Pathophysiology Of Bipolar Disorder Research Articles

CircRNAs as a novel class of potential diagnostic biomarkers in bipolar disorders.

Bipolar disorder (BD) is a severe mood disorder with uncertain causes and debilitating signs and symptoms. Gene expression is crucial to the pathophysiology of BD and could be influenced by genetic or epigenetic factors, by either direct modification of mRNA templates or by regulation of post-transcriptional translation. Recent evidence has shown that several critical processes in psychiatric diseases, such as neuronal activity or plasticity, synaptic transmission, and neuronal depolarization, have all been linked to circular RNAs (circRNAs). The circRNA profile of neuronal cells, which may be easily ascertained by a liquid biopsy, may shed light on the molecular pathophysiology of psychiatric disorders, including BD. This approach could aid in future development in diagnosis and treatment. In this review, we provide an in-depth understanding of the roles of circRNAs in the pathophysiology of BD and offer new insight into their potential as emerging diagnostic tools and therapeutic targets.

Unearthing the hidden links: Investigating the functional connectivity between amygdala subregions and brain networks in bipolar disorder through resting-state fMRI

IntroductionBipolar disorder is a multifaceted psychiatric condition characterized by fluctuating activity levels and dysfunctional mood states, oscillating between manic and depressive episodes. These mood disturbances are accompanied by persistent functional and cognitive impairments, even during periods of euthymia. Prior studies have underscored the critical role of amygdala activity in the pathophysiology of bipolar disorder. This research aims to utilize resting-state functional Magnetic Resonance Imaging (rs-fMRI) to explore the functional modifications in the six sub-regions that compose the amygdala of individuals diagnosed with bipolar disorder. MethodThe study encompassed 80 participants, bifurcated into two groups: 40 individuals with bipolar disorder and 40 healthy controls. Each group comprised an equal gender distribution of 20 females and 20 males, ranging in age from 21 to 50 years. Using rs-fMRI, we examined the functional connectivity within six amygdala sub-regions across eight regional functional networks. ResultsComparative analysis between the control group and the bipolar patients revealed that all six amygdala sub-regions demonstrated connectivity with the eight functional brain networks. Notable similarities and disparities were observed in the connectivity patterns between the bipolar group and controls, particularly within the amygdala's sub-regions and other brain networks. The most significant functional connectivity alterations were found with the salience network and the default mode network. Additionally, alterations in the functional connectivity between the amygdala, sensory-motor, and visual networks were noted in bipolar patients. ConclusionThe study's findings highlight the distinct patterns of resting-state functional connectivity of the amygdala and various brain networks in differentiating bipolar patients from healthy controls. These variations suggest the existence of multiple pathophysiological mechanisms contributing to emotional dysregulation in bipolar disorder.

Patterns of Immune Dysregulation in Bipolar Disorder.

Bipolar disorder is a debilitating mood disorder associated with a high risk of suicide and characterized by immune dysregulation. In this study, we used a multi-faceted approach to better distinguish the pattern of dysregulation of immune profiles in individuals with BD. We analyzed peripheral blood mononuclear cells (bipolar disorder N=39, control N=30), serum cytokines (bipolar disorder N=86, control N=58), whole blood RNA (bipolar disorder N=25, control N=25), and whole blood DNA (bipolar disorder N=104, control N=66) to identify immune-related differences in participants diagnosed with bipolar disorder compared to controls. Flow cytometry revealed a higher proportion of monocytes in participants with bipolar disorder together with a lower proportion of T helper cells. Additionally, the levels of 18 cytokines were significantly elevated, while two were reduced in participants with bipolar disorder. Most of the cytokines altered in individuals with bipolar disorder were proinflammatory. Forty-nine genes were differentially expressed in our bipolar disorder cohort and further analyses uncovered several immune-related pathways altered in these individuals. Genetic analysis indicated variants associated with inflammatory bowel disease also influences bipolar disorder risk. Our findings indicate a significant immune component to bipolar disorder pathophysiology and genetic overlap with inflammatory bowel disease. This comprehensive study supports existing literature, whilst also highlighting novel immune targets altered in individuals with bipolar disorder. Specifically, multiple lines of evidence indicate differences in the peripheral representation of monocytes and T cells are hallmarks of bipolar disorder.

