Maurício Kunz

Elevated serum superoxide dismutase and thiobarbituric acid reactive substances in different phases of bipolar disorder and in schizophrenia

UNLABELLED There is an increasing body of evidence suggesting that oxidative stress may play a role in the pathophysiology of both schizophrenia (SZ) and bipolar disorder (BD). METHODS We compared the antioxidant enzyme, serum superoxide dismutase (SOD) and the lipid peroxidation product, thiobarbituric acid reactive substances (TBARS) as assessed in depressed (N=21), manic (N=32) and euthymic (N=31) bipolar patients, and in chronically medicated patients with schizophrenia (N=97), all fulfilling DSM-IV diagnostic criteria, and a group of healthy controls (N=32). RESULTS Serum SOD (U/mg protein) activity was significantly increased (p<0.001) in manic (7.44+/-3.88) and depressed (6.12+/-4.64) BD patients and SZ (9.48+/-4.51) when compared to either controls (1.81+/-0.63) or euthymic (2.75+/-1.09) BD patients. TBARS (mol/L) levels were significantly higher in the SZ group (4.95+/-1.56, p=0.016), bipolar euthymic (6.36+/-1.46, p<0.001), bipolar manic (7.54+/-1.74, p<0.001), and bipolar depressed patients (5.28+/-1.54, p=0.028) compared to controls (3.96+/-1.51). DISCUSSION Our findings show increased SOD activity in SZ, as well as in depressed and manic bipolar patients, but not in euthymic BD subjects. This suggests a dysregulation in oxidative defenses in both disorders. It is likely that such changes reflect state changes in bipolar disorder. It is possible that this is a compensatory response to the oxidative stress that occurs in the acute phase of bipolar episodes. TBARS results show increases in lipid peroxidation in mania. TBARS levels in SZ and in euthymic as well as depressed individuals with BD were higher than in controls. This suggests persistent increases in SZ, which may reflect ongoing symptomatology or treatment, and a state dependent gradient in BD, with greatest oxidative stress in mania. These data support oxidative biology as both a key component of the pathophysiology of both BD and SZ, and the use of agents that modulate oxidative biology as a promising avenue for intervention in both disorders.

Serum levels of brain-derived neurotrophic factor in patients with schizophrenia and bipolar disorder.

There is evidence that major psychiatric discords such as schizophrenia (SZ) and bipolar disorder (BD) are associated with dysregulation of synaptic plasticity with downstream alterations of neurotrophins. Brain-derived neurotrophic factor (BDNF) is the most widely distributed neurotrophin in the central nervous system (CNS), and performs many biological functions such as promoting the survival, differentiation, and plasticity of neurons. Variants in the BDNF gene increase the risk of SZ and bipolar disorder. Chronic administration of drugs used to treat SZ and BD, such as lithium, valproate, quetiapine, clozapine, and olanzapine, increases BDNF expression in rat brain. To examine serum BDNF, three groups of chronically medicated DSM-IV SZ patients, on treatment with clozapine (n=27), typical (n=14), and other atypical antipsychotics (n=19), 30 euthymic BD patients, and 26 healthy control had 5 ml blood samples collected by venipuncture. Serum BDNF levels were significantly higher in SZ patients (p<0.001) when compared to either controls or euthymic BD patients. Increased BDNF in SZ patients might be related to the course of illness or to treatment variables. Prospective studies are warranted.

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.

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.

Increased oxidative stress and DNA damage in bipolar disorder: A twin-case report

OBJECTIVE There is an emerging body of data suggesting that oxidative stress may be associated with the pathophysiology of bipolar disorder (BD). In the present study we investigated the oxidative stress profile in two monozygotic twins during a manic episode. METHODS Two monozygotic twins diagnosed as currently manic by the Structured Clinical Interview for DSM-IV were studied. Serum thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD) and catalase (CAT) were measured as parameters of oxidative stress. DNA damage was assessed using the single cell gel electrophoresis technique (Comet Assay). All biochemical measures were conducted at baseline and after a 6-week treatment. RESULTS Bipolar twins had higher TBARS, SOD and DNA damage, and lower CAT than the healthy control. TBARS and SOD were normalized after mood stabilization, whereas CAT and DNA damage remained altered at week 6. CONCLUSIONS These findings support that oxidative stress may play a role in the pathophysiology of BD and that pharmacological treatment may exert antioxidant effects. Studies with larger samples are warranted to further clarify this issue.

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.

The Role of BDNF as a Mediator of Neuroplasticity in Bipolar Disorder

The cognitive impairment and neuroanatomical changes that takes place among patients with bipolar disorder (BD) patients has been well described. Recent data suggest that changes in neuroplasticity, cell resilience and connectivity are the main neuropathological findings in BD. Data from differential lines of research converges to the brain-derived neurotrophic factor (BDNF) as an important contributor to the neuroplasticity changes described among BD patients. BDNF serum levels have been shown to be decreased in depressive and manic episodes, returning to normal levels in euthymia. BDNF has also been shown to decrease as the disorder progresses. Moreover, factors that negatively influence the course of BD, such as life stress and trauma have been shown to be associated with a decrease in BDNF serum levels. These findings suggest that BDNF plays a central role in the progression of BD. The present review discusses the role of BDNF as a mediator of the neuroplastic changes that occur in portion with mood episodes and the potential use of serum BDNF as a biomarker in BD.

