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Background: The balance between neurotoxic and neuroprotective effects of kynurenine pathway (KP) components has been recently proposed as a key element in the pathophysiology of bipolar disorder (BD) and related mood episodes. This comprehensive overview explored the link of KP with symptom severity and other clinical features of BD., Methods: We searched Medline, Embase, and PsycInfo electronic databases for studies assessing the association of peripheral and/or central concentrations of KP metabolites with putative clinical features, including symptom severity and other clinical domains in BD., Results: We included the findings of 13 observational studies investigating the possible variations of KP metabolites according to symptom severity, psychotic features, suicidal behaviors, and sleep disturbances in BD. Studies testing the relationship between KP metabolites and depression severity generated mixed and inconsistent findings. No statistically significant correlations with manic symptoms were found. Moreover, heterogeneous variations of the KP across different clinical domains were shown. Few available studies found (a) higher levels of cerebrospinal fluid kynurenic acid and lower of plasma quinolinic acid in BD with psychotic features, (b) lower central and peripheral picolinic acid levels in BD with suicide attempts, and (c) no significant correlations between KP metabolites and BD-related sleep disturbances., Conclusions: An imbalance of KP metabolism toward the neurotoxic branches is likely to occur in people with BD, though evidence on variations according to specific clinical features of BD is less clear. Additional research is needed to clarify the role of KP in the etiopathogenesis of BD and related clinical features.

Impaired hormonal regulation of appetite may contribute to higher cardiovascular risk in bipolar disorder (BD). We performed a systematic review and meta-analysis of studies investigating peripheral blood levels of appetite-regulating hormones in BD and controls. A total of 32 studies were included. Leptin and insulin levels were significantly elevated in patients with BD during euthymia, but not in other mood states. Greater differences in the number of male participants between patients with BD and healthy controls were associated with higher effect size estimates for the levels of insulin. There were significant positive correlations of effect size estimates for the levels of adiponectin with the percentage of individuals with type I BD and duration of BD. Our findings point to the mechanisms underlying high rates of cardiometabolic comorbidities in BD. Moreover, they suggest that investigating hormonal regulation of appetite might help to understand differences in the neurobiology of BD types., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Growing evidence suggests that a dysregulation of the kynurenine pathway (KP) occurs in bipolar disorder (BD). This systematic review and meta-analysis aimed at assessing the possible differences in peripheral blood levels of KP metabolites between individuals with BD and healthy controls. We searched Medline, Embase, and PsycInfo electronic databases for articles indexed up to February 2020. We included any observational study comparing the peripheral blood levels of at least one KP metabolite between adults with BD and healthy controls. Random-effects meta-analyses were carried out generating pooled standardized mean differences (SMDs). Heterogeneity between studies was estimated using the I 2 index. Meta-regression and sensitivity analyses were conducted. Sixteen studies met inclusion criteria and were included in our study. Meta-analyses showed that individuals with BD have lower peripheral blood levels of tryptophan (SMD = -0.29), kynurenine (SMD = -0.28), kynurenic acid (SMD = -0.30), and xanthurenic acid (SMD = -0.55), along with lower kynurenic acid to kynurenine (SMD = -0.60) and kynurenic acid to quinolinic acid (SMD = -0.37) ratios, than healthy controls. Individuals with a manic episode showed the greatest reductions in tryptophan levels (SMD = -0.51), whereas kynurenic acid levels were more reduced among subjects in a depressive phase (SMD = -0.70). Meta-regression and sensitivity analyses confirmed our results. The findings of the present meta-analysis support the hypothesis of an abnormality of the KP in BD. Considering the partial inconsistency of the findings and the small-to-medium magnitude of the estimated effect sizes, additional research assessing possible mediators or confounders is needed., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

We aimed to perform a systematic review and meta-analysis of studies examining the levels of chemokines in peripheral blood of patients with bipolar disorder (BD) and healthy controls. Meta-analysis was based on random-effects models with Hedges' g as the effect size estimate. We included 13 eligible studies (1221 BD patients and 663 controls). The following chemokines were analysed: interleukin-8 (IL-8), monocyte-chemoattractant protein-1 (MCP-1), eotaxin-1, eotaxin-2 and interferon-γ-induced protein 10 (IP-10). The levels of IL-8 (N = 8, g = 0.26, 95%CI: 0.11-0.41, p < 0.001), MCP-1 (N = 8, g = 0.40, 95%CI: 0.18-0.63), eotaxin-1 (N = 3, g = 0.55, 95%CI: 0.21-0.89, p = 0.001) and IP-10 (N = 4, g = 0.95, 95%CI: 0.67-1.22, p < 0.001) were significantly higher in BD patients as compared with controls. Subgroup analyses revealed that elevated levels of IL-8 (N = 5, g = 0.75, 95%CI: 0.42-1.07, p < 0.001) and MCP-1 (N = 4, g = 0.57, 95%CI: 0.28-0.86, p < 0.001) appeared only in BD patients during their depressive phase. Illness duration was associated with significantly lower levels of IL-8 in meta-regression analysis. In turn, elevated levels of IP-10 were present during euthymia (N = 2, g = 0.76, 95%CI: 0.43-1.10, p < 0.001) but not depression (N = 2, g = 1.81, 95%CI: -0.16 to 3.77, p = 0.072). The analysis of eotaxin-1 levels was mainly based on studies of euthymic BD patients (N = 3). Our results suggest that chemokine alterations in BD might be related to mood state. Elevated levels of IL-8 and MCP-1 might be specific to depression. Available evidence indicates that increased levels of eotaxin-1 and IP-10 appear in euthymia; however, more studies are needed to address these alterations in other mood states., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

