Depression and anxiety disorders are associated with increased release of peripheral cytokines; however, their functional relevance remains unknown. Using a social stress model in mice, we find ...preexisting individual differences in the sensitivity of the peripheral immune system that predict and promote vulnerability to social stress. Cytokine profiles were obtained 20 min after the first social stress exposure. Of the cytokines regulated by stress, IL-6 was most highly up-regulated only in mice that ultimately developed a susceptible behavioral phenotype following a subsequent chronic stress, and levels remained elevated for at least 1 mo. We confirmed a similar elevation of serum IL-6 in two separate cohorts of patients with treatment-resistant major depressive disorder. Before any physical contact in mice, we observed individual differences in IL-6 levels from ex vivo stimulated leukocytes that predict susceptibility versus resilience to a subsequent stressor. To shift the sensitivity of the peripheral immune system to a pro- or antidepressant state, bone marrow (BM) chimeras were generated by transplanting hematopoietic progenitor cells from stress-susceptible mice releasing high IL-6 or from IL-6 knockout (IL-6 ⁻/⁻) mice. Stress-susceptible BM chimeras exhibited increased social avoidance behavior after exposure to either subthreshold repeated social defeat stress (RSDS) or a purely emotional stressor termed witness defeat. IL-6 ⁻/⁻ BM chimeric and IL-6 ⁻/⁻ mice, as well as those treated with a systemic IL-6 monoclonal antibody, were resilient to social stress. These data establish that preexisting differences in stress-responsive IL-6 release from BM-derived leukocytes functionally contribute to social stress-induced behavioral abnormalities.
Significance Depression and anxiety have been linked to increased inflammation. However, we do not know if inflammatory status predates onset of disease or whether it contributes to depression symptomatology. We report preexisting individual differences in the peripheral immune system that predict and promote stress susceptibility. Replacing a stress-naive animal’s peripheral immune system with that of a stressed animal increases susceptibility to social stress including repeated social defeat stress (RSDS) and witness defeat (a purely emotional form of social stress). Depleting the cytokine IL-6 from the whole body or just from leukocytes promotes resilience, as does sequestering IL-6 outside of the brain. These studies demonstrate that the emotional response to stress can be generated or blocked in the periphery, and offer a potential new form of treatment for stress disorders.
Digital mental health technologies such as mobile health (mHealth) tools can offer innovative ways to help develop and facilitate mental health care provision, with the COVID-19 pandemic acting as a ...pivot point for digital health implementation. This viewpoint offers an overview of the opportunities and challenges mHealth innovators must navigate to create an integrated digital ecosystem for mental health care moving forward. Opportunities exist for innovators to develop tools that can collect a vast range of active and passive patient and transdiagnostic symptom data. Moving away from a symptom-count approach to a transdiagnostic view of psychopathology has the potential to facilitate early and accurate diagnosis, and can further enable personalized treatment strategies. However, the uptake of these technologies critically depends on the perceived relevance and engagement of end users. To this end, behavior theories and codesigning approaches offer opportunities to identify behavioral drivers and address barriers to uptake, while ensuring that products meet users’ needs and preferences. The agenda for innovators should also include building strong evidence-based cases for digital mental health, moving away from a one-size-fits-all well-being approach to embrace the development of comprehensive digital diagnostics and validated digital tools. In particular, innovators have the opportunity to make their clinical evaluations more insightful by assessing effectiveness and feasibility in the intended context of use. Finally, innovators should adhere to standardized evaluation frameworks introduced by regulators and health care providers, as this can facilitate transparency and guide health care professionals toward clinically safe and effective technologies. By laying these foundations, digital services can become integrated into clinical practice, thus facilitating deeper technology-enabled changes.
There have been no new drugs for the treatment of schizophrenia in several decades and treatment resistance represents a major unmet clinical need. The drugs that exist are based on serendipitous ...clinical observations rather than an evidence-based understanding of disease pathophysiology. In the present review, we address these bottlenecks by integrating common, rare, and expression-related schizophrenia risk genes with knowledge of the druggability of the human genome as a whole. We highlight novel drug repurposing opportunities, clinical trial candidates which are supported by genetic evidence, and unexplored therapeutic opportunities in the lesser-known regions of the schizophrenia genome. By identifying translational gaps and opportunities across the schizophrenia disease space, we discuss a framework for translating increasingly well-powered genetic association studies into personalized treatments for schizophrenia and initiating the vital task of characterizing clinically relevant drug targets in underexplored regions of the human genome.
