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BACKGROUND: Phospholipase A2 (PLA2) is a large family of enzymes involved in the inflammatory process that catalyzes the hydrolysis of membrane phospholipids, leading to the production of free fatty acids and lysophospholipids, starting the arachidonic acid cascade. Their expression has been related to the behavior of several cancers. Our objective is to search for PLA2 expression in prostate cancer (PCa) tissue that correlates with prognosis and survival. METHODS: Using qRT-PCR, we analyzed the expression levels of PLA2G1B, PLA2G2A, PLA2G2D, PLA2G4A, PLA2G4B, PLA2G4C, PLA2G4D, PLA2G4E, PLA2G4F, PLA2G6, PLA2G7, PLA2G16, PNPLA1, and PNPLA2 in PCa tissue from 108 patients submitted to radical prostatectomy, followed by a mean time of 163 months. RESULTS: All PLA2 was overexpressed in PCa compared to normal tissue. Interestingly, higher expression of some PLA2 was related to favorable prognostic factors: lower levels of PSA (PLA2G2A, PLA2G4D), lower rates of lymph node metastasis (PLA2G16 and PLA2G1B), and organ-confined disease (PLA2G4A). Most importantly, PLAG4B was independently related to longer disease-free survival. CONCLUSION: This is the first study exploring comprehensively the expression levels of PLA2 in PCa, showing that the higher expression of some PLA2 should be used as biomarkers of good prognosis and longer disease-free survival.

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In this study, we obtained a lipidomic profile of plasma samples from drug-naïve patients with schizophrenia (SZ) and bipolar disorder (BD) in comparison to healthy controls. The sample cohort consisted of 30 BD and 30 SZ patients and 30 control individuals. An untargeted lipidomics strategy using liquid chromatography coupled with high-resolution mass spectrometry was employed to obtain the lipid profiles. Data were preprocessed, then univariate (t-test) and multivariate (principal component analysis and orthogonal partial least squares discriminant analysis) statistical tools were applied to select differential lipids, which were putatively identified. Afterward, multivariate receiver operating characteristic tests were performed, and metabolic pathway networks were constructed, considering the differential lipids. Our results demonstrate alterations in distinct lipid pathways, especially in glycerophospholipids, sphingolipids and glycerolipids, between SZ and BD patients. The results obtained in this study may serve as a basis for differential diagnosis, which is crucial for effective treatment and improving the quality of life of patients with psychotic disorders.

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OBJECTIVES: Studies have suggested Brain-Derived Neurotrophic Factors (BDNF) increase after electroconvulsive therapy (ECT) although they were methodologically limited and enrolled small sample sizes. We aimed at updating a systematic review and meta-analysis to explore BDNF changes after ECT for the treatment of depression. METHODS: PubMed, PsycInfo, Embase and Global health were searched (March, 2021). Clinical trials that measured BDNF in the blood before and after ECT in adults (≥ 18 years old) with depression (major depressive disorder or bipolar disorder) were eligible. Data were pooled through random-effects meta-analyses. RESULTS: Twenty-eight studies involving 778 participants were included. Meta-analysis showed a significant increase in BDNF levels after ECT (Hedges' g = 0.28; 95% CI: 0.10, 0.46) while there was evidence of significant heterogeneity (I2 = 67.64%) but not publication bias/small-study effect. Subgroup analyses and meta-regressions were underpowered to detect significant differences. Meta-analysis of depression severity scores demonstrated a considerable larger treatment effect in reducing depressive symptoms after ECT (Hedge's g = -3.72 95% CI: -4.23, -3.21). CONCLUSION: This updated review showed that BDNF blood levels increased after ECT treatment. However, there was still evidence of substantial heterogeneity and there were limited sample sizes to investigate factors driving the variability of effects across studies. Importantly, the increase in BDNF levels was substantially smaller than the observed in depressive symptomatology, which could be indicative that the former was independent than the latter. Additional studies with larger sample sizes are currently required.

