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INTRODUCTION: Bipolar disorder (BD) is a complex psychiatric disease characterized by alternating mood episodes. As for any other psychiatric illness, currently there is no biochemical test that is able to support diagnosis or therapeutic decisions for BD. In this context, the discovery and validation of biomarkers are interesting strategies that can be achieved through proteomics and metabolomics. AREAS COVERED: In this descriptive review, a literature search including original articles and systematic reviews published in the last decade was performed with the objective to discuss the results of BD proteomic and metabolomic profiling analyses and indicate proteins and metabolites (or metabolic pathways) with potential clinical value. EXPERT OPINION: A large number of proteins and metabolites have been reported as potential BD biomarkers; however, most studies do not reach biomarker validation stages. An effort from the scientific community should be directed toward the validation of biomarkers and the development of simplified bioanalytical techniques or protocols to determine them in biological samples, in order to translate proteomic and metabolomic findings into clinical routine assays.

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Psychiatric disorders affect 970 million people worldwide, representing a significant source of disability. Although the underlying neurobiological traits for these disorders are not fully understood, a complex interplay between psychological, environmental, and biological factors contributes to their outcomes. Recent advances in lipidomic analysis and artificial intelligence algorithms have improved the identification of selective lipid species modulating the susceptibility to mental disorders. Sphingolipids (SLs) and ceramides-related SLs are among the most abundant lipids species in the brain that support major key pathways during neurodevelopment and brain plasticity. High levels of ceramides in plasma and brain contribute to psychiatric illness susceptibility in humans and animal models. However, the neuropathological mechanism regarding the involvement of ceramides in these disorders remain inconclusive. The brain is highly susceptible to nutritional insults, which could lead to functional impairment and influence the development and progression of psychiatric disorders. While the brain relies on glucose metabolism to support its physiological needs, a selective nutrient formula appears to have greater effects on brain health than others. For instance, consumption of high-energy diets is associated with brain anatomical, physiological, and metabolic changes, including ceramides metabolism. Herein, we will address the contribution of ceramides metabolism as a modulator of major psychiatric disorders such as depression, anxiety, bipolar disorder, schizophrenia, and attention deficit-hyperactivity disorder. We will also describe molecular and cellular targets of ceramides metabolism assisting the maintenance and progression of psychiatric disorders and their modulation by dietary formulas as non-pharmacologic treatments.

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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.

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BACKGROUND: Childhood abuse (CA) is a risk factor for a number of psychiatric disorders and has been associated with higher risk of developing bipolar disorders (BD). CA in BD has been associated with more severe clinical outcomes, but the neurobiological explanation for this is unknown. Few studies have explored in vivo measurement of brain metabolites using proton magnetic resonance spectroscopy (1H-MRS) in CA and no studies have investigated the association of CA severity with brain neurometabolites in BD. OBJECTIVE: To investigate whether CA severity is associated with changes in anterior cingulate cortex (ACC) neurometabolite profile in BD and HC subjects. METHODS: Fifty-nine BD I euthymic patients and fifty-nine HC subjects were assessed using the Childhood Trauma Questionnaire (CTQ) and underwent a 3-Tesla 1H-MRS scan. Severity of childhood abuse (physical, sexual and emotional) and its association with levels of brain metabolites was analyzed within each group. RESULTS: BD patients had higher total scores on the CTQ and higher severity rates of sexual and physical abuse compared to HC subjects. Greater severity of physical and sexual abuse was associated with increased ACC PCr level and lower Cr/PCr ratio in the BD group only. CONCLUSION: Sexual and physical abuse in BD patients, but not in HC subjects, appeared to be associated with creatine metabolism in the ACC, which can influence neuronal mitochondrial energy production. Further studies should investigate whether this is the mechanism underlying the association between CA and worse clinical outcomes in BD.

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Bipolar disorder (BD) is characterized by unstable mood states ranging from mania to depression. Although there is some evidence that mood instability may result from an imbalance between excitatory glutamatergic and inhibitory GABA-ergic neurotransmission, few proton magnetic resonance spectroscopy (1H-MRS) studies have measured these two neurometabolites simultaneously in BD. The enzyme glutamic acid decarboxylase (GAD1) catalyzes the decarboxylation of glutamate (Glu) to GABA, and its single nucleotide polymorphisms (SNPs) might influence Glu/GABA ratio. Thus, we investigated Glu/GABA ratio in the dorsal anterior cingulate cortex (dACC) of euthymic BD type I patients and healthy controls (HC), and assessed the influence of both mood stabilizers and GAD1 SNPs on this ratio. Eighty-eight subjects (50 euthymic BD type I patients and 38 HC) underwent 3T 1H-MRS in the dACC (2 × 2 × 4.5 cm3) using a two-dimensional JPRESS sequence and all subjects were genotyped for 4 SNPs in the GAD1 gene. BD patients had lower dACC Glu/GABA ratio compared to HC, where this was influenced by anticonvulsant and antipsychotic medications, but not lithium. The presence of GAD1 rs1978340 allele A was associated with higher Glu/GABA ratio in BD, while patients without this allele taking mood stabilizers had a lower Glu/GABA ratio. The lowering of dACC Glu/GABA could be one explanation for the mood stabilizing action of anticonvulsants and antipsychotics in BD type I euthymia. Therefore, this putative role of Glu/GABA ratio and the influence of GAD1 genotype interacting with mood stabilization medication should be confirmed by further studies involving larger samples and other mood states.ClincalTrials.gov registration: NCT01237158.

