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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. [ABSTRACT FROM AUTHOR]

Objectives The putative neuroprotective effects of lithium treatment rely on the fact that it modulates several homeostatic mechanisms involved in the neurotrophic response, autophagy, oxidative stress, inflammation, and mitochondrial function. Lithium is a well-established therapeutic option for the acute and long-term management of bipolar disorder and major depression. The aim of this study was to evaluate the effects of subtherapeutic and therapeutic concentrations of chronic lithium treatment on brain-derived neurotrophic factor ( BDNF) synthesis and secretion. Methods Primary cultures of cortical and hippocampal neurons were treated with different subtherapeutic (0.02 and 0.2 mM) and therapeutic (2 mM) concentrations of chronic lithium treatment in cortical and hippocampal cell culture. Results Lithium treatment increased the intracellular protein expression of cortical neurons (10% at 0.02 mM) and hippocampal neurons (28% and 14% at 0.02 mM and 0.2 mM, respectively). Extracellular BDNF of cortical neurons increased 30% and 428% at 0.02 and 0.2 mM, respectively and in hippocampal neurons increased 44% at 0.02 mM. Conclusion The present study indicates that chronic, low-dose lithium treatment up-regulates BDNF production in primary neuronal cell culture. [ABSTRACT FROM AUTHOR]

The anterior cingulate cortex (ACC) is a key area in mood regulation. To date, no longitudinal study has specifically evaluated lithium׳s effects on ACC metabolites using 1 H-MRS, as well as its association with clinical improvement in bipolar depression. This 1 H-MRS (TE=35 ms) study evaluated 24 drug-free BD patients during depressive episodes and after lithium treatment at therapeutic levels. Brain metabolite levels (N-acetyl aspartate (NAA), creatine (tCr), choline, myo-inositol, and glutamate levels) were measured in the ACC at baseline (week 0) and after lithium monotherapy (week 6). The present investigation showed that ACC glutamate (Glu/tCr) and glutamate+glutamine (Glx/tCr) significantly increased after six weeks of lithium therapy. Regarding the association with clinical improvement, remitters showed an increase in myoinositol levels (mI/tCr) after lithium treatment compared to non-remitters. The present findings reinforce a role for ACC glutamate-glutamine cycling and myoinositol pathway as key targets for lithium׳s therapeutic effects in BD. [ABSTRACT FROM AUTHOR]

The article focuses on the RISPALI (risperidone-paliperidone) study on the effects of oral paliperidone extended-release (ER) in Brazilian adults with schizophrenia. Topics include the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) of adults with chronic schizophrenia, potential issues regarding the treatment and conduction of the study in accordance with the guidelines of the International Conference on Harmonization for Good Clinical Practice (ICH GCP).

Abstract: Objective: The aim of this work was to investigate whether increased activity of the enzyme phospholipase A2 (PLA2) in the brain, as frequently reported in schizophrenia, is also related to psychosis in epilepsy. Our working hypothesis was based on the increased prevalence of schizophrenia-like psychosis in patients with temporal lobe epilepsy (TLE) secondary to mesial temporal sclerosis (MTS), as compared to patients with other forms of epilepsy. Methods: We determined PLA2 activity in hippocampal tissue from 7 patients with TLE-MTS and psychosis, as compared to 9 TLE-MTS patients without psychosis. Hippocampal tissue was obtained from patients who underwent an anterior temporal lobectomy due to therapy-resistant epilepsy. Results: We found that patients with TLE-MTS and psychosis had a significantly increased calcium-independent PLA2 activity as compared to patients without psychosis (p = 0.016). Conclusion: Our finding suggest that an increment in brain PLA2 activity is not specific for schizophrenia, but rather may be associated to the manifestation of schizophrenia-like psychotic symptoms in general. [Copyright &y& Elsevier]

Understanding the molecular basis of schizophrenia is essential for disease management, and several molecular biology tools have been employed for this purpose. Mass spectrometry, which is used mostly in proteomic and metabolomic studies, is one such tool. Here, we present the first psychiatric study to use mass spectrometry imaging (MSI) with desorption electrospray ionization (DESI). Preparation of samples for use with DESI-MSI is remarkably simple and quick and preserves the spatial distribution of analytes. By using this tool, we found differences in the phospholipid content in schizophrenia postmortem brains. These results validate both the role of phospholipids in schizophrenia and the value of this MS tool in furthering the understanding of the molecular aspects of the disease. [ABSTRACT FROM AUTHOR]

Abstract: Schizophrenia is likely to be a consequence of serial alterations in a number of genes that, together with environmental factors, will lead to the establishment of the illness. The dorsolateral prefrontal cortex (Brodmann’s Area 46) is implicated in schizophrenia and executes high functions such as working memory, differentiation of conflicting thoughts, determination of right and wrong concepts, correct social behavior and personality expression. We performed a comparative proteome analysis using two-dimensional gel electrophoresis of pools from 9 schizophrenia and 7 healthy control patients’ dorsolateral prefrontal cortex aiming to identify, by mass spectrometry, alterations in protein expression that could be related to the disease. In schizophrenia-derived samples, our analysis revealed 10 downregulated and 14 upregulated proteins. These included alterations previously implicated in schizophrenia, such as oligodendrocyte-related proteins (myelin basic protein and transferrin), as well as malate dehydrogenase, aconitase, ATP synthase subunits and cytoskeleton-related proteins. Also, six new putative disease markers were identified, including energy metabolism, cytoskeleton and cell signaling proteins. Our data not only reinforces the involvement of proteins previously implicated in schizophrenia, but also suggests new markers, providing further information to foster the comprehension of this important disease. [Copyright &y& Elsevier]

