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Major depressive disorder (MDD) is one of the most prevalent and debilitating psychiatric disorders, with a large number of patients not showing an effective therapeutic response to available treatments. Several biopsychosocial factors, such as stress in childhood and throughout life, and factors related to biological aging, may increase the susceptibility to MDD development. Included in critical biological processes related to aging and underlying biological mechanisms associated with MDD is the shortening of telomeres and changes in telomerase activity. This comprehensive review discusses studies that assessed the length of telomeres or telomerase activity and function in peripheral blood cells and brain tissues of MDD individuals. Also, results from in vitro protocols and animal models of stress and depressive-like behaviors were included. We also expand our discussion to include the role of telomere biology as it relates to other relevant biological mechanisms, such as the hypothalamic-pituitary-adrenal (HPA) axis, oxidative stress, inflammation, genetics, and epigenetic changes. In the text and the discussion, conflicting results in the literature were observed, especially considering the size of telomeres in the central nervous system, on which there are different protocols with divergent results in the literature. Finally, the context of this review is considering cell signaling, transcription factors, and neurotransmission, which are involved in MDD and can be underlying to senescence, telomere shortening, and telomerase functions.

Background Opioid use disorder (OUD) affects millions of people, causing nearly 50 000 deaths annually in the United States. While opioid exposure and OUD are known to cause widespread transcriptomic and epigenetic changes, few studies in human samples have been conducted. Understanding how OUD affects the brain at the molecular level could help decipher disease pathogenesis and shed light on OUD treatment. Methods We generated genome-wide transcriptomic and DNA methylation profiles of 22 OUD subjects and 19 non-psychiatric controls. We applied weighted gene co-expression network analysis to identify genetic markers consistently associated with OUD at both transcriptomic and methylomic levels. We then performed functional enrichment for biological interpretation. We employed cross-omics analysis to uncover OUD-specific regulatory networks. Results We found 6 OUD-associated co-expression gene modules and 6 co-methylation modules (false discovery rate Conclusions Our integrative analysis of multi-omics data in OUD postmortem brain samples suggested complex gene regulatory mechanisms involved in OUD-associated expression patterns. Candidate genes and their upstream regulators revealed in astrocyte, and glial cells could provide new insights into OUD treatment development.

Background There has been growing scientific evidence in recent years that bipolar disorder (BD) is associated with alterations in the kynurenine (KYN) pathway. However, many of these studies have been limited by their focus on adults. Thus, this preliminary study investigated differences in the peripheral levels of KYN metabolites in children and adolescents with BD, unaffected offspring of parents with BD, and healthy controls (HCs). Methods Plasma samples were collected from 49 youths with BD, 19 bipolar offspring, and 31 HCs. Tryptophan (TRP), KYN, and kynurenic acid (KYNA) were separated using electrospray ionization. Results One-Way ANCOVA after controlling for age, gender, race, BMI-for-age, and smoking status showed that BD had lower levels of KYN, while unaffected high-risk offspring subjects had lower levels of TRP, KYN, and KYNA when compared to HCs. Moreover, we found that KYN, KYN/TRP, and KYNA/KYN levels predicted the severity of depressive symptoms, while the YMRS score was not associated with any metabolite. Conclusions In summary, this preliminary study has shown that KYN metabolites are decreased in both affected and unaffected subjects, strengthening the idea that the KYN pathway might underlie the familial risk of BD shown by high-risk offspring individuals. However, longitudinal studies are needed to examine whether the alterations observed in this study represent early markers of risk for later developing BD.

Objectives Evidence suggests accelerated aging mechanisms in bipolar disorder (BD), including DNA methylation (DNAm) aging in blood. However, it is unknown whether such mechanisms are also evident in the brain, in particular in association with other biological clocks. To investigate this, we interrogated genome-wide DNAm in postmortem hippocampus from 32 BD-I patients and 32 non-psychiatric controls group-matched for age and sex from the NIMH Human Brain Collection Core. Methods DNAm age and epigenetic aging acceleration were estimated using the Horvath method. Telomere length (TL) and mitochondrial DNA (mtDNA) copy number were quantified by real-time PCR. Between-group differences were assessed by linear regression and univariate general linear models with age, sex, race, postmortem interval, tissue pH, smoking, and body mass index included as co-variates. Results Groups did not differ for epigenetic aging acceleration when considering the entire sample. However, after splitting the sample by the median age, an epigenetic aging acceleration was detected in patients compared to controls among older subjects (P = .042). While TL did not differ between groups, a reduction in mtDNA copy number was observed in patients compared to controls (P = .047). In addition, significant correlations were observed between epigenetic aging acceleration and TL (r = -.337, P = .006), as well as between TL and mtDNA copy number (r = .274, P = .028). Conclusions Hippocampal aging may underlie neurocognitive dysfunctions observed in BD patients. Moreover, our results suggest a complex cross-talk between biological clocks in hippocampus that may underlie clinical manifestations of premature aging in BD.

