Proteomic Insights into Biology of Bipolar Disorder: Implications for Health Complexity and Mortality.

OBJECTIVE: The present study has the following objectives: 1) identify differentially expressed proteins and pathways in blood samples of BD compared to healthy controls by employing high-throughput proteomics and bioinformatics and 2) characterize disease-related molecular signatures through in-depth analysis of the differentially expressed proteins and pathways. METHODS: Blood samples from BD patients (n=10) classified into high (BD+) or poor functioning (BD-), based on functional and cognitive status, and healthy controls (n=5) were analyzed using mass spectrometry-based proteomic analysis. Bioinformatics was performed to detect biological processes, pathways, and diseases related to BD. RESULTS: Eight proteins exclusively characterized the molecular profile of patients with BD+ compared to HC, while 26 altered proteins were observed in the BD- group. These altered proteins were mainly enriched in biological processes related to lipid metabolism, complement system and coagulation cascade, and cardiovascular diseases; all these changes were more prominent in the BD- group. CONCLUSION: These findings may represent systemic alterations that occur with the progression of the illness and a possible link between BD and medical comorbidities. Such comprehensive understanding provides valuable insights for targeted interventions, addressing mental and physical health aspects in subjects with BD. Despite these promising findings, further research is warranted, encompassing larger sample cohorts and incorporating biological validation through molecular biology methods.

Drug Repurposing and Personalized Treatment Strategies for Bipolar Disorder Using Transcriptomic.

OBJECTIVE: The present study combined transcriptomic data and computational techniques based on gene expression signatures to identify novel bioactive compounds or FDA-approved drugs for the management of Bipolar Disorder (BD). METHODS: Five transcriptomic datasets, comprising a total of 165 blood samples from BD case-control, were selected from the Gene Expression Omnibus repository (GEO). The number of subjects varied from 6 to 60, with a mean age ranging from 35 to 48, with a gender variation between them. Most of the patients were on pharmacological treatment. Master Regulator Analysis (MRA) and Gene Set Enrichment Analysis (GSEA) were performed to identify statistically significant genes between BD and HC and their association with the mood states of BD. Additionally, existing molecules with the potential to reverse the transcriptomic profiles of disease-altered regulons in BD were identified using the LINCS and cMap databases. RESULTS: MRA identified 59 potential MRs candidates modulating the regulatory units enriched with genes altered in BD, while the GSEA identified 134 enriched genes, and a total of 982 regulons had their activation state determined. Both analyses showed genes exclusively associated with mania, depression, or euthymia, and some genes were common between the three mood states. We identified bioactive compounds and licensed drug candidates, including antihypertensives and antineoplastics, as promising candidates for treating BD. Nevertheless, experimental validation is essential to authenticate these findings in subsequent studies. CONCLUSION: Although preliminary, our data provides some insights regarding the biological patterns of BD into distinct mood states and potential therapeutic targets. The combined transcriptomic and bioinformatics strategy offers a route to advance drug discovery and personalized medicine by tapping into gene expression information.

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.

Is (R)-ketamine a potential therapeutic agent for treatment-resistant depression with less detrimental side effects? A review of molecular mechanisms underlying ketamine and its enantiomers.

Approximately one-third of individuals with major depressive disorder are resistant to conventional antidepressants (i.e., monoamine-based therapies), and, even among respondents, a proper therapeutic effect may require weeks of treatment. Ketamine, a racemic mixture of the two enantiomers, (R)-ketamine and (S)-ketamine, is an N-methyl-d-aspartate receptor (NMDAR) antagonist and has been shown to have rapid-acting antidepressant properties in patients with treatment-resistant depression (TRD). Although (R)-ketamine has a lower affinity for NMDAR, it presents greater potency and longer-lasting antidepressant properties, with no major side effects, than racemic ketamine or (S)-ketamine in preclinical findings. Thereby, ketamine and its enantiomers have not only an antagonistic effect on NMDAR but also a strong synaptogenic-modulatory effect, which is impaired in TRD pathophysiology. In this review, we summarize the current evidence regarding the modulation of neurotransmission, neuroplasticity, and neural network activity as putative mechanisms of these rapid-acting antidepressants, highlighting differences on intracellular signaling pathways of synaptic proteins such as mammalian target of rapamycin (mTOR), extracellular signal-regulated kinase (ERK) and brain-derived neurotrophic factor (BDNF). In addition, we discuss probable mechanisms involved in the side effects of ketamine and its enantiomers.

Targeting Inflammatory-Mitochondrial Response in Major Depression: Current Evidence and Further Challenges.

