Márcia Kauer-Sant'Anna

Oxidative stress markers in bipolar disorder: A meta-analysis

BACKGROUND Oxidative stress is thought to mediate neuropathological processes of a number of neuropsychiatric disorders and recent data suggest that oxidative stress may be involved in the pathophysiology of bipolar disorder (BD). In the present investigation, we conducted a meta-analysis of studies that evaluated markers of oxidative stress in individuals with BD, as compared to healthy controls. METHODS A Medline search was conducted to identify studies that measured peripheral markers of oxidative stress in bipolar disorder. Data were subjected to meta-analysis using a random effects model to examine the effect sizes of the pooled results. Bias assessment (Eggers test) and assessment of heterogeneity (I(2)) were also carried out. RESULTS Thiobarbituric acidic reactive substances (TBARS) (p = 0.001) as well as NO activity (p = 0.02) were significantly increased in BD with a large effect size for TBARS and a moderate effect size for increase in NO. No significant effect sizes were observed for the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase (all p>0.05). LIMITATIONS Some caution is warranted in interpreting these results: (1) Eggers test was positive for SOD, suggesting that SOD results may have been influenced by a publication bias. (2) We analyzed the absolute values of each antioxidant enzyme separately and the literature suggests that an imbalance between the antioxidant enzymes is a better indication of the presence of oxidative stress. CONCLUSIONS The present meta-analysis suggests that oxidative stress markers are increased in BD and that oxidative stress may play a role in the pathophysiology of BD.

Brain-derived neurotrophic factor and inflammatory markers in patients with early- vs. late-stage bipolar disorder

Bipolar I disorder (BD) has a poorer longer-term outcome than previously thought, with persistent cognitive impairment and functional decline. The neurobiological underpinnings that might underlie these changes remain unknown. Changes in brain-derived neurotrophic factor (BDNF) levels and cytokines are potential candidates. The aim of this study was to examine both cytokine and BDNF levels and their relationship in BD patients in the early and late stages of the disorder. We measured serum BDNF, TNF-alpha, IL-6 and IL-10 levels in a total of 60 patients with BD I and we compared those in early stages of illness with those in late stages of illness and also compared both groups with 60 matched healthy controls. BDNF was decreased only in those patients in the late stage of bipolar disorder. Moreover, BDNF levels were negatively correlated with length of illness. In contrast, all interleukins and TNF-alpha were increased in the early stages of BD, compared to controls. While TNF-alpha and IL-6 continued to be significantly higher than controls at late stages of BD, IL-10 did not. When levels were compared between patients at early and late stages of illness, there was a significant decrease in BDNF and IL-6 in the later stage of BD compared to the early stage. Inversely, TNF-alpha showed a significant increase at the later stage. Failure of inflammatory defences in the late stage of the disorder may account for reduction in BDNF and continued elevations in cytokines; thus these may have the potential to serve as markers of illness progression in BD.

Dopamine dysregulation syndrome: Implications for a dopamine hypothesis of bipolar disorder

Objective:  Rational therapeutic development in bipolar is hampered by a lack of pathophysiological model. However, there is a wealth of converging data on the role of dopamine in bipolar disorder. This paper therefore examines the possibility of a dopamine hypothesis for bipolar disorder.

Clinical implications of a staging model for bipolar disorders

A model of staging in the field of bipolar disorder (BD) should offer a means for clinicians to predict response to treatment and more general outcome measures, such as the level of functioning and autonomy. The present staging model emphasizes the assessment of patients in the interepisodic period and includes: latent phase: individuals who present mood and anxiety symptoms and increased risk for developing threshold BD; Stage I – patients with BD who present well established periods of euthymia and absence of overt psychiatric morbidity between episodes; Stage II – patients who present rapid cycling or current axis I or II comorbidities; Stage III – patients who present a clinically relevant pattern of cognitive and functioning deterioration, as well as altered biomarkers; and Stage IV – patients who are unable to live autonomously and present altered brain scans and biomarkers. Such a model implies a longitudinal appraisal of clinical variables, as well as assessment of neurocognition and biomarkers in the interepisodic period. Staging facilitates understanding of the mechanisms underlying progression of the disorder, assists in treatment planning and prognosis and, finally, underscores the imperative for early intervention.

