Early growth response 1 (EGR1) is downregulated in peripheral blood from patients with major psychiatric disorders.

OBJECTIVES: To evaluate relative expression of genes with the potential to translate environmental stimuli into long-term alterations in the brain - namely Early Growth Response (EGR)1, EGR3, and Cryptochrome Circadian Regulator 2 (CRY2) - in peripheral blood from patients with Bipolar Disorder (BD), Schizophrenia (SZ), Major Depressive Disorder (MDD) and healthy controls (HC). METHODS: Thirty individuals ranging from 18 to 60 years were recruited for each group (BD, SZ, MDD or HC) from a Brazilian public hospital. Therefore, individuals' peripheral blood was collected and EGR1, EGR3 and CRY2 gene expression analyzed by PCR Real Time. RESULTS: EGR1 mRNA levels are significantly lower in psychiatric patients when compared to HC, but there is no difference for EGR3 and CRY2. Exploring the findings for each diagnosis, there is a significant difference between each diagnosis group only for EGR1, which was lower in BD, MDD and SZ as compared to HC. No significant correlations were found between gene expression and clinical features. CONCLUSIONS: EGR1 is downregulated in psychiatric patients, regardless of the diagnosis and may be a potential common target in major psychiatric disorders. EGR1, as a transcription factor, modulates many other genes and participates in crucial neuronal and synaptic processes, such as plasticity, neurotransmitters metabolism, vesicular transport and signaling pathways. The study of EGR1 and its upstream regulators in psychiatry might lead to potential new therapeutic targets.

A five-year follow-up of the verbal memory performance of individuals with bipolar disorder and schizophrenia: evidence of unchanging deficits under treatment.

OBJECTIVE: Bipolar disorder (BD) and schizophrenia (SZ) are chronic and heterogeneous mental disorders that present cognitive and functional impairments. Verbal memory is considered an important predictor of functioning and a domain vulnerable to the aging process. However, only few studies investigate the progression of memory longitudinally in BD and SZ, especially in lower- and middle-income countries. Therefore, we aim to evaluate the course of verbal memory in individuals with BD and SZ. METHODS: We assessed 31 individuals with BD and 27 individuals with SZ under treatment at outpatient clinics at baseline and after five years. They were assessed through a sociodemographic questionnaire, memory and estimated IQ (eIQ) instruments, and clinical scales. RESULTS: Individuals with SZ showed worse verbal memory performance in comparison to BD, however, we did not observe changes over time within patient groups. Individuals with BD with higher eIQ showed a better verbal memory performance, while no effect of eIQ was found for subjects with SZ. CONCLUSION: Patients with SZ and BD showed different levels of verbal memory impairment, although they had similar unchanging trajectories after 5 years under psychiatric treatment. This finding indicates a relative stable cognitive course for both disorders.

Bipolar disorder: an association between body mass index and cingulate gyrus fractional anisotropy not mediated by systemic inflammation.

OBJECTIVE: To investigate associations between body mass index (BMI), white matter fractional anisotropy (FA), and C-reactive protein (CRP) in a group of individuals with bipolar disorder (BD) during euthymia and compare them with a control group of healthy subjects (CTR). METHODS: The sample consisted of 101 individuals (BD n = 35 and CTR n = 66). Regions of interest (ROI) were defined using a machine learning approach. For each ROI, a regression model tested the association between FA and BMI, controlling for covariates. Peripheral CRP levels were assayed, correlated with BMI, and included in a mediation analysis. RESULTS: BMI predicted the FA of the right cingulate gyrus in BD (AdjR2 = 0.312 F(3) = 5.537 p = 0.004; ß = -0.340 p = 0.034), while there was no association in CTR. There was an interaction effect between BMI and BD diagnosis (F(5) = 3.5857 p = 0.012; Fchange = 0.227 AdjR2 = 0.093; ß = -1.093, p = 0.048). Furthermore, there was a positive correlation between BMI and CRP in both groups (AdjR2 = 0.170 F(3) = 7.337 p < 0.001; ß = 0.364 p = 0.001), but it did not act as a mediator of the effect on FA. CONCLUSION: Higher BMI is associated with right cingulate microstructure in BD, but not in CTR, and this effect could not be explained by inflammatory mediation alone.

