The main objective of the present study was to identify and quantify the demographic and clinical correlates of attempted and completed suicide in people with bipolar disorder. Methods Within the framework of the International Society for Bipolar Disorders Task Force on Suicide , a systematic review of articles published since 1980, characterized by the key terms bipolar disorder and ‘ suicide attempts ’ or ‘ suicide ’, was conducted, and data extracted for analysis from all eligible articles. Demographic and clinical variables for which ≥ 3 studies with usable data were available were meta‐analyzed using fixed or random‐effects models for association with suicide attempts and suicide deaths. There was considerable heterogeneity in the methods employed by the included studies. Results Variables significantly associated with suicide attempts were: female gender, younger age at illness onset, depressive polarity of first illness episode, depressive polarity of current or most recent episode, comorbid anxiety disorder, any comorbid substance use disorder, alcohol use disorder, any illicit substance use, comorbid cluster B/borderline personality disorder, and first‐degree family history of suicide. Suicide deaths were significantly associated with male gender and first‐degree family history of suicide. Conclusions This paper reports on the presence and magnitude of the correlates of suicide attempts and suicide deaths in bipolar disorder. These findings do not address causation, and the heterogeneity of data sources should limit the direct clinical ranking of correlates. Our results nonetheless support the notion of incorporating diagnosis‐specific data in the development of models of understanding suicide in bipolar disorder.

Suicide and related behaviors are complex phenomena associated with different risk factors. Although most individuals who display suicidal behavior do not have a history of early-life adversity, a significant minority does. Recent animal and human data have suggested that early-life adversity leads to epigenetic regulation of genes involved in stress-response systems. Here, we review this evidence and suggest that early-life adversity increases risk of suicide in susceptible individuals by influencing the development of stable emotional, behavioral and cognitive phenotypes that are likely to result from the epigenetic regulation of the hypothalamic-pituitary-adrenal axis and other systems involved in responses to stress.

Gustavo Turecki and colleagues report that miR-1202, a miRNA specific to primates, is decreased in individuals with depression and seems to be differentially regulated in individuals who will end up showing beneficial responses to antidepressant treatment compared to those who will not respond. Major depressive disorder (MDD) is a prevalent mood disorder that is associated with differential prefrontal brain expression patterns1. Treatment of MDD includes a variety of biopsychosocial approaches. In medical practice, antidepressant drugs are the most common treatment for depressive episodes, and they are among the most prescribed medications in North America2,3. Although antidepressants are clearly effective, particularly for moderate to severe depressive episodes, there is variability in how individuals respond to antidepressant treatment. Failure to respond has individual, economic and social consequences for patients and their families4. Several lines of evidence demonstrate that genes are regulated through the activity of microRNAs (miRNAs), which act as fine-tuners and on-off switches of gene expression5,6,7. Here we report on complementary studies using postmortem human brain samples, cellular assays and samples from clinical trials of patients with depression and show that miR-1202, a miRNA specific to primates and enriched in the human brain, is differentially expressed in individuals with depression. Additionally, miR-1202 regulates expression of the gene encoding metabotropic glutamate receptor-4 (GRM4) and predicts antidepressant response at baseline. These results suggest that miR-1202 is associated with the pathophysiology of depression and is a potential target for new antidepressant treatments.

Astrocytes are glial cells specific to the central nervous system and involved in numerous brain functions, including regulation of synaptic transmission and of immune reactions. There is mounting evidence suggesting astrocytic dysfunction in psychopathologies such as major depression, however, little is known about the underlying etiological mechanisms. Here we report a two-stage study investigating genome-wide DNA methylation associated with astrocytic markers in depressive psychopathology. We first characterized prefrontal cortex samples from 121 individuals (76 who died during a depressive episode and 45 healthy controls) for the astrocytic markers GFAP, ALDH1L1, SOX9, GLUL, SCL1A3, GJA1 and GJB6. A subset of 22 cases with consistently downregulated astrocytic markers was then compared with 17 matched controls using methylation binding domain-2 (MBD2) sequencing followed by validation with high-resolution melting and bisulfite Sanger sequencing. With these data, we generated a genome-wide methylation map unique to altered astrocyte-associated depressive psychopathology. The map revealed differentially methylated regions (DMRs) between cases and controls, the majority of which displayed reduced methylation levels in cases. Among intragenic DMRs, those found in GRIK2 (glutamate receptor, ionotropic kainate 2) and BEGAIN (brain-enriched guanylate kinase-associated protein) were most significant and also showed significant correlations with gene expression. Cell-sorted fractions were investigated and demonstrated an important non-neuronal contribution of methylation status in BEGAIN. Functional cell assays revealed promoter and enhancer-like properties in this region that were markedly decreased by methylation. Furthermore, a large number of our DMRs overlapped known Encyclopedia of DNA elements (ENCODE)-identified regulatory elements. Taken together, our data indicate significant differences in the methylation patterns specific to astrocytic dysfunction associated with depressive psychopathology, providing a potential framework for better understanding this disease phenotype.

Abstract Background Microglia can adopt different morphologies, ranging from a highly ramified to an amoeboid-like phenotype. Although morphological properties of microglia have been described in rodents, little is known about their fine features in humans. The aim of this study was to characterize the morphometric properties of human microglia in gray and white matter of dorsal anterior cingulate cortex (dACC), a region implicated in behavioral adaptation to neuroinflammation. These properties were compared to those of murine microglia in order to gain a better appreciation of the differences displayed by these cells across species. Methods Postmortem dACC samples were analyzed from 11 individuals having died suddenly without any history of neuroinflammatory, neurodegenerative, nor psychiatric illness. Tissues were sectioned and immunostained for the macrophage marker Ionized calcium binding adaptor molecule 1 (IBA1). Randomly selected IBA1-immunoreactive (IBA1-IR) cells displaying features corresponding to commonly accepted microglial phenotypes (ramified, primed, reactive, amoeboid) were reconstructed in 3D and all aspects of their morphologies quantified using the Neurolucida software. The relative abundance of each morphological phenotype was also assessed. Furthermore, adult mouse brains were similarly immunostained, and IBA1-IR cells in cingulate cortex were compared to those scrutinized in human dACC. Results In human cortical gray and white matter, all microglial phenotypes were observed in significant proportions. Compared to ramified, primed microglia presented an average 2.5 fold increase in cell body size, with almost no differences in branching patterns. When compared to the primed microglia, which projected an average of six primary processes, the reactive and amoeboid phenotypes displayed fewer processes and branching points, or no processes at all. In contrast, the majority of microglial cells in adult mouse cortex were highly ramified. This was also the case following a postmortem interval of 43 hours. Interestingly, the morphology of ramified microglia was strikingly similar between species. Conclusions This study provides fundamental information on the morphological features of microglia in the normal adult human cerebral cortex. These morphometric data will be useful for future studies of microglial morphology in various illnesses. Furthermore, this first direct comparison of human and mouse microglia reveals that these brain cells are morphologically similar across species, suggesting highly conserved functions.

Suicide ranks among the leading causes of death around the world and takes a heavy emotional and public health toll on most societies. Both distal and proximal factors contribute to suicidal behaviour. Distal factors - such as familial and genetic predisposition, as well as early-life adversity - increase the lifetime risk of suicide. They alter responses to stress and other processes through epigenetic modification of genes and associated changes in gene expression, and through the regulation of emotional and behavioural traits. Proximal factors are associated with the precipitation of a suicidal event and include alterations in key neurotransmitter systems, inflammatory changes and glial dysfunction in the brain. This Review explores the key molecular changes that are associated with suicidality and discusses some promising avenues for future research.

Suicide is the 15th most common cause of death worldwide. Although relatively uncommon in the general population, suicide rates are much higher in people with mental health problems. Clinicians often have to assess and manage suicide risk. Risk assessment is challenging for several reasons, not least because conventional approaches to risk assessment rely on patient self reporting and suicidal patients may wish to conceal their plans. Accurate methods of predicting suicide therefore remain elusive and are actively being studied. Novel approaches to risk assessment have shown promise, including empirically derived tools and implicit association tests. Service provision for suicidal patients is often substandard, particularly at times of highest need, such as after discharge from hospital or the emergency department. Although several drug based and psychotherapy based treatments exist, the best approaches to reducing the risk of suicide are still unclear. Some of the most compelling evidence supports long established treatments such as lithium and cognitive behavioral therapy. Emerging options include ketamine and internet based psychotherapies. This review summarizes the current science in suicide risk assessment and provides an overview of the interventions shown to reduce the risk of suicide, with a focus on the clinical management of people with mental disorders.

Childhood maltreatment (CM) has estimated prevalence among Western societies between 10% and 15%. As CM associates with increased risk of several psychiatric disorders, early age of illness onset, increased comorbidity and negative clinical outcome, it imposes a major public health, social and economic impact. Although the clinical consequences of CM are well characterized, a major challenge remains to understand how negative early-life events can affect brain function over extended periods of time. We review here both animal and human studies indicating that the epigenetic mechanism of DNA methylation is a crucial mediator of early-life experiences, thereby maintaining life-long neurobiological sequelae of CM, and strongly determining psychopathological risk.

More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium.The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders.Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%).This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.

Abstract Tissue differences are one of the largest contributors to variability in the human DNA methylome. Despite the tissue-specific nature of DNA methylation, the inaccessibility of human brain samples necessitates the frequent use of surrogate tissues such as blood, in studies of associations between DNA methylation and brain function and health. Results from studies of surrogate tissues in humans are difficult to interpret in this context, as the connection between blood–brain DNA methylation is tenuous and not well-documented. Here, we aimed to provide a resource to the community to aid interpretation of blood-based DNA methylation results in the context of brain tissue. We used paired samples from 16 individuals from three brain regions and whole blood, run on the Illumina 450 K Human Methylation Array to quantify the concordance of DNA methylation between tissues. From these data, we have made available metrics on: the variability of cytosine-phosphate-guanine dinucleotides (CpGs) in our blood and brain samples, the concordance of CpGs between blood and brain, and estimations of how strongly a CpG is affected by cell composition in both blood and brain through the web application BECon (Blood–Brain Epigenetic Concordance; https://redgar598.shinyapps.io/BECon/ ). We anticipate that BECon will enable biological interpretation of blood-based human DNA methylation results, in the context of brain.

Phenotypic misclassification (between cases) has been shown to reduce the power to detect association in genetic studies. However, it is conceivable that complex traits are heterogeneous with respect to individual genetic susceptibility and disease pathophysiology, and that the effect of heterogeneity has a larger magnitude than the effect of phenotyping errors. Although an intuitively clear concept, the effect of heterogeneity on genetic studies of common diseases has received little attention. Here we investigate the impact of phenotypic and genetic heterogeneity on the statistical power of genome wide association studies (GWAS). We first performed a study of simulated genotypic and phenotypic data. Next, we analyzed the Wellcome Trust Case-Control Consortium (WTCCC) data for diabetes mellitus (DM) type 1 (T1D) and type 2 (T2D), using varying proportions of each type of diabetes in order to examine the impact of heterogeneity on the strength and statistical significance of association previously found in the WTCCC data. In both simulated and real data, heterogeneity (presence of "non-cases") reduced the statistical power to detect genetic association and greatly decreased the estimates of risk attributed to genetic variation. This finding was also supported by the analysis of loci validated in subsequent large-scale meta-analyses. For example, heterogeneity of 50% increases the required sample size by approximately three times. These results suggest that accurate phenotype delineation may be more important for detecting true genetic associations than increase in sample size.