Background The search for biomarkers of bipolar disorder (BD), including epigenetic alterations, has heavily relied on peripheral investigations that do not necessarily reflect brain-specific mechanisms. In this study we aimed to assess peripheral extracellular vesicles (EVs)’ microRNAs and determine their use as a novel source of biomarkers in BD. Methods We assessed peripheral blood EVs’ microRNAs from 20 patients with BD type I and 21 age- and sex-matched healthy controls by microarray, and further explored the predicted biological functions of significantly differentially expressed microRNAs. Results Our results identified 33 nominally significant microRNAs (p 1.5) altered in BD patients, including miRNAs previously reported to be altered in post-mortem tissues of patients. Pathway analyses identified some brain-relevant mechanisms enriched in these miRNAs, including axon guidance by netrin and the serotonin receptor pathway. Limitations Relatively small sample size, potential confounding effects of mood states, medication use, and comorbidities, analysis of total rather than brain-specific EVs, and lack of validation of significant miRNAs by other methods. Conclusions This study provides important preliminary evidence of the potential use of EVs as a novel source of biomarkers in BD. Overall, our findings of brain-relevant mechanisms in these vesicles suggest their potential use in living patients as a peripheral window to the brain.

Evidence on the relationship between genetics and mental health are flourishing. However, few studies are evaluating early biomarkers that might link genes, environment, and psychopathology. We aimed to study telomere length (TL) and epigenetic age acceleration (AA) in a cohort of adolescents with and without anxiety disorders (N = 234). We evaluated a representative subsample of participants at baseline and after 5 years (n = 76) and categorized them according to their anxiety disorder diagnosis at both time points: (1) control group (no anxiety disorder, n = 18), (2) variable group (anxiety disorder in one evaluation, n = 38), and (3) persistent group (anxiety disorder at both time points, n = 20). We assessed relative mean TL by real-time quantitative PCR and DNA methylation by Infinium HumanMethylation450 BeadChip. We calculated AA using the Horvath age estimation algorithm and analyzed differences among groups using generalized linear mixed models. The persistent group of anxiety disorder did not change TL over time (p = 0.495). The variable group had higher baseline TL (p = 0.003) but no accelerated TL erosion in comparison to the non-anxiety control group (p = 0.053). Furthermore, there were no differences in AA among groups over time. Our findings suggest that adolescents with chronic anxiety did not change telomere length over time, which could be related to a delay in neuronal development in this period of life.

Genome-wide screenings of “essential genes”, i.e., genes required for an organism or cell survival, have been traditionally conducted in vitro in cancer cell lines, limiting the translation of results to other tissues and non-cancerous cells. Recently, an in vivo screening was conducted in adult mouse striatum tissue, providing the first genome-wide dataset of essential genes in neuronal cells. Here, we aim to investigate the role of essential genes in brain development and disease risk with a comprehensive set of bioinformatics tools, including integration with transcriptomic data from developing human brain, publicly available data from genome-wide association studies, de novo mutation datasets for different neuropsychiatric disorders, and case–control transcriptomic data from postmortem brain tissues. For the first time, we found that the expression of neuronal essential genes (NEGs) increases before birth during the early development of human brain and maintains a relatively high expression after birth. On the contrary, common essential genes from cancer cell line screenings (ACEGs) tend to be expressed at high levels during development but quickly drop after birth. Both gene sets were enriched in neurodevelopmental disorders, but only NEGs were robustly associated with neuropsychiatric disorders risk genes. Finally, NEGs were more likely to show differential expression in the brains of neuropsychiatric disorders patients than ACEGs. Overall, genome-wide central nervous system screening of essential genes can provide new insights into neuropsychiatric diseases.