Bipolar disorder: an association between body mass index and cingulate gyrus fractional anisotropy not mediated by systemic inflammation

Abstract Objective To investigate associations between body mass index (BMI), white matter fractional anisotropy (FA), and C-reactive protein (CRP) in a group of individuals with bipolar disorder (BD) during euthymia and compare them with a control group of healthy subjects (CTR). Methods The sample consisted of 101 individuals (BD n = 35 and CTR n = 66). Regions of interest (ROI) were defined using a machine learning approach. For each ROI, a regression model tested the association between FA and BMI, controlling for covariates. Peripheral CRP levels were assayed, correlated with BMI, and included in a mediation analysis. Results BMI predicted the FA of the right cingulate gyrus in BD (AdjR2 = 0.312 F(3) = 5.537 p = 0.004; β = -0.340 p = 0.034), while there was no association in CTR. There was an interaction effect between BMI and BD diagnosis (F(5) = 3.5857 p = 0.012; Fchange = 0.227 AdjR2 = 0.093; β = -1.093, p = 0.048). Furthermore, there was a positive correlation between BMI and CRP in both groups (AdjR2 = 0.170 F(3) = 7.337 p < 0.001; β = 0.364 p = 0.001), but it did not act as a mediator of the effect on FA. Conclusion Higher BMI is associated with right cingulate microstructure in BD, but not in CTR, and this effect could not be explained by inflammatory mediation alone.

Accelerated aging signatures in subjects with schizophrenia and their unaffected siblings.

Schizophrenia (SZ) is a chronic debilitating disease. Subjects with SZ have significant shorter life expectancy. Growing evidence suggests that a process of pathological accelerated aging occurs in SZ, leading to early development of severe clinical diseases and worse morbimortality. Furthermore, unaffected relatives can share certain endophenotypes with subjects with SZ. We aim to characterize accelerated aging as a possible endophenotype of schizophrenia by using a machine learning (ML) model of peripheral biomarkers to accurately differentiate subjects with SZ (n = 35), their unaffected siblings (SB, n = 36) and healthy controls (HC, n = 47). We used a random forest algorithm that included biomarkers related to aging: eotaxins CCL-11 and CCL-24; the oxidative stress markers thiobarbituric acid-reactive substances (TBARS), protein carbonyl content (PCC), glutathione peroxidase (GPx); and telomere length (TL). The ML algorithm of biomarkers was able to distinguish individuals with SZ from HC with prediction accuracy of 79.7%, SZ from SB with 62.5% accuracy and SB from HC with 75.5% accuracy. These results support the hypothesis that a pathological accelerated aging might occur in SZ, and this pathological aging could be an endophenotype of the disease, once this profile was also observed in SB, suggesting that SB might suffer from an accelerated aging in some level.

Clozapine use decreases the number of hospitalizations per year in patients with treatment-resistant schizophrenia

For years, the management of schizophrenia has represented a challenge for clinicians, with antipsychotic treatments usually resulting in relapses and new hospitalizations. Clozapine has been shown to be an effective medication for treatment-resistant schizophrenia (TRS), but is currently underused due to its potential side effects. Nevertheless, research has suggested that clozapine reduces future hospitalizations in patients with TRS. This study aims to verify the rates of hospitalizations in patients with TRS under long-term use of clozapine. We retrospectively analyzed clinical data from 52 individuals with TRS before and after the use of clozapine. The mean duration of treatment with and without clozapine was 6.6 (± 3.9) and 8.5 years (± 6.6), respectively. Patients had a median of 0.5 (0.74) hospitalizations per year before the use of clozapine and 0 (0.74) hospitalizations after it (p = 0.001). Therefore, the use of clozapine resulted in an expected reduction in the number of hospitalizations per year in individuals with TRS. (AU)

Perda significativa de peso em pacientes com esquizofrenia na dieta hipocalórica de longo prazo: estudo piloto / Significant weight loss in patients with schizophrenia in long-term hypocaloric diet: a pilot study