Objective Gene expression changes have been reported in the brains of suicide completers. More recently, differences in promoter DNA methylation between suicide completers and comparison subjects in specific genes have been associated with these changes in gene expression patterns, implicating DNA methylation alterations as a plausible component of the pathophysiology of suicide. The authors used a genome-wide approach to investigate the extent of DNA methylation alterations in the brains of suicide completers. Method Promoter DNA methylation was profiled using methylated DNA immunoprecipitation (MeDIP) followed by microarray hybridization in hippocampal tissue from 62 men (46 suicide completers and 16 comparison subjects). The correlation between promoter methylation and expression was investigated by comparing the MeDIP data with gene expression profiles generated through mRNA microarray. Methylation differences between groups were validated on neuronal and nonneuronal DNA fractions isolated by fluorescence-assisted cell sorting. Results The authors identified 366 promoters that were differentially methylated in suicide completers relative to comparison subjects (273 hypermethylated and 93 hypomethylated). Overall, promoter methylation differences were inversely correlated with gene expression differences. Functional annotation analyses revealed an enrichment of differential methylation in the promoters of genes involved, among other functions, in cognitive processes. Validation was performed on the top genes from this category, and these differences were found to occur mainly in the neuronal cell fraction. Conclusions These results suggest broad reprogramming of promoter DNA methylation patterns in the hippocampus of suicide completers. This may help explain gene expression alterations associated with suicide and possibly behavioral changes increasing suicide risk.

The transcription factor ΔFosB and the brain-enriched calcium/calmodulin-dependent protein kinase II (CaMKIIα) are induced in the nucleus accumbens (NAc) by chronic exposure to cocaine or other psychostimulant drugs of abuse, in which the two proteins mediate sensitized drug responses. Although ΔFosB and CaMKIIα both regulate AMPA glutamate receptor expression and function in NAc, dendritic spine formation on NAc medium spiny neurons (MSNs), and locomotor sensitization to cocaine, no direct link between these molecules has to date been explored. Here, we demonstrate that ΔFosB is phosphorylated by CaMKIIα at the protein-stabilizing Ser27 and that CaMKII is required for the cocaine-mediated accumulation of ΔFosB in rat NAc. Conversely, we show that ΔFosB is both necessary and sufficient for cocaine induction of CaMKIIα gene expression in vivo, an effect selective for D1-type MSNs in the NAc shell subregion. Furthermore, induction of dendritic spines on NAc MSNs and increased behavioral responsiveness to cocaine after NAc overexpression of ΔFosB are both CaMKII dependent. Importantly, we demonstrate for the first time induction of ΔFosB and CaMKII in the NAc of human cocaine addicts, suggesting possible targets for future therapeutic intervention. These data establish that ΔFosB and CaMKII engage in a cell-type- and brain-region-specific positive feedforward loop as a key mechanism for regulating the reward circuitry of the brain in response to chronic cocaine.

Child abuse has devastating and long-lasting consequences, considerably increasing the lifetime risk of negative mental health outcomes such as depression and suicide. Yet the neurobiological processes underlying this heightened vulnerability remain poorly understood. The authors investigated the hypothesis that epigenetic, transcriptomic, and cellular adaptations may occur in the anterior cingulate cortex as a function of child abuse.Postmortem brain samples from human subjects (N=78) and from a rodent model of the impact of early-life environment (N=24) were analyzed. The human samples were from depressed individuals who died by suicide, with (N=27) or without (N=25) a history of severe child abuse, as well as from psychiatrically healthy control subjects (N=26). Genome-wide DNA methylation and gene expression were investigated using reduced representation bisulfite sequencing and RNA sequencing, respectively. Cell type-specific validation of differentially methylated loci was performed after fluorescence-activated cell sorting of oligodendrocyte and neuronal nuclei. Differential gene expression was validated using NanoString technology. Finally, oligodendrocytes and myelinated axons were analyzed using stereology and coherent anti-Stokes Raman scattering microscopy.A history of child abuse was associated with cell type-specific changes in DNA methylation of oligodendrocyte genes and a global impairment of the myelin-related transcriptional program. These effects were absent in the depressed suicide completers with no history of child abuse, and they were strongly correlated with myelin gene expression changes observed in the animal model. Furthermore, a selective and significant reduction in the thickness of myelin sheaths around small-diameter axons was observed in individuals with history of child abuse.The results suggest that child abuse, in part through epigenetic reprogramming of oligodendrocytes, may lastingly disrupt cortical myelination, a fundamental feature of cerebral connectivity.

Ten-eleven translocation (TET) enzymes mediate the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which is enriched in brain, and its ultimate DNA demethylation. However, the influence of TET and 5hmC on gene transcription in brain remains elusive. We found that ten-eleven translocation protein 1 (TET1) was downregulated in mouse nucleus accumbens (NAc), a key brain reward structure, by repeated cocaine administration, which enhanced behavioral responses to cocaine. We then identified 5hmC induction in putative enhancers and coding regions of genes that have pivotal roles in drug addiction. Such induction of 5hmC, which occurred similarly following TET1 knockdown alone, correlated with increased expression of these genes as well as with their alternative splicing in response to cocaine administration. In addition, 5hmC alterations at certain loci persisted for at least 1 month after cocaine exposure. Together, these reveal a previously unknown epigenetic mechanism of cocaine action and provide new insight into how 5hmC regulates transcription in brain in vivo.

Antidepressants (ADs) are the most common treatment for major depressive disorder (MDD). However, only ∼30% of patients experience adequate response after a single AD trial, and this variability remains poorly understood. Here, we investigated microRNAs (miRNAs) as biomarkers of AD response using small RNA-sequencing in paired samples from MDD patients enrolled in a large, randomized placebo-controlled trial of duloxetine collected before and 8 weeks after treatment. Our results revealed differential expression of miR-146a-5p, miR-146b-5p, miR-425-3p and miR-24-3p according to treatment response. These results were replicated in two independent clinical trials of MDD, a well-characterized animal model of depression, and post-mortem human brains. Furthermore, using a combination of bioinformatics, mRNA studies and functional in vitro experiments, we showed significant dysregulation of genes involved in MAPK/Wnt signalling pathways. Together, our results indicate that these miRNAs are consistent markers of treatment response and regulators of the MAPK/Wnt systems.

The different serotonin (5-HT) receptors, including the serotonin transporter (5-HTT), are excellent candidate genes for suicide and suicidal behavior, and thus, they have been investigated in a large number of allelic association studies. The individual results of these studies have been inconsistent and definite conclusions are difficult to establish. A reliable method for assessing individual studies and generating combined results is provided by systematic reviews using meta-analytical techniques. In this study, we carried out a systematic review of studies investigating 5-HT receptors and the 5-HTT in suicidal behavior. Studies were identified by means of MEDLINE database searches and by scanning reference lists. More than 190 articles were reviewed and 26 met the inclusion criteria. In all, 14 studies investigated six different 5-HT receptor loci and 12 studies investigated the 5-HTT promoter 44 bp insertion/deletion polymorphism. Two specific meta-analyses were carried out, pooling studies investigating the 5-HT2A 102 T/C and the 5-HTT promoter loci that included, respectively, a total of 1599 and 2539 subjects. The combined evidence was significant for association with the 5-HTT locus (Mantel-Haenszel weighted odds ratio (M-H(w) OR)=1.17 CI : 1.04-1.32, P=0.009), but not for the 5-HT2A 102 T/C variant (M-H(w) OR)=1.09 CI : 0.93-1.27, P=0.319). The 5-HTT result was robust and remained significant following sensitivity analysis, suggesting that 5-HTT may play a role in the predisposition to suicide.

Restless legs syndrome (RLS) is a neurological disorder characterized by leg paresthesia associated with an irresistible urge to move that often interferes with nocturnal sleep, leading to chronic sleep deprivation. To map genes that may play a role in the vulnerability to RLS, a genomewide scan was conducted in a large French-Canadian family. Significant linkage was established on chromosome 12q, for a series of adjacent microsatellite markers with a maximum two-point LOD score of 3.42 (recombination fraction.05; P=6x10(-4); autosomal recessive mode of inheritance), whereas multipoint linkage calculations yielded a LOD score of 3.59. Haplotype analysis refined the genetic interval, positioning the RLS-predisposing gene in a 14.71-cM region between D12S1044 and D12S78. These findings represent the first mapping of a locus conferring susceptibility to RLS.

The different 5-HT (serotonin) receptors including the serotonin transporter (5-HTT) are candidate genes for affective disorders such as major depressive disorder (MDD) and bipolar disorder (BD). They have been investigated in a number of allelic association studies where the individual results have been inconsistent, and therefore, definite conclusions are difficult to make. Systematic reviews using meta-analytical techniques are a reliable method for objectively and reproducibly assessing individual studies and generating combined result. This study aimed at reviewing published studies investigating the association between affective disorders (MDD and BD) and variation at genes coding for serotonin receptors and the serotonin transporter. We performed National Library of Medicine database searches to identify potential studies. More than 430 articles were reviewed and 86 studies met the inclusion criteria for participation in our review. Of these, 41 studies investigated 45 different 5-HT receptor variants and 45 studies investigated at least one of two commonly studied 5-HTT polymorphisms in MDD. Many studies investigated the association between MDD and BD with the 5-HT2A 102 T/C, the 5-HTT promoter 44 bp insertion/deletion and the intron 2 VNTR polymorphisms, and thus, these could be pooled using meta-analytic techniques. The overall odds ratio (OR) for the combined individual results was significant for BD and the two 5-HTT polymorphisms: Mantel-Haenszel weighted OR=1.14, CI: 1.03-1.26, P=0.015 for the promoter locus (N=3467) and Mantel-Haenszel Weighted odds ratio OR=1.18, CI: 1.05-1.32, P=0.004 for the VNTR locus (N=3620). However, sensitivity analysis indicated that, in each case, the overall positive association could be mostly attributed to the large effect of one individual study. Therefore, these results suggest that, although promising, further studies are required to assess appropriately the evidence suggesting an association between BD and 5-HTT.