White matter (WM) abnormalities in patients with cocaine use disorder (CUD) have been studied; however, the reported effects on the human brain are heterogenous and most results have been obtained from male participants. In addition, biological data supporting the imaging findings and revealing possible mechanisms underlying the neurotoxic effects of chronic cocaine use (CU) on WM are largely restricted to animal studies. To evaluate the neurotoxic effects of CU in the WM, we performed an in vivo diffusion tensor imaging assessment of male and female cocaine users (n = 75) and healthy controls (HC) (n = 58). Moreover, we performed an ex vivo large-scale proteomic analysis using liquid chromatography-tandem mass spectrometry in postmortem brains of patients with CUD (n = 8) and HC (n = 12). Compared with the HC, the CUD group showed significant reductions in global fractional anisotropy (FA) (p p p = 0.0421) and female sex (p p = 0.006) and higher RD (p p = 0.019). Proteomics analyses in BA9 found 11 proteins differentially expressed between cocaine users and controls. Among these, were proteins related to myelination and neuroinflammation. In summary, we demonstrate convergent evidence from in vivo diffusion tensor imaging and ex vivo proteomics analysis of WM disruption in CUD.

Opioid use disorder (OUD) is a public health crisis in the U.S. that causes over 50 thousand deaths annually due to overdose. Using next-generation RNA sequencing and proteomics techniques, we identified 394 differentially expressed (DE) coding and long noncoding (lnc) RNAs as well as 213 DE proteins in Brodmann Area 9 of OUD subjects. The RNA and protein changes converged on pro-angiogenic gene networks and cytokine signaling pathways. Four genes (LGALS3, SLC2A1, PCLD1, and VAMP1) were dysregulated in both RNA and protein. Dissecting these DE genes and networks, we found cell type-specific effects with enrichment in astrocyte, endothelial, and microglia correlated genes. Weighted-genome correlation network analysis (WGCNA) revealed cell-type correlated networks including an astrocytic/endothelial/microglia network involved in angiogenic cytokine signaling as well as a neuronal network involved in synaptic vesicle formation. In addition, using ex vivo magnetic resonance imaging, we identified increased vascularization in postmortem brains from a subset of subjects with OUD. This is the first study integrating dysregulation of angiogenic gene networks in OUD with qualitative imaging evidence of hypervascularization in postmortem brain. Understanding the neurovascular effects of OUD is critical in this time of widespread opioid use.

Bipolar disorder (BD) is a severe, chronic, and multifactorial psychiatric disorder thought to result from an interaction between genetic susceptibility factors and environmental triggers. Part of BD’s heritability might be accounted for by epigenetic mechanisms, which mainly include DNA methylation, histone modifications, chromatin remodeling, and the actions of noncoding RNAs that can modulate gene expression in response to the environment. Epigenetic modifications, described as hereditary but potentially reversible alterations, have been consistently implicated in the pathogenesis of BD, with several studies suggesting that epigenetic alterations may alter the regulation of gene expression in BD, with a great potential use both for discovering disease biomarkers and for therapeutic interventions. This chapter aims to review evidence of the potential key role of epigenetic alterations in the pathophysiology of BD.

Bipolar disorder (BD) is a complex and potentially severe psychiatric disorder associated with high heritability estimates and a multifactorial polygenic genetic basis. Although the latest genome-wide association studies have successfully suggested many common genetic variants to be involved with BD, its genetic basis remains only partly explained and does not fully incorporate relevant information regarding ‘gene by environment’ interactions thought to play a key role in this disorder. In this chapter, we review and discuss evidence of epigenetic alterations in patients with BD, focusing on alterations reported in both central and peripheral tissues involving changes to DNA, histone proteins, and the regulatory role of non-coding RNAs. As discussed in details, these mechanisms are not only thought to underlie important pathophysiological features of disease, but also to play important roles in the mechanisms of action of mood stabilizers and antipsychotic medications.

Mental and behavioral disorders are becoming the leading cause of disability across the world. Along with the ongoing development of biomedical and computational technologies, more and more data are being constantly produced, including genomic, transcriptomic, metabolomic, proteomic, clinical, and imaging resources. As a consequence, scientists in the psychiatric field are actively changing their research ways from studies focused on individual investigators to large international consortia, which accelerate the data accumulation and increase its size. This chapter discusses the current publicly available data sets on psychiatry disorders and neuroscience, as well as their integrated analysis. The authors also list some studies using novel types of data, which will further extent the potential of big data in the study of psychiatric disorders.