Objetivo: A esquizofrenia está associada ao aumento da obesidade e morbidade por doença cardiovascular. O objetivo do presente estudo foi avaliar alterações no peso e índice de massa corporal (IMC) de pacientes com esquizofrenia após tratamento nutricional de longo prazo. Método: Estudo piloto retrospectivo envolvendo 42 indivíduos com esquizofrenia em tratamento nutricional entre 2004 e 2010. Os prontuários médicos foram revisados após aprovação institucional e coleta de dados para peso, índice de massa corporal (IMC), idade, gênero e dieta. O peso e o IMC foram avaliados no início do tratamento nutricional, após seis meses, após 12 meses e no momento da coleta de dados. Resultados: Houve perda significativa de peso e diminuição significativa do IMC quando comparados a cada grupo com o valor basal (p<0,001). Conclusões: Demonstramos que as intervenções nutricionais podem promover uma significativa perda de peso na esquizofrenia. Estes resultados suportam a importância da intervenção nutricional na esquizofrenia e trazem evidências de que a perda de peso permanece ao longo do tempo.(AU)

Objective: Schizophrenia is associated with increased obesity and morbidity from cardiovascular disease. The aim of the present study was to evaluate changes in weight and body mass index (BMI) of patients with schizophrenia following a long-term nutritional treatment. Methods: Retrospective pilot study involving 42 individuals with schizophrenia on nutritional treatment from 2004 to 2010. Medical charts were reviewed after institutional approval and data collection was conducted for weight, body mass index (BMI), age, gender and diet prescription. Weight and BMI were evaluated at baseline of nutrition treatment, after six months, after 12 months and at the time of data collection. Results: There was a significant weight loss and significant decreased in BMI when compared each group to baseline (p<0.001). Conclusions: We demonstrate that nutritional interventions can promote a significant weight loss in schizophrenia. These results support the importance of nutritional intervention in schizophrenia and bring evidences that weight loss remains along the time.(AU)

Pinocembrin Provides Mitochondrial Protection by the Activation of the Erk1/2-Nrf2 Signaling Pathway in SH-SY5Y Neuroblastoma Cells Exposed to Paraquat.

Pinocembrin (PB; 5,7-dihydroxyflavanone; C15H12O4) is a flavonoid found in propolis and exerts antioxidant, anti-inflammatory, and antimicrobial effects. Furthermore, PB has been studied as a neuroprotective agent. However, it remains to be understood whether and how PB would induce mitochondrial protection in mammalian cells. Therefore, we investigated here the mechanism involved in the protective effects elicited by PB in paraquat (PQ; 100 µM)-treated SH-SY5Y neuroblastoma cells. PB (25 µM) pretreatment (for 4 h) downregulated the levels of Bcl-2-associated X protein (Bax), blocked the release of cytochrome c to the cytosol, and inhibited the PQ-induced activation of caspase-9 and caspase-3. Besides, PB prevented mitochondrial dysfunction by suppressing the PQ-elicited inhibition of complexes I and V. Moreover, PB abrogated the loss of mitochondrial membrane potential (MMP) and the decline in ATP levels in the cells exposed to PQ. PB exerted antioxidant effects on mitochondria by decreasing the levels of redox impairment markers in mitochondrial membranes. Importantly, PB enhanced the levels of mitochondrial reduced glutathione (GSH). Upregulation of enzymes involved in the synthesis of GSH was seen in the cells exposed to PB. PB afforded mitochondrial protection by activating the extracellular signal-regulated kinase/nuclear factor erythroid 2-related factor 2 (Erk1/2-Nrf2) axis, since inhibition of Erk1/2 or silencing of Nrf2 abrogated these effects. Therefore, PB exerted mitochondrial and cellular protection by an Erk1/2-Nrf2-dependent mechanism.

Telomere length in subjects with schizophrenia, their unaffected siblings and healthy controls: Evidence of accelerated aging.

Schizophrenia (SZ) is associated with broad burden. The clinical manifestations of SZ are related to pathophysiological alterations similar to what is seen in normal aging. Our aim was to evaluate the differences in telomere length (TL), a biomarker of cellular aging, in subjects with SZ (n=36), unaffected siblings (SB, n=36) and healthy controls (HC, n=47). SZ had shorter TL compared to HC, but no difference was found in SB comparing to SZ. These findings indicate that a pathological accelerated aging profile could be present in the course of SZ and further studies are needed to confirm TL as potential endophenotype, especially in at risk populations.

Alpha-lipoic acid alone and combined with clozapine reverses schizophrenia-like symptoms induced by ketamine in mice: Participation of antioxidant, nitrergic and neurotrophic mechanisms.