Although most of the effort to understand the neurobiology of depressive states and suicide has focused on neuronal processes, recent studies suggest that astroglial dysfunction may play an important role. A truncated variant of the tropomyosin-related kinase B (TrkB.T1) is expressed in astrocytes, and brain-derived neurotrophic factor-TrkB signaling has been linked to mood disorders.To test the hypothesis that TrkB.T1 expression is downregulated in suicide completers and that this downregulation is mediated by an epigenetic process.Postmortem case-control study. Patients, Setting, andThirty-nine French Canadian men underwent screening at the Douglas Hospital Research Institute using the HG-U133 plus 2 microarray chip. Nine frontal cortical regions and the cerebellum were assessed using a microarray screening approach for extreme expression differences across subjects and a conventional screening approach. Results were validated by quantitative polymerase chain reaction and Western blot analyses. Animal experiments were performed to control for drug and alcohol effects. Genetic and epigenetic studies were performed by means of direct sequencing and bisulfite mapping.We found that 10 of 28 suicide completers (36%) demonstrated significant decreases in different probe sets specific to TrkB.T1 in Brodmann areas 8 and 9. These findings were generalizable to other frontal regions but not to the cerebellum. The decrease in TrkB expression was specific to the T1 splice variant. Our results were not accounted for by substance comorbidity or by reduction in astrocyte number. We found no effect of genetic variation in a 2500-base pair promoter region or at relevant splice junctions; however, we detected an effect of methylation state at particular CpG dinucleotides on TrkB.T1 expression.A reduction of TrkB.T1 expression in the frontal cortex of a subpopulation of suicide completers is associated with the methylation state of the promoter region.

One of the enzymes involved in the production of free radicals in atherosclerotic plaques is myeloperoxidase (MPO). There is a functional G/A polymorphism 463 bp upstream of the transcription start site of the enzyme with the G allele associated with a higher level of MPO expression than the A allele. Considering the potential role of MPO in the process of atherosclerosis, studying the relationship between this polymorphism and the incidence of coronary artery disease (CAD) seems reasonable.We performed a case-control study. The case group consisted of 229 patients who had angiographically proved atherosclerotic plaques in their coronary arteries. The control group consisted of 217 individuals who did not have a history of coronary artery disease, stroke, or peripheral vascular disease.We found that allele A of the MPO gene was less frequent in cases with CAD. In a recessive model patients with the AA genotype had a decreased risk of CAD (odds ratio 0.138, 95% confidence interval 0.040-0.474). In a dominant model a significant protective role for AA or AG versus GG was also detected (odds ratio 0.639, 95% confidence interval 0.436-0.937).Our findings suggest that the -463 G/A polymorphism of the MPO gene influences the risk of CAD. This effect may be mediated by the effect of this polymorphism on the transcription level of the MPO gene.

Although childhood abuse is an important correlate of suicidality, not all individuals who were abused as children attempt suicide.To identify correlates and moderators of suicide attempts in adults reporting childhood physical abuse, contact sexual abuse, or both.A French-Canadian, school-based cohort (n=1684) was prospectively followed.The identity of the abuser moderated the relationship of abuse frequency and suicide attempts, with individuals abused by their immediate family being at highest risk. Although paternal education exhibited negative associations (OR=0.71, 95% CI 0.58-0.88), several externalising phenotypes had positive associations with suicide attempts: disruptive disorders (OR=3.10, 95% CI 1.05-9.15), conduct problems (OR=1.09, 95% CI 1.01-1.19) and childhood aggression (OR=1.41, 95% CI 1.08-1.83).Characteristics of the abuser and abusive acts may be important additional indicators of risk for suicide attempts. Future research needs to employ developmental approaches to examine the extent and mechanisms by which childhood abuse contributes to the shared variance of suicidality, maladaptive traits and psychopathology.

To summarize and discuss the conceptual and operational definitions of treatment resistant/refractory depression (TRD) by systematically reviewing randomized controlled trials (RCTs) on its somatic treatment.We searched the MEDLINE, Cochrane Library, PsycINFO, and EMBASE for potentially relevant RCTs on the somatic treatment of TRD published from January 1996 to June 2006.Studies were included if they: (a) enrolled patients at least 18 years old with a primary diagnosis of unipolar major depression considered resistant/refractory to treatment at baseline, (b) had a randomized design, (c) were published in peer-reviewed journals, and (d) were written in English. Trials that enrolled patients with secondary depression were excluded from our review. Finally, the bibliographies of relevant articles were hand-searched for additional references. In total, 233 full electronic references were retrieved, from which 47 meet the inclusion criteria.Through a standardized form, we collected data describing the diagnostic procedure, the terminology and definition of TRD employed, the methodology for assessing the adequacy of previous treatments (in terms of type of ascertainment, dose, and duration), and the minimum required depressive symptoms at baseline.Overall, RCTs diverged regarding the majority of the conceptual and methodological issues involved in the ascertainment of TRD. For example, eleven terms were used to describe resistance/refractoriness in depression, and six different criteria were employed to define the categorical presence of TRD (ranging form non-response to one antidepressant to non-response to two or more antidepressants from different pharmacological classes). Regarding the evaluation of previous treatments, the majority of RCTs did not use systematic methods to gather data, and diverge substantially on the minimum acceptable medication doses and trial durations.There is a clear need for an internationally shared framework of concepts and methods for the investigation of TRD that could reduce current idiosyncrasies and provide a reference system. Such a foundation is essential for the interpretation of research findings and for their translation to clinical practice.

Increasing evidence suggests that cortical astrocytic function is disrupted in mood disorders and suicide. The fine neuroanatomy of astrocytes, however, remains to be investigated in these psychiatric conditions. In this study, we performed a detailed morphometric analysis of 3D-reconstructed gray and white matter astrocytes in Golgi-impregnated anterior cingulate cortex (ACC) samples from depressed suicides and matched controls. Postmortem ACC samples (BA24) from 10 well-characterized depressed suicides and 10 matched sudden-death controls were obtained from the Quebec Suicide Brain Bank. Golgi-impregnated protoplasmic astrocytes (gray matter, layer VI) and fibrous astrocytes (adjacent white matter) were reconstructed, and their morphometric features were analyzed using the Neurolucida software. For each cell, the soma size as well as the number, length, and branching of processes were determined. The densities of thorny protrusions found along the processes of both astrocytic subtypes were also determined. Protoplasmic astrocytes showed no significant difference between groups for any of the quantified parameters. However, fibrous astrocytes had significantly larger cell bodies, as well as longer, more ramified processes in depressed suicides, with values for these parameters being about twice as high as those measured in controls. These results provide the first evidence of altered cortical astrocytic morphology in mood disorders. The presence of hypertrophic astrocytes in BA24 white matter is consistent with reports suggesting white matter alterations in depression, and provides further support to the neuroinflammatory theory of depression.

The main challenge in addressing the role of DNA methylation in human behaviour is the fact that the brain is inaccessible to epigenetic analysis in living humans. Using positron emission tomography (PET) measures of brain serotonin (5-HT) synthesis, we found in a longitudinal sample that adult males with high childhood-limited aggression (C-LHPA) had lower in vivo 5-HT synthesis in the orbitofrontal cortex (OBFC). Here we hypothesized that 5-HT alterations associated with childhood aggression were linked to differential DNA methylation of critical genes in the 5-HT pathway and these changes were also detectable in peripheral white blood cells. Using pyrosequencing, we determined the state of DNA methylation of SLC6A4 promoter in T cells and monocytes isolated from blood of cohort members (N = 25) who underwent a PET scan, and we examined whether methylation status in the blood is associated with in vivo brain 5-HT synthesis. Higher levels of methylation were observed in both T cells and monocytes at specific CpG sites in the C-LHPA group. DNA methylation of SLC6A4 in monocytes appears to be associated more reliably with group membership than T cells. In both cell types the methylation state of these CpGs was associated with lower in vivo measures of brain 5-HT synthesis in the left and right lateral OBFC (N = 20) where lower 5-HT synthesis in C-LHPA group was observed. Furthermore, in vitro methylation of the SLC6A4 promoter in a luciferase reporter construct suppresses its transcriptional activity supporting a functional role of DNA methylation in SLC6A4 promoter regulation. These findings indicate that state of SLC6A4 promoter methylation is altered in peripheral white blood cells of individuals with physical aggression during childhood. This supports the relevance of peripheral DNA methylation for brain function and suggests that peripheral SLC6A4 DNA methylation could be a marker of central 5-HT function.

This study examined the relation of coping strategies, social support, and hope to psychological distress [symptoms of posttraumatic stress disorder (PTSD) and general distress] among Hurricane Katrina survivors. The research questions concerned whether different coping strategies (problem-focused or avoidant coping), perceptions of social support, and hope were associated with psychological distress within this sample, as well as whether level of hope moderated the relations between coping/social support and psychological distress. Results indicate that avoidant coping was positively related to PTSD symptoms and general psychological distress, hope was negatively associated with PTSD symptoms and general psychological distress, problem-focused coping was associated with many PTSD symptoms, and social support was associated with low general psychological distress. Hope moderated the relation between avoidant coping and general psychological distress. These results are important for extending research on various psychosocial factors as they relate to psychological distress among a sample of survivors of a major traumatic event.

OBJECTIVE: The main purpose of this study was to investigate whether the method of suicide is a valid behavioral marker of a lifetime history of aggression. METHOD: The authors applied the psychological autopsy method to investigate 310 individuals who committed suicide. They used structured clinical assessments and personality trait scales in interviews with family members of the deceased. RESULTS: Violent method was associated with a higher level of lifetime aggression and a higher level of impulsivity. In addition, violent method was associated with lifetime substance abuse or dependence and psychotic disorders. Controlling for age, sex, substance disorders, and other major psychopathology, the authors found that lifetime aggression and the interaction between impulsivity and aggressive behavior remained associated with violent method. CONCLUSIONS: These results support the use of violent method of suicide as a behavioral marker of a higher level of lifetime impulsive-aggressive behaviors.

Impulsivity is a personality trait thought to be linked to suicide. Yet, not all suicides are highly impulsive. We aimed to better understand clinical, behavioral and psychosocial correlates of the association between suicide and impulsive behavior. One hundred sixty four suicide cases with impulsivity scores based on the Barratt Impulsivity Scale (BIS) were investigated. To examine the most extreme phenotypes, one hundred suicide cases, representing subjects with BIS scores above the 70th percentile and below the 30th percentile, were compared on clinical, behavioral and psychosocial suicide risk factors assessed by way of structured psychological autopsy methods with best informants. The impulsive suicide cases were significantly younger, exhibited higher measures of aggressive behavior, and were more likely to have a cluster B diagnosis as well as lifetime and 6-month prevalence of alcohol and drug abuse/dependence. They also differed significantly from their non-impulsive counterparts on all subscales of the TCI except for Harm Avoidance and Reward Dependence. Impulsive suicide completers were more likely to have had a history of childhood abuse and to have experienced a triggering life event up to a week preceding their death. A multivariate analysis indicated that 6-month prevalence of substance abuse/dependence and high aggressive behavior remained significant even after controlling for other significant variables. This study was carried out using proxy-based interviews. Most of the known clinical and behavioral risk factors commonly associated with suicide are particularly valid for impulsive suicide completers. Further, triggering and adverse life events seem to play a role primarily in impulsive suicide.