Global proteomic analysis of post-mortem anterior temporal lobe samples from schizophrenia patients and non-schizophrenia individuals was performed using stable isotope labeling and shotgun proteomics. Our analysis resulted in the identification of 479 proteins, 37 of which showed statistically significant differential expression. Pathways affected by differential protein expression include transport, signal transduction, energy pathways, cell growth and maintenance and protein metabolism. The collection of protein alterations identified here reinforces the importance of myelin/oligodendrocyte and calcium homeostasis in schizophrenia, and reveals a number of new potential markers that may contribute to the understanding of the pathogenesis of this complex disease. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia is likely to be a consequence of DNA alterations that, together with environmental factors, will lead to protein expression differences and the ultimate establishment of the illness. The superior temporal gyrus is implicated in schizophrenia and executes functions such as the processing of speech, language skills and sound processing. Methods: We performed an individual comparative proteome analysis using two-dimensional gel electrophoresis of 9 schizophrenia and 6 healthy control patients' left posterior superior temporal gyrus (Wernicke's area -- BA22p) identifying by mass spectrometry several protein expression alterations that could be related to the disease. Results: Our analysis revealed 11 downregulated and 14 upregulated proteins, most of them related to energy metabolism. Whereas many of the identified proteins have been previously implicated in schizophrenia, such as fructose-bisphosphate aldolase C, creatine kinase and neuronspecific enolase, new putative disease markers were also identified such as dihydrolipoyl dehydrogenase, tropomyosin 3, breast cancer metastasis-suppressor 1, heterogeneous nuclear ribonucleoproteins C1/C2 and phosphate carrier protein, mitochondrial precursor. Besides, the differential expression of peroxiredoxin 6 (PRDX6) and glial fibrillary acidic protein (GFAP) were confirmed by western blot in schizophrenia prefrontal cortex. Conclusion: Our data supports a dysregulation of energy metabolism in schizophrenia as well as suggests new markers that may contribute to a better understanding of this complex disease. [ABSTRACT FROM AUTHOR]

Alzheimer disease (AD), a progressive neurodegenerative disorder, is the leading cause of dementia in the elderly. A combination of cholinergic and glutamatergic dysfunction appears to underlie the symptomatology of AD, and thus, treatment strategies should address impairments in both systems. Evidence suggests the involvement of phospholipase A2 (PLA2) enzyme in memory impairment and neurodegeneration in AD via actions on both cholinergic and glutamatergic systems. To review cholinergic and glutamatergic alterations underlying cognitive impairment and neuropathology in AD and attempt to link PLA2 with such alterations. Medline databases were searched (no date restrictions) for published articles with links among the terms Alzheimer disease (mild, moderate, severe), mild cognitive impairment, choline acetyltransferase, acetylcholinesterase, NGF, NGF receptor, muscarinic receptor, nicotinic receptor, NMDA, AMPA, metabotropic glutamate receptor, atrophy, glucose metabolism, phospholipid metabolism, sphingolipid, membrane fluidity, phospholipase A2, arachidonic acid, attention, memory, long-term potentiation, β-amyloid, tau, inflammation, and reactive species. Reference lists of the identified articles were checked to identify additional studies of interest. Overall, results suggest the hypothesis that persistent inhibition of cPLA2 and iPLA2 isoforms at early stages of AD may play a central role in memory deficits and β-amyloid production through down-regulation of cholinergic and glutamate receptors. As the disease progresses, β-amyloid induced up-regulation of cPLA2 and sPLA2 isoforms may play critical roles in inflammation and oxidative stress, thus participating in the neurodegenerative process. Activation and inhibition of specific PLA2 isoforms at different stages of AD could be of therapeutic importance and delay cognitive dysfunction and neurodegeneration. [ABSTRACT FROM AUTHOR]

Serotonergic pharmacological challenges have failed to produce consensual results in patients with obsessive–compulsive disorder (OCD), suggesting a heterogeneous 5-hydroxytryptamine (5-HT) activity in this disorder. The aim of this study was to compare the neuroendocrine response to a serotonergic challenge in OCD patient responders (RP) and nonresponders (NR) to serotonin reuptake inhibitors treatment and healthy volunteers. Thirty OCD treatment NR, 30 RP, and 30 controls (CN) matched for sex and age were included. Each subject received 20 mg of intravenous citalopram. Prolactin, cortisol, and growth hormone plasma concentration were measured at times—20, 0, 20, 40, 60, 80, 100, 120, 140, and 160 min after the onset of citalopram infusion. Citalopram did not induce anxiety or OCD symptoms in patients. Citalopram was associated with stronger prolactin response in the CN group (maximal percentage variation [max%Δ] = 65.76 ± 105.1) than in NR (max%Δ = 17.41 ± 31.06) and RP groups (max%Δ = 15.87 ± 31.71; p = 0.032; Friedman χ 2 = 6.87; df = 2). On the other hand, cortisol response did not differ between CN and RP groups and was blunted in the NR group (NR max%Δ = 20.98 ± 58.14 vs RP max%Δ = 47.69 ± 66.94; CN max%Δ = 63.58 ± 88.4; p = 0.015; Friedman χ 2 = 8.60; df = 2). Compared to CN, both treatment RP and NR patients showed blunted prolactin response to citalopram, but only NR patients showed an attenuated cortisol response, suggesting a more disrupted central serotonergic transmission in this group. [ABSTRACT FROM AUTHOR]