Pharmacological Mechanism of Herbal Interventions for Bipolar Disorder

: Bipolar disorder is a neuropsychiatric disease characterized by an abundance of undesired ideas and thoughts associated with recurrent episodes of mania or hypomania and depression. Alterations in the circuits, including the prefrontal cortex, striatum, and limbic system, regulate mood and cause variation in several crucial neurotransmitters, including serotonin, dopamine, GABA, and glutamate. Imbalances in dopamine levels have been implicated in the manic phase, while variance in serotonin is linked to depressive episodes. The precise pathophysiology of bipolar disorder is still unknown. Though different treatments are available, like lithium, risperidone, valproic acid, etc., which are widely used, they come with certain limitations, including narrow therapeutic index, hypothyroidism, weight gain, extrapyramidal symptoms, etc. The interest in herbal- based treatments for bipolar disorder arises from the desire for alternative, potentially more natural, and holistic approaches with fewer side effects. The current review focuses on the potential effects of herbal drugs and their derivatives to alleviate the symptoms of bipolar disorder.

The potential inflammatory biomarker of bipolar disorder: Neutrophil-to-lymphocyte Ratio – A hospital-based cross-sectional study

Objectives: Inflammation has been hypothesized as one of the pathophysiological factor for mood disorders. The neutrophil-to-lymphocyte ratio (NLR) has been proposed as a potential peripheral biomarker of mood episodes, as this is an economical and accessible marker of inflammation. This study aims to determine the role of inflammation in the pathophysiology of bipolar disorder (BD) and the potential of NLR as a marker for differentiating mood disorders. Materials and Methods: A cross-sectional study was conducted on 195 patients who met the inclusion criteria, of whom 80 were diagnosed with BD (mania), 47 with BD (depression), and 68 with major depressive disorder (MDD). Sociodemographic details and a blood sample were taken for hemogram measures. The NLR and MLR were calculated using the following formula: NLR = neutrophil count/lymphocyte count and MLR = monocyte count/lymphocyte count, and statistical analysis was done. Results: The mean age (±standard deviation) of patients with mania, bipolar depression, and MDD were 35.97 (±13.14), 39.27 (±14.28), and 33.41 (±13.21) years, respectively, with an almost equal representation of male and female gender. The NLR ratio of 2.41 ± 0.84 was highest in BD (mania), followed by 1.75 ± 0.41 in bipolar depression and 1.67 ± 0.45 in MDD, which was significant (P < 0.001), while MLR ratio in BD (mania) was highest, followed by MDD and bipolar depression. Conclusion: Our result indicates NLR as a marker of differentiation and, thus, strengthens the pathophysiological importance of inflammation in mood disorders.

Functional connectivity of the amygdala subnuclei in various mood states of bipolar disorder.

Amygdala functional dysconnectivity lies at the heart of the pathophysiology of bipolar disorder (BD). Recent preclinical studies suggest that the amygdala is a heterogeneous group of nuclei, whose specific connectivity could drive positive or negative emotional valence. We investigated functional connectivity (FC) changes within these circuits emerging from each amygdala's subdivision in 127 patients with BD in different mood states and 131 healthy controls (HC), who underwent resting-state functional MRI. FC was evaluated between lateral and medial nuclei of amygdalae, and key subcortical regions of the emotion processing network: anterior and posterior parts of the hippocampus, and core and shell parts of the nucleus accumbens. FC was compared across groups, and subgroups of patients depending on their mood states, using linear mixed models. We also tested correlations between FC and depression (MADRS) and mania (YMRS) scores. We found no difference between the whole sample of BD patients vs. HC but a significant correlation between MADRS and right lateral amygdala /right anterior hippocampus, right lateral amygdala/right posterior hippocampus and right lateral amygdala/left anterior hippocampus FC (r = -0.44, r = -0.32, r = -0.27, respectively, all pFDR<0.05). Subgroup analysis revealed decreased right lateral amygdala/right anterior hippocampus and right lateral amygdala/right posterior hippocampus FC in depressed vs. non-depressed patients and increased left medial amygdala/shell part of the left nucleus accumbens FC in manic vs non-manic patients. These results demonstrate that acute mood states in BD concur with FC changes in individual nuclei of the amygdala implicated in distinct emotional valence processing. Overall, our data highlight the importance to consider the amygdala subnuclei separately when studying its FC patterns including patients in distinct homogeneous mood states.