The prevalence of psychiatric disorders has increased in recent years. Among existing mental disorders, major depressive disorder (MDD) has emerged as one of the leading causes of disability worldwide, affecting individuals throughout their lives. Currently, MDD affects 15% of adults in the Americas. Over the past 50 years, pharmacotherapy, psychotherapy, and brain stimulation have been used to treat MDD. The most common approach is still pharmacotherapy; however, studies show that about 40% of patients are refractory to existing treatments. Although the monoamine hypothesis has been widely accepted as a molecular mechanism to explain the etiology of depression, its relationship with other biochemical phenomena remains only partially understood. This is the case of the link between MDD and inflammation, mitochondrial dysfunction, and oxidative stress. Studies have found that depressive patients usually exhibit altered inflammatory markers, mitochondrial membrane depolarization, oxidized mitochondrial DNA, and thus high levels of both central and peripheral reactive oxygen species (ROS). The effect of antidepressants on these events remains unclear. Nevertheless, the effects of ROS on the brain are well known, including lipid peroxidation of neuronal membranes, accumulation of peroxidation products in neurons, protein and DNA damage, reduced antioxidant defenses, apoptosis induction, and neuroinflammation. Antioxidants such as ascorbic acid, tocopherols, and coenzyme Q have shown promise in some depressive patients, but without consensus on their efficacy. Hence, this paper provides a review of MDD and its association with inflammation, mitochondrial dysfunction, and oxidative stress and is aimed at thoroughly discussing the putative links between these events, which may contribute to the design and development of new therapeutic approaches for patients.

BDNF prevents central oxidative damage in a chronic unpredictable mild stress model: The possible role of PRDX-1 in anhedonic behavior.

Prolonged activation of the hypothalamic-pituitary-adrenal (HPA) axis and sustained increase of glucocorticoids have been evidenced in major depression and are related to changes involving neurotrophins and markers of oxidative stress in response to inflammation. This study aimed to evaluate central measures of brain-derived neurotrophic factor (BDNF), oxidative damage and total antioxidant capacity in rats submitted to chronic unpredictable mild stress (CUMS), as well as to investigate the relationship between BDNF levels and differentially processes. For this purpose, male Wistar rats were submitted to CUMS for six weeks. Based on a sucrose preference test (SPT), the animals were divided into anhedonic or non-anhedonic clusters. Afterwards, forced swim test (FST) and open field test (OFT) were performed, and the animals were euthanized. Brain tissue was collected, followed by quantification of oxidative damage, total antioxidant capacity and BDNF levels. Anhedonic behavior was evidenced in stress-susceptible animals through decreased sucrose preference. No differences were found in FST or OFT results. We observed increased BDNF levels in the hippocampus (HPC) of animals exposed to the CUMS protocol, accompanied by decreased total antioxidant capacity, despite the absence of oxidative damage to lipids and proteins. Moreover, we used a bioinformatics approach to identify proteins involved in oxidative stress and inflammation pathways, which were differentially expressed in anhedonic animals from other studies with similar experimental protocol. expressed proteins (DEP) involved in oxidative stress and inflammatory biological Anhedonic behavior was associated with peroxiredoxin-1 (PRDX-1) up-regulation and down-regulation of proteins involved with apoptotic and inflammation signaling (RELA, ASK-1 and TAK-1) in the HPC. Taken together, these data suggest that BDNF and PRDX-1 might be involved in initial stress response, playing a compensatory role by preventing oxidative damage to lipids and proteins through the modulation of antioxidant defense after CUMS in anhedonic animals.

Decoding rumination: A machine learning approach to a transdiagnostic sample of outpatients with anxiety, mood and psychotic disorders.

OBJECTIVE: To employ machine learning algorithms to examine patterns of rumination from RDoC perspective and to determine which variables predict high levels of maladaptive rumination across a transdiagnostic sample. METHOD: Sample of 200 consecutive, consenting outpatient referrals with clinical diagnoses of schizophrenia, schizoaffective, bipolar, depression, anxiety disorders, obsessive compulsive and post-traumatic stress. Machine learning algorithms used a range of variables including sociodemographics, serum levels of immune markers (IL-6, IL-1ß, IL-10, TNF-α and CCL11) and BDNF, psychiatric symptoms and disorders, history of suicide and hospitalizations, functionality, medication use and comorbidities. RESULTS: The best model (with recursive feature elimination) included the following variables: socioeconomic status, illness severity, worry, generalized anxiety and depressive symptoms, and current diagnosis of panic disorder. Linear support vector machine learning differentiated individuals with high levels of rumination from those ones with low (AUC = 0.83, sensitivity = 75, specificity = 71). CONCLUSIONS: Rumination is known to be associated with poor prognosis in mental health. This study suggests that rumination is a maladaptive coping style associated not only with worry, distress and illness severity, but also with socioeconomic status. Also, rumination demonstrated a specific association with panic disorder.