Patients with substance use disorders (SUD) are at high risk to die by suicide. So far, the neurobiology of the suicide-SUD association has not been elucidated. This study aimed to identify potential pharmacological targets among hub genes from brain gene co-expression networks of individuals with SUD in a suicidal and non-suicidal context. Post-mortem samples from the prefrontal cortex of 79 individuals were analyzed. Individuals were classified into the following groups: suicides with SUD (n = 28), suicides without SUD (n = 23), nonsuicides with SUD (n = 9), nonsuicides without SUD (n = 19). Gene expression profiles were evaluated with the Illumina HumanHT-12 v4 array. Co-expression networks were constructed in WGCNA using the differentially expressed genes found in the comparisons: (a) suicides with and without SUD and (b) nonsuicides with and without SUD. Hub genes were selected for drug-gene interaction testing in the DGIdb database. Among drugs interacting with hub genes in suicides we found MAOA inhibitors and dextromethorphan. In the nonsuicide individuals, we found interactions with eglumegad and antipsychotics (olanzapine, clozapine, loxapine). Modafinil was found to interact with genes in both suicides and nonsuicides. These drugs represent possible candidate treatments for patients with SUD with and without suicidal behavior and their study in each context is encouraged.

Background Gene expression alterations have been implicated in suicide pathology. However, the study of the regulatory effect of DNA methylation on gene expression in the suicidal brain has been restricted to candidate genes. Objective The objective of the study was to identify genes whose expression levels are correlated with DNA methylation in the prefrontal cortex of suicides. Methods Postmortem prefrontal cortex samples from 21 suicides and six non-suicides were collected. Transcriptomic and DNA methylation profiles were evaluated with microarrays; cis correlations between gene expression and CpG methylation were screened. We then analyzed the presence of transcription factor (TF) binding sites (TFBS) at CpG sites correlated with gene expression. Gene expression of TFs involved in neurodevelopmental binding to predicted TFBS was determined in the BrainSpan database. Results We identified 22 CpG sites whose methylation levels correlated with gene expression in the prefrontal cortex of suicides. Genes annotated to identified CpG sites were involved in neurodevelopment (BBS4, NKX6-2, AXL, CTNND1, and MBP) and polyamine metabolism (polyamine oxidase [PAOX]). Such correlations were not detected in the nonsuicide group. Nine TFs (USF1, TBP, SF1, NRF1, RFX1, SP3, PKNOX1, MAZ, and POU3F2) showed differential expression in pre- and post-natal developmental periods, according to BrainSpan database. Conclusions The integration of different omic technologies provided novel candidates for the investigation of genes whose expression is altered in the suicidal brain and their potential regulatory mechanisms.

There is an increasing interest in the putative role of glucagon-like peptide 1 receptor (GLP-1R) agonists as novel therapeutic agents for mental disorders. Herein, we investigated the expressions of GLP-1R and GLP-2R genes, and its relationship with body mass index (BMI), in the post-mortem brain tissue of patients with mood (MD) and psychotic disorders. Brain samples were localized to the dorsolateral prefrontal cortex (dlPFC) (n = 459) and hippocampus (n = 378). After adjustment for age, sex, ethnicity, post-mortem interval (PMI) and BMI, we observed significant differences, between healthy controls and MD subjects, in GLP-1R and GLP-2R gene expression in the dlPFC (β = 1.504, p = 0.004; and β = 1.305, p = 0.011, respectively); whereas in the hippocampus, only GLP-1R expression was significantly associated with MD (β = −1.28, p = 0.029). No significant differences were found in relation to schizophrenia. In addition, we observed a moderating effect of MD diagnosis on the associations between BMI, GLP-1R and GLP-2R expression values in the dlPFC (β = −0.05, p = 0.003; and β = −0.04, p = 0.004, respectively). There was a similar moderating effect for GLP-1R in the hippocampus (β = 0.043, 95% CI 0.003; 0.08 p = 0.03), but in an opposite direction than observed in the dlPFC. This is the first evidence of abnormal gene expression of GLP-1R and GLP-2R in postmortem brain of individuals with MD, providing a rationale for further inquiry and proof of principle interventional studies.

