Flávio Pereira Kapczinski

The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders.

Psychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia, affect a significant percentage of the world population. These disorders are associated with educational difficulties, decreased productivity and reduced quality of life, but their underlying pathophysiological mechanisms are not fully elucidated. Recently, studies have suggested that psychiatric disorders could be considered as inflammatory disorders, even though the exact mechanisms underlying this association are not known. An increase in inflammatory response and oxidative stress may lead to inflammation, which in turn can stimulate microglia in the brain. Microglial activation is roused by the M1 phenotype, which is associated with an increase in interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). On the contrary, M2 phenotype is associated with a release of anti-inflammatory cytokines. Thus, it is possible that the inflammatory response from microglial activation can contribute to brain pathology, as well as influence treatment responses. This review will highlight the role of inflammation in the pathophysiology of psychiatric disorders, such as MDD, BD, schizophrenia, and autism. More specifically, the role of microglial activation and associated molecular cascades will also be discussed as a means by which these neuroinflammatory mechanisms take place, when appropriate.

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.

Inflammatory mediators of cognitive impairment in bipolar disorder

OBJECTIVES Recent studies have pointed to neuroinflammation, oxidative stress and neurotrophic factors as key mediators in the pathophysiology of mood disorders. Little is however known about the cascade of biological episodes underlying the cognitive deficits observed during the acute and euthymic phases of bipolar disorder (BD). The aim of this review is to assess the potential association between cognitive impairment and biomarkers of inflammation, oxidative stress and neurotrophic activity in BD. METHODS Scopus (all databases), Pubmed and Ovid Medline were systematically searched with no language or year restrictions, up to November 2013, for human studies that collected both inflammatory markers and cognitive data in BD. Selected search terms were bipolar disorder, depression, mania, psychosis, inflammatory, cognitive and neurotrophic. RESULTS Ten human studies satisfied the criteria for consideration. The findings showed that high levels of peripheral inflammatory-cytokine, oxidative stress and reduced brain derived neurotrophic factor (BDNF) levels were associated with poor cognitive performance. The BDNF val66met polymorphism is a potential vulnerability factor for cognitive impairment in BD. CONCLUSIONS Current data provide preliminary evidence of a link between the cognitive decline observed in BD and mechanisms of neuroinflammation and neuroprotection. The identification of BD specific inflammatory markers and polymorphisms in inflammatory response genes may be of assistance for therapeutic intervention.

Neuroprogression and Cognitive Functioning in Bipolar Disorder: A Systematic Review

Bipolar disorder (BD) has been associated with impairments in a range of cognitive domains including attention, verbal learning, and mental flexibility. These deficits are increased during the acute phases of the illness and worsen over the course of BD. This review will examine the literature in relation to potential mechanisms associated with cognitive decline in BD. Scopus (all databases), Pubmed, and Ovid Medline were systematically searched with no language or year restrictions, up to January 2015, for human studies that collected cross-sectional and longitudinal cognitive data in adults with BD and matched healthy controls (HC). Selected search terms were “bipolar,” “cognitive,” “aging,” “illness duration,” “onset,” and “progression.” Thirty-nine studies satisfied the criteria for consideration. There is evidence that cognitive function in BD is negatively associated with features of illness progression such as number of mood episodes, illness duration, and hospitalizations. Aging does not appear to affect cognitive functioning to a greater extent than in HC. Furthermore, the small number of longitudinal studies in this field does not allow to reaching firm conclusion in terms of which sub-populations would be more prone to cognitive decline in BD. The decline in cognitive abilities over the course of the BD seems to be associated with the number of episodes and number of hospitalizations. No meaningful interaction of age and bipolar disorder has been found in terms of cognitive decline. Future large-scale longitudinal studies are necessary to confirm these findings and assist in the development of preventive interventions in vulnerable individuals.

Common biological mechanisms between bipolar disorder and type 2 diabetes: Focus on inflammation.

INTRODUCTION Bipolar disorder (BD) patients present a 3-5 fold greater risk of developing type 2 diabetes (T2D) compared to general population. The underlying mechanisms for the increased prevalence of T2D in BD population are poorly understood. OBJECTIVES The purpose of this review is to critically review evidence suggesting that inflammation may have an important role in the development of both BD and T2D. RESULTS The literature covered in this review suggests that inflammatory dysregulation take place among many BD patients. Such dysregulated and low grade chronic inflammatory process may also increase the prevalence of T2D in BD population. Current evidence supports the hypothesis of dysregulated inflammatory processes as a critical upstream event in BD as well as in T2D. CONCLUSIONS Inflammation may be a factor for the development of T2D in BD population. The identification of inflammatory markers common to these two medical conditions will enable researchers and clinicians to better understand the etiology of BD and develop treatments that simultaneously target all aspects of this multi-system condition.

Biological rhythms in bipolar and depressive disorders: A community study with drug-naïve young adults

AIM To assess biological rhythm disruptions among drug-naïve young adults with bipolar disorder (BD), major depressive disorder (MDD), and community controls. METHODS This was a cross-sectional study nested in a population-based study. BD and MDD were diagnosed using the Structured Clinical Interview for DSM-IV. Biological rhythm disruptions were assessed using the Biological Rhythm Interview of Assessment in Neuropsychiatry (BRIAN). RESULTS Two hundred seventeen subjects were assessed (49 BD, 74 MDD, and 94 community controls). Biological rhythm disruption was higher in subjects with BD (40.32±9.92; p<0.001) and MDD (36.23±8.71; p<0.001) than community controls (27.67±6.88). Subjects with BD had a higher BRIAN total score (p=0.028) and higher disruption in sleep/social domains (p=0.018) as compared to MDD. In addition, the BRIAN scores were higher in current MDD, euthymic BD, and BD in current episode group, as compared to community controls. LIMITATION Cross-sectional design. Absence of assessment of biomarkers of biological rhythms. CONCLUSION Bipolar disorder and major depressive disorder are associated with disruption in biological rhythm. In addition, disruption in sleep/social rhythms is higher in subjects with BD when compared to subjects with MDD. We also verified biological rhythm disruption in subjects with BD during euthymic status, but not in remitted MDD. Regulation of biological rhythm may be a means to identify patients with mood disorders and potentially differentiate MDD from BD.