Abstract: Abnormality in neurodevelopment is one of the most robust hypotheses on the etiology of schizophrenia and has found substantial support from brain imaging and genetic studies. Neurodevelopmental processes involve several signaling pathways, including the Notch, but little is known at present regarding their possible involvement in schizophrenia. In the present study we investigated the link of non-synonymous variants of five genes of the Notch pathway (NOTCH2, NOTCH3, JAGGED2, ASCL1 and NUMBL) to schizophrenia in a group of 200 Brazilian patients and 200-paired controls. Also, we replicated the association of the NUMBL variant, our most promising finding, in an unrelated set of 684 Danish patients and controls. When the Brazilian and Danish cohorts were merged, a total of 1084 subjects, we found the allele 18 CAG of NUMBL (p =0.003, x 2 =8.88, OR=1.30, 95% CI 1.09–1.56) as well as the 18/18 CAG genotype (p =0.002, x 2 =9.46, OR=1.46, 95% CI 1.15–1.87) to be associated with schizophrenia. The consistency of this finding in two independent and unrelated populations reinforces the veracity of this association. [Copyright &y& Elsevier]

Rationale: Phospholipase A2 (PLA2) is a family of enzymes that cleave membrane phospholipids generating important lipid mediators in signal transduction. In rat hippocampal slices, both intracellular cytosolic Ca2+-dependent PLA2 (cPLA2) and Ca2+-independent PLA2 (iPLA2) have been implicated in mechanisms of synaptic plasticity underlying memory processes. In mice, intraperitoneal injections of a selective iPLA2 inhibitor impaired spatial learning. Accordingly, reduced cPLA2 and iPLA2 activities were found in postmortem hippocampus of patients with Alzheimer's disease. Objective: This study investigates the effects of injections of PLA2 inhibitors directly into rat hippocampus on the acquisition of short-term (STM) and long-term memory (LTM) of a one-trial step-down inhibitory avoidance (IA) task. Methods: Wistar rats were bilaterally implanted with cannulae in the CA1 region of the dorsal hippocampus. After surgery, the rats received bilateral injections of a vehicle, or of dual cPLA2 and iPLA2 inhibitors (MAFP or PACOCF3), or a selective iPLA2 inhibitor (bromoenol lactone) before training in IA. The animals were tested 1.5 h (for STM) and 24 h (for LTM) after training. Results: Significant inhibition of iPLA2 activity in rat hippocampus impaired acquisition of STM and LTM. Memory impairment did not result from neuronal death after iPLA2 inhibition. Moreover, IA training per se increased significantly hippocampal PLA2 activity. Conclusion: The present results suggest a functional effect of hippocampal PLA2 on the neurochemistry of memory acquisition and support the hypothesis that reduced PLA2 activity may contribute to memory impairment in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: Transcranial magnetic stimulation (TMS) is a noninvasive method to stimulate the cortex, and the treatment of depression is one of its potential therapeutic applications. Three recent meta analyses strongly suggest its benefits in the treatment of depression. The present study investigates whether repetitive TMS (rTMS) accelerates the onset of action and increases the therapeutic effects of amitriptyline. Methods: Forty-six outpatients meeting DSM-IV criteria for nonpsychotic depressive episode were randomly assigned to receive rTMS (n = 22) or sham repetitive TMS (sham) (n = 24) during 4 weeks over dorsolateral prefrontal cortex (DLPFC) in this double-blind controlled trial. All patients were concomitantly taking amitriptyline (mean dose 110 mg/d). The rTMS group received 20 sessions (5 sections per week) of 5 Hz rTMS (120% of motor threshold and 1250 pulses per session). Sham stimulation followed the same schedule, however, using a sham coil. The efficacy variables were the Hamilton Depression Rating Scale-17 items (HAM-D/17), the Montgomery-Åsberg Depression Rating Scale (MADRS), a Visual Analogue Scale (VAS), and the Clinical Global Impression (CGI). Tolerability was assessed by clinical examination and a safety screening of TMS side effects. Results: Repetitive TMS had a significantly faster response to amitriptyline. There was a significant decrease in HAM-D/17 scores, already after the first week of treatment (p < .001 compared with baseline and p < .001 compared with sham). The decrease in HAM-D/17 scores in the rTMS group was significantly superior compared with the sham group throughout the study (p < .001 at fourth week). Conclusions: Repetitive TMS at 5 Hz accelerated the onset of action and augmented the response to amitriptyline. [Copyright &y& Elsevier]

Examines the risk factors involved in the development of schizophrenia based on a model that the disease is a disorder of brain maturation. Overview of risk factors associated with schizophrenia; Discussion on the occurrence of synaptogenesis in human neocortex; Evaluation on the role of meningitis infection in psychosis and schizophrenia.

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. [ABSTRACT FROM AUTHOR]

The etiology of schizophrenia is still unclear. It is well-known that pro-inflammatory cytokines are higher in schizophrenia patients since the first episode psychosis comparing to healthy controls. Inflammatory downstream cascades influence different cellular pathways, like the displacement of the tryptophan (TRP) metabolism to the production of kynurenine (KYN) instead of serotonin, which results in the generation of several neuro and immunoactive metabolites. The aim of this study was to determine TRP, KYN and IL-1β plasma levels in first-onset schizophrenia (n = 28) and healthy controls (n = 30). The plasmatic levels of TRP and KYN were decreased in schizophrenic patients (p = 0.004 and p = 0.002, respectively), but there was no difference in the ratio of KYN/TRP (p = 0.554) or either in IL-1β (p = 0.101). Positive correlation was observed between KYN and IL-1β only in the schizophrenia group (r = 0.461, p = 0.021). And, there was also positive correlation between KYN and Positive and Negative Symptoms Scale (PANSS) (r = 0.395, p = 0.037). There is no correlation between the other analytes and other parameters of PANSS. Although our results of KYN have been different than expected and there was no difference in the KYN/TRP ratio, we observed a positive correlation between IL-1β and KYN, corroborating findings that pro-inflammatory agents hold up the KYN pathway. [ABSTRACT FROM AUTHOR]