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The onset of frank psychosis is usually preceded by a prodromal phase characterized by attenuated psychotic symptoms. Currently, research on schizophrenia prodromal phase (ultra-high risk for psychosis [UHR]) has focused on the risk of developing psychosis, on the transition to full blown psychosis and on its prediction. Neurobiological differences between UHR individuals who fully recover (remitters) versus those who show persistent/progressive prodromal symptoms (nonremitters) have been little explored. The endocannabinoid system constitutes a neuromodulatory system that plays a major role in brain development, synaptic plasticity, emotional behaviours and cognition. It comprises two cannabinoid receptors (CB1/CB2), two endocannabinoid ligands, arachidonylethanolamide (AEA) and 2-arachidonoylglycerol (2AG) along with their inactivation enzymes. Despite much evidence that the endocannabinoid system is imbalanced during psychosis, very little is known about it in UHR. Therefore, we aimed to quantify the plasma endocannabinoid levels in UHR and healthy controls (HC) and verify if these metabolites could differentiate between remitters and nonremitters. Circulating concentrations of AEA (p = .003) and 2AG (p < .001) were lower in UHR when compared with HC, with no difference between remitters and nonremitters. Regarding clinical evolution, it was observed that out of 91 UHRs initially considered, 16 had psychiatric complaints (3 years of follow-up). Considering those subjects, there were weak correlations between clinical parameters and plasma concentrations of endocannabinoids. Our results suggest that the endocannabinoids are imbalanced before frank psychosis and that changes can be seen in plasma of UHR individuals. These molecules proved to be potential biomarkers to identify individuals in the prodromal phase of psychosis.

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BACKGROUND: The identification of Ultra-High Risk (UHR) individuals is thought to be useful for early intervention to improve psychosis outcomes. However, transition rates vary widely, and there is an effort to make these criteria more specific and accurate. Neuroinflammation has been discussed in the pathophysiology of psychosis. The metabolism of eicosanoids is a key process in inflammatory states. Therefore, we investigated whether the study of the inflammatory COX-2 pathway through the quantification of the eicosanoid levels can be a useful approach for the characterisation of UHR individuals. METHODS: One hundred and twenty-two individuals were included in this study (67 UHR and 55 controls) based on performance on the Prodromal Questionnaire. UHR status was assessed by Structured Interview for Prodromal Syndromes (SIPS). We determined the levels of Prostaglandin F2α (PGF2α), Prostaglandin E2 (PGE2), and Thromboxane B2 (TxB2) in plasma using ELISA assays. RESULTS: Concentrations of PGE2 and TxB2 were increased in UHR compared to controls (p = 0.01 and p < 0.05, respectively). PGE2 and PGF2α levels were correlated to negative symptoms (p < 0.01 and p < 0.05), whereas TxB2 correlated with positive symptoms (p = 0.05) as assessed by the SIPS. CONCLUSIONS: Our findings suggest that overactivation of the COX-2 pathway may be related to an increased risk for psychosis. However, our data do not allow us to draw conclusions related to the cause-effect mechanisms. Future studies should determine whether the levels of the eicosanoids have a predictive value for the transition of UHR to frank psychosis.

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Antipsychotics may prolong or retain telomere length, affect mitochondrial function, and then affect the metabolism of nerve cells. To validate the hypothesis that antipsychotics can prolong telomere length after oxidative stress injury, leukocytes from healthy volunteers were extracted using Ficoll-Histopaque density gradient. The mononuclear cells layer was resuspended in cell culture medium. Oxidative stress was induced with hydrogen peroxide in cultured leukocytes. Four days later, leukocytes were treated with aripiprazole, haloperidol or clozapine for 7 days. Real-time PCR revealed that treatments with aripiprazole and haloperidol increased the telomere length by 23% and 20% in peripheral blood mononuclear cells after acute oxidative stress injury. These results suggest that haloperidol and aripiprazole can reduce the damage to telomeres induced by oxidative stress. The experiment procedure was approved by the Ethics Committee of Faculty of Medicine of the University of São Paulo (FMUSP/CAAE approval No. 52622616.8.0000.0065).

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Objective: To assess the influence of migration on the psychopathological presentation of individuals at ultra-high risk for psychosis (UHR) in São Paulo, Brazil. Methods: This study is part of the Subclinical Symptoms and Prodromal Psychosis (SSAPP) project, a cohort study in São Paulo, Brazil, designed to follow individuals at UHR. After screening with the Prodromal Questionnaire (PQ) and a clinical interview, the Global Assessment of Functioning (GAF) was administered, a neuropsychological assessment was performed, sociodemographic and migration data were obtained. We then analyzed UHR individuals who had migration data to see if migration had any effect on their cognition and psychopathology. Chi-square tests were used for categorical variables, and Student's t test or analysis of variance (ANOVA) were used for nonparametric and parametric distributions, respectively. Results: The sample was composed of 42 at-risk subjects, of whom 5 had a migration history in the past two generations. Those with migration history showed significantly more formal thought disturbances (p = 0.012) and sleeping problems (p = 0.033) compared to those without. Conclusions: Our data reinforce migration as a risk factor for psychosis in developing countries as well, and highlights the importance of studying the specific effect of this factor in UHR psychopathology.