Human-induced pluripotent stem cells (hiPSCs) allow for the establishment of brain cellular models of psychiatric disorders that account for a patient’s genetic background. Here, we conducted an RNA-sequencing profiling study of hiPSC-derived cell lines from schizophrenia (SCZ) subjects, most of which are from a multiplex family, from the population isolate of the Central Valley of Costa Rica. hiPSCs, neural precursor cells, and cortical neurons derived from six healthy controls and seven SCZ subjects were generated using standard methodology. Transcriptome from these cells was obtained using Illumina HiSeq 2500, and differential expression analyses were performed using DESeq2 (|fold change|>1.5 and false discovery rate

Bipolar disorder (BD) is a chronic mental illness characterized by changes in mood that alternate between mania and hypomania or between depression and mixed states, often associated with functional impairment. Although effective pharmacological and non-pharmacological treatments are available, several patients with BD remain symptomatic. The advance in the understanding of the neurobiology underlying BD could help in the identification of new therapeutic targets as well as biomarkers for early detection, prognosis, and response to treatment in BD. In this review, we discuss genetic, epigenetic, molecular, physiological and neuroimaging findings associated with the neurobiology of BD. Despite the advances in the pathophysiological knowledge of BD, the diagnosis and management of the disease are still essentially clinical. Given the complexity of the brain and the close relationship between environmental exposure and brain function, initiatives that incorporate genetic, epigenetic, molecular, physiological, clinical, environmental data, and brain imaging are necessary to produce information that can be translated into prevention and better outcomes for patients with BD.

Bipolar disorder (BD) has been previously associated with accelerated aging, and recent investigations have started to explore the potential anti-aging effects of BD treatments. Lithium, the most commonly used mood stabilizer, has been suggested to impact telomere length in specific populations, although its effects on other aging biomarkers, such as epigenetic aging, have never been investigated. We assessed the in vitro effects of lithium on telomere length and epigenetic aging in lymphoblastoid cell lines (LCLs) from 14 patients with BD and 14 controls, all matched for age, sex, and ethnicity. Our results showed that telomere length significantly correlated with chronological age in LCLs in both groups and that BD patients have shorter telomere lengths compared to controls at baseline (vehicle treatment), confirming previous in vivo findings. Moreover, lithium treatment significantly increased telomere length in LCLs from patients, but not in controls. On the other hand, epigenetic age did not correlate with chronological age and was not shown to differ between patients and controls. In addition, lithium did not induce any changes in epigenetic age in cells from either patients or controls. Overall, our results support previous reports of an anti-aging effect of lithium based on its modulation of telomere length and suggest a different lithium effect in cells from patients and controls. Finally, we also discuss the limitations of using transformed LCLs for the study of DNA methylation mechanisms.

Bipolar disorder (BD) is a chronic, debilitating illness with a global prevalence of up to 4.8%. The importance of understanding how dysfunctional mitochondria and mitophagy contribute to cell survival and death in BD is becoming increasingly apparent. Therefore, the purpose of this study was to evaluate the mitophagic pathway and NLRP3 inflammasome activation in peripheral blood mononuclear cells (PBMCs) of patients with BD and healthy individuals. Since 18-kDa translocator protein (TSPO) plays an important role in regulating mitochondrial function and since TSPO itself impairs cellular mitophagy, we also investigated the changes in the TSPO-related pathway. Our results showed that patients with BD had lower levels of Parkin, p62/SQSTM1 and LC3A and an upregulation of TSPO pathway proteins (TSPO and VDAC), both in terms of mRNA and protein levels. Additionally, we found a negative correlation between mitophagy-related proteins and TSPO levels, while VDAC correlated negatively with p62/SQSTM1 and LC3 protein levels. Moreover, we found that the gene expression levels of the NLRP3-related proteins NLRP3, ASC, and pro-casp1 were upregulated in BD patients, followed by an increase in caspase-1 activity as well as IL-1β and IL-18 levels. As expected, there was a strong positive correlation between NLRP3-related inflammasome activation and TSPO-related proteins. The data reported here suggest that TSPO-VDAC complex upregulation in BD patients, the simultaneous downregulation of mitophagic proteins and NLRP3 inflammasome activation could lead to an accumulation of dysfunctional mitochondria, resulting in inflammation and apoptosis. In summary, the findings of this study provide novel evidence that mitochondrial dysfunction measured in peripheral blood is associated with BD.