A large body of evidence suggests that predisposition to suicide, an important public health problem, is mediated to a certain extent by neurobiological factors.To investigate patterns of expression in suicide with and without major depression and to identify new molecular targets that may play a role in the neurobiology of these conditions.Brain gene expression analysis was performed using the Affymetrix HG-U133 chipset in the orbital cortex (Brodmann area [BA] 11), the dorsolateral prefrontal cortex (BA8/9), and motor cortex (BA4). Subsequent studies were carried out in independent samples from adjacent areas to validate positive findings, confirm their relevance at the protein level, and investigate possible effects of genetic variation.We investigated 12 psychiatrically normal control subjects and 24 suicide victims, including 16 with and 8 without major depression, in the brain gene expression analysis, validation, and protein studies. The genetic studies included 181 suicide completers and 80 psychiatrically normal controls. All subjects investigated were male and of French Canadian origin.Gene expression measures from microarray, semiquantitative reverse transcription-polymerase chain reaction, immunohistochemistry, and Western blot analyses.Twenty-six genes were selected because of the consistency of their expression pattern (fold change, >1.3 in either direction [P<or=.01] in at least 2 regions). The spermine/spermidine N(1)-acetyltransferase gene (SSAT) was successfully validated by reverse transcription-polymerase chain reaction, immunohistochemistry, and Western blot analyses. A variant located in the SSAT polyamine-responsive element regulatory region (SSAT342A/C) demonstrated a significant effect of genotype on SSAT brain expression levels (F(1) = 5.34; P = .02). Further investigation of this variant in an independent sample of 181 male suicide completers and 80 male controls showed a higher frequency of the SSAT342C allele among suicide cases (odds ratio, 2.7; 95% confidence interval, 1.4-5.3; P = .005), suggesting that this allele may increase predisposition to suicide.These data suggest a role for SSAT, the rate-limiting enzyme in the catabolism of polyamines, in suicide and depression and a role for the SSAT342 locus in the regulation of SSAT gene expression.

Brain imaging studies of major depressive disorder have shown alterations in the brain regions typically involved in episodic memory, including the prefrontal cortex and medial temporal areas. Some studies of major depressive disorder have linked episodic memory performance to treatment response. In this study, we sought to identify brain regions whose activity, measured during the encoding of pictures, predicted symptomatic improvement after 8 weeks of citalopram treatment.We included 20 unmedicated depressed patients. These patients performed an episodic recognition memory task during functional magnetic resonance imaging. During the encoding phase, 150 pictures depicting emotionally positive, negative or neutral content were presented, and the participants were required to classify each picture according to its emotional valence. The same 150 pictures were presented, along with 150 new ones, for a recognition task. We asked participants to distinguish the old pictures from the new ones. We assessed symptom severity by use of the 21-item Hamilton Rating Scale for Depression (HAM-D) at baseline and after 8 weeks of citalopram treatment. We performed subsequent memory effect analyses using SPM2 software. We explored the relation between brain activation during successful encoding of pictures and symptomatic improvement.Patients showed a mean symptomatic improvement of 54.5% on the HAM-D after 8 weeks. Symptomatic improvement was significantly and positively correlated with picture recognition memory accuracy. We also found that the activity of the ventromedial prefrontal cortex and anterior cingulate cortex during successful encoding was significantly correlated with symptomatic improvement. Finally, we found greater activation in the ventromedial prefrontal cortex during the successful encoding of positive pictures in comparison with neutral pictures.During the recognition memory task, 5 participants (among the best responders to treatment) were not included in the valence-specific analyses because they had very few errors. A more challenging task would have allowed the inclusion of most patients.Different types of functional imaging paradigms have been used to explore whether the activity of specific brain regions measured at baseline is predictive of a better response to treatment in major depressive disorder. Among these regions, the medial prefrontal cortex and anterior cingulate cortex usually show the strongest predictive value. According to our results, the medial prefrontal cortex and anterior cingulate cortex could have an effect on treatment response in major depressive disorder by contributing to the successful encoding of positively valenced information.

The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the "Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" scale currently used in the Consortium on Lithium Genetics (ConLiGen) study.Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (κ)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling.Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (κ = 0.66 and κ = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders).We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.

Objective: There is substantial evidence suggesting that suicide aggregates in families. However, the extent of overlap between the liability to suicide and psychiatric disorders, particularly major depressive disorder, remains an important issue. Similarly, factors that account for the familial transmission of suicidal behavior remain unclear. Thus, through direct and blind assessment of first-degree relatives, the authors conducted a family study of suicide by examining three proband groups: probands who committed suicide in the context of major depressive disorder, living depressed probands with no history of suicidal behavior, and psychiatrically normal community comparison probands. Method: Participants were 718 first-degree relatives from 120 families: 296 relatives of 51 depressed probands who committed suicide, 185 relatives of 34 nonsuicidal depressed probands, and 237 relatives of 35 community comparison subjects. Psychopathology, suicidal behavior, and behavioral measures were assessed via interviews. Results: The relatives of probands who committed suicide had higher levels of suicidal behavior (10.8%) than the relatives of nonsuicidal depressed probands (6.5%) and community comparison probands (3.4%). Testing cluster B traits as intermediate phenotypes of suicide showed that the relatives of depressed probands who committed suicide had elevated levels of cluster B traits; familial predisposition to suicide was associated with increased levels of cluster B traits; cluster B traits demonstrated familial aggregation and were associated with suicide attempts among relatives; and cluster B traits mediated, at least in part, the relationship between familial predisposition and suicide attempts among relatives. Analyses were repeated for severity of attempts, where cluster B traits also met criteria for endophenotypes of suicide. Conclusions: Familial transmission of suicide and major depression, while partially overlapping, are distinct. Cluster B traits and impulsive-aggressive behavior represent intermediate phenotypes of suicide.

The present study was designed to evaluate psychiatric risk factors for child and adolescent suicide, and to determine the association between impulsive-aggressive and other personality traits, and suicide completion in this population.Psychiatric diagnoses, impulsive-aggressive and other personality traits were assessed in 55 child and adolescent suicide victims and 55 community controls using semi-structured proxy-based interviews and questionnaires.The most significant psychiatric risk factors associated with child and adolescent suicide were depressive disorders (OR=48.414, 95% CI 6.247-375.185), substance/alcohol abuse disorder (OR=5.365, 95% CI 1.434-20.076), and disruptive disorders (OR=13.643, 95% CI 2.292-23.16). Additionally, suicide victims showed higher scores on lifetime aggression/impulsivity, and harm avoidance. However, after logistic regression, the only independent significant predictors of suicide in this age group were the presence of depressive disorders (Adjusted OR (AOR)=39.652, 95% CI 4.501-349.345), substance/alcohol abuse disorders (AOR=7.325, 95% CI 1.127-47.62), and disruptive disorders (AOR=6.464, 95% CI 1.422-29.38).Relatively small sample size, and cross-sectional design.Our findings confirm the existence of a particular clinical profile of children and adolescents at high risk for suicide. Additionally, our results reinforce the need for improved understanding of the interrelationships between stressors, depression, substance/alcohol abuse disorders, disruptive disorders and personality traits/dimensions in youth suicidal behavior.

Some individuals suffering from posttraumatic stress disorder (PTSD) exhibit lower basal salivary cortisol and higher glucocorticoid receptor (GR) sensitivity. Recent studies suggest that epigenetic mechanisms regulate the activity of cortisol and GR. As a means to combine and cross-validate those findings, we compared cortisol, GR expression and promoter methylation levels in peripheral T lymphocytes of healthy controls versus individuals endorsing a diagnosis of lifetime PTSD. Thirty subjects with lifetime (current or remitted) PTSD and 16 subjects never exposed to trauma were recruited. Salivary cortisol was collected at six time points over the course of a single weekday and analyzed utilizing a time-resolved fluorescence immunoassay. GR expression (GRtotal, 1B, 1C, 1F and 1H) was measured by quantitative RT-PCR. DNA methylation levels in human glucocorticoid receptor (hGR) 1B and 1C variant's promoter were quantified by epityper in T lymphocytes isolated by magnetic-assisted cell sorting. Individuals with lifetime PTSD have lower morning cortisol release, higher mRNA expression of hGRtotal, 1B, and 1C and lower overall methylation levels in hGR 1B and 1C promoters. Cortisol levels were inversely correlated with hGR 1B mRNA expression. Moreover, overall and CpG site-specific methylation levels were inversely correlated with hGRtotal and 1B mRNA expression. There was no difference between current and remitted PTSD across cortisol, GR expression mRNA and DNA methylation data. Traumatic events induce DNA methylation alterations in distinct promoters of hGR with transcriptional modifications that associate with hypoactive hypothalamus-pituitary-adrenal axis in individuals with PTSD. Our results also point toward an important role of hGR 1B variant in PTSD.

Borderline personality disorder is a major risk factor for suicidal behavior, yet prediction of suicide completion remains unclear. It has been proposed that impulsivity and aggression interact to increase suicide risk. Death by suicide in borderline personality disorder, then, may be the result of impulsivity, a core feature of the disorder, interacting with violent-aggressive tendencies. Using a case-control design, this study investigated clinical and behavioral risk factors for suicide completion in borderline personality disorder.One hundred twenty subjects meeting DSM-IV criteria for borderline personality disorder, 50 controls and 70 who died by suicide between 2001 and 2005, were investigated by means of proxy-based interviews using structured diagnostic instruments and personality trait assessments.Borderline personality disorder suicides had fewer psychiatric hospitalizations and suicide attempts than borderline personality disorder controls. Borderline personality disorder suicides were also more likely to meet criteria for current and lifetime substance dependence disorders. They had higher levels of current and lifetime Axis I comorbidity, novelty seeking, impulsivity, hostility, and comorbid personality disorders, while exhibiting lower levels of harm avoidance. Most importantly, borderline personality disorder suicides were more likely to have cluster B comorbidity. Impulsivity and aggression interacted to predict suicide, though not after controlling for cluster B comorbidity.Borderline personality disorder individuals who die by suicide differ from those borderlines typically encountered in acute psychiatric settings. Our results suggest that the lethality of borderline personality disorder suicide attempts results from an interaction between impulsivity and the violent-aggressive features associated with cluster B comorbidity. Further, the anxious trait of harm avoidance appears to be protective against suicidal behavior resulting in death.

It is unclear whether certain DSM-IV depressive symptoms are more prevalent among individuals who die in the context of a major depressive episode and those who do not, whether this is associated with proximal or distal suicide risk, and whether depressive symptoms cluster to indicate suicide risk.A psychological autopsy method with best informants was used to investigate DSM-IV depressive symptoms among 156 suicides who died in the context of a major depressive episode and 81 major depressive controls.Suicides' depressive symptoms were more likely to include weight or appetite loss, insomnia, feelings of worthlessness or inappropriate guilt as well as recurrent thoughts of death or suicidal ideation. Fatigue and difficulties concentrating or indecisiveness were less prevalent among depressed suicides. These associations were independent of concomitant axis I and II psychopathology. The concomitant presence of (a) fatigue as well as impaired concentration or indecisiveness and (b) weight or appetite gain and hypersomnia was associated with decreased suicide risk. Inter-episode symptom concordance suggests that insomnia is an immediate indicator of suicide risk, while weight or appetite loss and feelings of worthlessness or guilt are not.This study employed proxy-based interviews.We found that discrete DSM-IV depressive symptoms and clusters of depressive symptoms help differentiate depressed individuals who die by suicide and those who do not. Moreover, some DSM-IV depressive symptoms are associated with an immediate risk for suicide, while others may result from an etiology of depression common to suicide without directly increasing suicide risk.