Schizophrenia-related psychosis is associated with abnormalities in white matter (WM) microstructure and structural brain dysconnectivity. However, the pathological process underlying such changes is unknown. We sought to investigate the potential association between peripheral cytokine levels and WM microstructure during the acute phase of first-episode psychosis (FEP) in a cohort of drug-naïve patients. Twenty-five non-affective FEP patients and 69 healthy controls underwent MRI scanning and blood collection at study entry. After achieving clinical remission, 21 FEP were reassessed; 38 age and biological sex-matched controls also had a second assessment. We measured fractional anisotropy (FA) of selected WM regions-of-interest (ROIs) and plasma levels of four cytokines (IL-6, IL-10, IFN-γ, and TNF-α). At baseline (acute psychosis), the FEP group showed reduced FA relative to controls in half the examined ROIs. Within the FEP group, IL-6 levels were negatively correlated with FA values. Longitudinally, patients showed increments of FA in several ROIs affected at baseline, and such changes were associated with reductions in IL-6 levels. A state-dependent process involving an interplay between a pro-inflammatory cytokine and brain WM might be associated with the clinical manifestation of FEP. This association suggests a deleterious effect of IL-6 on WM tracts during the acute phase of psychosis. [ABSTRACT FROM AUTHOR]

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. 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. 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). 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. [ABSTRACT FROM AUTHOR]

Background: Comorbid anxiety is pervasive and carries an immense psychosocial burden for patients with bipolar disorder. Despite this, trials reporting anxiety-related outcomes in this population are uncommon, particularly with regards to monotherapies.Methods: Patients (n = 31) with both bipolar I or II disorder in current depressive episodes were enrolled in a six-week, open-label, single-center trial assessing the efficacy of lithium monotherapy in treating symptoms depression and comorbid anxiety. Patients were mostly medication-free and lithium-naïve at baseline.Results: Significant improvements in depression (HAMD) and anxiety (HAM-A) were observed at the six-week endpoint, with remission and response rates greater than 50%. There was a positive correlation between endpoint HAM-A scores and HAM-D scores, r = 0.80, (p < 0.01). Improvements were realized at low serum lithium concentrations (0.49 ± 0.20 mEq/L).Limitations: Lack of placebo control and small sample size warrants validation in larger randomized studies.Conclusions: Taken in the context of prior evidence, lithium may have an important role in treating comorbid anxiety in bipolar disorder, both as adjunct and monotherapy. Lower doses of lithium may provide equivalent efficacy and enhance tolerability and compliance. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

In view of the growing prevalence of Alzheimer's disease (AD) worldwide, there is an urgent need for the development of better diagnostic tools and more effective therapeutic interventions. At the earliest stages of AD, no significant cognitive or functional impairment is detected by conventional clinical methods. However, new technologies based on structural and functional neuroimaging, and on the biochemical analysis of cerebrospinal fluid (CSF) may reveal correlates of intracerebral pathology in individuals with mild, predementia symptoms. These putative correlates are commonly referred to as AD-related biomarkers. The relevance of the early diagnosis of AD relies on the hypothesis that pharmacological interventions with disease-modifying compounds are likely to produce clinically relevant benefits if started early enough in the continuum towards dementia. Here we review the clinical characteristics of the prodromal and transitional states from normal cognitive ageing to dementia in AD. We further address recent developments in biomarker research to support the early diagnosis and prediction of dementia, and point out the challenges and perspectives for the translation of research data into clinical practice. [ABSTRACT FROM AUTHOR]

Abstract: Data from two major government-funded studies of comparative antipsychotic effectiveness in schizophrenia contradict the widely prevalent belief that the newer second-generation medications are vastly superior to the older first-generation drugs. This has caused uncertainty among patients, clinicians and policy-makers about the relative utility of first- and second- generation antipsychotic agents in its treatment. To reduce confusion and provide a contextual understanding of the new data, the World Psychiatry Association Section on Pharmacopsychiatry comprehensively reviewed the literature on the comparative effectiveness of different antipsychotic treatments for schizophrenia and developed this update. Utilizing data from the approximately 1,600 randomized controlled trials of antipsychotic treatment in schizophrenia, we applied the two indirect and one direct method to comparing the effectiveness of 62 currently-available antipsychotic agents. The subclasses of 51 first-generation and 11 second-generation antipsychotics were both found to be very heterogeneous, with substantial differences in side-effect profiles among members. Second-generation antipsychotic agents were found to be inconsistently more effective than first-generation agents in alleviating negative, cognitive, and depressive symptoms and had a lower liability to cause tardive dyskinesia; these modest benefits were principally driven by the ability of second-generation antipsychotics to provide equivalent improvement in positive symptoms along with a lower risk of causing extrapyramidal side-effects. Clozapine was found to be more efficacious than other agents in treatment-refractory schizophrenia. There were no consistent differences in efficacy among other second-generation antipsychotic agents; if such differences exist, they are likely small in magnitude. Dosing was found to be a key variable in optimizing effectiveness of both first- and second- generation antipsychotic agents. There was enormous individual variability in antipsychotic response and vulnerability to various adverse effects. In contrast to their relatively similar efficacy in treating positive symptoms, there were substantial differences among both first- and second- generation antipsychotic agents with regard to their propensity to cause extrapyramidal, metabolic and other adverse effects; second-generation agents have a lower liability to cause acute extrapyramidal symptoms and tardive dyskinesia along with a tendency to cause greater metabolic side-effects than first-generation agents. Based on these data about the comparative effectiveness of different antipsychotic treatment options, we summarize elements of current best antipsychotic practice for the treatment of schizophrenia and discuss the role of government and the pharmaceutical industry in obtaining and disseminating information which can facilitate best practice. [Copyright &y& Elsevier]