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Phospholipase A2 is the main enzyme in the metabolism of membrane phospholipids. It comprises a family of enzymes divided into iPLA2, cPLA2 and sPLA2. Studies have reported increased PLA2 activity in psychotic patients, which suggests an accelerated breakdown of membrane phospholipids. In the present study we investigated whether increased PLA2 activity is also present in individuals at ultra-high risk (UHR) for psychosis. One-hundred fifty adults were included in this study (85 UHR and 65 controls). UHR was assessed using the "structured interview for prodromal syndromes". PLA2 activity was determined in platelets by a radio-enzymatic assay. We found in UHR individuals increased activities of iPLA2 (p < 0.001) and cPLA2 (p = 0.012) as compared to controls. No correlations were found between socio-demographic and clinical parameters and PLA2 activity. Our findings suggest that increased PLA2 activities may be useful as a biological risk-marker for psychotic disorders.

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BACKGROUND: Mood disorders are the most frequent psychiatric disorders in patients with temporal lobe epilepsy caused by hippocampal sclerosis (TLE-HS). The pathophysiological mechanisms in common between TLE and mood disorders include abnormalities in the serotonergic pathway. We aimed to evaluate the association between serotonin transporter genetic polymorphisms - 5-HTTLPR and 5-HTTVNTR - and the presence of mood disorders in patients with TLE-HS. METHODS: We evaluated 119 patients with TLE-HS, with and without psychiatric disorder; 146 patients diagnosed with major depressive disorder (MDD), and 113 healthy volunteers. Individuals were genotyped for the 5-HTTLPR and 5-HTTVNTR polymorphisms. RESULTS: No difference was observed between the TLE-HS groups, healthy controls, and MDD without epilepsy. There was a correlation between the 12-allele of the 5-HTTVNTR and the family history of patients with epilepsy with TLE-HS (p = 0.013). CONCLUSIONS: In this study conducted in two Brazilian centers, the serotonin transporter polymorphisms evaluated cannot be associated with depressive disorder in patients with TLE-HS. Still, they do have some influence over some clinical characteristics of epilepsy in TLE-HS. These data may not be reproduced in other populations with distinct ethnic characteristics.

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OBJECTIVE: To assess the influence of migration on the psychopathological presentation of individuals at ultra-high risk for psychosis (UHR) in São Paulo, Brazil. METHODS: This study is part of the Subclinical Symptoms and Prodromal Psychosis (SSAPP) project, a cohort study in São Paulo, Brazil, designed to follow individuals at UHR. After screening with the Prodromal Questionnaire (PQ) and a clinical interview, the Global Assessment of Functioning (GAF) was administered, a neuropsychological assessment was performed, sociodemographic and migration data were obtained. We then analyzed UHR individuals who had migration data to see if migration had any effect on their cognition and psychopathology. Chi-square tests were used for categorical variables, and Student's t test or analysis of variance (ANOVA) were used for nonparametric and parametric distributions, respectively. RESULTS: The sample was composed of 42 at-risk subjects, of whom 5 had a migration history in the past two generations. Those with migration history showed significantly more formal thought disturbances (p = 0.012) and sleeping problems (p = 0.033) compared to those without. CONCLUSIONS: Our data reinforce migration as a risk factor for psychosis in developing countries as well, and highlights the importance of studying the specific effect of this factor in UHR psychopathology.

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BACKGROUND: Paliperidone palmitate is a long-acting, second-generation antipsychotic (SGA) indicated for the treatment of acute exacerbations and maintenance treatment of adults with schizophrenia. This study addressed the response to paliperidone palmitate in Latin American patients with acute symptoms and recently diagnosed schizophrenia. OBJECTIVE: Explore the efficacy and tolerability of paliperidone palmitate administered once a month for 4 months in patients with acute phase and recent diagnosis (within 1-6 years) of schizophrenia in 3 Latin American countries. METHODS: This was a non-randomized, open-label, multicenter study with paliperidone palmitate injected intramuscularly in the deltoid muscle at an initial loading dose of 150 mg eq. (234 mg) on day 1 and 100 mg eq. (156 mg) on day 8 (± 4 days). The recommended maintenance dose was 75 mg eq. (117 mg) from day 36 to day 92. Efficacy was evaluated with PANSS and CGI-S. The last observation carried forward (LOCF) was used for efficacy analysis for imputation of missing data; no adjustments were made for multiplicity. Adverse events were evaluated during treatment. RESULTS: The patient retention rate was 84.0% (144 patients received study drug; 121 finished the study). The percentage of patients with a reduction of at least 30% in PANSS total score compared to baseline gradually increased during the study, and at the end, 78.4% of patients showed response. The PANSS total score and CGI-S scores decreased significantly from baseline to LOCF endpoint (P <0.0001 for both); significant reduction in PANSS total score was observed at day 8 and persisted to the end of the study. Most common adverse events were muscle rigidity (11.8%), akathisia (11.1%), injection-site pain (7.6%), weight gain (7.6%), and insomnia (7.6%). CONCLUSION: Paliperidone palmitate was efficacious in Latin American patients studied with an acute exacerbation and recent diagnosis of schizophrenia, and no new safety signals were identified.