Effects of lithium on inflammatory and neurotrophic factors after an immune challenge in a lisdexamfetamine animal model of mania

Objective: To evaluate whether an animal model of mania induced by lisdexamfetamine dimesylate (LDX) has an inflammatory profile and whether immune activation by lipopolysaccharides (LPS) has a cumulative effect on subsequent stimuli in this model. We also evaluated the action of lithium (Li) on inflammatory and neurotrophic factors. Methods: Adult male Wistar rats were subjected to an animal model of mania. After the open-field test, they were given LPS to induce systemic immune activation. Subsequently, the animals' blood was collected, and their serum levels of brain-derived neurotrophic factor and inflammatory markers (tumor necrosis factor [TNF]-α, interleukin [IL]-6, IL-1β, IL-10, and inducible nitric oxide synthase [iNOS]) were measured. Results: LDX induced hyperactivity in the animals, but no inflammatory marker levels increased except brain-derived neurotrophic factor (BDNF). Li had no effect on serum BDNF levels but prevented iNOS levels from increasing in animals subjected to immune activation. Conclusion: Although Li prevented an LPS-induced increase in serum iNOS levels, its potential anti-inflammatory effects in this animal model of mania were conflicting.

Anxiety disorders in childhood are associated with youth IL-6 levels: A mediation study including metabolic stress and childhood traumatic events.

Anxiety disorders (ADs) are chronic conditions that often have their onset in childhood and adolescence. Inflammation and oxidative stress markers have been associated with the vulnerability to ADs, however it is not known if ADs in childhood can influence these biomarkers levels longitudinally. This study aims to investigate a possible association between ADs and serum levels of IL-10, IL-6, IL-1ß, TNF-α, BDNF, and protein carbonyl content, assessed after 5 years of follow-up. Moreover, we studied possible mediators for these associations, including physical activity, metabolic markers and childhood trauma. From 240 individuals evaluated at baseline, 73 were re-evaluated in the follow-up. Psychiatric diagnoses were assessed with the K-SADS or the MINI and child trauma questionnaire (CTQ) to evaluate presence of trauma. We searched serum levels of IL-10, IL-6, IL-1ß and TNF-α (flow cytometry), BDNF (sandwich-ELISA) and carbonyl content in proteins (PCC method). We found a significant direct association between ADs at baseline and log IL-6 (B = 0.34, S.E. = 0.11, p = 0.002) and between AD and log BDNF (B = -0.10, S.E. = 0.05, p = 0.033) five years later. Searching for possible mediators of these association, we found that levels of HDL-cholesterol (ΔB = -0.148) partially mediated the association between ADs and IL-6. No significant mediators were found in the association between ADs and BDNF. Moreover, this association is no longer significant after controlling for the presence of depression. Our results demonstrated that previous AD diagnosis was associated with higher levels of IL-6 in the follow-up evaluation, suggesting that the presence of anxiety in childhood could influence altered inflammatory markers.

Effects of lithium on inflammatory and neurotrophic factors after an immune challenge in a lisdexamfetamine animal model of mania.

OBJECTIVE: To evaluate whether an animal model of mania induced by lisdexamfetamine dimesylate (LDX) has an inflammatory profile and whether immune activation by lipopolysaccharides (LPS) has a cumulative effect on subsequent stimuli in this model. We also evaluated the action of lithium (Li) on inflammatory and neurotrophic factors. METHODS: Adult male Wistar rats were subjected to an animal model of mania. After the open-field test, they were given LPS to induce systemic immune activation. Subsequently, the animals' blood was collected, and their serum levels of brain-derived neurotrophic factor and inflammatory markers (tumor necrosis factor [TNF]-α, interleukin [IL]-6, IL-1ß, IL-10, and inducible nitric oxide synthase [iNOS]) were measured. RESULTS: LDX induced hyperactivity in the animals, but no inflammatory marker levels increased except brain-derived neurotrophic factor (BDNF). Li had no effect on serum BDNF levels but prevented iNOS levels from increasing in animals subjected to immune activation. CONCLUSION: Although Li prevented an LPS-induced increase in serum iNOS levels, its potential anti-inflammatory effects in this animal model of mania were conflicting.