Oxidative stress has important implications in schizophrenia. Alpha-lipoic acid (ALA) is a natural antioxidant synthesized in human tissues with clinical uses. We studied the effect of ALA or clozapine (CLZ) alone or in combination in the reversal of schizophrenia-like alterations induced by ketamine (KET). Adult male mice received saline or KET for 14 days. From 8th to 14th days mice were additionally administered saline, ALA (100 mg/kg), CLZ 2.5 or 5 mg/kg or the combinations ALA+CLZ2.5 or ALA+CLZ5. Schizophrenia-like symptoms were evaluated by prepulse inhibition of the startle (PPI) and locomotor activity (positive-like), social preference (negative-like) and Y maze (cognitive-like). Oxidative alterations (reduced glutathione - GSH and lipid peroxidation - LP) and nitrite in the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) and BDNF in the PFC were also determined. KET caused deficits in PPI, working memory, social interaction and hyperlocomotion. Decreased levels of GSH, nitrite (HC) and BDNF and increased LP were also observed in KET-treated mice. ALA and CLZ alone reversed KET-induced behavioral alterations. These drugs also reversed the decreases in GSH (HC) and BDNF and increase in LP (PFC, HC and ST). The combination ALA+CLZ2.5 reversed behavioral and some neurochemical parameters. However, ALA+CLZ5 caused motor impairment. Therefore, ALA presented an antipsychotic-like profile reversing KET-induced positive- and negative-like symptoms. The mechanism partially involves antioxidant, neurotrophic and nitrergic pathways. The combination of ALA+CLZ2.5 improved most of the parameters evaluated in this study without causing motor impairment demonstrating, thus, that possibly when combined with ALA a lower dose of CLZ is required.

Evidences for a progressive microglial activation and increase in iNOS expression in rats submitted to a neurodevelopmental model of schizophrenia: reversal by clozapine.

Schizophrenia was proposed as a progressive neurodevelopmental disorder. In this regard herein we attempted to determine progressive inflammatory and oxidative alterations induced by a neonatal immune challenge and its possible reversal by clozapine administration. For this end, Wistar rats at postnatal day (PN) 5-7 were administered the viral mimetic polyriboinosinic-polyribocytidilic acid (polyI:C) or saline. A distinct group of animals additionally received the antipsychotic drug clozapine (25mg/kg) from PN60 to 74. At PN35 (periadolescence), 60 (adult) and 74 (adulthood) the animals were submitted to behavioral determinations of prepulse inhibition of the startle (PPI) and Y maze task for working memory evaluation. At PN35 and 74 the animals were sacrificed and the hippocampus (HC), prefrontal cortex (PFC) and striatum (ST) immunostained for Iba-1, a microglial marker, and inducible nitric oxide synthase (iNOS). At PN74 oxidative stress parameters, such as, reduced glutathione levels (GSH) and lipid peroxidation were determined. The results showed a progressive increase of microglial activation and iNOS immunostaining from PN35 to PN74 mainly in the CA2 and CA3 regions of the HC and in the ST. At PN74 neonatal challenge also induced an oxidative imbalance. These inflammatory alterations were accompanied by deficits in PPI and working memory only in adult life that were reversed by clozapine. Clozapine administration reversed microglial activation and iNOS increase, but not the alterations of oxidative stress parameters. Taken together these results give further evidences for a neuroprogressive etiology and course of schizophrenia and that clozapine may partly alleviate this process.

Mitochondrial activity and oxidative stress markers in peripheral blood mononuclear cells of patients with bipolar disorder, schizophrenia, and healthy subjects.

Evidence suggests that mitochondrial dysfunction is involved in the pathophysiology of psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BD). However, the exact mechanisms underlying this dysfunction are not well understood. Impaired activity of electron transport chain (ETC) complexes has been described in these disorders and may reflect changes in mitochondrial metabolism and oxidative stress markers. The objective of this study was to compare ETC complex activity and protein and lipid oxidation markers in 12 euthymic patients with BD type I, in 18 patients with stable chronic SZ, and in 30 matched healthy volunteers. Activity of complexes I, II, and III was determined by enzyme kinetics of mitochondria isolated from peripheral blood mononuclear cells (PBMCs). Protein oxidation was evaluated using the protein carbonyl content (PCC) method, and lipid peroxidation, the thiobarbituric acid reactive substances (TBARS) assay kit. A significant decrease in complex I activity was observed (p = 0.02), as well as an increase in plasma levels of TBARS (p = 0.00617) in patients with SZ when compared to matched controls. Conversely, no significant differences were found in complex I activity (p = 0.17) or in plasma TBARS levels (p = 0.26) in patients with BD vs. matched controls. Our results suggest that mitochondrial complex I dysfunction and oxidative stress play important roles in the pathophysiology of SZ and may be used in potential novel adjunctive therapy for SZ, focusing primarily on cognitive impairment and disorder progression.