Schizophrenia is a severe neuropsychiatric disorder that is hypothesized to result from disturbances in early brain development. There is mounting evidence to support a role for developmentally regulated epigenetic variation in the molecular etiology of the disorder. Here, we describe a systematic study of schizophrenia-associated methylomic variation in the adult brain and its relationship to changes in DNA methylation across human fetal brain development. We profile methylomic variation in matched prefrontal cortex and cerebellum brain tissue from schizophrenia patients and controls, identifying disease-associated differential DNA methylation at multiple loci, particularly in the prefrontal cortex, and confirming these differences in an independent set of adult brain samples. Our data reveal discrete modules of co-methylated loci associated with schizophrenia that are enriched for genes involved in neurodevelopmental processes and include loci implicated by genetic studies of the disorder. Methylomic data from human fetal cortex samples, spanning 23 to 184 days post-conception, indicates that schizophrenia-associated differentially methylated positions are significantly enriched for loci at which DNA methylation is dynamically altered during human fetal brain development. Our data support the hypothesis that schizophrenia has an important early neurodevelopmental component, and suggest that epigenetic mechanisms may mediate these effects.

In this review, we examine the history of the neurobiology of suicide, as well as the genetics, molecular and neurochemical findings in suicide research. Our analysis begins with a summary of family, twin, and adoption studies, which provide support for the investigation of genetic variation in suicide risk. This leads to an overview of neurochemical findings restricted to neurotransmitters and their receptors, including recent findings in whole genome gene expression studies. Next, we look at recent studies investigating lipid metabolism, cell signalling with a particular emphasis on growth factors, stress systems with a focus on the role of polyamines, and finally, glial cell pathology in suicide. We conclude with a description of new ideas to study the neurobiology of suicide, including subject-specific analysis, protein modification assessment, neuroarchitecture studies, and study design strategies to investigate the complex suicide phenotype.

DNA methylation is an epigenetic mark that balances plasticity with stability. While DNA methylation exhibits tissue specificity, it can also vary with age and potentially environmental exposures. In studies of DNA methylation, samples from specific tissues, especially brain, are frequently limited and so surrogate tissues are often used. As yet, we do not fully understand how DNA methylation profiles of these surrogate tissues relate to the profiles of the central tissue of interest. We have adapted principal component analysis to analyze data from the Illumina 450K Human Methylation array using a set of 17 individuals with 3 brain regions and whole blood. All of the top five principal components in our analysis were associated with a variable of interest: principal component 1 (PC1) differentiated brain from blood, PCs 2 and 3 were representative of tissue composition within brain and blood, respectively, and PCs 4 and 5 were associated with age of the individual (PC4 in brain and PC5 in both brain and blood). We validated our age-related PCs in four independent sample sets, including additional brain and blood samples and liver and buccal cells. Gene ontology analysis of all five PCs showed enrichment for processes that inform on the functions of each PC. Principal component analysis (PCA) allows simultaneous and independent analysis of tissue composition and other phenotypes of interest. We discovered an epigenetic signature of age that is not associated with cell type composition and required no correction for cellular heterogeneity.

Alterations in brain plasticity are increasingly thought to play important roles in major depressive disorder (MDD) and suicide. To gain a better understanding of the gross structural changes observed in the brains of major depressed and suicide subjects, a number of recent investigations have scrutinized the cellular integrity of brain regions implicated in mood disorders. The purpose of this review is to summarize the current knowledge on the microscopic features of neuronal and glial cell populations in these different brain regions, namely the prefrontal cortex, hippocampus, amygdala, raphe nucleus and locus coeruleus. In general, evidence from this burgeoning field supports the hypothesis of altered cell plasticity in MDD and suicide occurring mainly in key fronto-limbic areas. Interestingly, reported morphometric and cell density alterations are generally region-specific and implicate several neuromodulatory systems, notably GABAergic, serotonergic, noradrenergic and glutamatergic pathways. Cell-specific changes involve reductions in densities of astrocytes and oligodendrocytes, while increases in microglial densities have also been reported. Furthermore, increases in neuronal densities have been found in subcortical regions. The implication of such findings for our understanding of the cellular and molecular underpinnings of MDD and suicide are discussed, and the strengths and weaknesses of morphological approaches used to analyse human postmortem brain tissues are evaluated.

Several lines of evidence support the role of brain-derived neurotrophic factor (BDNF) in the pathophysiology and pharmacotherapy of depression.1 The neurotrophin hypothesis of depression postulates that stress and depression are associated with decreased BDNF expression, which can be reversed by antidepressant treatment.2 The goal of the present study was to investigate the effect of antidepressant treatment on the epigenetic regulation of BDNF in major depressive disorder (MDD).

Objectives: Bipolar disorder is associated with elevated risk of suicide attempts and deaths. Key aims of the International Society for Bipolar Disorders Task Force on Suicide included examining the extant literature on epidemiology, neurobiology and pharmacotherapy related to suicide attempts and deaths in bipolar disorder. Methods: Systematic review of studies from 1 January 1980 to 30 May 2014 examining suicide attempts or deaths in bipolar disorder, with a specific focus on the incidence and characterization of suicide attempts and deaths, genetic and non-genetic biological studies and pharmacotherapy studies specific to bipolar disorder. We conducted pooled, weighted analyses of suicide rates. Results: The pooled suicide rate in bipolar disorder is 164 per 100,000 person-years (95% confidence interval = [5, 324]). Sex-specific data on suicide rates identified a 1.7:1 ratio in men compared to women. People with bipolar disorder account for 3.4–14% of all suicide deaths, with self-poisoning and hanging being the most common methods. Epidemiological studies report that 23–26% of people with bipolar disorder attempt suicide, with higher rates in clinical samples. There are numerous genetic associations with suicide attempts and deaths in bipolar disorder, but few replication studies. Data on treatment with lithium or anticonvulsants are strongly suggestive for prevention of suicide attempts and deaths, but additional data are required before relative anti-suicide effects can be confirmed. There were limited data on potential anti-suicide effects of treatment with antipsychotics or antidepressants. Conclusion: This analysis identified a lower estimated suicide rate in bipolar disorder than what was previously published. Understanding the overall risk of suicide deaths and attempts, and the most common methods, are important building blocks to greater awareness and improved interventions for suicide prevention in bipolar disorder. Replication of genetic findings and stronger prospective data on treatment options are required before more decisive conclusions can be made regarding the neurobiology and specific treatment of suicide risk in bipolar disorder.

To test whether adolescents who are victimized by peers are at heightened risk for suicidal ideation and suicide attempt, using both cross-sectional and prospective investigations.Participants are from the Quebec Longitudinal Study of Child Development, a general population sample of children born in Quebec in 1997 through 1998 and followed up until 15 years of age. Information about victimization and serious suicidal ideation and suicide attempt in the past year was obtained at ages 13 and 15 years from self-reports (N = 1,168).Victims reported concurrently higher rates of suicidal ideation at age 13 years (11.6-14.7%) and suicide attempt at age 15 years (5.4-6.8%) compared to those who had not been victimized (2.7-4.1% for suicidal ideation and 1.6-1.9% for suicide attempt). Being victimized by peers at 13 years predicted suicidal ideation (odds ratio [OR] = 2.27; 95% CI = 1.25-4.12) and suicide attempt (OR = 3.05, 95% CI = 1.36-6.82) 2 years later, even after adjusting for baseline suicidality and mental health problems and a series of confounders (socioeconomic status, intelligence, family's functioning and structure, hostile-reactive parenting, maternal lifetime suicidal ideation/suicide attempt). Those who were victimized at both 13 and 15 years had the highest risk of suicidal ideation (OR = 5.41, 95% CI = 2.53-11.53) and suicide attempt (OR = 5.85, 95% CI = 2.12-16.18) at 15 years.Victimization is associated with an increased risk of suicidal ideation and suicide attempt over and above concurrent suicidality and prior mental health problems. The longer the history of victimization, the greater the risk.

<h3>Background:</h3> Patients prescribed antiplatelet treatment to prevent recurrent acute myocardial infarction are often also given a selective serotonin reuptake inhibitor (SSRI) to treat coexisting depression. Use of either treatment may increase the risk of bleeding. We assessed the risk of bleeding among patients taking both medications following acute myocardial infarction. <h3>Methods:</h3> We conducted a retrospective cohort study using hospital discharge abstracts, physician billing information, medication reimbursement claims and demographic data from provincial health services administrative databases. We included patients 50 years of age or older who were discharged from hospital with antiplatelet therapy following acute myocardial infarction between January 1998 and March 2007. Patients were followed until admission to hospital due to a bleeding episode, admission to hospital due to recurrent acute myocardial infarction, death or the end of the study period. <h3>Results:</h3> The 27 058 patients in the cohort received the following medications at discharge: acetylsalicylic acid (ASA) (<i>n</i> = 14 426); clopidogrel (<i>n</i> = 2467), ASA and clopidogrel (<i>n</i> = 9475); ASA and an SSRI (<i>n</i> = 406); ASA, clopidogrel and an SSRI (<i>n</i> = 239); or clopidogrel and an SSRI (<i>n</i> = 45). Compared with ASA use alone, the combined use of an SSRI with antiplatelet therapy was associated with an increased risk of bleeding (ASA and SSRI: hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.08–1.87; ASA, clopidogrel and SSRI: HR 2.35, 95% CI 1.61–3.42). Compared with dual antiplatelet therapy alone (ASA and clopidogrel), combined use of an SSRI and dual antiplatelet therapy was associated with an increased risk of bleeding (HR 1.57, 95% CI 1.07–2.32). <h3>Interpretation:</h3> Patients taking an SSRI together with ASA or dual antiplatelet therapy following acute myocardial infarction were at increased risk of bleeding.

Family studies have shown an aggregation of suicidal behavior in families. Yet, molecular studies are needed to identify loci accounting for genetic heritability. We conducted a genome-wide association study and estimated single nucleotide polymorphisms (SNP) heritability for a suicide attempt. In a case-cohort study, national data on all individuals born in Denmark after 1981 and diagnosed with severe mental disorders prior to 2013 (n = 57,377) and individuals from the general population (n = 30,000) were obtained. After quality control, the sample consisted of 6024 cases with an incidence of suicide attempt and 44,240 controls with no record of a suicide attempt. Suggestive associations between SNPs, rs6880062 (p-value: 5.4 × 10−8) and rs6880461 (p-value: 9.5 × 10−8), and suicide attempt were identified when adjusting for socio-demographics. Adjusting for mental disorders, three significant associations, all on chromosome 20, were identified: rs4809706 (p-value: 2.8 × 10−8), rs4810824 (p-value: 3.5 × 10−8), and rs6019297 (p-value: 4.7 × 108). Sub-group analysis of cases with affective disorders revealed SNPs associated with suicide attempts when compared to the general population for gene PDE4B. All SNPs explained 4.6% [CI-95: 2.9–6.3%] of the variation in suicide attempt. Controlling for mental disorders reduced the heritability to 1.9% [CI-95: 0.3–3.5%]. Affective and autism spectrum disorders exhibited a SNP heritability of 5.6% [CI-95: 1.9–9.3%] and 9.6% [CI-95: 1.1–18.1%], respectively. Using the largest sample to date, we identified significant SNP associations with suicide attempts and support for a genetic transmission of suicide attempt, which might not solely be explained by mental disorders.