Previous studies have implicated platelet amyloid precursor protein (APP) as a candidate biomarker for Alzheimer’s disease (AD). Platelets contain more than 95% of the circulating APP and enclose the enzymatic machinery for the APP metabolism yielding both soluble APP and amyloid-β peptides. The objective of this study is to compare the ratio of 130- to 110-kDa fragments of APP in platelets from patients with AD, mild cognitive impairment (MCI), and elderly controls. After subjects were grouped according to diagnosis, APP ratio in platelets was evaluated by means of Western blot analysis. The APP ratio was significantly lower in AD patients (1.01 ± 0.21) as compared to controls (1.24 ± 0.21, p = 0.001) and MCI patients (1.18 ± 0.21, p = 0.027), but no significant differences were found between MCI and controls ( p = 0.904). In addition, we found positive correlations between the APP ratio and 1,6-diphenyl-1,3,5-hexatriene anisotropy ( r = 0.3, p = 0.01), as well as with certain parameters of cognitive decline, namely, the mini-mental state examination score ( r = 0.33, p = 0.003), the total Cambridge cognitive test (CAMCOG) score ( r = 0.37, p = 0.001), and the score on the memory subscale of the CAMCOG ( r = 0.38, p = 0.001). The pattern of platelet APP fragments was altered in patients with AD but not in patients with MCI. The alteration of APP fragments was correlated with membrane fluidity and the cognitive decline. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Cognitive deficits and negative symptoms in schizophrenia are associated with poor functional outcomes and limited in terms of treatment. The Schizophrenia Treatment With Electric Transcranial Stimulation (STARTS) trial has shown efficacy of transcranial direct current stimulation (tDCS) for improving negative symptoms. In this secondary analysis, we investigate its effects on cognitive performance. In STARTS, a double-blinded, sham-controlled, randomized clinical trial, patients were treated with twice-daily, 20-min, 2-mA fronto-temporal tDCS over 5 days or sham-tDCS. In 90 patients, we evaluated the cognitive performance up to 12 weeks post-treatment. We found that active-tDCS showed no beneficial effects over sham-tDCS in any of the tests. Based on a 5-factor cognitive model, improvements of executive functions and delayed memory were observed in favor of sham-tDCS. Overall, the applied active-tDCS protocol, primarily designed to improve negative symptoms, did not promote cognitive improvement. We discuss possible protocol modification potentially required to increase tDCS effects on cognition. ClinicalTrials.gov identifier: NCT02535676. [ABSTRACT FROM AUTHOR]

Objective: To assess the influence of migration on the psychopathological presentation of individuals at ultra-high risk for psychosis (UHR) in Sião Paulo, Brazil. Methods: This study is part of the Subclinical Symptoms and Prodromal Psychosis (SSAPP) project, a cohort study in Sao 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Cognitive deficits in major depressive disorder (MDD) are associated with low quality of life and higher suicide risk. Antidepressant drugs have modest to null effects in improving such deficits. Therefore, we investigated the cognitive effects of transcranial direct current stimulation (tDCS), which is a promising antidepressant non-pharmacological intervention, in MDD.Methods: An exploratory analysis on cognitive performance was conducted in 243 depressed patients from the Escitalopram vs. Electric Current Therapy for Treating Depression Clinical Study (ELECT-TDCS), a sham-controlled study comparing the efficacy of tDCS vs. escitalopram. A neuropsychological battery was applied at baseline and endpoint (10 weeks of treatment) to create composite cognitive scores (processing speed, working memory, and verbal fluency). Linear mixed regression models were used to evaluate changes according to intervention groups, adjusted for confounding variables (age, years of schooling, gender, and benzodiazepine use) and depression improvement.Results: No cognitive deterioration was observed in any group. Patients receiving tDCS presented reduced practice gains compared to placebo in processing speed. In patients receiving escitalopram vs. placebo and in the subgroup of clinical responders (>50% depression improvement from baseline), those receiving tDCS vs. placebo presented increased performance in verbal fluency. No significant differences between tDCS and escitalopram groups were detected.Limitations: Absence of healthy controls.Conclusion: Prefrontal tDCS did not lead to cognitive deficits in depressed patients, although it reduced practice effects in processing speed. tDCS responders presented increased performance in verbal fluency. Further investigation of tDCS cognitive effects in depression is warranted. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder (MDD) and bipolar depression (BD) both share increased immune-inflammatory activation. However, there are unclear patterns of differences in peripheral immune profiles between them.Methods: We examined such differences in 245 MDD and 59 BD patients, recruited in the same center, who were in an acute depressive episode of moderate severity. Hierarchical binary logistic regression analyses and generalized linear models were used to compare levels of plasma biomarkers between groups and to predict dichotomous classification.Results: Interleukin (IL)-1β, tumor necrosis factor (TNF)-α, soluble TNF receptor (sTNFR)1, IL-12 and IL-10 were significantly higher in MDD than in BD, whereas IL-6, sTNFR2, IL-18, IL-33, ST2 (IL1R Like 1) and KLOTHO were significantly higher in BD than in MDD. Moreover, logistic regression analyses correctly classified BD and MDD patients with 98.1% accuracy, using a combination of IL-6, IL-8, ST2, sTNFR2 (directly associated with BD) and IL-12 and TNF-α (directly associated with MDD). Patients with MDD with melancholic features showed higher IL-1β levels than those without melancholia. The sTNFR1 / sTNFR2 ratio significantly predicted MDD and state and trait anxiety and negative affect. Results remained significant after covariate adjustment, including drug use.Limitations: Cross-sectional study. Lack of control comparison group. Differences in exposure to medications among participants.Conclusions: Differences in immune profiles between BD and MDD patients exist, especially for the compensatory immune-regulatory system (CIRS): increased IL-10 is the primary immune-regulatory mechanism in MDD, while increased sTNFR2 and KLOTHO are the primary regulatory mechanisms in BD. [ABSTRACT FROM AUTHOR]