AI algorithm combined with RNA editing-based blood biomarkers to discriminate bipolar from major depressive disorders in an external validation multicentric cohort

Bipolar disorder (BD) is a leading cause of disability worldwide, as it can lead to cognitive and functional impairment and premature mortality. The first episode of BD is usually a depressive episode and is often misdiagnosed as major depressive disorder (MDD). Growing evidence indicates that peripheral immune activation and inflammation are involved in the pathophysiology of BD and MDD. Recently, by developing a panel of RNA editing-based blood biomarkers able to discriminate MDD from depressive BD, we have provided clinicians a new tool to reduce the misdiagnosis delay observed in patients suffering from BD. The present study aimed at validating the diagnostic value of this panel in an external independent multicentric Switzerland-based cohort of 143 patients suffering from moderate to major depression. The RNA-editing based blood biomarker (BMK) algorithm developped allowed to accurately discriminate MDD from depressive BD in an external cohort, with high accuracy, sensitivity and specificity values (82.5 %, 86.4 % and 80.8 %, respectively). These findings further confirm the important role of RNA editing in the physiopathology of mental disorders and emphasize the possible clinical usefulness of the biomarker panel for optimization treatment delay in patients suffering from BD.

Drug repurposing as add-on treatment strategy for mania and bipolar depression: systematic synthesis and qualitative appraisal of the existing meta-analytic evidence

IntroductionIn the complex pathophysiology of bipolar disorder (BD), increasing evidence supports the involvement of neurobiological abnormalities beyond the classical ones, suggesting them as potential alternative therapeutic targets. Several drugs approved for different indications have thus been repurposed for the treatment of BD, all of them supported by a plausible biological rationale. Some recent reviews have provided an update on these possible additional treatment options for mania and bipolar depression, but no systematic synthesis and qualitative evaluation of meta-analytic findings has been made.ObjectivesTo provide a guidance on the available evidence on these treatments and their potential role in clinical practice, we conducted an umbrella review of meta-analyses of randomized placebo-controlled trials investigating drugs repurposed as add-on treatments for mania and bipolar depression.MethodsWe performed a systematic search and screening of the existing literature looking for the most up-to-date or comprehensive meta-analyses of randomized controlled trials (RCTs) on adults suffering from BD during an acute mood episode (mania or depression) which compared a repurposed drug and placebo as adjunctive treatments. We performed a critical appraisal according to “A MeaSurement Tool to Assess systematic Reviews” Version 2 (AMSTAR 2). We synthesized meta-analytic findings regarding efficacy, tolerability, and safety, also assessing the quality of evidence using the “Grading of Recommendations, Assessment, Development and Evaluations” (GRADE) approach.ResultsIn nine eligible meta-analyses investigating 12 drugs (four for mania and eight for bipolar depression) we observed a heterogeneous quality of reporting was according to AMSTAR 2.In mania, allopurinol (for symptoms reduction and remission at 4-8 weeks) and tamoxifen (for response and symptoms reduction at 4-6 weeks) showed higher efficacy than placebo, with evidence of low and very low quality, respectively.In bipolar depression, modafinil/armodafinil (for response, remission, and symptoms reduction at 6-8 weeks) and pramipexole (for response and symptoms reductionat 6 weeks) were superior to placebo, with low-quality evidence. Results on celecoxib and N-acetylcysteine were of low quality and limited to certain outcomes.ConclusionsOverall, the lack of evidence of high and moderate quality does not allow firm conclusions on the clinical utility of repurposed drugs as adjunctive treatments for mania and bipolar depression, limiting recommendations for their use in clinical practice. However, since some lines of evidence seem to hold some potential, and standard treatments for mania and bipolar depression remain not entirely satisfactory, the search for novel therapeutic targets and strategies for the management of BD warrants further research in the field.Disclosure of InterestNone Declared