To document the short-term efficacy of omega-3 supplementation in reducing depressive symptoms in patients experiencing a major depressive episode (MDE).Inclusive, double-blind, randomized, controlled, 8-week, parallel-group trial, conducted October 17, 2005 through January 30, 2009 in 8 Canadian academic and psychiatric clinics. Adult outpatients (N = 432) with MDE (Mini-International Neuropsychiatric Interview, version 5.0.0, criteria) lasting at least 4 weeks, including 40.3% taking antidepressants at baseline, were randomly assigned to 8 weeks of 1,050 mg/d of eicosapentaenoic acid (EPA) and 150 mg/d of docosahexaenoic acid (DHA) or matched sunflower oil placebo (2% fish oil). The primary outcome was the self-report Inventory of Depressive Symptomatology (IDS-SR(30)); the secondary outcome was the clinician-rated Montgomery-Åsberg Depression Rating Scale (MADRS).The adjusted mean difference between treatment and placebo was 1.32 points (95% CI, -0.20 to 2.84; P = .088) on the IDS-SR(30) and 0.97 points (95% CI, -0.012 to 1.95; P = .053) on the MADRS. Planned subgroup analyses revealed a significant interaction of comorbid anxiety disorders and study group (P = .035). For patients without comorbid anxiety disorders (n = 204), omega-3 supplementation was superior to placebo, with an adjusted mean difference of 3.17 points on the IDS-SR(30) (95% CI, 0.89 to 5.45; P = .007) and 1.93 points (95% CI, 0.50 to 3.36; P = .008) on the MADRS.In this heterogeneous sample of patients with MDE, there was only a trend toward superiority of omega-3 supplementation over placebo in reducing depressive symptoms. However, there was a clear benefit of omega-3 supplementation among patients with MDE without comorbid anxiety disorders.controlled-trials.com Identifier: ISRCTN47431149.

Background Suicide is an important public health problem that results from the interaction of both psychosocial and biological factors. Although it is known that particular neurobiological processes underlie suicidal ideation and behavior, there still remains limited knowledge about the specific factors involved. Methods To explore the neurobiology of suicide we generated microarray data from dorsal lateral prefrontal cortex (DLPFC) in each of 28 male French-Canadian subjects (20 suicide completers). These results were followed up in a larger French-Canadian sample (n = 47, 38 suicide completers) and in microarray data available from the Stanley Foundation (n = 100, 36 suicide completers). To investigate the molecular mechanisms of this finding, we performed RNA interference and electrophoretic mobility shift assays. Animal behavioral experiments were done to control for drug and alcohol effects. Results We found reduced expression of Cx30 and Cx43 in DLPFC of suicide completers. We identified a previously unknown function for Sox9 as a transcription factor affecting expression of Cx30 in brain. Conclusions These results suggest that alterations of astrocyte connexins might be involved in the suicide process and provide further evidence implicating astrocytes in psychopathology. Suicide is an important public health problem that results from the interaction of both psychosocial and biological factors. Although it is known that particular neurobiological processes underlie suicidal ideation and behavior, there still remains limited knowledge about the specific factors involved. To explore the neurobiology of suicide we generated microarray data from dorsal lateral prefrontal cortex (DLPFC) in each of 28 male French-Canadian subjects (20 suicide completers). These results were followed up in a larger French-Canadian sample (n = 47, 38 suicide completers) and in microarray data available from the Stanley Foundation (n = 100, 36 suicide completers). To investigate the molecular mechanisms of this finding, we performed RNA interference and electrophoretic mobility shift assays. Animal behavioral experiments were done to control for drug and alcohol effects. We found reduced expression of Cx30 and Cx43 in DLPFC of suicide completers. We identified a previously unknown function for Sox9 as a transcription factor affecting expression of Cx30 in brain. These results suggest that alterations of astrocyte connexins might be involved in the suicide process and provide further evidence implicating astrocytes in psychopathology.

Genetic epidemiology research has shown that genes contribute to suicide risk. Unfortunately, the first 30 years of candidate-based association studies have provided little information about the specific genetic contributors. This article reviews genetic association studies of suicidal phenotypes published to date. Possible theoretical, methodological, and operational challenges accounting for the modest success of association studies in the field are also discussed. The authors conclude that future research may benefit from using a more systematic and comprehensive selection of candidate genes and variants, examining gene-environment and gene-gene interactions, and investigating higher-order moderators.

Child maltreatment is associated with an increased risk of psychiatric disorders, and a range of health problems later in life. Research suggests that adverse events early in life can lead to changes in gene expression through epigenetic mechanisms that alter stress reactivity, brain function, and behaviour. Although epigenetic changes are often long lasting, they can be reversed with pharmacological and environmental manipulations. The complexity of the epigenome is not fully understood. The aim of this Review is to assess emerging data for the role of epigenetic mechanisms in stress-related psychiatric disorders with a focus on future research. We describe the epigenetic processes, key findings in this specialty, clinical implications of research, and methodological issues. Studies are needed to investigate new epigenetic processes other than methylation and assess the efficacy of interventions to reverse epigenetic processes associated with the effects of early life adversity.

Suicide is a major public health concern and a leading cause of death in most societies. Suicidal behaviour is complex and heterogeneous, likely resulting from several causes. It associates with multiple factors, including psychopathology, personality traits, early-life adversity and stressful life events, among others. Over the past decades, studies in fields ranging from neuroanatomy, genetics and molecular psychiatry have led to a model whereby behavioural dysregulation, including suicidal behaviour (SB), develops as a function of biological adaptations in key brain systems. More recently, the unravelling of the unique epigenetic processes that occur in the brain has opened promising avenues in suicide research. The present review explores the various facets of the current knowledge on suicidality and discusses how the rapidly evolving field of neurobehavioural epigenetics may fuel our ability to understand, and potentially prevent, SB.

Major Depressive Disorder (MDD) is among the most prevalent and disabling medical conditions worldwide. Identification of clinical and biological markers ("biomarkers") of treatment response could personalize clinical decisions and lead to better outcomes. This paper describes the aims, design, and methods of a discovery study of biomarkers in antidepressant treatment response, conducted by the Canadian Biomarker Integration Network in Depression (CAN-BIND). The CAN-BIND research program investigates and identifies biomarkers that help to predict outcomes in patients with MDD treated with antidepressant medication. The primary objective of this initial study (known as CAN-BIND-1) is to identify individual and integrated neuroimaging, electrophysiological, molecular, and clinical predictors of response to sequential antidepressant monotherapy and adjunctive therapy in MDD.CAN-BIND-1 is a multisite initiative involving 6 academic health centres working collaboratively with other universities and research centres. In the 16-week protocol, patients with MDD are treated with a first-line antidepressant (escitalopram 10-20 mg/d) that, if clinically warranted after eight weeks, is augmented with an evidence-based, add-on medication (aripiprazole 2-10 mg/d). Comprehensive datasets are obtained using clinical rating scales; behavioural, dimensional, and functioning/quality of life measures; neurocognitive testing; genomic, genetic, and proteomic profiling from blood samples; combined structural and functional magnetic resonance imaging; and electroencephalography. De-identified data from all sites are aggregated within a secure neuroinformatics platform for data integration, management, storage, and analyses. Statistical analyses will include multivariate and machine-learning techniques to identify predictors, moderators, and mediators of treatment response.From June 2013 to February 2015, a cohort of 134 participants (85 outpatients with MDD and 49 healthy participants) has been evaluated at baseline. The clinical characteristics of this cohort are similar to other studies of MDD. Recruitment at all sites is ongoing to a target sample of 290 participants. CAN-BIND will identify biomarkers of treatment response in MDD through extensive clinical, molecular, and imaging assessments, in order to improve treatment practice and clinical outcomes. It will also create an innovative, robust platform and database for future research.ClinicalTrials.gov identifier NCT01655706 . Registered July 27, 2012.

Variations in the expression of the Netrin-1 guidance cue receptor DCC (deleted in colorectal cancer) appear to confer resilience or susceptibility to psychopathologies involving prefrontal cortex (PFC) dysfunction.With the use of postmortem brain tissue, mouse models of defeat stress, and in vitro analysis, we assessed microRNA (miRNA) regulation of DCC and whether changes in DCC levels in the PFC lead to vulnerability to depression-like behaviors.We identified miR-218 as a posttranscriptional repressor of DCC and detected coexpression of DCC and miR-218 in pyramidal neurons of human and mouse PFC. We found that exaggerated expression of DCC and reduced levels of miR-218 in the PFC are consistent traits of mice susceptible to chronic stress and of major depressive disorder in humans. Remarkably, upregulation of Dcc in mouse PFC pyramidal neurons causes vulnerability to stress-induced social avoidance and anhedonia.These data are the first demonstration of microRNA regulation of DCC and suggest that, by regulating DCC, miR-218 may be a switch of susceptibility versus resilience to stress-related disorders.

There is mounting evidence to suggest aberrant astrocytic function in depression and suicide. Independent studies have reported astrocytic abnormalities in certain brain regions, but it remains unclear whether this is a brain-wide phenomenon. The present study examined this question by measuring glial fibrillary acidic protein (GFAP) expression in postmortem brain samples from suicide completers and matched non-psychiatric controls. Suicide completers were selected based on their recent characterization as low GFAP expressors in the prefrontal cortex, (Brodmann areas 8/9 and 10). Real-time PCR and immunoblotting were used to measure GFAP gene expression and protein levels in BA4 (primary motor cortex), BA17 (primary visual cortex), cerebellar cortex, mediodorsal thalamus and caudate nucleus. We found downregulation of GFAP mRNA and protein in the mediodorsal thalamus and caudate nucleus of depressed suicides compared with controls, whereas GFAP expression in other brain regions was similar between groups. Furthermore, a regional comparison including all samples revealed that GFAP expression in both subcortical regions was, on average, between 11- and 15-fold greater than in cerebellum and neocortex. Examining astrocyte morphology by immunohistochemistry showed that astrocytes in both thalamus and caudate displayed larger cell bodies and extended more ramified processes across larger domains than the previously described cortical astrocytes. This study reveals that astrocytic abnormalities are not brain wide and suggests that they are restricted to cortical and subcortical networks known to be affected in mood disorders. Additionally, our results show a greater diversity in human astrocytic phenotypes than previously thought.