Hippocampal volume and verbal memory performance in late-stage bipolar disorder

Studies about changes in hippocampal volumes in subjects with bipolar disorder (BD) have been contradictory. Since the number of manic episodes and hospitalization has been associated with brain changes and poor cognitive outcomes among BD patients, we have hypothesized that these variables could clarify this issue. We stratified subjects with BD in early (BD-Early), intermediate (BD-intermediate) and late (BD-Late) stages as a function of number of manic episodes and prior hospitalization. Then, we compared their hippocampal volumes and California Verbal Learning Test-II (CVLT-II) scores with healthy controls (HC) using the general linear model. A total of 173 subjects were included in the study (112 HC, 15 BD-Early, 30 BD-Intermediate, and 16 BD-Late). We found a significant group effect on hippocampus volume (F(3,167) = 3.227, p = 0.024). Post-hoc analysis showed that BD-Late subjects had smaller hippocampus than HC (p = 0.017). BD-Early and BD-Intermediate subjects showed no significant difference in hippocampus volume compared to HC and BD-Late subjects. The CVLT trial 1 to 5 scores were significantly different across the groups (F(3,167) = 6.371, p < 0.001). Post-hoc analysis showed that BD-Intermediate (p = 0.006) and BD-Late (p = 0.017) subjects had worse memory performance during immediate recall than HC, while the performance difference between BD-Early subjects and HC was not significant (p = 0.208). These findings add to the notion that BD is a neuroprogressive disorder with brain changes and cognitive impairment according to prior morbidity (number of manic episodes and hospitalization). Also, they suggest that hippocampus is a brain marker and a potential therapeutic target for patients at late stage.

Is bipolar disorder associated with accelerating aging? a meta-analysis of telomere length studies

BACKGROUND Bipolar disorder (BD) is associated with a reduced life expectancy compared to the general population mainly due to a high prevalence of comorbid somatic illnesses. A model of accelerated aging has been proposed as a potential explanation to these epidemiological findings. Nevertheless, studies measuring telomere length (TL) in patients with BD compared to healthy controls have provided mixed results. OBJECTIVE To compare TL between BD patients and healthy controls, and to search for potential modeP<rators for observed differences. METHODS We performed a systematic review and meta-analysis of original studies comparing TL in patients with BD vs. healthy controls published up to February 24th, 2015 in main electronic databases. Heterogeneity was explored through meta-regression and subgroup analysis. RESULTS Seven studies met inclusion criteria (N=1115). There was no difference in TL between participants with BD and healthy controls (Hedgess g=-0.012; 95% CI=-0.418 to 0.393, P=0.952). There was no evidence for publication bias. Heterogeneity was high (I(2)=89.65%). In meta-regression analyses, the percentage of females in healthy control samples (P=0.04) and the methodological quality of included studies (P<0.001) emerged as significant moderators, while subgroup analyses suggest that the type of assay employed to measure TL and age- and gender-matching of BD and HC participants may contribute to heterogeneity. CONCLUSIONS Telomere length does not differ between participants with BD vs. healthy controls; this finding does not support the view of BD as an illness associated with accelerated cellular aging. However, more studies controlling for potential confounders are necessary.

Childhood trauma, family history, and their association with mood disorders in early adulthood

To assess the prevalence of childhood trauma and types of trauma on mood disorders among young adults in a population‐based sample. We further gathered data on family history of mood disorders to test the hypothesis that childhood trauma is a mediating factor for the association between family history of mood disorder and mood disorder in adulthood.

Intracerebral Administration of BDNF Protects Rat Brain Against Oxidative Stress Induced by Ouabain in an Animal Model of Mania

Several studies have suggested that alterations in brain-derived neurotrophic factor (BDNF) and increased oxidative stress have a central role in bipolar disorder (BD). Intracerebroventricular (ICV) injection of ouabain (OUA) in rats alters oxidative stress parameters and decreases BDNF levels in the brain. In this context, the present study aims to investigate the effects of BDNF ICV administration on BDNF levels and oxidative stress parameters in brains of rats submitted to animal model of mania induced by OUA. Wistar rats received an ICV injection of OUA, artificial cerebrospinal fluid (ACSF), OUA plus BDNF, or ACSF plus BDNF. Locomotor activity and risk-taking behavior in the rats were measured using the open-field test. In addition, we analyzed the BDNF levels and oxidative stress parameters (TBARS, Carbonyl, CAT, SOD, GR, and GPx) in the frontal cortex and hippocampus of rats. The BDNF was unable to reverse the ouabain-induced hyperactivity and risk-taking behavior. Nevertheless, BDNF treatment increased BDNF levels, modulated the antioxidant enzymes, and protected the OUA-induced oxidative damage in the brain of rats. These results suggest that BDNF alteration observed in BD patients may be associated with oxidative damage, both seen in this disorder.