Metabolic Markers in Bipolar Disorder with Childhood Trauma Exposure: A Systematic Review.

Brain-derived neurotrophic factor in bipolar disorder: Associations with age at onset and illness duration

Recent evidence suggests that deficits of working memory may be a promising neurocognitive endophenotype of bipolar affective disorder. However, little is known about the neurobiological correlates of these deficits. The aim of this study was to determine possible pathophysiological trait markers of bipolar disorder in neural circuits involved in working memory. Functional magnetic resonance imaging was performed in 18 euthymic bipolar patients and 18 matched healthy volunteers using two circuit-specific experimental tasks established by prior systematic neuroimaging studies of working memory. Both euthymic bipolar patients and healthy controls showed working memory-related brain activations that were highly consistent with findings from previous comparable neuroimaging studies in healthy subjects. While these patterns of brain activation were completely preserved in the bipolar patients, only the patients exhibited activation of the right amygdala during the articulatory rehearsal task. In the same task, functional activation in right frontal and intraparietal cortex and in the right cerebellum was significantly enhanced in the patients. These findings indicate that the right amygdala is pathologically activated in euthymic bipolar patients during performance of a circuit-specific working memory task (articulatory rehearsal). This pathophysiological abnormality appears to be a trait marker in bipolar disorders that can be observed even in the euthymic state and that seems to be largely independent of task performance and medication.

Trauma exposure is strongly linked to maternal posttraumatic stress disorder (PTSD) and depressive symptoms during the perinatal period; however, childhood trauma exposure is often assessed without accounting for adult exposure. This study tested the unique impacts of childhood and adulthood trauma exposure on PTSD and depressive symptoms among pregnant women (N = 107, 82.9% Latina) enrolled in a nonrandomized intervention study. Regression analyses at baseline showed positive associations between trauma exposure and PTSD symptoms irrespective of trauma timing, childhood: B = 1.62, t(91) = 2.11, p = .038; adulthood: B = 2.92, t(91) = 3.04, p = .003. However only adulthood trauma exposure, B = 1.28, t(94) = 2.94, p = .004, was positively associated with depressive symptoms. Mixed-effects analyses of variance revealed interaction effects of time and adulthood trauma exposure, indicating that women with high degrees of adulthood trauma exposure had higher baseline levels of PTSD, F(1, 76.4) = 6.45, p = .013, and depressive symptoms, F(1, 87.2) = 4.88, p = .030, but showed a more precipitous decrease posttreatment than women with lower levels of adulthood trauma exposure. These findings support the clinical relevance of assessing both childhood and adulthood trauma exposure during the perinatal period given their impacts on baseline symptoms and psychotherapy response.

Differences in bipolar disorder type I and type II exposed to childhood trauma: A retrospective cohort study

Schizophrenia (SZ) and bipolar disorder (BD) are severe psychiatric disorders which result from complex interplay between genetic and environmental factors. It is well-established that they are highly heritable disorders, and considerable progress has been made identifying their shared and distinct genetic risk factors. However, the 15–40% of risk that is derived from environmental sources is less definitively known. Environmental factors that have been repeatedly investigated and often associated with SZ include: obstetric complications, infections, winter or spring birth, migration, urban living, childhood adversity, and cannabis use. There is evidence that childhood adversity and some types of infections are also associated with BD. Evidence for other risk factors in BD is weaker due to fewer studies and often smaller sample sizes. Relatively few environmental exposures have ever been examined for SZ or BD, and additional ones likely remain to be discovered. A complete picture of how genetic and environmental risk factors confer risk for these disorders requires an understanding of how they interact. Early gene-by-environment interaction studies for both SZ and BD often involved candidate genes and were underpowered. Larger samples with genome-wide data and polygenic risk scores now offer enhanced prospects to reveal genetic interactions with environmental exposures that contribute to risk for these disorders. Overall, although some environmental risk factors have been identified for SZ, few have been for BD, and the extent to which these account for the total risk from environmental sources remains unknown. For both disorders, interactions between genetic and environmental risk factors are also not well understood and merit further investigation. Questions remain regarding the mechanisms by which risk factors exert their effects, and the ways in which environmental factors differ by sex. Concurrent investigations of environmental and genetic risk factors in SZ and BD are needed as we work toward a more comprehensive understanding of the ways in which these disorders arise.