A composite immune and vascular stress marker in patients newly diagnosed with bipolar disorder and their unaffected first-degree relatives

AimsSubstantial evidence emphasizes immune dysregulation in patients with bipolar disorder (BD). However, whether immune dysregulation is present already in the early illness stages of BD or even precedes development of BD is largely unknown. In this study we compared immune and vascular stress markers in patients newly diagnosed with BD, their unaffected first-degree relatives (UR) and healthy control individuals (HC) and investigated the ability a composite immune and vascular stress marker to discriminate between the three groups of participants. MethodsIn a unique sample including 373 patients newly diagnosed with BD, 95 UR and 190 HC, we compared 47 immune and vascular stress markers at the baseline visit in the ongoing longitudinal Bipolar Illness Onset study. For comparison of individual immune and vascular stress markers between groups, we applied linear mixed models, whereas the composite immune and vascular stress marker was investigated using the SuperLearner ensemble-method. ResultsCompared with HC, patients newly diagnosed with BD had higher levels of the anti-inflammatory interleukin-1 receptor antagonist (IL-1RA) and IL-10, and of the pro-inflammatory IL-6, eotaxin, monocyte chemoattractant protein-1 (MCP-1), MCP-4, Macrophage Derived Chemokine (MDC), and Thymus and Activation-Regulated Chemokine (TARC) in analyses adjusted for sex and age ranging from 26 % higher levels of IL-6 (1.26, 95 %CI: [1.12–1.43], p < 0.001, adjusted p = 0.009) and IL-10 (1.26, 95 %CI: [1.09–1.46], p = 0.002, adjusted p = 0.049), respectively, to 9 % higher eotaxin levels (1.09, 95 %CI: [1.04–1.15], p = 0.001, adjusted p = 0.024). Of these, MDC levels were 12 % higher in BD compared with UR (1.12, 95 %CI: [1.02–1.22], p = 0.001, adjusted p = 0.024). For all other markers, UR showed no difference from patients with BD or HC.Based on a data-driven model, a composite marker including all 47 immune and vascular stress markers, sex, age, BMI, smoking status, and alcohol intake, discriminated patients with BD from HC with a with an area under the receiver operating curve (AUC) of 0.76 (95 % CI: 0.75–0.77) ConclusionsHigher levels of pro-inflammatory and anti-inflammatory immune markers are present in patients newly diagnosed with BD but not in UR compared with HC, supporting immune dysregulation playing a role in the pathophysiology of BD.

The emerging neuroimmune hypothesis of bipolar disorder: An updated overview of neuroimmune and microglial findings.

Bipolar disorder (BD) is a severe and multifactorial disease, with onset usually in young adulthood, which follows a progressive course throughout life. Replicated epidemiological studies have suggested inflammatory mechanisms and neuroimmune risk factors as primary contributors to the onset and development of BD. While not all patients display overt markers of inflammation, significant evidence suggests that aberrant immune signaling contributes to all stages of the disease and seems to be mood phase dependent, likely explaining the heterogeneity of findings observed in this population. As the brain's immune cells, microglia orchestrate the brain's immune response and play a critical role in maintaining the brain's health across the lifespan. Microglia are also highly sensitive to environmental changes and respond to physiological and pathological events by adapting their functions, structure, and molecular expression. Recently, it has been highlighted that instead of a single population of cells, microglia comprise a heterogeneous community with specialized states adjusted according to the local molecular cues and intercellular interactions. Early evidence has highlighted the contribution of microglia to BD neuropathology, notably for severe outcomes, such as suicidality. However, the roles and diversity of microglial states in this disease are still largely undermined. This review brings an updated overview of current literature on the contribution of neuroimmune risk factors for the onset and progression of BD, the most prominent neuroimmune abnormalities (including biomarker, neuroimaging, exvivo studies) and the most recent findings of microglial involvement in BD neuropathology. Combining these different shreds of evidence, we aim to propose a unifying hypothesis for BD pathophysiology centered on neuroimmune abnormalities and microglia. Also, we highlight the urgent need to apply novel multi-system biology approaches to characterize the diversity of microglial states and functions involved in this enigmatic disorder, which can open bright perspectives for novel biomarkers and therapeutic discoveries.