S100 calcium-binding protein B (S100B) and neuron-specific enolase (NSE) might be peripheral markers reflecting glia and neuronal abnormalities in subjects with bipolar disorder. We carried out a systematic review and meta-analysis, searching for studies indexed in main electronic databases, to clarify whether S100B and NSE blood levels might be increased in bipolar disorder. Eleven studies met eligibility criteria, with data on S100B levels and/or NSE levels in subjects with bipolar disorder and healthy controls, respectively. Random-effects meta-analysis estimated higher levels of S100B in bipolar disorder (standardized mean difference [SMD] = 0.81; p < .001), with some inconsistency across studies (I 2  = 81.7%). Findings were confirmed by relevant sensitivity analyses. Meta-regression analyses did not estimate any effect for tested covariates. On the other hand, no differences in NSE levels between individuals with bipolar disorder and healthy controls were estimated (SMD = -0.32; p = .374), with high heterogeneity across studies (I 2  = 89.9%). Meta-regression analyses showed that the effect size was influenced by both mean age (p < .001) and illness duration (p = .001) of subjects with bipolar disorders. Our findings support the hypothesis of a possible role of glial abnormalities in the pathophysiology of bipolar disorder., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Bipolar disorder (BD) is associated with high prevalence rates of obesity-related conditions and subclinical inflammation. Adiponectin is produced by adipose tissue and exerts anti-inflammatory activities. We aimed to perform a systematic review and meta-analysis of studies investigating adiponectin levels in BD patients and healthy controls. Electronic databases were searched from their inception until 15th Jan 2019. Random-effects models with the Hedges' g as the effect size (ES) estimate were used. We included 11 studies, representing 477 patients and 380 controls. Pooled data analysis revealed no significant differences in adiponectin levels between BD patients and controls (ES = 0.28, 95%CI: -0.34 - 0.90, p = 0.372). The levels of adiponectin were significantly higher during euthymia (ES = 1.09, 95%CI: 0.03-2.16, p = 0.044). The levels of adiponectin in depressed patients were lower, but this result did not reach statistical significance (ES = -0.90, 95%CI: -1.85 - 0.05, p = 0.063). Due to low number of studies, the subgroup analysis of manic patients was not performed; however, a severity of manic symptoms was not associated with the ES estimates. Longer illness duration and a higher percentage of BD type I (BD-I) patients were associated with higher ES estimates. A higher severity of depressive symptoms was associated with lower ES estimates. Heterogeneity was significant in all analyses. Results of the Egger's test were insignificant, showing no publication bias. Our results indicate that adiponectin might be a state marker of BD as it appears to be elevated in euthymia and decreased in depression. Illness progression and a diagnosis of BD-I might contribute to higher adiponectin levels., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Schizophrenia and bipolar disorder (BD) are complex and multidimensional disorders with high heritability rates. The contribution of genetic factors to the etiology of these disorders is increasingly being recognized as the action of multiple risk variants with small effect sizes, which might explain only a minor part of susceptibility. On the other site, numerous environmental factors have been found to play an important role in their causality. Therefore, in recent years, several studies focused on gene × environment interactions that are believed to bridge the gap between genetic underpinnings and environmental insults. In this article, we performed a systematic review of studies investigating gene × environment interactions in BD and schizophrenia spectrum phenotypes. In the majority of studies from this field, interacting effects of variation in genes encoding catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF), and FK506-binding protein 5 (FKBP5) have been explored. Almost consistently, these studies revealed that polymorphisms in COMT, BDNF, and FKBP5 genes might interact with early life stress and cannabis abuse or dependence, influencing various outcomes of schizophrenia spectrum disorders and BD. Other interactions still require further replication in larger clinical and non-clinical samples. In addition, future studies should address the direction of causality and potential mechanisms of the relationship between gene × environment interactions and various categories of outcomes in schizophrenia and BD.

