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

Brain-Region Size May Be Long-Sought Biomarker

Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive, degenerative disease that leads to the motor neurons depletion in the spinal cord anterior horn and pyramidal tract. Several evaluations have been proposed in order to provide a better follow-up and management of secondary complications. However, the biggest difficulty is to select a single instrument to objectively assess the neurological deficit, the

There is growing evidence that inflammation is an important mediator of pathophysiology in bipolar disorder. The omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acid (PUFA) metabolic pathways participate in several inflammatory processes and have been linked through epidemiologic and clinical studies to bipolar disorder and its response to treatment. We review the data on PUFAs as biomarkers in bipolar disorder and n-3 PUFA used as treatment for bipolar disorder. PubMed and CINAHL were searched for articles on PUFA and bipolar disorder published in the English language through November 6, 2013, with an updated search conducted on August 20, 2015. Keywords searched included omega 3 fatty acids and bipolar disorder, omega 3 fatty acids and bipolar mania, omega 3 fatty acids and bipolar depression, omega 3 fatty acids and mania, omega 3 fatty acids and cyclothymia, omega 3 fatty acids and hypomania, fatty acids and bipolar disorder, essential fatty acids and bipolar disorder, polyunsaturated fatty acids and bipolar disorder, DHA and bipolar disorder, and EPA and bipolar disorder. Studies selected measured PUFAs as biomarkers or introduced n-3 PUFA as treatment. We identified 17 relevant human clinical articles that either compared PUFA levels between a bipolar disorder group and a control group or used a PUFA intervention to treat depression or mania in bipolar disorder. Human studies suggest low n-3 red blood cell PUFA concentrations and correlations with clinical severity in studies of plasma concentrations in symptomatic bipolar disorder. Results of published n-3 PUFA dietary supplementation trials for bipolar disorder indicate efficacy in treatment for mania or depression in 5 of 5 open-label trials, efficacy in treatment of depression in 1 of 7 randomized controlled trials, and a signal for treatment of depression in 1 meta-analysis. Biomarker studies of PUFA and treatment studies of n-3 PUFA in bipolar disorder show promise for indicating a way forward in the study of PUFA in bipolar disorder. Investigation of the intake and metabolism of the n-3 and n-6 PUFA when supplementation is provided in treatment trials might offer clues for identification of when and how PUFA may be important for treatment in bipolar disorder.

Bipolar disorder (BD) is a common and debilitating mental disorder. However, there are no biomarkers available to aid in the diagnosis of this disorder. Here, we used a gas chromatography-mass spectrometry (GC-MS) based metabonomic method to characterize the urinary metabolic profiling of BD subjects and healthy controls to identify and validate urinary metabolite biomarkers for BD. Multivariate statistical analysis was used to visualize group discrimination and identify differentially expressed urinary metabolites in BD subjects relative to the healthy controls. Multivariate statistical analysis showed that the BD group was significantly distinguishable from the healthy control. Totally, 37 urinary metabolites responsible for discriminating BD subjects from healthy controls were identified. Interestingly, of 37 differential metabolites, 2,4-dihydroxypyrimidine was identified as an effective diagnostic biomarker for BD, yielding an area under the receiver operating characteristic curve (AUC) of 0.889 in the training samples (45 BD subjects and 61 healthy controls) and 0.805 in the test samples (26 BD subjects and 33 healthy controls). Our findings suggest that 2,4-dihydroxypyrimidine is a promising candidate urinary biomarker for BD, which may facilitate development of a urine-based diagnostic test for BD.