Cognitive deficits, in relation to ventral and dorsal prefrontal cortex dysfunctions, have been associated with a higher risk of suicidal acts in young adult patients. Although a public health concern, much less is known about the neurocognitive basis of suicidal behavior in elderly. Here, we aimed at assessing alterations in cognitive inhibition, a suspected major mechanism of the suicidal vulnerability, in suicidal depressed elderly.We compared 20 currently depressed patients, aged 65 and older who recently attempted suicide to 20 elderly subjects with a current depression but no personal history of suicide attempt and 20 elderly controls. Using an extensive neuropsychological battery, we particularly examined different aspects of cognitive inhibition: access to relevant information (using the Reading with distraction task), suppression of no longer relevant information (Trail Making Test, Rule Shift Cards), and restraint of cognitive resources to relevant information (Stroop test, Hayling Sentence Completion test, Go/No-Go).After adjustment for age, intensity of depression, Mini-Mental State Examination score and speed of information processing, suicidal depressed elderly showed significant impairments in all 3 domains of cognitive inhibition in comparison to both control groups.Our results need replication in a larger sample size.Our study suggests that the inability to inhibit neutral information access to working memory, restrain and delete irrelevant information may impair the patient's capacity to respond adequately to stressful situations subsequently leading to an increased risk of suicidal behavior during late-life depression. Interventions may be developed to specifically target cognitive impairment in the prevention of suicide in depressed elderly.

To compare levels of methylation of the glucocorticoid receptor (GR) gene (NR3C1) promoter between women with bulimia nervosa (BN) and women with no eating disorder (ED), and also to explore, in women with BN, the extent to which methylation of the GR gene promoter corresponds to childhood abuse, suicidality, or borderline personality disorder (BPD).We measured methylation levels in selected NR3C1 promoter regions using DNA obtained from lymphocytes in 64 women with BN (32 selected as having a history of severe childhood abuse and 32 selected as having no such history) and 32 comparison women with no ED or history of childhood abuse.Compared to noneating disordered women, women with BN and comorbid BPD (or BN with a history of suicidality) showed significantly more methylation of specific exon 1C sites. There was also a (nonsignificant) result indicative of greater methylation in some 1C sites among women with BN, when compared (as a group) to women with no ED. No parallel effects owing to childhood abuse were observed.Our findings associate BN (when accompanied by BPD or suicidality) with hypermethylation of certain GR exon 1C promoter sites. We discuss theoretical and clinical implications of our findings.

Suicidal ideation and suicide attempt (suicidality) are common in adolescence and a public health concern. Childhood depression is a key risk factor for later suicidality and often co-occurs with irritability. No study to date has examined the joint association of depressive mood and irritability during childhood with later suicidality.To investigate the association of childhood irritability and depressive/anxious mood profiles with adolescent suicidality.This population-based cohort study included 1430 participants in the Québec Longitudinal Study of Child Development. Participants underwent assessment yearly or bi-yearly (5 months to 17 years). Data were collected from March 16, 1998, through July 17, 2015.Profiles defined by the joint developmental trajectories of irritability and depressive/anxious mood at 6 to 12 years of age.Self-reported past-year suicidality (ie, serious suicidal ideation or suicide attempt) at 13, 15, and 17 years of age. Irritability and depressive/anxious mood were assessed using teacher report 5 times from 6 to 12 years of age.The study included 1430 participants (676 boys [47.3%] and 754 girls [52.7%]) followed up to 17 years of age. Group-based multitrajectory modeling identified the following profiles: combined no irritability and low depressive/anxious mood with low irritability and low depressive/anxious mood (831 [58.1%]; reference group), moderate irritability and low depressive/anxious mood (353 [24.7%]), high depressive/anxious mood only (94 [6.6%]), and high irritability and depressive/anxious mood (152 [10.6%]). Children with high irritability and high depressive/anxious mood reported higher rates of suicidality (25 of 152 [16.4%]) compared with the group with the lowest symptom levels (91 of 831 [11.0%]). In logistic regression analyses, the high irritability and depressive/anxious mood profile (odds ratio [OR], 2.22; 95% CI, 1.32-3.74; number needed to be exposed [NNE], 18) was associated with suicidality. To a lesser extent, the moderate irritability and low depressive/anxious mood profile was also associated with suicidality (OR, 1.51; 95% CI, 1.02-2.25; NNE = 48). The high depressive/anxious mood only profile was not associated with later suicidality (OR, 0.96; 95% CI, 0.47-1.95; NNE = -320). The high irritability and depressive/anxious mood profile was associated with a higher suicidal risk compared with the depressive/anxious mood only profile (OR, 2.28; 95% CI, 1.02-5.15). Girls with the high irritability and high depressive/anxious mood profile had higher risk for suicidality (OR, 3.07; 95% CI, 1.54-6.12; NNE = 5).Children with high irritability and depressive/anxious mood and, to a lesser extent, with moderate irritability only had a higher suicidal risk during adolescence compared with children with low symptom levels. Early manifestation of chronic irritability during childhood, especially when combined with depressive/anxious mood, may be associated with an elevated risk for adolescent suicidality. The putatively causal role of irritability should be investigated.

Cognitive inhibition deficits have previously been found in suicide attempters. This study examined the neural basis for these deficits in depressed patients with and without a history of suicidal behavior.Functional magnetic resonance imaging was used to measure brain activation during the Go/No-Go response inhibition task in 25 unmedicated and depressed middle-aged suicide attempters, 22 unmedicated depressed patient controls with no personal or family history of suicidal behavior, and 27 healthy controls. Whole-brain analyses were conducted with SPM12.Suicide attempters exhibited an elevated number of commission errors relative to both control groups. However, suicide attempters did not differ from patient controls in terms of brain activation for any contrast. Analyses showed a significant association between depression and brain activation in the left inferior frontal gyrus and medial thalamus during Go v. No-Go, and in the bilateral parietal cortex and left orbitofrontal cortex during No-Go v. baseline. These regions were correlated with psychological pain, suicidal ideation and global functioning. There was no association between brain activation and personal histories of suicidal act.Our study suggests that deficits in cognitive inhibition, in relation to the inferior frontal gyrus, thalamus, orbitofrontal cortex and parietal cortex, are related to the depressive state and not specifically to suicide vulnerability. We hypothesize that state-related deficits may add to trait-like cognitive impairments to facilitate suicidal acts. These different types of cognitive impairments may necessitate different therapeutic strategies for the prevention of suicide.

Depression affects 10-15% of pregnant women and has been associated with preterm delivery and later developmental, behavioural and learning disabilities. We tested the hypothesis that maternal depression is associated with DNA methylation alterations in maternal T lymphocytes, neonatal cord blood T lymphocytes and adult offspring hippocampi. Genome-wide DNA methylation of CD3+ T lymphocytes isolated from 38 antepartum maternal and 44 neonatal cord blood samples were analyzed using Illumina Methylation 450 K microarrays. Previously obtained methylation data sets using methylated DNA immunoprecipitation and array-hybridization of 62 postmortem hippocampal samples of adult males were re-analyzed to test associations with history of maternal depression. We found 145 (false discovery rate (FDR) q<0.05) and 2520 (FDR q<0.1) differentially methylated CG-sites in cord blood T lymphocytes of neonates from the maternal depression group as compared with the control group. However, no significant DNA methylation differences were detected in the antepartum maternal T lymphocytes of our preliminary data set. We also detected 294 differentially methylated probes (FDR q<0.1) in hippocampal samples associated with history of maternal depression. We observed a significant overlap (P=0.002) of 33 genes with changes in DNA methylation in T lymphocytes of neonates and brains of adult offspring. Many of these genes are involved in immune system functions. Our results show that DNA methylation changes in offspring associated with maternal depression are detectable at birth in the immune system and persist to adulthood in the brain. This is consistent with the hypothesis that system-wide epigenetic changes are involved in life-long responses to maternal depression in the offspring.

Adolescence is a period of heightened susceptibility to psychiatric disorders of medial prefrontal cortex (mPFC) dysfunction and cognitive impairment. mPFC dopamine (DA) projections reach maturity only in early adulthood, when their control over cognition becomes fully functional. The mechanisms governing this protracted and unique development are unknown. Here we identify dcc as the first DA neuron gene to regulate mPFC connectivity during adolescence and dissect the mechanisms involved. Reduction or loss of dcc from DA neurons by Cre-lox recombination increased mPFC DA innervation. Underlying this was the presence of ectopic DA fibers that normally innervate non-cortical targets. Altered DA input changed the anatomy and electrophysiology of mPFC circuits, leading to enhanced cognitive flexibility. All phenotypes only emerged in adulthood. Using viral Cre, we demonstrated that dcc organizes mPFC wiring specifically during adolescence. Variations in DCC may determine differential predisposition to mPFC disorders in humans. Indeed, DCC expression is elevated in brains of antidepressant-free subjects who committed suicide.

Objectives: Many factors influence the likelihood of suicide attempts or deaths in persons with bipolar disorder. One key aim of the International Society for Bipolar Disorders Task Force on Suicide was to summarize the available literature on the presence and magnitude of effect of these factors. Methods: A systematic review of studies published from 1 January 1980 to 30 May 2014 identified using keywords ‘bipolar disorder’ and ‘suicide attempts or suicide’. This specific paper examined all reports on factors putatively associated with suicide attempts or suicide deaths in bipolar disorder samples. Factors were subcategorized into: (1) sociodemographics, (2) clinical characteristics of bipolar disorder, (3) comorbidities, and (4) other clinical variables. Results: We identified 141 studies that examined how 20 specific factors influenced the likelihood of suicide attempts or deaths. While the level of evidence and degree of confluence varied across factors, there was at least one study that found an effect for each of the following factors: sex, age, race, marital status, religious affiliation, age of illness onset, duration of illness, bipolar disorder subtype, polarity of first episode, polarity of current/recent episode, predominant polarity, mood episode characteristics, psychosis, psychiatric comorbidity, personality characteristics, sexual dysfunction, first-degree family history of suicide or mood disorders, past suicide attempts, early life trauma, and psychosocial precipitants. Conclusion: There is a wealth of data on factors that influence the likelihood of suicide attempts and suicide deaths in people with bipolar disorder. Given the heterogeneity of study samples and designs, further research is needed to replicate and determine the magnitude of effect of most of these factors. This approach can ultimately lead to enhanced risk stratification for patients with bipolar disorder.

MicroRNAs (miRNAs) are small, non-coding RNA molecules that play an important role in the post-transcriptional regulation of mRNA. These molecules have been the subject of growing interest as they are believed to control the regulation of a large number of genes, including those expressed in the brain. Evidence suggests that miRNAs could be involved in the pathogenesis of neuropsychiatric disorders. Alterations in metabolic enzymes of the polyamine system have been reported to play a role in predisposition to suicidal behaviour. We have previously shown the expression of the polyamine genes SAT1 and SMOX to be down-regulated in the brains of suicide completers. In this study, we hypothesized that the dysregulation of these genes in depressed suicide completers could be influenced by miRNA post-transcriptional regulation. Using a stringent target prediction analysis, we identified several miRNAs that target the 3'UTR of SAT1 and SMOX. We profiled the expression of 10 miRNAs in the prefrontal cortex (BA44) of suicide completers (N = 15) and controls (N = 16) using qRT-PCR. We found that several miRNAs showed significant up-regulation in the prefrontal cortex of suicide completers compared to psychiatric healthy controls. Furthermore, we demonstrated a significant correlation between these miRNAs and the expression levels of both SAT1 and SMOX. Our results suggest a relationship between miRNAs and polyamine gene expression in the suicide brain, and postulate a mechanism for SAT1 and SMOX down-regulation by post-transcriptional activity of miRNAs.