Preclinical studies implicate insulin signaling as a modulator of dopamine transmission, but human data is currently limited. We hypothesize that changes in the expression of insulin receptor-related genes in the post-mortem brain tissue of patients with mood and psychotic disorders mediate the expression of dopamine regulation-related genes. From a database containing microarray data from the post-mortem dorsolateral prefrontal cortex (dlPFC) (healthy controls [HC]: n = 209; patients: n = 321) and hippocampus (HC: n = 180; patients: n = 196), we conducted a hypothesis-driven analysis through the a priori selection of 12 dopamine- and 3 insulin-related genes. Mediation and moderated mediation models, accounting for the role of body mass index (BMI), were used. In the dlPFC, expressions of insulin receptor- and dopamine regulation-related genes were moderated by BMI, with significantly lower expression in high BMI patients. In the hippocampus, there were significantly lower expressions of these genes, which were not moderated by BMI. Illnesses by BMI effects on expression of dopamine genes were fully mediated by expression of insulin receptor gene (INSR). Analysis of conditional indirect effects showed interactions between INSR and BMI, indicating significantly stronger indirect effects at higher BMI values. In the hippocampus we observed that expression of insulin receptor substrate 1 and 2 fully mediated the effects of illnesses on expression of dopamine genes. In conclusion, differential expression of dopamine-related genes was related to altered expression of insulin signaling genes. BMI had region-specific effects, supporting the hypothesis that metabolic systems are critical mediators of dopaminergic function.

Bipolar disorder (BD) is a chronic psychiatric disorder marked by clinical and pathophysiological heterogeneity. There is a high expectation that personalized approaches can improve the management of patients with BD. For that, identification and validation of potential biomarkers are fundamental. Areas covered: This manuscript will critically review the current status of different biomarkers for BD, including peripheral, genetic, neuroimaging, and neurophysiological candidates, discussing the challenges to move the field forward. Expert commentary: There are no lab or complementary tests currently recommended for the diagnosis or management of patients with BD. Panels composed by multiple biomarkers will probably contribute to stratifying patients according to their clinical stage, therapeutic response, and prognosis.

Objective Evidence has suggested that immune imbalance is involved with bipolar disorder (BD); however, its precise mechanism is poorly understood. This study investigated whether biochemical changes in the serum from BD patients could modulate the phenotype of cultured macrophages. Methods Eighteen subjects with BD and five healthy individuals were included in this study. The human monocyte cell line U-937 was activated with phorbol 12-myristate 13-acetate (PMA) and polarization was induced with RPMI-1640 media supplemented with 10% serum from each patient for 24 hours. Gene expression of selected M1 and M2 markers was assessed by quantitative PCR. Results Macrophages exposed to serum of manic and depressive BD patients displayed an increase of interleukin-1β (6.40±3.47 and 9.04±5.84 vs. 0.23±0.11; p＜0.05) and tumor necrosis factor-α (2.23±0.91 and 2.03±0.45 vs. 0.62±0.24; p=0.002 and p=0.004, respectively) compared to euthymic group (there was no difference between euthymic and controls). In parallel, U-937 macrophages treated with serum of patients in acute episode displayed a down-regulation of CXCL9 (0.29±0.20 vs. 1.86±1.61; p=0.006) and CXCL10 expression (0.36±0.15 and 0.86±0.24 vs. 1.83±0.88; p＜0.000 and p=0.04) compared to the euthymia group. Conclusion Our results are consistent with previous studies showing that changes in peripheral blood markers could modulate M1/M2 polarization in BD. The evidence of macrophages as source of inflammatory cytokines might be helpful to unravel how the mononuclear phagocyte system is involved in the etiology of BD.

This study aimed to test whether a dysregulation of gene expression may be the underlying cause of previously reported elevated levels of inflammatory cytokines in veterans with schizophrenia. We performed a genome-wide expression analysis in peripheral blood mononuclear cells from veterans with schizophrenia and controls, and our results show that 167 genes and putative loci were differently expressed between groups. These genes were enriched primarily for pathways related to inflammatory mechanisms and formed networks related to cell death and survival, immune cell trafficking, among others, which is in line with previous reports and further validates the inflammatory hypothesis of schizophrenia.