Chapter 1 - Biomarkers in bipolar disorder: an overview

Objectives The number of studies investigating inflammatory biomarkers in bipolar disorder has increased significantly in recent years. The neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and monocyte to lymphocyte ratio (MLR) are inexpensive and easy to obtain values used to measure the level of inflammation. This study compared the NLR, PLR, and MLR values in the manic and euthymic phases of the same patients. Methods Patients who met the inclusion criteria and were hospitalized due to bipolar affective disorder manic episodes at the Ondokuz Mayis University Faculty of Medicine inpatient psychiatry clinic between 01.01.2013 and 01.01.2019 were enrolled in the study. One hundred thirteen patients undergoing manic episodes were included. White blood cells, neutrophil, lymphocyte, platelet, and monocyte counts were retrospectively recorded from complete blood count data collected during the hospital stay, and NLR, PLR, and MLR values were calculated from these. Results Neutrophil, platelet, and monocyte counts, as well as NLR, PLR, and MLR values were higher in the manic episodes of bipolar disorder compared to the control group. Decreased neutrophil and lymphocyte counts, and decreased NLR, PLR, and MLR were observed in the remission period after-treatment of the manic bipolar disorder episodes. In the euthymic phase of bipolar disorder, however, platelet and monocyte counts and MLR were higher than in the control group. Conclusions The study indicates that NLR and PLR may be used as state markers and that MLR may be used as a trait marker in bipolar disorder.

Bipolar disorder (BD) is a serious mental disorder that globally affected 40 million people in 2019. According to the National Alliance on Mental Illness (NAMI), the present state of scientific knowledge only permits psychiatrists to diagnose BD using subjective and imprecise questionnaires. Therefore, developing a diagnostic tool with objective and precise biomarkers should be a major focus of research in this field. Among the potential biomarkers for BD, electroencephalogram (EEG)-based signatures of BD are considered to be the most optimal marker due to their strong links with behavioural symptoms and also their non-invasiveness. The goal of this review is to give a detailed summary of current techniques for investigating the traces of BD through EEG abnormalities. In this review, 13 studies from databases such as ScienceDirect and PubMed seeking to utilize EEG characteristics to diagnose BD were selected. The search keywords were “EEG in BD diagnosis”, “EEG microstates in BD”, and “EEG features for BD patients”. The publication date was set from 2007 to 2021. From these studies, we synthesize the effects of BD on each EEG feature, as well as detail the pros and cons when using each feature as a biomarker for BD. Results showed that EEG microstates demonstrate their potential among the seven EEG properties discussed in this article, as shown by several studies. By definition, EEG microstates are a dynamic representation of the spatial distribution of the scalp's electric potential as it varies over time. Specifically, four microstate classes recorded in different brain regions are classified into A (right-frontal left-posterior), B (left-frontal right-posterior), C (midline frontal-occipital), and D (midline frontal topographies). Greater presence of microstate class B in BD patients during task-free resting states are a distinctive characteristic of BD patients from which BD can be differentiated from other psychiatric illnesses. Besides microstates, EEG resting states are also considered to have a bright future in BD diagnosis. Specifically, by investigating brain frequency bands, researchers have discovered that BD patients exhibit abnormal delta and alpha signals as compared to healthy controls (HCs). The abnormalities of microstate B in EEG microstate characteristics would be the most promising biomarker for detecting BD. In addition, anomalies in delta and alpha signals during resting EEG states are possible BD diagnostic indicators.

Review the current evidence on biomarkers for bipolar disorder in the older adults. We conducted a systematic search of PubMed MEDLINE, PsycINFO, and Web of Science databases using the MeSH search terms "Biomarkers", "Bipolar Disorder", "Aged" and and "Aged, 80 and over". Studies were included if they met the following criteria: (1) the mean age of the study population was 50 years old or older, (2) the study included patients with bipolar disorder, and (3) the study examined one type of biomarkers or more including genetic, neuroimaging, and biochemical biomarkers. Reviews, case reports, studies not in English and studies for which no full text was available were excluded. A total of 26 papers were included in the final analysis. Genomic markers of bipolar disorder in older adults highlighted the implication of serotonin metabolism, while the expression of genes involved in angiogenesis was dysregulated. Peripheral blood markers were mainly related with low grade inflammation, axonal damage, endothelial dysfunction, and the dysregulation of the HPA axis. Neuroanatomical markers reflected a dysfunction of the frontal cortex, a loss of neurones in the anterior cingulate cortex and a reduction of the hippocampal volume (in patients older than 50 years old). While not necessarily limited to older adults, some of them may be useful for differential diagnosis (neurofilaments), disease staging (homocysteine, BDNF) and the monitoring of treatment outcomes (matrix metalloproteinases). Our review provides a comprehensive overview of the current evidence on biomarkers for bipolar disorder in the older adults. The identification of biomarkers may aid in the diagnosis, treatment selection, and monitoring of bipolar disorder in older adults, ultimately leading to improved outcomes for this population. Further research is needed to validate and further explore the potential clinical utility of biomarkers in this population.