Cardiovascular risk and bipolar disorder: factors associated with a positive coronary calcium score in patients with bipolar disorder type 1

Objective: Cardiovascular disease is the leading cause of death in patients with bipolar disorder. The aim of this study was to evaluate the factors associated with positive coronary calcium score (CCS) in individuals with bipolar disorder type 1. Methods: Patients from the Bipolar Disorder Program at Hospital de Clínicas de Porto Alegre, Brazil, underwent computed tomography scanning for calcium score measurement. Clinical and sociodemographic variables were compared between patients according to their CCS status: negative (CCS = 0) or positive (CCS > 0). Poisson regression analysis was used to examine the association of CCS with number of psychiatric hospitalizations. Results: Out of 41 patients evaluated, only 10 had a positive CCS. Individuals in the CCS-positive group were older (55.2±4.2 vs. 43.1±10.0 years; p = 0.001) and had more psychiatric hospitalizations (4.7±3.0 vs. 2.6±2.5; p = 0.04) when compared with CCS- negative subjects. The number of previous psychiatric hospitalizations correlated positively with CCS (p < 0.001). Conclusion: Age and number of psychiatric hospitalizations were significantly associated with higher CCS, which might be a potential method for diagnosis and stratification of cardiovascular disease in bipolar patients. There is a need for increased awareness of risk assessment in this population.

Cardiovascular risk and bipolar disorder: factors associated with a positive coronary calcium score in patients with bipolar disorder type 1.

OBJECTIVE: Cardiovascular disease is the leading cause of death in patients with bipolar disorder. The aim of this study was to evaluate the factors associated with positive coronary calcium score (CCS) in individuals with bipolar disorder type 1. METHODS: Patients from the Bipolar Disorder Program at Hospital de Clínicas de Porto Alegre, Brazil, underwent computed tomography scanning for calcium score measurement. Clinical and sociodemographic variables were compared between patients according to their CCS status: negative (CCS = 0) or positive (CCS > 0). Poisson regression analysis was used to examine the association of CCS with number of psychiatric hospitalizations. RESULTS: Out of 41 patients evaluated, only 10 had a positive CCS. Individuals in the CCS-positive group were older (55.2±4.2 vs. 43.1±10.0 years; p = 0.001) and had more psychiatric hospitalizations (4.7±3.0 vs. 2.6±2.5; p = 0.04) when compared with CCS- negative subjects. The number of previous psychiatric hospitalizations correlated positively with CCS (p < 0.001). CONCLUSION: Age and number of psychiatric hospitalizations were significantly associated with higher CCS, which might be a potential method for diagnosis and stratification of cardiovascular disease in bipolar patients. There is a need for increased awareness of risk assessment in this population.

The FKBP5 polymorphism rs1360780 is associated with lower weight loss after bariatric surgery: 26 months of follow-up.

BACKGROUND: Bariatric surgery is the most effective treatment choice for severe obesity. Recent literature indicates that FK506-binding protein 51 (FKBP51) could play a role in energy homeostasis, influencing adipogenesis and weight. OBJECTIVE: To evaluate if the presence of the T allele of the FKBP5 SNP rs1360780, associated with increased FKBP51 expression, could influence weight loss after bariatric surgery. SETTING: Hospital de Clínicas de Porto Alegre, Brazil. METHODS: Forty-two patients awaiting bariatric surgery were included, and the presence of the FKBP5 rs1360780 polymorphism was evaluated. During the postoperative period, a 26-month follow-up of weight loss was performed (n = 42, 36, 35, 35, and 30, from the first to fifth postoperative evaluation, respectively; loss to follow-up: 28.6%). RESULTS: Carriers of the T allele presented significantly lower weight loss compared with patients with the C/C genotype after the 12th to 14th month follow-up period. Differences in weight loss between genotypes ranged from 14.2% to 19.9% of excess weight loss (P = .045 and .004, respectively) and from 7.6% to 9.0% of total weight loss (P = .002 for both comparisons). Furthermore, carriers of the T allele also presented an earlier cessation of weight loss after surgery. CONCLUSION: The presence of the T allele of the FKBP5 SNP rs1360780 was associated with weight loss after bariatric surgery. Bariatric surgery can interact with genes involved in metabolic regulation, leading to different weight loss outcomes.

Brain-Derived Neurotrophic Factor Serum Levels and Hippocampal Volume in Mild Cognitive Impairment and Dementia due to Alzheimer Disease.

BACKGROUND/AIMS: Hippocampal atrophy is a recognized biomarker of Alzheimer disease (AD) pathology. Serum brain-derived neurotrophic factor (BDNF) reduction has been associated with neurodegeneration. We aimed to evaluate BDNF serum levels and hippocampal volume in clinical AD (dementia and mild cognitive impairment [MCI]). METHODS: Participants were 10 patients with MCI and 13 with dementia due to AD as well as 10 healthy controls. BDNF serum levels were determined by ELISA and volumetric measures with NeuroQuant®. RESULTS: MCI and dementia patients presented lower BDNF serum levels than healthy participants; dementia patients presented a smaller hippocampal volume than MCI patients and healthy participants. DISCUSSION: The findings support that the decrease in BDNF might start before the establishment of neuronal injury expressed by the hippocampal reduction.