Staging and neuroprogression in bipolar disorder: a systematic review of the literature.

INTRODUCTION: The use of clinical staging models is emerging as a novel and useful paradigm for diagnosing severe mental disorders. The term "neuroprogression" has been used to define the pathological reorganization of the central nervous system along the course of severe mental disorders. In bipolar disorder (BD), neural substrate reactivity is changed by repeated mood episodes, promoting a brain rewiring that leads to an increased vulnerability to life stress. METHOD: A search in the PubMed database was performed with the following terms: "staging", "neuroprogression", "serum", "plasma", "blood", "neuroimaging", "PET scan", "fMRI", "neurotrophins", "inflammatory markers" and "oxidative stress markers", which were individually crossed with "cognition", "functionality", "response to treatments" and "bipolar disorder". The inclusion criteria comprised original papers in the English language. Abstracts from scientific meetings were not included. RESULTS: We divided the results according to the available evidence of serum biomarkers as potential mediators of neuroprogression, with brain imaging, cognition, functioning and response to treatments considered as consequences. CONCLUSION: The challenge in BD treatment is translating the knowledge of neuronal plasticity and neurobiology into clinical practice. Neuroprogression and staging can have important clinical implications, given that early and late stages of the disorder appear to present different biological features and therefore may require different treatment strategies.

Staging and neuroprogression in bipolar disorder: a systematic review of the literature

INTRODUCTION: The use of clinical staging models is emerging as a novel and useful paradigm for diagnosing severe mental disorders. The term "neuroprogression" has been used to define the pathological reorganization of the central nervous system along the course of severe mental disorders. In bipolar disorder (BD), neural substrate reactivity is changed by repeated mood episodes, promoting a brain rewiring that leads to an increased vulnerability to life stress. METHOD: A search in the PubMed database was performed with the following terms: "staging", "neuroprogression", "serum", "plasma", "blood", "neuroimaging", "PET scan", "fMRI", "neurotrophins", "inflammatory markers" and "oxidative stress markers", which were individually crossed with "cognition", "functionality", "response to treatments" and "bipolar disorder". The inclusion criteria comprised original papers in the English language. Abstracts from scientific meetings were not included. RESULTS: We divided the results according to the available evidence of serum biomarkers as potential mediators of neuroprogression, with brain imaging, cognition, functioning and response to treatments considered as consequences. CONCLUSION: The challenge in BD treatment is translating the knowledge of neuronal plasticity and neurobiology into clinical practice. Neuroprogression and staging can have important clinical implications, given that early and late stages of the disorder appear to present different biological features and therefore may require different treatment strategies.

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.

Association of biomarkers and depressive symptoms in schizophrenia.

Emergence of depressive symptoms in schizophrenia results in a deteriorating course and poor prognosis. Schizophrenia and depressive disorder are both associated with low levels of brain-derived neurotrophic factor (BDNF) and with a longstanding low grade inflammatory state. The objective of this study is to analyze the relationship between these serum biomarkers and depressive and psychotic symptoms in schizophrenic patients. Thirty-nine individuals diagnosed with schizophrenia or schizoaffective disorder by Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), assessed by Structured Clinical Interview for DSM-IV (SCID), were included. Interviews were conducted with The Positive and Negative Syndrome Scale (PANSS) and The Calgary Depression Scale for Schizophrenia (CDSS). Blood samples were collected for determination of BDNF, IL-1beta, IL-6, IL-8, IL-10, IL-12 and TNF-alpha measurements. Positive correlations between BDNF and CDSS and between IL-1beta and severity in PANSS scores were found. BDNF levels were not correlated with any cytokine or with PANSS scores. The results of this study suggest that depressive and psychotic symptoms may be associated with different profiles of biomarkers in the association between schizophrenia and depression.

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.