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Bipolar disorder (BD) is a mood psychiatric disorder described by changes between depressive, hypomanic, or manic episodes. The aimed of the present study was evaluated possible changes in the AA pathway in BD through a systematic review of observational studies. A search in the electronic databases was proceeded, on Cochrane Library, MEDLINE, EMBASE, PsycINFO, Google Scholar and the British Library for studies published until August 2020. A search strategy was developed using the terms: "Bipolar Disorder" and "Phospholipase A2" or "Arachidonic Acids" or "Cyclooxygenase 2" or "Prostaglandins E" as text words and Medical Subject Headings (i.e., MeSH and EMTREE). Seven primary studies were included in the systematic review, with a total of 246 BD patients, 20 depression patients, and 425 heathy controls (HC). The studies showed contradictory results in the AA and PLA2, no primary articles with COX and PGE2 assessments were included in this review. According to the Newcastle-Ottawa quality score scale (NOS), our systematic review presented high quality. The investigation of the inflammatory pathway of AA still needs further investigation and evidence, given the growing number of studies suggesting the efficacy of anti-inflammatory drugs as adjunctive therapy in the pharmacological treatment of BD.

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INTRODUCTION: Similar effects in reducing the symptoms of the mood disorder are reported in the literature compared the action of drugs and aerobic exercise sessions, demonstrating the potential of exercise in the control and mood stabilization. Therefore, there are many reasons to believe that the increased cardiorespiratory fitness (VO2max) can be an important means of protection and a reducing potential of physical and mental damage in bipolar disorders (BD). This review will highlight the current pattern of response of exercise on the pathophysiology of BD, relating the possible mechanisms, and hypotheses based on exercises. AREAS COVERED: The mechanism of monoaminergic action and its relationship with exercise, role of physical conditioning and increased VO2Max on neurotrophin release, and new perspectives on long-term exercise will be reviewed. EXPERT OPINION: The adaptations to training, although little explored in the context of BD, can induce the expression of substances that co-regulate several processes related to the pathophysiology of BD. Furthermore, high intensity interval training (HIIT) can also be adjusted to improve the physical fitness and health in patients with BD. Future research is needed to adopt a training strategy that is both time efficient and adequate for the population in question.

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Bipolar Disorder (BD) is a chronic a multifactorial psychiatric illness that affects mood, cognition, and functioning. BD is associated with several psychiatric conditions as well clinical comorbidities, particularly cardiovascular diseases. The neurobiology of BD is complex and multifactorial and several systems have been implicated. Considering that the Renin Angiotensin System (RAS) plays an important role in cardiovascular diseases and that recently evidence has suggested its role in psychiatric disorders, the aim of the present study is to summarize and to discuss recent findings related to the modulation of RAS components in BD. A systematic search of the literature using the electronic databases MEDLINE and LILACS was conducted through March 2019. The search terms were: "Bipolar Disorder"; "Renin Angiotensin System"; "Angiotensin 2"; "Angiotensin receptors"; "Angiotensin 1-7"; "ACE"; "ACE2"; "Mas Receptor". We included original studies assessing RAS in BD patients. Two hundred twenty-two citations were initially retrieved. Eleven studies were included in our systematic review. In the majority of studies (6 of 8), the ACE insertion/deletion (I/D) polymorphism did not differ between BD patients and controls. BD patients presented higher plasma renin activity in comparison with controls. The studies evaluating the RAS molecules in BD are very scarce and heterogeneous. The literature suggests a potential role of RAS in BD. Further studies are necessary to investigate this relationship.

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The pathophysiology of bipolar disorder remains incompletely elucidated. The purinergic receptor, P2X7 (P2X7R), plays a central role in neuroinflammation, the establishment, and maintenance of microglial activation and neuronal damage/death, all characteristics of bipolar disorder pathology. The present study aims to explore the participation of the P2X7R in a preclinical pharmacological model of mania. We analyzed the modulatory effects of the P2X7R antagonist, brilliant blue, on behavior, monoamines, gene expression, serum purine levels, and cell typing in a pharmacological model of mania induced by D-amphetamine (AMPH) in mice. Our results corroborate an association between the P2X7 receptor and the preclinical animal model of mania, as demonstrated by the decreased responsiveness to AMPH in animals with pharmacologically blocked P2X7R. This study further suggests a possible dopaminergic mechanism for the action of P2X7 receptor antagonism. Additionally, we observed increased peripheral levels of adenosine, a neuroprotective molecule, and increased central expression of Entpd3 and Entpd1 leading to the hydrolysis of ATP, a danger signal, possibly as an attempt to compensate for the damage induced by AMPH. Lastly, P2X7R antagonism in the AMPH model was found to potentially modulate astrogliosis. Our results support the hypothesis that P2X7R plays a vital role in the pathophysiology of mania, possibly by modulating the dopaminergic pathway and astrogliosis, as reflected in the behavioral changes observed. Taken together, this study suggests that a purinergic system imbalance is associated with the AMPH-induced preclinical animal model of mania. P2X7R may represent a promising molecular therapeutic target for bipolar disorder.

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