Mental health disorders are a leading cause of disability worldwide. Challenges such as disease heterogeneity, incomplete characterization of the targets of existing drugs and a limited understanding ...of functional interactions of complex genetic risk loci and environmental factors have compromised the identification of novel drug candidates. There is a pressing clinical need for drugs with new mechanisms of action which address the lack of efficacy and debilitating side effects of current medications. Here we discuss a novel strategy for neuropsychiatric drug discovery which aims to address these limitations by identifying disease-related functional responses ('functional cellular endophenotypes') in a variety of patient-derived cells, such as induced pluripotent stem cell (iPSC)-derived neurons and organoids or peripheral blood mononuclear cells (PBMCs). Disease-specific alterations in cellular responses can subsequently yield novel drug screening targets and drug candidates. We discuss the potential of this approach in the context of recent advances in patient-derived cellular models, high-content single-cell screening of cellular networks and changes in the diagnostic framework of neuropsychiatric disorders.
Mammalian brain glycome remains a relatively poorly understood area compared to other large-scale “omics” studies, such as genomics and transcriptomics due to the inherent complexity and ...heterogeneity of glycan structure and properties. Here,we first performed spatial and temporal analysis of glycome expression patterns in the mammalian brain using a cutting-edge experimental tool based on liquid chromatography-mass spectrometry, with the ultimate aim to yield valuable implications on molecular events regarding brain functions and development. We observed an apparent diversity in the glycome expression patterns, which is spatially well-preserved among nine different brain regions in mouse. Next, we explored whether the glycome expression pattern changes temporally during postnatal brain development by examining the prefrontal cortex (PFC) at different time point across six postnatal stages in mouse. We found that glycan expression profiles were dynamically regulated during postnatal developments. A similar result was obtained in PFC samples from humans ranging in age from 39 d to 49 y. Novel glycans unique to the brain were also identified. Interestingly, changes primarily attributed to sialylated and fucosylated glycans were extensively observed during PFC development. Finally, based on the vast heterogeneity of glycans, we constructed a core glyco-synthesis map to delineate the glycosylation pathway responsible for the glycan diversity during the PFC development. Our findings reveal high levels of diversity in a glycosylation program underlying brain region specificity and age dependency, and may lead to new studies exploring the role of glycans in spatiotemporally diverse brain functions.
Abstract Schizophrenia has been associated with central nervous system and peripheral immune system imbalances. However, most studies have not yielded conclusive results due to limitations such as ...small sample size, dissimilarities in the clinical status of patients and the high variability of cytokine levels within the normal human population. Here, we have attempted to account for these limitations by carrying out standardised multiplex immunoassay analyses of 9 cytokines in serum from 180 antipsychotic-naïve first-episode schizophrenia patients and 350 matched controls across 5 clinical cohorts. All subjects were matched for potential confounding factors including age, gender, smoking and body mass index. We found that the levels of interleukin (IL)-1RA, IL-10 and IL-15 were increased significantly in patients across the cohorts. We also found that the levels of IL-1RA and IL-10 were decreased in 32 patients who had been followed up and treated for 6 weeks with atypical antipsychotics. Interestingly, we found that the changes in IL-10 levels were significantly correlated with the improvements in negative, general and total symptom scores. These results indicate that mixed pro- and anti-inflammatory responses may be altered in first onset patients, suggesting a role in the aetiology of schizophrenia. The finding that only the anti-inflammatory cytokine IL-10 responded to treatment in parallel with symptom improvement suggests that this could be used as a potential treatment response biomarker in future studies of schizophrenia.
The vast personal and economic burden of mood disorders is largely caused by their under- and misdiagnosis, which is associated with ineffective treatment and worsening of outcomes. Here, we aimed to ...develop a diagnostic algorithm, based on an online questionnaire and blood biomarker data, to reduce the misdiagnosis of bipolar disorder (BD) as major depressive disorder (MDD). Individuals with depressive symptoms (Patient Health Questionnaire-9 score ≥5) aged 18-45 years were recruited online. After completing a purpose-built online mental health questionnaire, eligible participants provided dried blood spot samples for biomarker analysis and underwent the World Health Organization World Mental Health Composite International Diagnostic Interview via telephone, to establish their mental health diagnosis. Extreme Gradient Boosting and nested cross-validation were used to train and validate diagnostic models differentiating BD from MDD in participants who self-reported a current MDD diagnosis. Mean test area under the receiver operating characteristic curve (AUROC) for separating participants with BD diagnosed as MDD (N = 126) from those with correct MDD diagnosis (N = 187) was 0.92 (95% CI: 0.86-0.97). Core predictors included elevated mood, grandiosity, talkativeness, recklessness and risky behaviour. Additional validation in participants with no previous mood disorder diagnosis showed AUROCs of 0.89 (0.86-0.91) and 0.90 (0.87-0.91) for separating newly diagnosed BD (N = 98) from MDD (N = 112) and subclinical low mood (N = 120), respectively. Validation in participants with a previous diagnosis of BD (N = 45) demonstrated sensitivity of 0.86 (0.57-0.96). The diagnostic algorithm accurately identified patients with BD in various clinical scenarios, and could help expedite accurate clinical diagnosis and treatment of BD.
