Differentially regulated targets in the fast-acting antidepressant effect of (R)-ketamine: A systems biology approach.

Approximately two-thirds of patients with major depressive disorder (MDD) fail to respond to conventional antidepressants, suggesting that additional mechanisms are involved in the MDD pathophysiology. In this scenario, the glutamatergic system represents a promising therapeutic target for treatment-resistant depression. To our knowledge, this is the first study using semantic approach with systems biology to identify potential targets involved in the fast-acting antidepressant effects of ketamine and its enantiomers as well as identifying specific targets of (R)-ketamine. We performed a systematic review, followed by a semantic analysis and functional gene enrichment to identify the main biological processes involved in the therapeutic effects of these agents. Protein-protein interaction networks were constructed, and the genes exclusively regulated by (R)-ketamine were explored. We found that the regulation of α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid (AMPA) receptor and N-methyl-d-aspartate (NMDA) receptor subunits-Postsynaptic Protein 95 (PSD-95), Brain Derived Neurotrophic Factor (BDNF), and Tyrosine Receptor Kinase B (TrkB) are shared by the three-antidepressant agents, reinforcing the central role of the glutamatergic system and neurogenesis on its therapeutic effects. Differential regulation of Transforming Growth Factor Beta 1 (TGF-ß1) receptors-Mitogen-Activated Protein Kinases (MAPK's), Receptor Activator of Nuclear Factor-Kappa Beta Ligand (RANKL), and Serotonin Transporter (SERT) seems to be particularly involved in (R)-ketamine antidepressant effects. Our data helps further studies investigating the relationship between these targets and the mechanisms of (R)-ketamine and searching for other therapeutic compounds that share the regulation of these specific biomolecules. Ultimately, this study could contribute to improve the fast management of depressive-like symptoms with less detrimental side effects than ketamine and (S)-ketamine.

Inflammation and damage-associated molecular patterns in major psychiatric disorders.

BACKGROUND: Emerging evidence indicates that inflammation plays an important role as a mechanism underlying mental disorders. However, most of the research on inflammatory mechanisms focuses on serum levels of interleukins and very few studies have investigated molecules that initiate and expand innate immune pathways such as damage-associated molecular patterns (DAMPs). OBJECTIVES: This study investigated the levels of DAMPs among patients diagnosed with major depressive disorder (MDD), bipolar disorder (BD) I and II, schizophrenia (SCZ), and generalized anxiety disorder (GAD). We quantified serum levels of heat shock proteins (HSPs) 70 and 60 and of S100 calcium-binding protein B (S100B). METHODS: Serum levels of HSP70, HSP60, and S100B were assessed in a sample of participants with psychiatric disorders (n = 191) and a control group (CT) (n = 59) using enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum HSP70 concentrations were significantly higher in the MDD group compared to the CT, SCZ, and BD groups. The GAD group had higher concentrations of HSP70 than the SCZ group. Exploring associations with medications, lithium (p = 0.003) and clozapine (p = 0.028) were associated with lower HSP70 levels. Approximately 64% of the sample had DAMPs levels below the limits of detection indicated by the respective ELISA kit. CONCLUSION: This was the first study to assess DAMPs levels in a transdiagnostic sample. Our preliminary findings suggest that HSP70 may be associated with MDD pathophysiology. Medications such as lithium and clozapine were associated with lower HSP70 levels in BD and SCZ groups, respectively. Therefore, it is worth mentioning that all participants were medicated and many psychotropic drugs exert an anti-inflammatory effect, possibly reducing the signs of inflammation.

Inflammation and damage-associated molecular patterns in major psychiatric disorders

Abstract Background Emerging evidence indicates that inflammation plays an important role as a mechanism underlying mental disorders. However, most of the research on inflammatory mechanisms focuses on serum levels of interleukins and very few studies have investigated molecules that initiate and expand innate immune pathways such as damage-associated molecular patterns (DAMPs). Objectives This study investigated the levels of DAMPs among patients diagnosed with major depressive disorder (MDD), bipolar disorder (BD) I and II, schizophrenia (SCZ), and generalized anxiety disorder (GAD). We quantified serum levels of heat shock proteins (HSPs) 70 and 60 and of S100 calcium-binding protein B (S100B). Methods Serum levels of HSP70, HSP60, and S100B were assessed in a sample of participants with psychiatric disorders (n = 191) and a control group (CT) (n = 59) using enzyme-linked immunosorbent assay (ELISA). Results Serum HSP70 concentrations were significantly higher in the MDD group compared to the CT, SCZ, and BD groups. The GAD group had higher concentrations of HSP70 than the SCZ group. Exploring associations with medications, lithium (p = 0.003) and clozapine (p = 0.028) were associated with lower HSP70 levels. Approximately 64% of the sample had DAMPs levels below the limits of detection indicated by the respective ELISA kit. Conclusion This was the first study to assess DAMPs levels in a transdiagnostic sample. Our preliminary findings suggest that HSP70 may be associated with MDD pathophysiology. Medications such as lithium and clozapine were associated with lower HSP70 levels in BD and SCZ groups, respectively. Therefore, it is worth mentioning that all participants were medicated and many psychotropic drugs exert an anti-inflammatory effect, possibly reducing the signs of inflammation.

Potential Candidates for Biomarkers in Bipolar Disorder: A Proteomic Approach through Systems Biology.