The article reports that translation and validation of the structured interview for Prodromal Syndromes (SIPS) to Portuguese. Topics include state represents wide and heterogeneous modifications of an individual's perception and behavior which can precede full-blown psychotic episodes; and Criteria of Prodromal Syndromes and Presence of Psychotic Syndrome used for determining the three prodromal syndromes and a full-blown psychosis.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Transcranial direct current stimulation (tDCS) holds promise as a therapeutic intervention for major depressive disorder (MDD). A more precise understanding of its underlying mechanisms may aid in the identification of subsets of patients responsive to tDCS within the context of precision psychiatry. Objective In this ancillary investigation of the Escitalopram vs. Electrical Current Therapy for Treating Depression Clinical Study (ELECT-TDCS), we investigated whether plasma levels of several cytokines and neurotrophic factors associated with major depression or antidepressant response predicted tDCS effects. Methods We examined, in 236 patients at 3 timepoints during a 10-week treatment course, plasma levels of nerve growth factor (NGF), brain-derived (BDNF), glial-cell line derived neurotrophic factor (GDNF), the interleukins (IL) IL-1ß, IL-6, IL-8, IL-10, IL-12p70, IL-18, IL-33, tumor necrosis factor-alpha (TNF-alpha), and its soluble receptors sTNFr1 and sTNFr2. General linear models and mixed-models analyses of variance were used to respectively assess whether plasma levels of these molecules (1) predicted tDCS antidepressant improvement and (2) changed over time. Results After correction for multiple comparisons (false discovery rate method), NGF baseline levels predicted early depression improvement for tDCS vs. escitalopram, whilst other biomarkers did not significantly predict treatment improvement. The levels of IL12p70, IL10, IL-1ß, IL-8 and sTNFr1 decreased over time, regardless of allocation group and clinical response. Conclusion In general, peripheral biomarkers were not associated with the outcome. The post-hoc finding of baseline NGF levels predicting early depression improvement for tDCS should be explored in further studies. [ABSTRACT FROM AUTHOR]

Cholesterol is an essential component in the structure and function of cell membranes and has been associated with the major pathological signatures of Alzheimer’s disease (AD). To maintain brain cholesterol homeostasis, it is converted into 24(S)-hydroxycholesterol (24OHC) which can be driven through the blood-brain barrier. Several studies have already described a decrease in 24OHC and an increase of 27(S)-hydroxycholesterol (27OHC) in AD, as a reflection of disease burden, the loss of metabolically active neurons and the degree of structural atrophy. It is also well known that peripheral cholesterol is altered in AD patients. However, there are no data regarding effects of AD treatment in this cholesterol pathway. Since a study from our group indicated a significant increase in membrane phospholipid metabolism by donepezil, the aim of this study was to evaluate the effect of short- and long-term donepezil treatment on cholesterol and metabolites 24OHC and 27OHC in plasma of AD patients and in healthy volunteers. At baseline, we found a decrease of 24OHC (p = 0.003) in AD patients. Cholesterol levels increased with donepezil treatment (p = 0.04) but no differences were observed regarding 24OHC and 27OHC. However, these results confirm and extend previous studies demonstrating disturbed cholesterol turnover in Alzheimer’s disease. [ABSTRACT FROM AUTHOR]

Past studies have linked intracellular pathways related to psychotic disorders to the GSK3B enzyme. This study aimed to investigate GSK3B protein expression and phosphorylation in drug-naïve first-episode psychosis patients (n=43) at baseline and following symptom remission, and in healthy controls (n=77). At baseline GSK3B total level was higher in patients (p<0.001). In schizophrenia spectrum patients (n=25) GSK3B total and phosphorylated levels were higher than in controls and patients with other non-affective psychotic disorders (n=18) (p<0.001; p=0.027; p=0.05 respectively). No enzyme changes were found after clinical remission. The implication of this finding for the biology of psychoses warrants further studies to clarify whether increased GSK3B may be useful as a biomarker for psychosis in general, and schizophrenia in particular. [ABSTRACT FROM AUTHOR]

Objectives:Despite progress in identifying molecular pathophysiological processes in schizophrenia, valid biomarkers are lacking for both the disease and treatment response. Methods:This comprehensive review summarises recent efforts to identify molecular mechanisms on the level of protein and gene expression and epigenetics, including DNA methylation, histone modifications and micro RNA expression. Furthermore, it summarises recent findings of alterations in lipid mediators and highlights inflammatory processes. The potential that this research will identify biomarkers of schizophrenia is discussed. Results:Recent studies have not identified clear biomarkers for schizophrenia. Although several molecular pathways have emerged as potential candidates for future research, a complete understanding of these metabolic pathways is required to reveal better treatment modalities for this disabling condition. Conclusions:Large longitudinal cohort studies are essential that pair a thorough phenotypic and clinical evaluation for example with gene expression and proteome analysis in blood at multiple time points. This approach might identify biomarkers that allow patients to be stratified according to treatment response and ideally also allow treatment response to be predicted. Improved knowledge of molecular pathways and epigenetic mechanisms, including their potential association with environmental influences, will facilitate the discovery of biomarkers that could ultimately be effective tools in clinical practice. [ABSTRACT FROM PUBLISHER]

Objective:Schizophrenia is a severe mental disorder and many patients are treated in primary care settings. Apart from the pharmacological management of disease-associated symptoms, the detection and treatment of side effects is of the utmost importance in clinical practice. The purpose of this publication is to offer relevant evidence-based recommendations for the biological treatment of schizophrenia in primary care. Methods:This publication is a short and practice-oriented summary of Parts I–III of the World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia. The recommendations were developed by the authors and consented by a task force of international experts. Guideline recommendations are based on randomized-controlled trials and supplemented with non-randomized trials and meta-analyses where necessary. Results:Antipsychotics of different chemical classes are the first-line pharmacological treatments for schizophrenia. Specific circumstances (e.g., suicidality, depression, substance dependence) may need additional treatment options. The pharmacological and non-pharmacological management of side effects is of crucial importance for the long-term treatment in all settings of the healthcare system. Conclusions:This summary of the three available evidence-based guidelines has the potential to support clinical decisions and can improve treatment of schizophrenia in primary care settings. [ABSTRACT FROM PUBLISHER]