Lower serum insulin-like growth factor 2 level in patients with bipolar disorder is associated with the severity of manic symptoms during manic episodes.

Accumulating evidence has indicated that neurodevelopmental defects may underlie the pathophysiology of bipolar disorder (BD). Insulin-like growth factors (IGFs) are a family of neurotrophic factors that are essential for the survival and development of neurons. The present study aims to investigate whether IGF-2 signaling is implicated in the pathophysiological processes of BD. 50 healthy controls and 78 patients with BD, including 23 patients who diagnosed acute depressive episode and 55 patients who diagnosed acute manic episode, were recruited in this study. The 17-item Hamilton Depression Rating Scale (HAMD-17) and the Young Mania Rating Scale (YMRS) were used to assess the severity of the depressive and manic symptoms, respectively. The serum IGF-2 level was determined by an enzyme-linked immunosorbent assay (ELISA). The Kolmogorov-Smirnov and Mann-Whitney U tests were used for between-group comparisons and spearman analysis was used to analyze correlations. Patients with BD had lower serum IGF-2 levels (66.08 ± 21.22 ng/ml) when compared to healthy controls (88.72 ± 31.55 ng/ml). BD patients were divided into manic episode and depressive episode subgroups. We found that serum IGF-2 levels were reduced in both the mania and depression subgroups (mania: 67.19 ± 21.52 ng/ml, depression: 63.43 ± 20.67 ng/ml; P < 0.001), while no significant difference was observed between two groups (P > 0.05). Spearman correlation analyses revealed that the levels of serum IGF-2 were negatively correlated with the YMRS scores in BD patients (r = -0.522, P < 0.001). Furthermore, IGF-2 was found to be an independent contributor to the severity of symptoms in patients with manic episodes (B = -0.610, t = -5.299, P < 0.001). Lower serum IGF-2 levels were found in BD patients and correlated with the severity of the manic symptoms in these patients during manic episodes. These results suggest that reduced IGF-2 levels might be involved in the pathophysiology of BD, and serum IGF-2 could be a peripheral biomarker for the evaluation of the severity of manic symptoms in BD patients.

Antimanic-like effect of dipyridamole in the methylphenidate-induced hyperlocomotion.

Adenosinergic system has been implicated in the pathophysiology of bipolar disorder and drugs that affect adenosine neurotransmission have shown some efficacy as add-on therapy in manic patients. Thus, the aim of the present study was to screen adenosinergic drugs for antimanic-like effect in methylphenidate (MPH)-induced hyperlocomotion in mice. Male and female Swiss mice received a single allopurinol (50 and 200 mg/kg, ip), dipyridamole (20 mg/kg, ip), or inosine (50 mg/kg, ip) administration before an acute MPH challenge (5mg/kg, sc). In experiments with repeated treatment, male mice received a daily administration of allopurinol (25 and 50 mg/kg, ip), dipyridamole (20 mg/kg, ip), or inosine (50 mg/kg, ip) for 14 days. Finally, pretreatment with aminophylline (2mg/kg, sc), an unspecific adenosine receptor antagonist, was used to evaluate a putative adenosinergic mediation. Locomotor activity was measured in the automated activity chamber for 20 min. Acute and repeated dipyridamole reduced the increase in locomotor activity induced by MPH, while allopurinol and inosine had no effect. Aminophylline blocked the effect of dipyridamole in MPH-induced hyperlocomotion. The present results suggest that dipyridamole may have an antimanic-like effect through adenosine receptors and reinforce the proposal that the adenosine system may be an interesting target for new antimanic drugs.