Bipolar disorder (BD) is one of the most disabling diseases characterized by severe humor fluctuation. It is accompanied by cognitive and functional impairment in addiction to high suicide rates. BD is often underdiagnosed and treated incorrectly because many of the reported symptoms are not exclusive to the disorder. Once the diagnosis is exclusively clinical, it is not possible to state precisely. From that, proteomic approaches were used to identify, in a large scale, all proteins involved in cellular or tissue processes. This review aggregate data from blood proteomes, by using protein association network, of subjects with BD and healthy controls to suggest dysfunctional molecular pathways involved in disease. Original articles containing proteomic analysis were searched in PubMed. Seven studies were selected and data were extracted for posterior analysis. A protein-protein interaction network was created by STRING database. A final set of proteins in this network were employed as input in ClueGO and, the main biological process was visualized using R package pathview. The analysis revealed proteins associated with many biological processes, including growth and endocrine regulation, iron transportation, protease inhibition, protection against pathogens and cholesterol transport. Moreover, pathway analysis indicated the association of uncovered proteins with two main metabolic pathways: complement system and coagulation cascade. Thus, a better understanding on the pathophysiology of psychiatric disorders and the identification of potential biomarker candidates are essential to improve diagnostic, prognostic and design pharmacological strategies.

Public perceptions of psychiatric, justice-involved, and elderly populations during the COVID-19 pandemic.

The novel coronavirus disease (COVID-19) has had a significant global impact, with all countries facing the challenge of mitigating its spread. An unprecedented shortage of medical resources has raised concerns regarding allocation and prioritization of supplies, which may exacerbate social discrepancies for already vulnerable populations. As public opinion can impact healthcare policies, we aimed to characterize perceptions of psychiatric, forensic psychiatry, correctional, and elderly populations regarding COVID-19-related issues. This web-based study recruited participants (n = 583) from the general population in North America. The survey included perceptions of the pandemic, hypothetical scenarios on resource prioritization, and Likert scale questions. The majority of participants were cisgender female (72.7%), aged 31-74 years (80.0%), married (48.0%), retired (52.7%), resided in Canada (73.9%), had a college/university degree (50.9%) and had never worked in healthcare (66.21%). Most respondents reported not having a criminal history (95.88%), or a psychiatric disorder (78.73%). Perceptions of vulnerable populations were significantly different for resource allocation and prioritization (e.g., ventilator and vaccine resources, all p < 0.001). Healthcare workers and the elderly were commonly ranked the highest priority for resources, while forensic psychiatry and correctional populations were given the lowest priority. A high rate of disagreement was found for the more stigmatizing questions in the survey (all p < 0.0001). Our results suggest that perception from members of the general public in North America is aligned with current practices for resource allocation. However, individuals that already face social and health disparities may face additional opposition in decision-making for COVID-19 resources.

Stigmatization of psychiatric and justice-involved populations during the COVID-19 pandemic.

Psychiatric and justice-involved populations are known to be stigmatized and particularly vulnerable to adverse outcomes during COVID-19. The increased attention toward vulnerable populations from healthcare authorities, the media, and the general public has made it critical to uncover any developing stigmatization toward these groups and the possible consequences. The prioritization of public safety and shift in the prioritization of resource allocation and service delivery could lead to a rise in negative perceptions toward these already stigmatized groups. Thus, it is imperative to consider how the unique characteristics of vulnerable groups may impact their physical and mental health as well as their care during this pandemic. In this paper, we describe the challenges that psychiatric, correctional, and forensic psychiatry populations have faced during COVID-19 and how a rise in stigmatization could lead to adverse outcomes. Specifically, we outline the influence of the media on public perceptions and how stigmatization may be reflected in the allocation of resources, policies, and related decision-making during COVID-19.

Depression and Mania Induce Pro-inflammatory Activation of Macrophages Following Application of Serum from Individuals with Bipolar Disorder.

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-1ß (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.

The effect of taurine and enriched environment on behaviour, memory and hippocampus of diabetic rats.

Diabetes mellitus (DM) has been studied recently as a major cause of cognitive deficits, memory and neurodegenerative damage. Taurine and enriched environment have stood out for presenting neuroprotective and stimulating effects that deserve further study. In this paper, we examined the effects of taurine and enriched environment in the context of diabetes, evaluating effects on behaviour, memory, death and cellular activity. Eighty-eight Wistar rats were divided into 2 groups (E=enriched environment; C=standard housing). Some animals (24/group) underwent induction of diabetes, and within each group, some animals (half of diabetics (D) and half of non-diabetics (ND)/group) were treated for 30days with taurine (T). Untreated animals received saline (S). In total, there were eight subgroups: DTC, DSC, NDTC, NDSC, DTE, DSE, NDTE and NDSE. During the experiment, short-term memory was evaluated. After 30th day of experiment, the animals were euthanized and was made removal of brains used to immunohistochemistry procedures for GFAP and cleaved caspase-3. As a result, we observed that animals treated with taurine showed better performance in behavioural and memory tasks, and the enriched environment had positive effects, especially in non-diabetic animals. Furthermore, taurine and enriched environment seemed to be able to interfere with neuronal apoptosis and loss of glial cells, and in some instances, these two factors seemed to have synergistic effects. From these data, taurine and enriched environment may have important neurostimulant and neuroprotective effects.