Comparative risks of treatment failure in bipolar 1 disorder : a population based study of lithium, valproate, olanzapine, quetiapine and aripiprazole in post mania relapse prevention

S100B is a calcium binding protein mainly produced by glial cells. Previous studies have shown elevated levels of S100B in patients with schizophrenia. We measured S100B levels in fasting plasma of 39 patients with schizophrenia and 19 adult healthy controls. We used linear regression to compare S100B between patients and controls. In patients only, we also investigated the relationship between S100B levels and psychotic symptoms (assessed by the Positive and Negative Syndrome Scale), and cognitive function (assessed by the NIH Toolbox Cognition Battery), respectively by calculating Pearson's correlation coefficients. Mean plasma S100B was significantly higher in the patient group than in the control group. There were no significant correlations between plasma S100B and psychotic symptoms or cognition.

Early-life stress exposure, regardless whether pre-, peri-, or post-natal, has been shown to increase the risk for psychiatric disorders in vulnerable subjects. One of the hypothesis that explains this association suggests that early-life stress can induce a programming of the main physiological system responsible for the stress response, namely, the hypothalamus-pituitary-adrenal (HPA) axis. Indeed, several lines of evidence suggest that exposure to early trauma or stressful events can induce permanent alterations in the HPA axis, some of which are also seen in patients with psychiatric disorders. This chapter will discuss clinical and preclinical evidence of HPA programming by early-life stress and the molecular mechanisms suggested to underlie it, i.e., inflammation and epigenetic mechanisms. Future perspectives and clinical implications of the HPA programming and its biological basis are also discussed.

Objective: Dual diagnosis (DD) is the co-occurrence of at least one substance use disorder and one or more mental disorders in a given individual. Despite this comorbidity being highly prevalent an...

Bipolar disorder (BD) has been associated with clinical signs of accelerated aging, which potentially underlies its association with several age-related medical conditions, such as hypertension, metabolic imbalances, dementia, and cancer. This paper aims to comprehensively review evidence of biological aging in BD and explore findings and controversies related to common biological clocks in patients, including telomere length, DNA methylation, mitochondrial DNA copy number, inflammation, and oxidative stress. Our results suggest a complex interplay between biological markers and a potential key role of environmental factors, such as childhood trauma and psychological stress, in determining premature aging in patients. Moreover, given its multifactorial nature, our summary evidences the need for further studies incorporating clinical evidence with biomarkers of accelerated aging in BD. Results of this review strongly suggest BD as an accelerated aging disease seen in both clinical and molecular aspects. Understanding the pathophysiology of aging in BD may ultimately lead to identification of pathways that can be targeted for prevention of premature aging in patients and early onset of aging-related conditions.

Background Suicide rates vary substantially by sex. Suicides committed by males significantly outnumber female suicides. Disparities in community and social factors provide a partial explanation for this phenomenon. Thus, the evaluation of sex differences at a biological level might contribute to the elucidation of the factors involved in this imbalance. The aim of the present study was to evaluate sex-specific gene expression patterns in the suicidal brain. Methods postmortem samples from the dorsolateral prefrontal cortex (DLPFC) of 75 Latino individuals were analyzed. We considered the following groups: i) male suicides (n = 38), ii) female suicides (n = 10), iii) male controls (n = 20), and iv) female controls (n = 7). Gene expression profiles were evaluated by microarrays. Differentially expressed genes among the groups were identified with a linear model. Similarities and differences in the gene sets between the sexes were identified. Results Differentially expressed genes were identified between suicides and controls of each sex: 1,729 genes in females and 1,997 genes in males. Female-exclusive suicide genes were related to cell proliferation and immune response. Meanwhile, male-exclusive suicide genes were associated to DNA binding and ribonucleic protein complex. Sex-independent suicide genes showed enrichment in mitochondrial and vesicular functions. Limitations Relatively small sample size. Our diagnosis approach was limited to information found on coroner's records. The analysis was limited to a single brain area (DLPFC) and we used microarrays. Conclusion Previously unexplored sex differences in the brain gene expression of suicide completers were identified, providing valuable foundation for the evaluation of sex-specific factors in suicide.