Background: The aim of this article was to perform a systematic review of studies investigating the association between peripheral levels of cytokines and C-reactive protein (CRP), cytokine gene polymorphisms and cognition in patients with schizophrenia and bipolar disorder (BD)., Methods: The following databases: PubMed, CINAHL Complete, Academic Search Complete, ERIC and Health Source: Nursing/Academic Edition databases were searched according to the PRISMA guidelines. We included studies that investigated the association between peripheral levels of CRP and cytokines, cytokine gene polymorphisms and cognitive performance in schizophrenia and/or BD patients. Subsequently, quality assessment of eligible publications was performed. Results were synthesized by discussing main findings around correlations between inflammatory markers and cognition., Results: Most consistent results indicate worse cognitive performance in schizophrenia patients with higher CRP levels. Less consistent evidence suggests better cognitive functioning of schizophrenia patients with higher levels of tumour necrosis factor-α (TNF-α). Evidence for the involvement of other cytokines in cognitive impairment in patients with schizophrenia is less convincing due to discordant results or scarcity of studies. Due to low number of studies, it is difficult to draw conclusions on the involvement of CRP and cytokine alterations in the development of cognitive deficits in BD. Single studies suggest the role of CRP, interleukin(IL)-1 receptor antagonist, IL-6 and TNF-α with its receptors in the development of cognitive impairment in BD., Conclusions: Peripheral inflammation might be related to cognitive deficits in schizophrenia and BD. Unequivocal conclusions cannot be made due to methodological heterogeneity and low number of studies investigating particular cytokines., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The new area of research in psychiatric disorders is concerned with abnormal regeneration processes. The role of brain neurogenesis has been studied for decades. New discoveries, concerned with the pluripotency of VSEL cells and the role of factors involved in stem cell trafficking in peripheral blood create hope that it will be possible to develop a better understanding of the processes of neuroregeneration/neurodegeneration. There is an ongoing research investigating concentrations of: sphingosine -1-phosphate, SDF-1, elements of complement cascade, and stem cells in peripheral blood, including their possible connection to psychiatric disorders. Collected data, suggesting an abnormal course of regeneration processes in psychiatric disorders, raises hope of finding new potential markers of psychosis and anxiety disorders., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Peer support is an established component of recovery from bipolar disorder, and online support groups may offer opportunities to expand the use of peer support at the patient's convenience. Prior research in bipolar disorder has reported value from online support groups., Aims: To understand the use of online support groups by patients with bipolar disorder as part of a larger project about information seeking., Methods: The results are based on a one-time, paper-based anonymous survey about information seeking by patients with bipolar disorder, which was translated into 12 languages. The survey was completed between March 2014 and January 2016 and included questions on the use of online support groups. All patients were diagnosed by a psychiatrist. Analysis included descriptive statistics and general estimating equations to account for correlated data., Results and Conclusions: The survey was completed by 1222 patients in 17 countries. The patients used the Internet at a percentage similar to the general public. Of the Internet users who looked online for information about bipolar disorder, only 21.0% read or participated in support groups, chats, or forums for bipolar disorder (12.8% of the total sample). Given the benefits reported in prior research, clarification of the role of online support groups in bipolar disorder is needed. With only a minority of patients using online support groups, there are analytical challenges for future studies.

There is considerable international interest in online education of patients with bipolar disorder, yet little understanding of how patients use the Internet and other sources to seek information. 1171 patients with a diagnosis of bipolar disorder in 17 countries completed a paper-based, anonymous survey. 81% of the patients used the Internet, a percentage similar to the general public. Older age, less education, and challenges in country telecommunications infrastructure and demographics decreased the odds of using the Internet. About 78% of the Internet users looked online for information on bipolar disorder or 63% of the total sample. More years of education in relation to the country mean, and feeling very confident about managing life decreased the odds of seeking information on bipolar disorder online, while having attended support groups increased the odds. Patients who looked online for information on bipolar disorder consulted medical professionals plus a mean of 2.3 other information sources such as books, physician handouts, and others with bipolar disorder. Patients not using the Internet consulted medical professionals plus a mean of 1.6 other information sources. The percentage of patients with bipolar disorder who use the Internet is about the same as the general public. Other information sources remain important., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Overwhelming evidence indicates that subthreshold inflammatory state might be implicated in the pathophysiology of schizophrenia (SCZ) and bipolar disorder (BPD). It has been reported that both groups of patients might be characterized by abnormal lymphocyte counts. However, little is known about alterations in lymphocyte proportions that may differentiate SCZ and BPD patients. Therefore, in this study we investigated blood cell proportions quantified by means of microarray expression deconvolution using publicly available data from SCZ and BPD patients. We found significantly lower counts of natural killer (NK) cells in drug-naïve and medicated SCZ patients compared to healthy controls across all datasets. In one dataset from SCZ patients, there were no significant differences in the number of NK cells between acutely relapsed and remitted SCZ patients. No significant difference in the number of NK cells between BPD patients and healthy controls was observed in all datasets. Our results indicate that SCZ patients, but not BPD patients, might be characterized by reduced counts of NK cells. Future studies looking at lymphocyte counts in SCZ should combine the analysis of data obtained using computational deconvolution and flow cytometry techniques., (Copyright © 2016 Elsevier Inc. All rights reserved.)