Reduced serum non-enzymatic antioxidant defense and increased lipid peroxidation in schizophrenic patients on a hypocaloric diet.

INTRODUCTION: Growing evidence suggests that oxidative stress (OS) may be associated with the pathophysiology underlying schizophrenia (SZ). Some studies indicate that nutritional supplements offer protection from OS, but there is no data about the effect of a hypocaloric diet on OS in this population. Therefore, we aimed to study the effect of a hypocaloric dietary intervention on OS in subjects with SZ. METHODS: A cross-sectional study of 96 participants in outpatient treatment for SZ comprised patients separated into two groups: one group of subjects followed a hypocaloric diet (HD) program (n=42), while the other group followed a regular diet (RD) with no nutritional restrictions (n=54). The serum total radical-trapping antioxidant parameter (TRAP), total antioxidant reactivity (TAR) and thiobarbituric acid reactive species (TBARS) levels were assessed. RESULTS: TRAP levels were lower and TBARS levels were higher in the HD group than in the RD group (p=0.022 and p=0.023, respectively). There were no differences in TAR levels between the groups. Additionally, there was a positive correlation between TRAP and TBARS levels after adjusting for BMI and clozapine dose (partial correlation=0.42, p<0.001). There were no correlations among the length of illness or diet and the levels of TRAP, TBARS, and TAR. CONCLUSIONS: Subjects with SZ on a hypocaloric diet displayed different OS parameters than those not following a HD. Serum TRAP levels were lower and TBARS levels were higher among SZ subjects with HD compared to SZ subjects without HD. Lower TRAP levels may reflect decreased oxidative stress, whereas higher TBARS levels most likely reflect a biochemical reaction to the decreased TRAP levels. Additionally, TAR levels were similar between groups, suggesting a similar quality of antioxidant defenses, despite quantitative differences between the two dietary protocols in SZ patients under outpatient care.

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.

Serum levels of IL-6, IL-10 and TNF-α in patients with bipolar disorder and schizophrenia: differences in pro- and anti-inflammatory balance / Níveis séricos de IL-6, IL-10 e TNF-α em pacientes com transtorno bipolar e esquizofrenia: diferenças no equilíbrio pró e antiinflamatório

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.

OBJETIVO: Pesquisas sugerem as citocinas como potenciais mediadores da interação entre os sistemas imune e neuroendócrino, e que existe um estado pró-inflamatório associado com transtorno bipolar e esquizofrenia. O objetivo deste estudo é comparar os níveis de citocinas entre os dois distúrbios. MÉTODO: Vinte pacientes com transtorno bipolar eutímicos, 53 pacientes com esquizofrenia crônica estabilizados e 80 controles saudáveis foram recrutados. Todos os indivíduos eram não-fumantes e não-obesos. As citocinas TNF-α, IL-6 e IL-10 foram examinadas por ELISA sanduíche. RESULTADOS: A IL-6 estava aumentada nos pacientes com esquizofrenia quando comparados aos controles (p < 0,0001) e aos pacientes bipolares eutímicos (p < 0,0001). Os níveis de IL-6 não foram diferentes nos controles em comparação com pacientes com transtorno bipolar eutímicos (p = 0,357). Os níveis de IL-10 foram menores nos controles quando comparados aos pacientes com esquizofrenia (p = 0,001) ou aos bipolares (p = 0,004). Não houve diferença significativa nos níveis séricos de TNF-α entre os grupos (p = 0,284). A separação por sexo não mostrou diferenças significativas e não houve correlação entre a dose de antipsicóticos e os níveis de citocinas em pacientes com esquizofrenia. DISCUSSÃO: Estes resultados evidenciam uma ativação imune crônica na esquizofrenia. O transtorno bipolar parece apresentar um aumento da atividade inflamatória relacionado ao episódio de humor. Níveis maiores de IL-10 no transtorno bipolar e esquizofrenia sugerem diferentes padrões de equilíbrio inflamatório entre esses dois transtornos. Resultados fornecem apoio adicional para a investigação de citocinas como possíveis biomarcadores para a atividade da doença ou resposta ao tratamento.