The link between alterations in circadian rhythms and lipid metabolism in bipolar disorder: the lipid droplets hypothesis.

Bipolar disorder (BD) is a neuropsychiatric illness characterized by recurrent episodes of mania and depression, leading to profound cognitive and functional impairments, psychiatric and metabolic comorbidities, and substantial healthcare costs. Due to its complex nature and absence of specific biomarkers, BD presents significant daily challenges for clinicians. Therefore, advancing our understanding of BD pathophysiology is essential to identify novel diagnostic biomarkers and potential therapeutic targets. Although its neurobiology remains unclear, disruption of circadian rhythms and lipid alterations have emerged as key hallmarks of BD. As essential components of the brain, lipids play a pivotal role in regulating synaptic activity and neuronal development. Thus, alterations in brain lipids may contribute to the neuroanatomical changes and reduced neuroplasticity observed in BD. The levels of toxic lipids inside the cell are buffered by lipid droplets that regulate the storage of neutral lipids. These dynamic organelles adapt to cellular needs, and their dysregulated accumulation has been linked to various pathological conditions. Notably, lipid droplets and various lipid classes display rhythmic oscillations throughout the 24-hour cycle, suggesting a link between lipid metabolism, circadian rhythms and lipid droplets. In this review, we explore the impairment of circadian rhythms and lipid metabolism in BD, along with evidence demonstrating that circadian clocks regulate the accumulation of lipid droplets. Importantly, we propose the "lipid droplets hypothesis for BD" that considers that the compromised lipid metabolism in BD is intimately associated with alterations in the lipid droplets homeostasis, which can be driven by disturbances in the circadian clocks.

Electroconvulsive therapy improves hematological inflammatory markers in bipolar disorder.

Immune dysfunction and inflammation participate in the pathophysiology of bipolar disorder (BD). Abnormal levels of inflammatory markers, namely, red cell distribution width (RDW) and platelet distribution width (PDW), were detected in BD. Electroconvulsive therapy (ECT) for various mental disorders including BD was linked to changes in these inflammatory mediators. Hence, we aimed to assess the impact of ECT on PDW and RDW in patients with BD. Seventy-two patients aged ≥ 16 were enrolled in the current prospective cohort study over 6 months, diagnosed as BD based on DSM-IV and indicated for ECT and complete blood count (CBC) drawn pre-ECT and after four ECT sessions. By the end of the ECT sessions, we noticed a significant elevation in PDW with lowering in RDW levels. However, no significant differences were detected before and after ECT regarding platelet (PLTs) count, mean platelet volume (MPV), and Plateletcrit (PCT). ECT seems to improve the CBC-derived inflammatory markers (RDW and PDW) subsequently, improving the underlying inflammatory process in BD without disturbing PLT homeostasis which support its anti-inflammatory role in BD.

Melatonin MT1 receptors as a target for the psychopharmacology of bipolar disorder: A translational study

The treatment of bipolar disorder (BD) still remains a challenge. Melatonin (MLT), acting through its two receptors MT1 and MT2, plays a key role in regulating circadian rhythms which are dysfunctional in BD. Using a translational approach, we examined the implication and potential of MT1 receptors in the pathophysiology and psychopharmacology of BD. We employed a murine model of the manic phase of BD (Clock mutant (ClockΔ19) mice) to study the activation of MT1 receptors by UCM871, a selective partial agonist, in behavioral pharmacology tests and in-vivo electrophysiology. We then performed a high-resolution Nuclear Magnetic Resonance study on isolated membranes to characterize the molecular mechanism of interaction of UCM871. Finally, in a cohort of BD patients, we investigated the link between clinical measures of BD and genetic variants located in the MT1 receptor and CLOCK genes. We demonstrated that: 1) UCM871 can revert behavioral and electrophysiological abnormalities of ClockΔ19 mice; 2) UCM871 promotes the activation state of MT1 receptors; 3) there is a significant association between the number of severe manic episodes and MLT levels, depending on the genetic configuration of the MT1 rs2165666 variant. Overall, this work lends support to the potentiality of MT1 receptors as target for the treatment of BD.