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The metabolomic profile of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) may suggest potential diagnostic biomarkers and provide information on the pathophysiology of dementia. Our aim was to quantify plasmatic metabolites of AD patients, MCI and controls. We investigated the metabolomic profile-using the AbsoluteIDQ®p180 assay-of 79 older adults with primary cognitive impairment (34 AD and 20 MCI) and 25 healthy elders (controls). A cluster analysis revealed that a combination C12-DC, C12 and PCaaC26:0 could differentiate the patients according to diagnostic. Future studies should combine metabolomic profiles with other biomarkers to identify diagnostic groups.

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The cellular and molecular mechanisms underlying onset and development of schizophrenia have not yet been completely elucidated, but the association of disturbed neuroplasticity and inflammation has gained particular relevance recently. These mechanisms are linked to annexins functions. ANXA3, particularly, is associated to inflammation and membrane metabolism cascades. The aim was to determine the ANXA3 levels in first-onset drug-naïve psychotic patients. We investigated by western blot the protein expression of annexin A3 in platelets of first-onset, drug-naïve psychotic patients (diagnoses according to DSM-IV: 28 schizophrenia, 27 bipolar disorder) as compared to 30 age- and gender-matched healthy controls. Annexin A3 level was lower in schizophrenia patients as compared to healthy controls (p < 0.001) and to bipolar patients (p < 0.001). Twenty out of 28 schizophrenic patients had undetectable annexin A3 levels, as compared to none from the bipolar and none from the control subjects. ANXA3 was reduced in drug-naïve patients with schizophrenia. ANXA3 affects neuroplasticity, inflammation and apoptosis, as well as it modulates membrane phospholipid metabolism. All these processes have been discussed in regard to the biology of schizophrenia. In face of these data, we feel that further studies with larger samples are warranted to investigate the possible role of reduced ANXA3 as a possible risk marker for schizophrenia.

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Abstract Background Current evidence suggests that upregulation of polyamines system plays a role both in cognitive deficit and synaptic loss observed in Alzheimer's disease (AD). Objective The aim of this study was to determine the plasmatic concentration of polyamines in mild cognitive impairment (MCI) and AD patients in comparison with healthy controls (HC). Methods Plasmatic polyamines were quantified using the AbsoluteIDQ® p180 and liquid chromatography coupled to tandem mass spectrometry (LC/MS-MS). Results The study group comprised 34 AD patients, 20 MCI and 25 HC. All individuals were followed for 4 years. During this period 8 amnestic MCI patients (40% of the MCI sample at baseline) converted to AD. Spermidine level was lower in both patient groups (AD; MCI) compared to HC (p = 0.007). Plasma levels of spermine were higher in the MCI group (p < 0.001), but decreased in the sub-sample of MCI patients who converted to AD (p = 0.043). No statistically significant differences were found in ornithine and putrescine levels (p = 0.056 and p = 0.126, respectively). Discussion Our results suggest dynamic changes in the expression of polyamines in the MCI-AD continuum.