Serum levels of IL-6, IL-10 and TNF-α in patients with bipolar disorder and schizophrenia: differences in pro- and anti-inflammatory balance

OBJECTIVE Previous reports suggest that cytokines act as potential mediators of the interaction between the immune and neuroendocrine systems, and that a proinflammatory state may be associated with bipolar disorder and schizophrenia. The aim is to compare cytokine levels in both disorders. METHOD Twenty euthymic bipolar disorder patients, 53 chronic stabilized schizophrenia patients and 80 healthy controls were recruited. Subjects were all non-smokers and non-obese. Cytokines TNF-α, IL-6, and IL-10 were examined by sandwich ELISA. RESULTS IL-6 levels were increased in schizophrenia patients when compared to controls (p < 0.0001) and euthymic bipolar disorder patients (p < 0.0001). IL-6 levels were no different in controls compared to euthymic bipolar disorder patients (p = 0.357). IL-10 was lower in controls compared to schizophrenia patients (p = 0.001) or to bipolar disorder patients (p = 0.004). There was no significant difference in TNF-α serum levels among the groups (p = 0.284). Gender-based classification did not significantly alter these findings, and no correlation was found between the antipsychotic dose administered and cytokine levels in patients with schizophrenia. DISCUSSION These findings evidence a chronic immune activation in schizophrenia. Bipolar disorder seems to present an episode-related inflammatory syndrome. Increased anti-inflammatory factor IL-10 in bipolar disorder and schizophrenia suggests different patterns of inflammatory balance between these two disorders. Results further support the need to investigate cytokines as possible biomarkers of disease activity or treatment response.

Increased oxidative stress as a mechanism for decreased BDNF levels in acute manic episodes

OBJECTIVE AND METHOD There is a growing amount of data indicating that alterations in brain-derived neurotrophic factor and increased oxidative stress may play a role in the pathophysiology of bipolar disorder. In light of recent evidence demonstrating that brain-derived neurotrophic factor levels are decreased in situations of increased oxidative stress, we have examined the correlation between serum thiobarbituric acid reactive substances, a measure of lipid peroxidation, and serum brain-derived neurotrophic factor levels in bipolar disorder patients during acute mania and in healthy controls. RESULTS Serum thiobarbituric acid reactive substances and brain-derived neurotrophic factor levels were negatively correlated in bipolar disorder patients (r = -0.56; p = 0.001), whereas no significant correlation was observed in the control group.. CONCLUSION These results suggest that alterations in oxidative status may be mechanistically associated with abnormal low levels of brain-derived neurotrophic factor observed in individuals with bipolar disorder.

Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression

BACKGROUND Studies investigating inflammatory markers in post-traumatic stress disorder (PTSD) have yielded mixed results. The aim of our study was to compare concentrations of inflammatory markers in patients with PTSD compared with healthy controls. METHODS We did a meta-analysis and meta-regression of studies comparing inflammatory markers between patients with PTSD and healthy controls by searching PubMed, Embase, Scopus, Web of Science, and PsycINFO for articles published between Jan 1, 1960, and April 7, 2015. From eligible studies (ie, cross-sectional studies or baseline data from longitudinal studies of peripheral blood cytokine concentrations that compared adults with PTSD with healthy controls), we extracted outcomes of interest, such as mean and SD of peripheral blood cytokines, the time of day blood was collected, whether the study allowed patients with comorbid major depressive disorder in the PTSD group, whether patients were medication free, and severity of PTSD symptoms. We undertook meta-analyses whenever values of inflammatory markers were available in two or more studies. A random-effects model with restricted maximum-likelihood estimator was used to synthesise the effect size (assessed by standardised mean difference [SMD]) across studies. FINDINGS 8057 abstracts were identified and 20 studies were included. Interleukin 6 (SMD 0.88; p=0.0003), interleukin 1β (SMD 1.42; p=0.045), and interferon γ (SMD 0.49; p=0.002) levels were higher in the PTSD group than in healthy controls. Subgroup meta-analysis of patients who were not given medication showed higher tumour necrosis factor α (TNFα; SMD 0.69, 95% CI 0.35-1.02; p<0.0001) in the PTSD group than the control group in addition to the aforementioned cytokines. TNFα (SMD 1.32, 0.13-2.50; p=0.003), interleukin 1β (SMD 2.35, 0.01-4.68; p=0.048), and interleukin 6 (SMD 1.75, 0.97-2.53; p<0.0001) levels remained increased in the PTSD group in a subgroup meta-analysis of studies that excluded comorbid major depressive disorder. Illness duration was positively associated with interleukin 1β levels (b=0.33, p<0.0001) and severity with interleukin 6 (b=0.02, p=0.042). A model composed of several variables-presence of comorbid major depressive disorder, use of psychotropic medications, assay used, and time of day blood was collected-explained the large amount of heterogeneity between interleukin 1β, interleukin 6, and C-reactive protein studies. Eggers linear regression test revealed a potential publication bias for interleukin 1β. Additionally, for most inflammatory markers, study heterogeneity was reported to be high (I(2)>75%). INTERPRETATION PTSD is associated with increased interleukin 6, interleukin 1β, TNFα, and interferon γ levels. This information might be useful for consideration of chronic low-grade inflammation as a potential target or biomarker in PTSD treatment. Use of psychotropic medication and presence of comorbid major depressive disorder were important moderators that might explain the inconsistency between results of previous studies. Our search strategy used a range of databases and we made exhaustive effort to acquire data by contacting the authors. Notably, high levels of between-study heterogeneity were recorded for most cytokine variables measured in our analysis. However, meta-regression analysis could explain a large amount of this heterogeneity. FUNDING None.

Neurocognitive Functioning in Patients With Bipolar I Disorder Recently Recovered From a First Manic Episode

OBJECTIVE Although cognitive impairment is an important clinical feature of bipolar disorder, it is unknown whether deficits are present at illness onset. The purpose of this study was to determine whether neuropsychological impairments are present in clinically stable patients with bipolar disorder shortly after resolution of their first manic episode. METHOD Within a large university medical center, 45 recently diagnosed (DSM-IV-TR) patients with bipolar disorder type I were evaluated after resolution of their first manic episode, along with 25 matched healthy comparison subjects. Participants were administered a neuropsychological battery evaluating 5 broad cognitive domains, including verbal/premorbid intellectual functioning, learning/memory, spatial/nonverbal reasoning, attention/processing speed, and executive function. Data were collected from July 2004 to August 2007. RESULTS Relative to controls, patients showed broad impairments in learning/memory, spatial/nonverbal reasoning, executive function, and some aspects of attention (all P < .01). Specifically, deficits were evident on tests assessing sustained attention, attentional and mental set shifting, spatial working memory, nonverbal reasoning, and verbal learning and recall (all P < .01). Cognitive impairments in patients could not be fully attributed to substance abuse, medication status, or residual mood symptoms. CONCLUSIONS Results indicate that core neuropsychological deficits in sustained attention, learning and recall, spatial/nonverbal reasoning, and several aspects of executive function are present at illness onset. Cognitive deficits in bipolar disorder are, thus, most likely not exclusively attributable to progressive decline associated with increased illness burden, cumulative treatment effects, or chronicity of illness. These findings may provide etiologic clues into the illness and identify clinical targets for early treatment.

Staging systems in bipolar disorder: an International Society for Bipolar Disorders Task Force Report.

We discuss the rationale behind staging systems described specifically for bipolar disorders. Current applications, future directions and research gaps in clinical staging models for bipolar disorders are outlined.

A systemic toxicity index developed to assess peripheral changes in mood episodes.

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