Objectives The enzyme glycogen synthase kinase-3β ( GSK3β) is involved in the mechanisms of action of lithium and may play a role in relation to affective states in bipolar disorder. The objectives of the present study were to compare the activity of GSK-3β (measured as levels of phosphorylated GSK-3β [p- GSK-3β]) between patients with bipolar disorder in the euthymic state and healthy control subjects, and to investigate whether GSK-3β activity varies with affective states in patients with bipolar I disorder. Methods In a prospective 6-12-month follow-up study, we investigated state-specific, intraindividual alterations in the activity of GSK-3β in 60 patients with bipolar I disorder with an acute severe manic index episode and in subsequent euthymic, depressive and manic states and compared this with repeated measurements in healthy control subjects. Data were analyzed using linear mixed-effects models. Results From baseline to the end of follow-up, blood samples were drawn from the 60 patients during 181 affective states, comprising 60 manic, 11 mixed, 23 depressive, and 87 states of euthymia. A total of 69 blood samples were drawn from 35 healthy control subjects, with two samples from the same subject taken three months apart. In mixed-model analysis, p- GSK-3β was decreased in the euthymic state of subjects with bipolar disorder compared with healthy control subjects ( b=0.63, 95% confidence interval [ CI]: 0.42-0.96, P=.03). In addition, p- GSK-3β varied with affective states, being increased in depressive ( b=1.68, 95% CI: 1.08-2.62, P=.02) and mixed ( b=2.07, 95% CI: 1.12-3.84, P=.02) states but not in mania compared with euthymia. Conclusions The activity of GSK-3β is altered in euthymic bipolar disorder compared with healthy control subjects and varies with affective states. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder (MDD) is a highly prevalent, heterogeneous and systemic medical condition. Treatment options are limited, and recent studies have suggested that physical exercise can play an important role in the therapeutics of MDD. The aim of this study was to evaluate the antidepressant efficacy of adjunctive aerobic activity in association with pharmacotherapy (selective serotonin reuptake inhibitor) in symptomatic MDD as well as its association with physiological biomarkers. Methods: In this randomized, single-blind, add-on, controlled clinical trial, 57 patients (18–55 years of age) were followed-up for 28 days. All patients were drug-free, had been diagnosed with symptomatic MDD and received flexible dose of sertraline during the trial. Patients were randomized to either a 4-week program (4x/week) of add-on aerobic exercise (exercise group, N = 29) or no activity (control group, N = 28). Depression severity was assessed using the Hamilton Rating Scale for Depression (HAM-D) as the primary outcome. At baseline and endpoint, all patients underwent a comprehensive metabolic/cardiopulmonary exercise testing—including determination of maximal oxygen uptake (VO2max), VO2 at the second ventilatory threshold (VO2-VT2), and oxygen pulse (O2 pulse). Results: Depression scores significantly decreased in both groups after intervention. Importantly, patients in the aerobic exercise group required lower sertraline dose compared to the control group (sertraline monotherapy). The VO2max and O2 pulse parameters increased over time only in the exercise group and remained unchanged in the control group. Conclusions: The present findings suggest that a 4-week training of aerobic exercise significantly improves functional capacity in patients with MDD and may be associated with antidepressant efficacy. This approach may also decrease the need for higher doses of antidepressants to achieve response. Further studies in unmedicated and treatment-resistant MDD patients are needed in order to confirm the utility of short-term aerobic exercise as an alternative therapeutic approach in MDD. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Objectives Cognitive impairment is a common feature of late-life bipolar disorder ( BD). Yet, there is limited information on the biological mechanisms associated with this process. It is uncertain whether cognitively impaired patients with BD may present the Alzheimer's disease ( AD) bio-signature in the cerebrospinal fluid ( CSF), defined as a combination of low concentrations of the amyloid-beta peptide (Aβ1-42) and high concentrations of total tau (T-tau) and tau phosphorylated at threonine 181 (P-tau). In this study, we sought to determine whether cognitive impairment in elderly patients with BD is associated with the AD CSF bio-signature. Methods Seventy-two participants were enrolled in the study. The test group comprised older adults with BD and mild cognitive impairment ( BD- MCI; n = 16) and the comparison groups comprised patients with dementia due to AD (n = 17), patients with amnestic MCI ( aMCI; n = 14), and cognitively healthy older adults (control group; n = 25). CSF samples were obtained by lumbar puncture and concentrations of Aβ1-42, T-tau and P-tau were determined. Results CSF concentrations of all biomarkers were significantly different in the AD group compared to all other groups, but did not differentiate BD- MCI subjects from aMCI subjects and controls. BD- MCI patients had a non-significant reduction in CSF Aβ1-42 compared to controls, but this was still higher than in the AD group. Concentrations of T-tau and P-tau in BD- MCI patients were similar to those in controls, and significantly lower than those in AD. Conclusions Cognitively impaired patients with BD do not display the so-called AD bio-signature in the CSF. We therefore hypothesize that cognitive deterioration in BD is not associated with the classical pathophysiological mechanisms observed in AD, i.e., amyloid deposition and hyperphosphorylation of microtubule-associated tau protein. [ABSTRACT FROM AUTHOR]