Purpose of review Major depressive disorder (MDD) is among the most prevalent and disabling medical conditions worldwide. Despite its considerable burden, our understanding of its pathophysiology remains rudimentary, and a validated biomarker has yet to be identified. Antidepressants are the most common treatment for MDD, yet roughly one-third of patients experience an inadequate response. Thus, there is a great need for not only identifying biomarkers of MDD but also those that can predict and monitor or just monitor response to treatment. Recent findings MicroRNAs (miRNAs) act as endogenous fine-tuners and on–off switches of gene expression. Several lines of evidence now suggest that miRNAs are involved in the pathogenesis of neuropsychiatric disorders. As such, miRNAs offer great hope as biomarkers of disease and response to treatment. Summary In this review, we discuss the growing field, investigating peripheral miRNAs as potential biomarkers of major depression and treatment response. A noninvasive and validated biomarker of MDD or treatment response will help clinicians guide treatment selection. Ultimately, these findings provide important steps in the development of early diagnostic tools, preventive strategies, and effective pharmacological treatment for psychiatric disorders.

Chronic social defeat stress in mice produces a susceptible phenotype characterized by several behavioral abnormalities consistent with human depression that are reversed by chronic but not acute exposure to antidepressant medications. Recent work in addiction models demonstrates that the transcription factor ΔFosB and protein kinase calmodulin-dependent protein kinase II (CaMKII) are co-regulated in nucleus accumbens (NAc), a brain reward region implicated in both addiction and depression models including social defeat. Previous work has also demonstrated that ΔFosB is induced in NAc after chronic social defeat stress or after chronic antidepressant treatment, wherein it mediates a pro-resilience or antidepressant-like phenotype. Here, using chromatin immunoprecipitation assays, we found that ΔFosB binds the CaMKIIα gene promoter in NAc and that this binding increases after mice are exposed to chronic social defeat stress. Paradoxically, chronic exposure to the antidepressant fluoxetine reduces binding of ΔFosB to the CaMKIIα promoter and reduces CaMKII expression in NAc, despite the fact that ΔFosB is induced under these conditions. These data suggest a novel epigenetic mechanism of antidepressant action, whereby fluoxetine induces some chromatin change at the CaMKIIα promoter, which blocks the ΔFosB binding. Indeed, chronic fluoxetine reduces acetylation and increases lysine-9 dimethylation of histone H3 at the CaMKIIα promoter in NAc, effects also seen in depressed humans exposed to antidepressants. Overexpression of CaMKII in NAc blocks fluoxetine's antidepressant effects in the chronic social defeat paradigm, whereas inhibition of CaMKII activity in NAc mimics fluoxetine exposure. These findings suggest that epigenetic suppression of CaMKIIα expression in NAc is behaviorally relevant and offer a novel pathway for possible therapeutic intervention in depression and related syndromes.

Glutamate is the major excitatory transmitter in the brain. Vesicular glutamate transporters (VGLUT1-3) are responsible for uploading glutamate into synaptic vesicles. VGLUT1 and VGLUT2 are considered as specific markers of canonical glutamatergic neurons, while VGLUT3 is found in neurons previously shown to use other neurotransmitters than glutamate. Although there exists a rich literature on the localization of these glutamatergic markers in the rodent brain, little is currently known about the distribution of VGLUT1-3 in the human brain. In the present study, using subtype specific probes and antisera, we examined the localization of the three vesicular glutamate transporters in the human brain by in situ hybridization, immunoautoradiography and immunohistochemistry. We found that the VGLUT1 transcript was highly expressed in the cerebral cortex, hippocampus and cerebellum, whereas VGLUT2 mRNA was mainly found in the thalamus and brainstem. VGLUT3 mRNA was localized in scarce neurons within the cerebral cortex, hippocampus, striatum and raphe nuclei. Following immunoautoradiographic labeling, intense VGLUT1- and VGLUT2-immunoreactivities were observed in all regions investigated (cerebral cortex, hippocampus, caudate-putamen, cerebellum, thalamus, amygdala, substantia nigra, raphe) while VGLUT3 was absent from the thalamus and cerebellum. This extensive mapping of VGLUT1-3 in human brain reveals distributions that correspond for the most part to those previously described in rodent brains.

Brain-derived neurotrophic factor (BDNF) is a critical effector of depression-like behaviors and antidepressant responses. Here, we show that VGF (non-acronymic), which is robustly regulated by BDNF/TrkB signaling, is downregulated in hippocampus (male/female) and upregulated in nucleus accumbens (NAc) (male) in depressed human subjects and in mice subjected to chronic social defeat stress (CSDS). Adeno-associated virus (AAV)-Cre-mediated Vgf ablation in floxed VGF mice, in dorsal hippocampus (dHc) or NAc, led to pro-depressant or antidepressant behaviors, respectively, while dHc- or NAc-AAV-VGF overexpression induced opposite outcomes. Mice with reduced VGF levels in the germ line (Vgf+/-) or in dHc (AAV-Cre-injected floxed mice) showed increased susceptibility to CSDS and impaired responses to ketamine treatment in the forced swim test. Floxed mice with conditional pan-neuronal (Synapsin-Cre) but not those with forebrain (αCaMKII-Cre) Vgf ablation displayed increased susceptibility to subthreshold social defeat stress, suggesting that neuronal VGF, expressed in part in inhibitory interneurons, regulates depression-like behavior. Acute antibody-mediated sequestration of VGF-derived C-terminal peptides AQEE-30 and TLQP-62 in dHc induced pro-depressant effects. Conversely, dHc TLQP-62 infusion had rapid antidepressant efficacy, which was reduced in BDNF floxed mice injected in dHc with AAV-Cre, and in NBQX- and rapamycin-pretreated wild-type mice, these compounds blocking α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and mammalian target of rapamycin (mTOR) signaling, respectively. VGF is therefore a critical modulator of depression-like behaviors in dHc and NAc. In hippocampus, the antidepressant response to ketamine is associated with rapid VGF translation, is impaired by reduced VGF expression, and as previously reported, requires coincident, rapid BDNF translation and release.

Genome wide array studies have reported limited success in identifying genetic markers conferring risk for suicidal behavior (SB). This may be attributable to study designs with primary outcome other than SB. We performed a GWAS on suicides and cases with a history of nonfatal suicide attempts compared with psychiatric controls and healthy volunteers. A consortium of USA, Canadian and German teams assembled two groups of cases (suicide attempters and suicides, N = 577) and non-attempter psychiatric and healthy controls (N = 1,233). Logistic regression was used to test genotype-suicidal behavior association. The test was repeated separating suicide attempt and completed suicide as outcomes. No SNP reached genome-wide significance, but several SNPs within STK3, ADAMTS14, PSME2, and TBX20 genes reached P < 1 × 10(-5) . The top SNPs for the suicide attempt analysis included two from DPP10, one from CTNNA3 and one from STK32B. In the suicide analysis we found seven SNPs from the TBX20 gene in the top hits. Pathway analysis identified the following pathways: "Cellular Assembly and Organization," "Nervous System Development and Function," "Cell Death and Survival," "Immunological Disease," "Infectious Disease," and "Inflammatory Response." The top genes in the SB analysis did not overlap with those in the ideation analysis. No genome wide significant results suggest that susceptibility to SB has genetic risk factors with smaller effect sizes. The strongest candidate genes, ADAMTS14, and PSME2 (both linked to inflammatory response), STK3 (neuronal cell death), and TBX20 (brainstem motor neuron development), have not been previously reported in association with suicide and warrant further study.

Glutamate receptors are promising drug targets for the treatment of urgent suicide ideation and chronic major depressive disorder (MDD) that may lead to suicide completion. Antagonists of glutamatergic NMDA receptors reduce depressive symptoms faster than traditional antidepressants, with beneficial effects occurring within hours. Glutamate is the prominent excitatory input to the noradrenergic locus coeruleus (LC). The LC is activated by stress in part through this glutamatergic input. Evidence has accrued demonstrating that the LC may be overactive in MDD, while treatment with traditional antidepressants reduces LC activity. Pathological alterations of both glutamatergic and noradrenergic systems have been observed in depressive disorders, raising the prospect that disrupted glutamate-norepinephrine interactions may be a central component to depression and suicide pathobiology. This study examined the gene expression levels of glutamate receptors in post-mortem noradrenergic LC neurons from subjects with MDD (most died by suicide) and matched psychiatrically normal controls. Gene expression levels of glutamate receptors or receptor subunits were measured in LC neurons collected by laser capture microdissection. MDD subjects exhibited significantly higher expression levels of the NMDA receptor subunit genes, GRIN2B and GRIN2C, and the metabotropic receptor genes, GRM4 and GRM5, in LC neurons. Gene expression levels of these receptors in pyramidal neurons from prefrontal cortex (BA10) did not reveal abnormalities in MDD. These findings implicate disrupted glutamatergic-noradrenergic interactions at the level of the stress-sensitive LC in MDD and suicide, and provide a theoretical mechanism by which glutamate antagonists may exert rapid antidepressant effects.

Cocaine-mediated repression of the histone methyltransferase (HMT) G9a has recently been implicated in transcriptional, morphological and behavioral responses to chronic cocaine administration. Here, using a ribosomal affinity purification approach, we found that G9a repression by cocaine occurred in both Drd1-expressing (striatonigral) and Drd2-expressing (striatopallidal) medium spiny neurons. Conditional knockout and overexpression of G9a within these distinct cell types, however, revealed divergent behavioral phenotypes in response to repeated cocaine treatment. Our studies further indicated that such developmental deletion of G9a selectively in Drd2 neurons resulted in the unsilencing of transcriptional programs normally specific to striatonigral neurons and in the acquisition of Drd1-associated projection and electrophysiological properties. This partial striatopallidal to striatonigral 'switching' phenotype in mice indicates a new role for G9a in contributing to neuronal subtype identity and suggests a critical function for cell type-specific histone methylation patterns in the regulation of behavioral responses to environmental stimuli.

Improved treatment for major depressive disorder (MDD) remains elusive because of the limited understanding of its underlying biological mechanisms. It is likely that stress-induced maladaptive transcriptional regulation in limbic neural circuits contributes to the development of MDD, possibly through epigenetic factors that regulate chromatin structure. We establish that persistent upregulation of the ACF (ATP-utilizing chromatin assembly and remodeling factor) ATP-dependent chromatin-remodeling complex, occurring in the nucleus accumbens of stress-susceptible mice and depressed humans, is necessary for stress-induced depressive-like behaviors. We found that altered ACF binding after chronic stress was correlated with altered nucleosome positioning, particularly around the transcription start sites of affected genes. These alterations in ACF binding and nucleosome positioning were associated with repressed expression of genes implicated in susceptibility to stress. Together, our findings identify the ACF chromatin-remodeling complex as a critical component in the development of susceptibility to depression and in regulating stress-related behaviors.