Binocular rivalry refers to a situation where contradictory information is presented simultaneously to the same location of each eye. This leads to the alternation of images every few seconds. The rate of alternation between images has been shown to be slower in euthymic participants with bipolar disorder than in healthy controls. The alternation rate is not uniformly slowed in bipolar disorder patients and may be influenced by clinical variables. The present study examined whether bipolar disorder patients have slower alternation rates, examined the influence of depression and explored the role of clinical variables and cognitive functions on alternation rate. Ninety-six patients with bipolar disorder and 24 control participants took part in the study. Current mood status and binocular rivalry performance were analysed with nonparametric tests. A slow and a normal alternation group were created by median split. We subsequently explored the distribution of several clinical variables across these groups. Further, we investigated associations between alternation rate and various cognitive functions, such as visual processing, memory, attention and general motor speed. The median alternation rate was significantly slower for participants with bipolar disorder type I (0.39 Hz) and for participants with bipolar spectrum disorder (0.43 Hz) than for control participants (0.47 Hz). Depression had no effect on alternation rate. There were no differences between participants with bipolar disorder type I and type II and in regard to medication regime and predominance of one rivalry image. There were also no differences in regard to the clinical variables and no significant associations between alternation rate and the cognitive functions explored. We replicated a slowing in alternation rate in some bipolar disorder participants. The alternation rate was not affected by depressed mood or any of the other factors explored, which supports views of binocular rivalry rates as a trait marker in bipolar disorder.

27.3 Brain Activation in Response to Fearful and Happy Stimuli: A Marker of Bipolar Disorder Across the Lifespan

Objectives Research on new serum parameters in bipolar disorder (BD) and schizophrenia is crucial for early diagnosis and understanding of disease pathophysiology. The arginine metabolic pathway has been found to be associated with several neuropsychiatric disorders in recent years. This study aims to investigate the role of serum markers involved in different steps of the arginine metabolic pathway in BD and schizophrenia. Methods Sixty healthy volunteers, sixty patients with schizophrenia and sixty patients with BD were included in the study. We analysed ornithine decarboxylase (ODC), arginine decarboxylase (ADC) and agmatinase levels using enzyme-linked immunosorbent assay. Enzymatic colorimetric methods were used for nitric oxide (NO), nitric oxide synthase (NOS) and arginase measurement. Results Serum agmatinase levels were significantly lower in BD and schizophrenia (p < 0.01). ODC and ADC levels were significantly lower in BD group compared to the control and schizophrenia groups (p < 0.001; p < 0.01). Serum NO levels were significantly higher and NOS levels were significantly lower in BD (p < 0.001; p < 0.05). Arginase levels were also lower in BD (p < 0.05). Conclusions Enzymes and substrates of the arginine metabolic pathway are promising markers in BD and schizophrenia. These markers can also be used to enable the diagnosis, when an adequate verbal communication is impossible.

A reliable biomarker signature for bipolar disorder sensitive to illness phase would be of considerable clinical benefit. Among circulating blood-derived markers there has been a significant amount of research into inflammatory markers, neurotrophins and oxidative stress markers.AimsTo synthesise and interpret existing evidence of inflammatory markers, neurotrophins and oxidative stress markers in bipolar disorder focusing on the mood phase of illness. Following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) guidelines, a systematic review was conducted for studies investigating peripheral biomarkers in bipolar disorder compared with healthy controls. We searched Medline, Embase, PsycINFO, SciELO and Web of Science, and separated studies by bipolar mood phase (mania, depression and euthymia). Extracted data on each biomarker in separate mood phases were synthesised using random-effects model meta-analyses. In total, 53 studies were included, comprising 2467 cases and 2360 controls. Fourteen biomarkers were identified from meta-analyses of three or more studies. No biomarker differentiated mood phase in bipolar disorder individually. Biomarker meta-analyses suggest a combination of high-sensitivity C-reactive protein/interleukin-6, brain derived neurotrophic factor/tumour necrosis factor (TNF)-α and soluble TNF-α receptor 1 can differentiate specific mood phase in bipolar disorder. Several other biomarkers of interest were identified. Combining biomarker results could differentiate individuals with bipolar disorder from healthy controls and indicate a specific mood-phase signature. Future research should seek to test these combinations of biomarkers in longitudinal studies.Declaration of interestNone.