Improvement of Negative and Positive Symptoms in Treatment-Refractory Schizophrenia: A Double-Blind, Randomized, Placebo-Controlled Trial With Memantine as Add-On Therapy to Clozapine

BACKGROUND Glutamate deregulation may be involved in the neuropathology of schizophrenia, mainly through N-methyl-d-aspartate (NMDA) receptor dysfunction. Memantine, a drug approved by the FDA for the treatment of moderate to severe Alzheimers disease, acts as a weak nonselective NMDA receptor antagonist. The aim of this study was to examine the efficacy of memantine as an adjunctive treatment to clozapine in patients with refractory schizophrenia. METHOD In this double-blind, placebo-controlled study, outpatients with refractory schizophrenia according to DSM-IV clinical criteria were randomly assigned, from March 2005 to February 2008, to receive either 20 mg/d memantine (n = 10) or placebo (n = 11), in addition to clozapine, for 12 weeks. The primary outcome measure was the total score on the 18-item Brief Psychiatry Rating Scale (BPRS) and BPRS subscales of positive and negative symptoms. Secondary outcomes were global severity of disease as measured by the Clinical Global Impressions scale (CGI), cognition as assessed by the Mini-Mental State Examination (MMSE), and extrapyramidal symptoms as assessed by the Simpson-Angus Scale (SAS). RESULTS Twenty-one participants completed the study and were used in the analysis. Significant improvement (P < .01) on the total BPRS score, its subscales of positive (effect size [ES] = -1.38) and negative (ES = -3.33) symptoms, the CGI score (ES = 1.56), and the MMSE score was observed with memantine as compared with placebo. No significant changes in extrapyramidal symptoms were observed. CONCLUSIONS Memantine add-on to clozapine therapy was associated with improvement in negative and positive symptoms in refractory schizophrenia patients. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00757978.

Staging and Neuroprogression in Bipolar Disorder

The apparently progressive nature of a considerable proportion of cases of bipolar disorder (BD) has been acknowledged in recently proposed clinical staging models. This has been part of an attempt to facilitate and refine diagnosis, treatment selection, and establish a prognosis. The study of the progressive nature of some cases of BD has given raise to the hypothesis of neuroprogression, which postulates that different stages of BD are associated with distinct neurobiological underpinnings. Given that BD may be intimately associated with chronic stress response and coping mechanisms over the course of illness, we propose that cellular resilience mechanisms may play a key role in the neuroprogression in BD. In the present study, we review neuroanatomical evidence of the progression that occurs in many cases of BD, as well as cellular resilience mechanisms and peripheral biomarkers associated with distinct stages of this disorder. In summary, cellular resilience mechanisms seem to be less efficient at later stages of BD, especially mitochondrial and endoplasmic reticulum-related responses to stress. These insights may help in developing staging models of BD, with a special emphasis on the search for biomarkers associated with illness progression.

Relationship between cognitive functioning and 6-month clinical and functional outcome in patients with first manic episode bipolar I disorder

BACKGROUND Although cognitive deficits in bipolar disorder have been associated with diminished functional outcome, this relationship has been studied primarily through cross-sectional designs, and has not been studied in patients early in the course of illness. The purpose of this study was to evaluate the impact of cognitive functioning on longitudinal 6-month functional and clinical outcome in recently diagnosed clinically stable patients with bipolar disorder. METHOD A total of 53 recently diagnosed patients with DSM-IV bipolar disorder type I were assessed within 3 months of their first manic episode using a neuropsychological battery measuring verbal/pre-morbid intellectual functioning, learning/memory, spatial/non-verbal reasoning, attention/processing speed and executive function. Functional outcome was assessed at baseline and 6 months using the Multidimensional Scale of Independent Functioning (MSIF) and DSM-IV Global Assessment of Functioning Scale (GAF). Clinical outcome was assessed with symptom ratings and by monitoring onset of new mood episodes. RESULTS Memory, particularly verbal learning/memory, was robustly associated with 6-month functional outcome on the MSIF, even after partialling out the influence of mood symptoms and substance abuse co-morbidity. Depression ratings at 6 months, but not cognitive variables, were associated with 6-month GAF scores. Cognitive functioning was not associated with 6-month clinical outcome. CONCLUSIONS Memory was associated with 6-month longitudinal functional but not clinical outcome in recently diagnosed patients with bipolar disorder. These data further support the distinction between clinical and functional outcome, and emphasize the need for identification of, and development of treatments for, cognitive impairments early in the course of bipolar disorder.