Šios atnaujintos Gairės remiasi Pasaulinės biologinės psichiatrijos draugijų Federacijos (WFSBP) pirmojo leidimo biologinio šizofrenijos gydymo gairėmis, kurios publikuotos 2005 ir 2006 m. Šioje 2015 m. peržiūroje buvo sistemiškai apžvelgtos visos prieinamos publikacijos, susijusios su biologiniu šizofrenijos gydymu, siekiant pateikti įrodymais pagrįstus atnaujinimus. Šios Gairės pateikia įrodymais pagrįstas praktines rekomendacijas, kurios kliniškai ir moksliškai yra patikimos. Jos skirtos visiems gydytojams diagnozuojant arba gydant šizofrenija sergančius pacientus. Remiantis pirmąją Gairių versija, šioms Gairėms atnaujinti atlikta sisteminė apžvalga, taip pat Gairės papildytos duomenimis iš Nacionalinių gairių. Nurodyta literatūra buvo vertinama remiantis patikimais veiksmingumo įrodymais ir vėliau sugrupuota į šešis įrodymo lygius (A-F) ir penkis rekomendacijos lygius (1-5). Ši atnaujintų Gairių 3-ioji dalis apima valdymą esant šioms gydymo aplinkybėms: komorbidinė depresija, polinkis į savižudybę, įvairūs komorbidiniai sutrikimai vartojant psichoaktyviąsias medžiagas (legalius ir nelegalius medikamentus), nėštumas ir maitinimas krūtimi. Šios Gairės pirmiausia yra susijusios su pacientų, sergančių šizofrenija, biologiniu gydymu (apimant antipsichozinius vaistus arba kitas farmakologinio gydymo galimybes). [ABSTRACT FROM AUTHOR]

Background The cytokine hypothesis of depression postulates that the pathophysiology of this illness incorporates an increased production of pro-inflammatory cytokines, which leads to an over-activation of the hypothalamic–pituitary–adrenal axis as well as monoaminergic disturbances. Nevertheless, it remains unclear whether the amelioration of depressive symptoms could decrease cytokine levels. Notwithstanding antidepressant drug therapy might exert anti-inflammatory effects, the effects of non-invasive neuromodulatory approaches like transcranial direct current stimulation (tDCS) on pro-inflammatory cytokine networks are largely unknown. Methods We evaluated, in the Sertraline vs. Electric Current Therapy for Treating Depression Clinical Study (SELECT-TDCS) trial, whether the plasma levels of the soluble TNF receptors 1 and 2 (sTNFRs) changed after antidepressant treatment in a sample of 73 antidepressant-free patients with unipolar depressive disorder in an episode of at least moderate intensity. Results Although both tDCS and sertraline exerted antidepressant effects, the plasma levels of sTNFRs did not change over time regardless of the intervention and clinical response. Also, baseline sTNFRs levels did not predict antidepressant response. Limitations Our negative findings could be a type II error, as this trial did not use an equivalence design. Conclusions To conclude, in this novel placebo-controlled trial prospectively evaluating the changes of sTNFRs in depressed patients, we found that these molecules are not surrogate biomarkers of treatment response of tDCS, whose antidepressant effects occurred regardless of normalization of immunological activity. [ABSTRACT FROM AUTHOR]

Several lines of evidence suggest a role for mitochondrial dysfunction in the pathophysiology of bipolar disorder (BD). The tricarboxylic acid cycle (TCA cycle) is fundamental for mitochondrial energy production and produces substrates used in oxidative phosphorylation by the mitochondrial electron transport chain. The activity of the key TCA cycle enzymes citrate synthase, malate dehydrogenase, and succinate dehydrogenase has never been evaluated in BD. In the present study, these enzymes were assayed from leukocytes of drug-naïve BD patients in a major depressive episode ( n = 18) and compared to 24 age-matched healthy controls. Drug-naïve BD patients did not show differences in activities of citrate synthase ( p = 0.79), malate dehydrogenase ( p = 0.17), and succinate dehydrogenase ( p = 0.35) compared with healthy controls. No correlation between any TCA cycle enzyme activity and severity of depressive symptoms was observed. Overall, these data suggest that the activities of the TCA cycle enzymes are not altered in major depressive episodes of recent-onset BD, which may support the concept of illness staging and neuroprogression in BD. [ABSTRACT FROM AUTHOR]

Objective: To assess the relationship between cognitive function, a proposed schizophrenia endophenotype, and two genetic polymorphisms related to dopamine function, catechol-O-methyl transferase (COMT) Val158Met and dopamine receptor 3 (DRD3) Ser9Gly. Methods: Fifty-eight outpatients with schizophrenia/schizoaffective disorder and 88 healthy controls underwent neurocognitive testing and genotyping. Analyses of covariance (ANCOVAs) using age, sex, and years of education as covariates compared cognitive performance for the proposed genotypes in patients and controls. ANCOVAs also tested for the epistatic effect of COMT and DRD3 genotype combinations on cognitive performance. Results: For executive functioning, COMT Val/Val patients performed in a similar range as controls (30.70-33.26 vs. 35.53-35.67), but as COMT Met allele frequency increased, executive functioning worsened. COMT Met/Met patients carrying the DRD3 Ser/Ser genotype performed poorest (16.184 vs. 27.388-31.824). Scores of carriers of this COMT/DRD3 combination significantly differed from all DRD3 Gly/Gly combinations (p < 0.05), from COMT Val/Met DRD3 Ser/Gly (p = 0.02), and from COMT Val/Val DRD3 Ser/Ser (p = 0.01) in patients. It also differed significantly from all control scores (p < 0.001). Conclusion: Combined genetic polymorphisms related to dopamine neurotransmission might influence executive function in schizophrenia. Looking at the effects of multiple genes on a single disease trait (epistasis) provides a comprehensive and more reliable way to determine genetic effects on endophenotypes. [ABSTRACT FROM AUTHOR]