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BACKGROUND: Experimental studies indicate that lithium may facilitate neurotrophic/protective responses in the brain. Epidemiological and imaging studies in bipolar disorder, in addition to a few trials in Alzheimer's disease support the clinical translation of these findings. Nonetheless, there is limited controlled data about potential use of lithium to treat or prevent dementia. AIMS: To determine the benefits of lithium treatment in patients with amnestic mild cognitive impairment (MCI), a clinical condition associated with high risk for Alzheimer's disease. METHOD: A total of 61 community-dwelling, physically healthy, older adults with MCI were randomised to receive lithium or placebo (1:1) for 2 years (double-blind phase), and followed-up for an additional 24 months (single-blinded phase) (trial registration at clinicaltrials.gov: NCT01055392). Lithium carbonate was prescribed to yield subtherapeutic concentrations (0.25-0.5 mEq/L). Primary outcome variables were the cognitive (Alzheimer's Disease Assessment Scale - cognitive subscale) and functional (Clinical Dementia Rating - Sum of Boxes) parameters obtained at baseline and after 12 and 24 months. Secondary outcomes were neuropsychological test scores; cerebrospinal fluid (CSF) concentrations of Alzheimer's disease-related biomarkers determined at 0, 12 and 36 months; conversion rate from MCI to dementia (0-48 months). RESULTS: Participants in the placebo group displayed cognitive and functional decline, whereas lithium-treated patients remained stable over 2 years. Lithium treatment was associated with better performance on memory and attention tests after 24 months, and with a significant increase in CSF amyloid-beta peptide (Aß1-42) after 36 months. CONCLUSIONS: Long-term lithium attenuates cognitive and functional decline in amnestic MCI, and modifies Alzheimer's disease-related CSF biomarkers. The present data reinforces the disease-modifying properties of lithium in the MCI-Alzheimer's disease continuum. DECLARATION OF INTEREST: None.

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BACKGROUND: The efficacy of transcranial direct current stimulation (tDCS) as a continuation therapy for the maintenance phase of the depressive episode is low and insufficiently investigated in literature. We investigated whether it could be enhanced by using a more intensive treatment regimen compared to previous reports. METHODS: Twenty-four patients (16 with unipolar depression and eight with bipolar depression) who presented acute tDCS response (≥50% depression improvement in the Hamilton Depression Rating Scale [HDRS]) after receiving 15 tDCS sessions were followed for up to 6 months or until relapse, defined as clinical worsening and/or HDRS > 15. Sessions were performed twice a week (maximum of 48 sessions) over 24 weeks. The anode and the cathode were positioned over the left and right dorsolateral prefrontal cortex (2 mA current, 30 min sessions were delivered). We performed Kaplan-Meier survival analysis and Cox proportional hazards ratios to evaluate predictors of relapse. RESULTS: Out of 24 patients, 18 completed the follow-up period. tDCS treatment was well tolerated. The mean survival duration was 17.5 weeks (122 days). The survival rate at the end of follow-up was 73.5% (95% confidence interval, 50-87). A trend (P = 0.09) was observed for lower relapse rates in nontreatment- vs. antidepressant treatment-resistant patients (7.7% vs. 45.5%, respectively). No differences in efficacy between unipolar and bipolar depression were observed. CONCLUSION: An intensive tDCS treatment regimen consisting of sessions twice a week achieved relatively low relapse rates after a 6-month follow up of tDCS responders, particularly for nontreatment-resistant patients.

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OBJECTIVES: Expression of phospholipids and related molecules could provide panels of multiple biomarkers searching for the signature of Alzheimer's disease (AD). The aim of the present study was to quantify ten phospholipids and simultaneously determine phospholipase A2 (PLA2) activity in blood of mild cognitive impairment (MCI) and AD patients. METHODS: Thirty-four AD, 20 MCI and 25 controls were enrolled. The phospholipids where analysed using the AbsoluteIDQ® p180 Kit. PLA2 activities were accessed in platelets by a radio-enzymatic assay. RESULTS: The study failed to fix the ten phospholipids as a panel to predict AD; the levels of PCaaC36:6, PCaaC40:6 and C16:1-OH were lower in MCI than in controls (P = 0.041, P = 0.012, P = 0.044 respectively). PCaaC40:2 levels were lower in MCI than in AD (P = 0.041). The converters MCI-AD showed at baseline lower levels of PCaaC40:2 (P = 0.050) and PCaaC40:6 (P = 0.037) than controls. iPLA2 activity was reduced in AD and MCI than in controls (P < 0.001). We found positive correlation in the control group between PCaaC38:6 and tPLA2 (r = 0.680; P = 0.001) and sPLA2 (r = 0.601; P = 0.004); PCaaC40:1 and iPLA2 (r = 0.503; P = 0.020); PCaaC40:6 and tPLA2 (r = 0.532; P = 0.013) and sPLA2 (r = 0.523; P = 0.015). CONCLUSIONS: Lipids metabolites in plasma might indirectly indicate changes in neuronal membrane and this deregulation can outline the transition between healthy and diseased brains.

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