Optical Coherence Tomography Findings in Bipolar Disorder Patients and the Related Factors.

This study's purpose is to determine the effects of current episode and the mood stabilizers on chorioretinal layer thicknesses of bipolar disorder (BD) patients using spectral-domain optical coherence tomography (SD-OCT). Sixty-seven patients were diagnosed with BD I and using lithium (Li) or valproic acid (VPA), of whom 20 were manic, 24 were depressive, and 23 were in remission, and 49 healthy individuals were included in the study. Peripapillary retinal nerve fiber layer (RNFL), ganglion cell layer, and macular thicknesses of the participants were measured automatically using SD-OCT, and their choroid layer thicknesses were measured manually using the depth imaging mode of SD-OCT. Statistical analysis of the data was performed using Statistical Package for the Social Sciences version 23.0. The patient group's mean age was 39.78 ± 11.78, and the control group's mean age was 42.06 ± 12.10. The mean disease duration was 13.22 ± 8.23 in the patient group, and 26 patients were using Li. While peripapillary RNFL thicknesses were lower in the patient group (P < .05), other layer measurements were similar between the groups. Moreover, the episodes experienced by BD patients did not affect chorioretinal SD-OCT measurements. The patients on VPA had significantly lower RNFL thicknesses compared to the control and the Li groups, and all chorioretinal measurements were similar between the Li and the control groups. As a result of the study, it was established that neurodegenerative processes play a role in the pathophysiology of BD and the usage of Li is protective against the neurodegeneration of RNFL. Retinal changes measured with SD-OCT can be used for the diagnosis and prognosis of BD and for evaluating responses to mood stabilizers.

Protocol for a systematic review and meta-analysis of coordinate-based network mapping of brain structure in bipolar disorder across the lifespan.

Studies about brain structure in bipolar disorder have reported conflicting findings. These findings may be explained by the high degree of heterogeneity within bipolar disorder, especially if structural differences are mapped to single brain regions rather than networks. We aim to complete a systematic review and meta-analysis to identify brain networks underlying structural abnormalities observed on T1-weighted magnetic resonance imaging scans in bipolar disorder across the lifespan. We also aim to explore how these brain networks are affected by sociodemographic and clinical heterogeneity in bipolar disorder. We will include case-control studies that focus on whole-brain analyses of structural differences between participants of any age with a standardised diagnosis of bipolar disorder and controls. The electronic databases Medline, PsycINFO and Web of Science will be searched. We will complete an activation likelihood estimation analysis and a novel coordinate-based network mapping approach to identify specific brain regions and brain circuits affected in bipolar disorder or relevant subgroups. Meta-regressions will examine the effect of sociodemographic and clinical variables on identified brain circuits. Findings from this systematic review and meta-analysis will enhance understanding of the pathophysiology of bipolar disorder. The results will identify brain circuitry implicated in bipolar disorder, and how they may relate to relevant sociodemographic and clinical variables across the lifespan.

Association between periodontal diseases and bipolar disorder: implications for therapeutic interventions: A narrative review

Chronic low-grade inflammation plays a role in the pathophysiology of bipolar disorder. Recent studies have shown that periodontitis can affect the central nervous system by activating inflammatory mediators in the brain. However, only a few studies have examined the association between periodontitis and bipolar disorder. Here, we aimed to review the current evidence on the association between periodontal diseases and bipolar disorder, its potential mechanisms, and future research directions. Studies so far suggested that periodontal diseases were more common in patients with bipolar disorder than in the general population. Patients with bipolar disorder generally have poor oral hygiene owing to poor self-care, smoking, alcohol abuse, and the effects of psychotropic medications. Proposed mechanisms underlying this association include the effects of inflammatory mediators, direct invasion of oral microbiota, modulation of the neurotransmitter system, and impact on the vagus nerve and hypothalamus-pituitary- adrenal axis. Additional clinical studies examining the prevalence of periodontal diseases and their association with the clinical features of bipolar disorder are necessary. Clinical studies targeting the treatment of periodontal diseases for primary or secondary prevention of bipolar disorder are warranted.