Introduction: Homocysteine levels have been associated with major depression, but associations with bipolar disorder remain less clear. Some data suggest homocysteine levels have potential as a biomarker of treatment response; however the literature is mixed.Areas covered: Oxidized forms of homocysteine can be potentially neurotoxic leading to glutamate toxicity, apoptotic transformation and neurodegenerative processes. High homocysteine may be a risk biomarker for bipolar disorders, but the empirical base remains too weak for firm conclusions. This review discusses the current literature for homocysteine levels as a biomarker.Expert opinion: It is premature to foreclose the utility of homocysteine levels as a biomarker for bipolar disorder due the methodological inadequacies in the existing literature. These methodological design issues include lack of control for the confounding variables of concurrent medication, phase of bipolar disorder, gender, age, nutritional status, thyroid, liver and renal function, smoking or lean body mass. Well-powered association studies with confounder control could help shed more light on the important clinical question of homocysteine’s utility as a biomarker in bipolar disorder. Future experiments are needed to examine the outcome of interventions modulating homocysteine for treating bipolar disorder. Only prospective randomized control trials will provide definitive evidence of the utility of homocysteine as a biomarker or therapeutic target.

Bipolar disorder (BD) is associated with increased rates of cardiovascular disease (CVD). Brain-derived neurotrophic factor (BDNF) and inflammatory markers are leading biomarkers in BD. We examined whether these biomarkers underlie the link between BD and CVD proxies among adolescents with bipolar spectrum disorders. Subjects were 60 adolescents, 13-19 years old (40 with BD and 20 healthy controls [HCs]). Semistructured interviews determined diagnoses based on DSM-IV. Serum was assayed for BDNF, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Carotid intima media thickness (cIMT) and flow-mediated dilation were assessed using ultrasound. Procedures were conducted at a subspecialty clinic (January 2011-May 2014). Adolescents with BD had significantly greater waist circumference (BD: 81.72 cm [11.67 cm], HC: 75.64 cm [8.63 cm]; U = 547.5, P = .021), body mass index (BMI) (BD: 25.50 kg/m²undefined[5.29 kg/m²], HC: 21.76 kg/m² [3.43 kg/m²]; U = 608.5, P < .0001), pulse pressure (BD: 42.31 mm Hg [10.57 mm Hg], HC: 33.84 mm Hg [6.69 mm Hg]; U = 561.5, P < .001), and IL-6 (BD: 8.93 pg/mL [7.71 pg/mL], HC: 4.96 pg/mL [6.38 pg/mL]; U = 516.0, P < .0001) than HC adolescents. Subjects with BD-I (n = 14) and BD-II (n = 16) had greater IL-6 versus HCs (F₃,₅₁ = 5.29, P = .003). Controlling for BMI and age did not alter these findings. IL-6 was higher in symptomatic (n = 19) and asymptomatic BD (n = 21) versus that found in HCs (F₂,₅₂ = 7.96, P = .001). In symptomatic BD, lower BDNF was associated with greater mean cIMT (ρ = -0.507, P = .037). This study found evidence of increased inflammation among adolescents with BD. While present findings suggest a potential interplay between symptomatic status, biomarkers, and atherosclerosis proxies, there were no significant differences in cIMT or flow-mediated dilation in adolescents with BD compared to HCs. This may indicate that there is potential opportunity for CVD prevention strategies in adolescents with BD.