Fatty acids and bipolar disorder

Background Bipolar disorder causes recurrent mania/hypomania and depression. According to the inflammatory idea, oxidative stress and antioxidants may be imbalanced throughout this illness. This study investigates the role of non-enzymatic antioxidants - serum uric acid, serum albumin, and serum bilirubin in different phases of bipolar disorder and compares them with healthy controls. Method Three groups were studied in this cohort research. One group had bipolar affective disorder patients with manic episodes, the second with depressed episodes, and the third with healthy controls. Serum uric acid, albumin, and bilirubin were measured before and after 4 weeks of treatment. The YRMS scale was used for manic episodes and the HAM-D scale was used for depressive episodes to assess disease severity. Results The study included 107 participants: 53 bipolar maniacs, 24 bipolar depressives, and 30 healthy controls. Bipolar mania was associated with considerably higher uric acid levels (5.40 mg/dl) compared to bipolar depression (4.09 mg/dl) and healthy controls (3.16 mg/dl) (p<0.001). Serum albumin levels were lower in bipolar depression (3.08 mg/dl) compared to mania (4.37 mg/dl) and healthy controls (4.60 mg/dl) (p<0.001). Results found no difference in serum bilirubin (p=0.367). Serum uric acid was reduced in bipolar mania (4.08 mg/dl) and depression (3.24 mg/dl) after 4 weeks (p<0.001), but albumin rose in depression (4.03 mg/dl) (p<0.001). Bipolar depression also increased serum bilirubin (0.72 mg/dl, p=0.01). Conclusion These findings suggest a potential role for serum uric acid and albumin as biomarkers in bipolar disorder, reflecting oxidative stress in these patients. This might also have a role in monitoring the progress and treatment of the patients. Recommendation Antioxidants can play a significant role in bipolar disorder but more research work is required. Further research with larger cohorts, consideration of confounding factors, and including measurement of more antioxidant molecules is essential to validate these findings.

Impact of depressive mixed state in an emergency psychiatry setting: A marker of bipolar disorder and a possible risk factor for emergency hospitalization

Cognitive deficits have been presupposed to be endophenotypic markers in bipolar disorder, but few studies have ascertained the cognitive deficits in healthy relatives of bipolar disorder patients. The aim of the present study was to assess the cognitive functions of first-degree relatives of patients with bipolar disorder and compare them with healthy controls. Ten first-degree apparently healthy relatives of patients with bipolar disorder were compared with 10 age- and education-matched control subjects on computer-based cognitive tests. As compared to the control group, the relatives group performed significantly poorly on tests for executive function and vigilance, while on the test for working memory the performance was not significantly different on most of the parameters. Executive functioning and vigilance could be potential markers of the endophenotype in bipolar patients.

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 worldwide, multifactorial mental disorder characterized by manic and depressive symptoms of varying degrees. Among all the genetic risk factors correlated with BD, brain-derived neurotrophic factor (BDNF) has emerged as a crucial neutropin that influences BD susceptibility with strong conservative across species and multiple downstream signaling pathways. However, the mechanisms of how BDNF polymorphism can contribute to BD are not yet lucid and systematically reviewed. BDNF Val66Met variant is capable of inducing neurodegenisis and Long-term Depression (LTD), both of which account for pathogenesis in BD. The Val66Met variant is associated with rapid cycling episodes in BD. Another variant, Arg125Met is a potential BD risk variant which elicits neuronal apoptosis by affecting the maturation of BDNF. In this paper, we briefly summarized BD epidemiology, symptoms, BDNF structure, and its action of function. We reviewed various mechanisms of BDNF Val66Met and Arg125Met variant for BD pathogenesis in detail and provided insights into possible BD clinical treatment targets. BDNF has been proven to be a noteworthy gene factor in BD and gene therapy targeted on BDNF is a promising therapeutic strategy that requires further research.