Imbalance of Plasma Copper and Zinc Levels and the Association Between the Cu/Zn Ratio and Lipid Peroxidation in Algerian Bipolar Patients.

Trace elements, through their interaction with biomolecules, can play an important role in the pathophysiology of bipolar disorder and protect against oxidative stress effects. The purpose of this study is to examine plasma concentration levels of zinc (Zn) and copper (Cu) of Algerian patients, diagnosed with bipolar disorder, and to compare these levels with those of healthy controls. The Cu/Zn ratio was calculated to explore a possible correlation between these elements and lipid peroxidation in the study groups. A total of 33 patients diagnosed with bipolar disorder and 38 healthy subjects participated in this study. Plasma copper and zinc concentrations were measured using a polarographic analyzer. The marker of plasma lipid peroxidation (Malondialdehyde:MDA) was determined by UV spectrophotometry. Plasma Cu concentrations were higher in patients compared to controls (p < 0.05), while the Zn level was significantly lower. Consequently, the Cu/Zn ratio was significantly different between patients and controls. Regarding MDA, no significant difference was noticed between the two study groups. However, in patients, a negative correlation was found between MDA and Cu/Zn ratio (r= -0.38, p= 0.027). These results suggested that an elevated Cu/Zn ratio is associated with attenuated lipid peroxidation in our bipolar patients.

Mitochondrial health index correlates with plasma circulating cell-free mitochondrial DNA in bipolar disorder.

Although mitochondrial dysfunction is known to play an essential role in the pathophysiology of bipolar disorder (BD), there is a glaring gap in our understanding of how mitochondrial dysfunction can modulate clinical phenotypes. An emerging paradigm suggests mitochondria play an important non-energetic role in adaptation to stress, impacting cellular resilience and acting as a source of systemic allostatic load. Known as mitochondrial allostatic load, this (phenomenon) occurs when mitochondria are unable to recalibrate and maintain cell homeostasis. This study aimed to evaluate the composite mitochondrial health index (MHI) in BD subjects and non-psychiatry controls. We will also explore whether lower MIH will be related to higher cell-free mtDNA (ccf-mtDNA) levels and poor clinical outcomes. In this study, 14 BD-I patients and 16 age- and sex-matched non-psychiatry controls were enrolled. Peripheral blood mononuclear cells (PBMCs) were used to measure the enzymatic activities of citrate synthase and complexes I, II, and IV and mtDNA copy number. Ccf-mtDNA was evaluated by qPCR in plasma. Mitochondrial quality control (MQC) proteins were evaluated by western blotting. After adjusting for confounding variables, such as age, sex, body mass index (BMI), and smoking status, patients with BD presented lower MHI compared to non-psychiatry controls, as well as higher ccf-mtDNA levels that negatively correlated with MHI. Because the MQC network is essential to maintain mitochondrial health, MHI and ccf-mtDNA were also examined in relation to several MQC-related proteins, such as Fis-1, Opa-1, and LC3. Our results showed that MHI correlated negatively with Fis-1 and positively with Opa-1 and LC3. Accordingly, ccf-mtDNA had a positive correlation with Fis-1 and a negative correlation with Opa-1 and LC3. Furthermore, we found a noteworthy inverse correlation between illness severity and MHI, with lower MHI and higher ccf-mtDNA levels in subjects with a longer illness duration, worse functional status, and higher depressive symptoms. Our findings indicate that mitochondrial allostatic load contributes to BD, suggesting mitochondria represent a potential biological intersection point that could contribute to impaired cellular resilience and increased vulnerability to stress and mood episodes. Ultimately, by linking mitochondrial dysfunction to disease progression and poor outcomes, we might be able to build a predictive marker that explains how mitochondrial function and its regulation contribute to BD development and that may eventually serve as a treatment guide for both old and new therapeutic targets.