Abnormal expression of microRNAs is connected to brain development and disease and could provide novel biomarkers for the diagnosis and prognosis of bipolar disorder. We performed a PubMed search for microRNA biomarkers in bipolar disorder and found 18 original research articles on studies performed with human patients and published from January 2011 to June 2023. These studies included microRNA profiling in blood- and brain-based materials. From the studies that had validated the preliminary findings, potential candidate biomarkers for bipolar disorder in adults could be miR-140-3p, -30d-5p, -330-5p, -378a-5p, -21-3p, -330-3p, -345-5p in whole blood, miR-19b-3p, -1180-3p, -125a-5p, let-7e-5p in blood plasma, and miR-7-5p, -23b-5p, -142-3p, -221-5p, -370-3p in the blood serum. Two of the studies had investigated the changes in microRNA expression of patients with bipolar disorder receiving treatment. One showed a significant increase in plasma miR-134 compared to baseline after 4 weeks of treatment which included typical antipsychotics, atypical antipsychotics, and benzodiazepines. The other study had assessed the effects of prescribed medications which included neurotransmitter receptor-site binders (drug class B) and sedatives, hypnotics, anticonvulsants, and analgesics (drug class C) on microRNA results. The combined effects of the two drug classes increased the significance of the results for miR-219 and -29c with miR-30e-3p and -526b* acquiring significance. MicroRNAs were tested to see if they could serve as biomarkers of bipolar disorder at different clinical states of mania, depression, and euthymia. One study showed that upregulation in whole blood of miR-9-5p, -29a-3p, -106a-5p, -106b-5p, -107, -125a-3p, -125b-5p and of miR-107, -125a-3p occurred in manic and euthymic patients compared to controls, respectively, and that upregulation of miR-106a-5p, -107 was found for manic compared to euthymic patients. In two other studies using blood plasma, downregulation of miR-134 was observed in manic patients compared to controls, and dysregulation of miR-134, -152, -607, -633, -652, -155 occurred in euthymic patients compared to controls. Finally, microRNAs such as miR-34a, -34b, -34c, -137, and -140-3p, -21-3p, -30d-5p, -330-5p, -378a-5p, -134, -19b-3p were shown to have diagnostic potential in distinguishing bipolar disorder patients from schizophrenia or major depressive disorder patients, respectively. Further studies are warranted with adolescents and young adults having bipolar disorder and consideration should be given to using animal models of the disorder to investigate the effects of suppressing or overexpressing specific microRNAs.

The interplay between state- and trait-related disruptions in structural networks remains unclear in bipolar disorder (BD), but graph theory can offer insights into global and local network changes. We sought to use diffusion-tensor imaging (DTI) and graph theory approaches to analyze structural topological properties across distinct mood states and identify high-risk individuals by examining state- and trait-related impairments in BD. We studied changes in white matter network among patients with BD and healthy controls, exploring relationships with clinical variables. Secondary analysis involved comparing patients with BD with unaffected people at high genetic risk for BD. We included 152 patients with BD, including 52 with depressive BD (DBD), 64 with euthymic BD (EBD) and 36 with manic BD (MBD); we also included 75 healthy controls. Secondary analyses involved 27 unaffected people at high genetic risk for BD. Patients with DBD and MBD exhibited significantly lower global efficiencies than those with EBD and healthy controls, with patients with DBD showing the lowest global efficiencies. In addition, patients with DBD displayed impaired local efficiency and normalized clustering coefficient (γ). At a global level, γ correlated negatively with depression and anxiety. Compared with healthy controls, and across mood states, patients with BD showed abnormal shortest path lengths in the frontolimbic circuit, a trend mirrored among those at high genetic risk for BD. Considerations include medication effects, absence of recorded BD episode counts and the cross-sectional nature of the study. Mood-specific whole-brain network metrics could serve as potential biomarkers in BD for transitions between mood states. Moreover, these findings contribute to evidence of trait-related frontolimbic circuit irregularities, shedding light on underlying pathophysiological mechanisms in BD.