Brain-derived neurotrophic factor as a state-marker of mood episodes in bipolar disorders: a systematic review and meta-regression analysis.

Brain-derived neurotrophic factor (BDNF) plays a central role in synaptic plasticity and neurogenesis. Bipolar disorder (BD) is among the most disabling of all psychiatric disorders and is associated with poor outcomes. Some studies suggest that BDNF levels decrease during mood states and remain normal during euthymia, but other studies have contradicted this paradigm. Therefore, the aim of this study was to perform a meta-analysis of all studies that measured peripheral BDNF levels in adults with BD. We conducted a systematic review using electronic databases. Inclusion criteria were studies that measured BDNF in plasma or serum in vivo in adult patients with BD. The resulting studies were compiled to measure the effect sizes (ESs) of the differences in BDNF levels between BD patients in different mood states and controls. Thirteen studies were included with a total of 1113 subjects. The BDNF levels were decreased in both mania and depression when compared to controls (ES -0.81, 95% CI -1.11 to -0.52, p < 0.0001 and ES -0.97, 95% CI -1.79 to -0.51, p = 0.02, respectively). The BDNF levels were not different in euthymia when compared to controls (ES -0.20, 95% CI -0.61 to 0.21, p = 0.33). Meta-regression analyses in euthymia showed that age (p < 0.0001) and length of illness (p = 0.04) influenced the variation in ES. There was also an increase in BDNF levels following the treatment for acute mania (ES -0.63, 95% CI -1.11 to -0.15, p = 0.01). In conclusion, BDNF levels are consistently reduced during manic and depressive episodes and recover after treatment for acute mania. In euthymia, BDNF decreases with age and length of illness. These data suggest that peripheral BDNF could be used as a biomarker of mood states and disease progression for BD.

Increased neurotrophin-3 in drug-free subjects with bipolar disorder during manic and depressive episodes.

Bipolar disorder (BD) has been increasingly associated with abnormalities in neuroplasticity. Previous studies demonstrated that neurotrophin-3 (NT-3) plays a role in the pathophysiology of mood disorders. The influence of medication in these studies has been considered a limitation. Thus, studies with drug-free vs. medicated patients are necessary to evaluate the role of medication in serum NT-3 levels. About 10 manic and 10 depressive drug-free, and 10 manic and 10 depressive medicated patients with BD type I were matched with 20 controls for sex and age. Patients were assessed using SCID-I, YMRS and HDRS. Serum NT-3 levels in drug-free and medicated patients is increased when compared with controls (2.51+/-0.59, 2.56+/-0.44 and 1.97+/-0.33, respectively, p<0.001 for drug-free/medicated vs. control). Serum NT-3 levels do not differ between medicated and drug-free patients. When analyzing patients according to mood states, serum NT-3 levels are increased in both manic and depressive episodes, as compared with controls (2.47+/-0.43, 2.60+/-0.59 and 1.97+/-0.33, respectively, p<0.001 for manic/depressive patients vs. controls). There is no difference in serum BDNF between manic and depressive patients. Results suggest that increased serum NT-3 levels in BD are likely to be associated with the pathophysiology of manic and depressive symptoms.

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 Alzheimer's 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.

Serum brain-derived neurotrophic factor in bipolar and unipolar depression: a potential adjunctive tool for differential diagnosis.