A MS‐based method for the quantification of proteins termed data‐independent analysis (or MSE) has been introduced recently. Although this method has been applied to the analysis of various types of ...biological samples, a thorough evaluation to assess the performance of this approach has yet to be conducted. Presented here is the first systematic and comprehensive study investigating the MSE approach for quantitative analysis of low‐, medium‐, and high‐complexity samples. We demonstrate that this method has a linear dynamic range spanning three orders of magnitude with a limit of quantification of 61 amol/uL in low‐complexity samples and 488 amol/uL in high‐complexity samples. In addition, comprehensive sequence coverage was obtained and accurate quantification achieved for expression ratios ranging from 1:1.5 to 1:6. However, underestimation of ratios was detected independent of sample type, consistent with other quantitative proteomic methods. The present study provides validation of the MSE approach for accurate quantitative proteomic analysis of biological samples while, at the same time, proving high sequence coverage of target proteins.
Schizophrenia (SCZ) and bipolar disorder are debilitating neuropsychiatric disorders arising from a combination of environmental and genetic factors. Novel open reading frames (nORFs) are genomic ...loci that give rise to previously uncharacterized transcripts and protein products. In our previous work, we have shown that nORFs can be biologically regulated and that they may play a role in cancer and rare diseases. More importantly, we have shown that nORFs may emerge in accelerated regions of the genome giving rise to species-specific functions. We hypothesize that nORFs represent a potentially important group of biological factors that may contribute to SCZ and bipolar disorder pathophysiology. Human accelerated regions (HARs) are genomic features showing human-lineage-specific rapid evolution that may be involved in biological regulation and have additionally been found to associate with SCZ genes. Transposable elements (TEs) are another set of genomic features that have been shown to regulate gene expression. As with HARs, their relevance to SCZ has also been suggested. Here, nORFs are investigated in the context of HARs and TEs. This work shows that nORFs whose expression is disrupted in SCZ and bipolar disorder are in close proximity to HARs and TEs and that some of them are significantly associated with SCZ and bipolar disorder genomic hotspots. We also show that nORF encoded proteins can form structures and potentially constitute novel drug targets.
Background:
Extensive research efforts have generated genomic, transcriptomic, proteomic, and functional data hoping to elucidate psychiatric pathophysiology. Selected reaction monitoring, a recently ...developed targeted proteomic mass spectrometric approach, has made it possible to evaluate previous findings and hypotheses with high sensitivity, reproducibility, and quantitative accuracy.
Methods:
Here, we have developed a labelled multiplexed selected reaction monitoring assay, comprising 56 proteins previously implicated in the aetiology of major psychiatric disorders, including cell type markers or targets and effectors of known psychopharmacological interventions. We analyzed postmortem anterior prefrontal cortex (Brodmann area 10) tissue of patients diagnosed with schizophrenia (n=22), bipolar disorder (n=23), and major depressive disorder with (n=11) and without (n=11) psychotic features compared with healthy controls (n=22).
Results:
Results agreed with several previous studies, with the finding of alterations of Wnt-signalling and glutamate receptor abundance predominately in bipolar disorder and abnormalities in energy metabolism across the neuropsychiatric disease spectrum. Calcium signalling was predominantly affected in schizophrenia and affective psychosis. Interestingly, we were able to show a decrease of all 4 tested oligodendrocyte specific proteins (MOG, MBP, MYPR, CNPase) in bipolar disorder and to a lesser extent in schizophrenia and affective psychosis. Finally, we provide new evidence linking ankyrin 3 specifically to affective psychosis and the 22q11.2 deletion syndrome-associated protein septin 5 to schizophrenia.
Conclusions:
Our study highlights the potential of selected reaction monitoring to evaluate the protein abundance levels of candidate markers of neuropsychiatric spectrum disorders, providing a high throughput multiplex platform for validation of putative disease markers and drug targets.
PDF