Gene expression in peripheral blood has the potential to inform on pathophysiological mechanisms and has emerged as a viable avenue for the identification of biomarkers. Here, we aimed to identify gene expression candidate genes and to explore the potential for a composite gene expression measure as a diagnostic and state biomarker in bipolar disorder. First, messenger RNA levels of 19 candidate genes were assessed in peripheral blood mononuclear cells of 37 rapid cycling bipolar disorder patients in different affective states (depression, mania and euthymia) during a 6–12-month period and in 40 age- and gender-matched healthy control subjects. Second, a composite gene expression measure was constructed in the first half study sample and independently validated in the second half of the sample. We found downregulation of POLG and OGG1 expression in bipolar disorder patients compared with healthy control subjects. In patients with bipolar disorder, upregulation of NDUFV2 was observed in a depressed state compared with a euthymic state. The composite gene expression measure for discrimination between patients and healthy control subjects on the basis of 19 genes generated an area under the receiver-operating characteristic curve of 0.81 (P<0.0001) in sample 1, which was replicated with a value of 0.73 (P<0.0001) in sample 2, corresponding with a moderately accurate test. The present findings of altered POLG, OGG1 and NDUFV2 expression point to disturbances within mitochondrial function and DNA repair mechanisms in bipolar disorder. Further, a composite gene expression measure could hold promise as a potential diagnostic biomarker.

Fractional anisotropy in the uncinate fasciculus and the cingulum may be biomarkers for bipolar disorder and may even be distinctly affected in different subtypes of bipolar disorder, an area in need of further research.AimsThis study aims to establish if fractional anisotropy in the uncinate fasciculus and cingulum shows differences between healthy controls, patients with bipolar disorder type I (BD-I) and type II (BD-II), and their unaffected siblings. Fractional anisotropy measures from the uncinate fasciculus, cingulum body and parahippocampal cingulum were compared with tractography methods in 40 healthy controls, 32 patients with BD-I, 34 patients with BD-II, 17 siblings of patients with BD-I and 14 siblings of patients with BD-II. The main effects were found in both the right and left uncinate fasciculus, with patients with BD-I showing significantly lower fractional anisotropy than both patients with BD-II and healthy controls. Participants with BD-II did not differ from healthy controls. Siblings showed similar effects in the left uncinate fasciculus. In a subsequent complementary analysis, we investigated the association between fractional anisotropy in the uncinate fasciculus and polygenic risk for bipolar disorder and psychosis in a large cohort (n = 570) of healthy participants. However, we found no significant association. Fractional anisotropy in the uncinate fasciculus differs significantly between patients with BD-I and patients with BD-II and healthy controls. This supports the hypothesis of differences in the physiological sub-tract between bipolar disorder subtypes. Similar results were found in unaffected siblings, suggesting the potential for this biomarker to represent an endophenotype for BD-I. However, fractional anisotropy in the uncinate fasciculus seems unrelated to polygenic risk for bipolar disorder or psychosis.Declaration of interestNone.

This study examines immune markers—P2X7, NACHT, and IL-6—as potential diagnostic and therapeutic biomarkers in Bipolar Disorder (BD). Among 120 participants (76 BD patients and 20 healthy controls), P2X7 levels were significantly elevated in BD patients both before (p = 0.001) and after treatment (p < 0.001), indicating strong diagnostic potential. NACHT levels also increased significantly after treatment (p = 0.007). Subgroup analysis revealed significantly higher P2X7 and NACHT levels in female BD patients compared to female controls (p < 0.001 for both). ROC curve analysis confirmed P2X7 as the most sensitive and specific marker for distinguishing BD from controls (p < 0.001), while NACHT showed predictive value after treatment (p < 0.05). Correlation analysis found significant associations between changes in P2X7 and NACHT levels and clinical improvement (p < 0.05). Despite limitations such as small sample size and potential medication effects, the findings support P2X7 and NACHT as promising biomarkers for BD diagnosis and treatment monitoring. The study contributes to the understanding of immune dysregulation in BD and suggests potential for immune-targeted therapies.