The differential diagnosis of Bipolar Disorder (BD) and Major Depressive Disorder (MDD) is a diagnostic challenge during depressive episodes. Noteworthy, the proper differentiation between BD depressive state and MDD has important treatment implications. BDNF levels may be valuable adjunctive tool for this differential diagnosis. Ten subjects with MDD, forty with BD type I and thirty healthy comparison subjects were recruited. All subjects had BDNF serum levels measured and, in patients, BDNF serum levels were assessed during acute depressive episode. Optimal sensitivity and specificity of serum BDNF for the differential diagnosis of unipolar and bipolar depression were determined by the receiver operating characteristic (ROC) curve analysis, using a nonparametric approach. Serum BDNF levels in depressive BD patients were lower compared to MDD patients and controls (0.15+/-0.08, 0.35+/-0.08, and 0.38+/-0.12, respectively, p<0.001). The area under the curve (AUC) of the ROC analysis in BD depression vs. MDD was 0.95 (ranged from 0.89 to 1.00). Overall, the AUC of the ROC analysis (BD depression vs. MDD and controls) was 0.94 (95% CI 0.89 to 0.99, p<0.001). A proposed "best" cutoff of 0.26 resulted in 88% sensitivity and 90% specificity. Serum BDNF levels appear as a promising tool to discriminate bipolar from unipolar depression. Our results suggest the role of BDNF as an adjunctive tool to promote prompt and accurate diagnosis of BD. However, further investigation and replication of these results are warranted.

Decreased brain-derived neurotrophic factor in medicated and drug-free bipolar patients.

Bipolar disorder (BD) has been associated with abnormalities in neuroplasticity and previous studies suggest an important role for BDNF in the pathophysiology of BD. The confounding effect of the use of medication in these studies has been considered a limitation. Thus, studies with both drug-free and medicated patients are necessary to assess the role of medication in serum BDNF levels. Twenty-two manic and depressed drug-free and 22 medicated BD type I patients were matched to 22 controls according to sex and age in a cross-sectional study. BDNF serum levels were assessed using sandwich-ELISA. Serum BDNF levels in drug-free (0.23+/-0.09), and medicated (0.29+/-0.19) BD patients were decreased when compared to controls (0.40+/-0.12) - drug-free/medicated vs. control p<0.001. The BDNF levels did not differ between medicated and drug-free BD patients. When analyzing patients according to mood states, serum BDNF levels were lower in BD patients during both manic (0.28+/-0.11) and depressive episodes (0.22+/-0.17), as compared with healthy controls (0.40+/-0.12) - manic/depressed patients vs. controls p<0.001. Results suggest that the association of lower serum BDNF and BD mood episodes is kept even in medicated patients, which strengthens the notion that BDNF serum levels may be considered a biomarker of mood episodes in BD.

Comparison of cytokine levels in depressed, manic and euthymic patients with bipolar disorder.

BACKGROUND: The neurobiology of bipolar disorder is not completely understood. Cytokines have received increasing attention as potential mediators of the interaction with immune, neuroendocrine system and specific pathways involved in mood, energy, and activity control. Previous reports have suggested the association of mania and bipolar depression with a proinflammatory state. However, they did not compare cytokine levels in all phases of bipolar disorder. METHODS: Sixty-one bipolar patients were recruited for assessment of serum cytokine levels. Of these, 14 were in euthymic state, 23 and 24 were in manic and depressive episodes, respectively. A healthy comparison group included 25 healthy volunteers. Cytokines involved in Th1/Th2 balance, such as TNF-alpha, IL-2, IL-4, IL-6, IL-10, IFN-gamma, were examined by flow cytometry. RESULTS: During mania, proinflammatory cytokines, IL-2, IL-4 and IL-6, were increased in comparison with healthy subjects. Patients in depressive episode showed only increased IL-6 levels. There were no significant differences in cytokine levels between patients in remission and healthy subjects, except for IL-4. Mood symptoms showed a positive correlation with IL-6 and IL-2. DISCUSSION: These findings suggest that mania, and to a less extent, depression are associated with a proinflammatory state. These changes seem to be related to mood state, as changes in cytokine profile were more pronounced during acute episodes than in euthymia. This study provides further support to investigate the immune system as a target for future treatment development.