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Although neurocognitive deficit is the best-recognized indicator of Alzheimer’s disease (AD), psychotic and other noncognitive symptoms are the prime cause of institutionalization. BACE1 is the rate-limiting enzyme in the production of Aβ of AD, and one of the promising therapeutic targets in countering cognitive decline and amyloid pathology. Changes in BACE1 activity have also emerged to cause significant noncognitive neuropsychiatric symptoms and impairments of circadian rhythms, as evident from clinical trials and reports in transgenic models. In this study, we consider key characteristics of BACE1 with its contribution to neurocognitive deficit and other psychiatric symptoms of AD. We argue that a growing list of noncognitive mental impairments related to pharmacological modulation of BACE1 might present a major obstacle in clinical translation of emerging therapeutic leads targeting this protease. The adverse effects of BACE1 inhibition on mental health call for a revision of treatment strategies that assume indiscriminate inhibition of this key protease, and stress the need for further mechanistic and translational studies.

BackgroundPositive symptoms are a useful predictor of aggression in schizophrenia. Although a similar pattern of abnormal brain structures related to both positive symptoms and aggression has been reported, this observation has not yet been confirmed in a single sample.MethodTo study the association between positive symptoms and aggression in schizophrenia on a neurobiological level, a prospective meta-analytic approach was employed to analyze harmonized structural neuroimaging data from 10 research centers worldwide. We analyzed brain MRI scans from 902 individuals with a primary diagnosis of schizophrenia and 952 healthy controls.ResultsThe result identified a widespread cortical thickness reduction in schizophrenia compared to their controls. Two separate meta-regression analyses revealed that a common pattern of reduced cortical gray matter thickness within the left lateral temporal lobe and right midcingulate cortex was significantly associated with both positive symptoms and aggression.ConclusionThese findings suggested that positive symptoms such as formal thought disorder and auditory misperception, combined with cognitive impairments reflecting difficulties in deploying an adaptive control toward perceived threats, could escalate the likelihood of aggression in schizophrenia.

BackgroundThe aim of the current study was to explore the effect of gender, age at onset, and duration on the long-term course of schizophrenia.MethodsTwenty-nine centers from 25 countries representing all continents participated in the study that included 2358 patients aged 37.21 ± 11.87 years with a DSM-IV or DSM-5 diagnosis of schizophrenia; the Positive and Negative Syndrome Scale as well as relevant clinicodemographic data were gathered. Analysis of variance and analysis of covariance were used, and the methodology corrected for the presence of potentially confounding effects.ResultsThere was a 3-year later age at onset for females (P P P P = .001). No significant effects were found concerning duration of illness.DiscussionOur results confirmed a later onset and a possibly more benign course and outcome in females. Age at onset manifested a single peak in both genders, and surprisingly, earlier onset was related to a slower progression of the illness. No effect of duration has been detected. These results are partially in accord with the literature, but they also differ as a consequence of the different starting point of our methodology (a novel staging model), which in our opinion precluded the impact of confounding effects. Future research should focus on the therapeutic policy and implications of these results in more representative samples.

Tuberous sclerosis complex (TSC) is a genetic disorder characterized by frequent noncancerous neoplasia in the brain, which can induce a range of severe neuropsychiatric symptoms in humans, resulting from out of control tissue growth. The causative spontaneous loss-of-function mutations have been also identified in rats. Herein, we studied histopathological and molecular changes in brain lesions of the Eker rat model carrying germline mutation of the tsc2 gene, predisposed to multiple neoplasias. Predominant subcortical tumors were analyzed, along with a rare form occurring within the pyriform lobe. The uniform composition of lesions supports the histochemical parity of malformations, with immunofluorescence data supporting their neuro-glial origin. Massive depletion of mature neurons and axonal loss were evident within lesions, with occasional necrotic foci implying advanced stage of pathology. Enrichment of mesenchymal-derived cell markers with hallmarks of neurogenesis and active microglia imply enhanced cell proliferation, with local immune response. The depletion of capillaries within the core was complemented by the formation of dense mesh of nascent vessels at the interface of neoplasia with healthy tissue, implying large-scale vascular remodeling. Taken as a whole, these findings present several novel features of brain tumors in Eker rat model, rendering it suitable for studies of the pathobiology and progression of primary brain tumors, with therapeutic interventions. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-019-00812-6) contains supplementary material, which is available to authorized users.

Methamphetamine is a potent and highly addictive psychostimulant, and one of the most widely used illicit drugs. Over recent years, its global usage and seizure have been on a rapid rise, with growing detrimental effects on mental and physical health, and devastating psychosocial impact pressing for intervention. Among the unwanted effects of methamphetamine, acute and long-term sleep impairments are of major concern, posing a significant therapeutic challenge, and a cause of addiction relapse. Unraveling mechanisms and functional correlates of methamphetamine-related sleep and circadian disruption are, therefore, of key relevance to translational and clinical psychiatry. In this article, we review the mounting evidence for the acute and long-term impairements of sleep–wake behavior and circadian activity caused by single or recurring methamphetamine usage and withdrawal. Factors contributing to the severity of sleep loss and related cognitive deficit, with risks of relapse are discussed. Key molecular players mediating methamphetamine-induced dopamine release and neuromodulation are considered, with wake-promoting effects in mesolimbic circuits. The effects on various sleep phases and related changes in dopamine levels in selected subcortical structures are reviewed and compared to other psychostimulants with similar action mechanisms. A critical appraisal is presented of the therapeutic use of modafinil, countering sleep, and circadian rhythm impairments. Finally, emerging knowledge gaps and methodical limitations are highlighted along with the areas for future research and therapeutic translation.

Ever since its first use in surgery, general anesthesia has been regarded as a medical miracle enabling countless life-saving diagnostic and therapeutic interventions without pain sensation and traumatic memories. Despite several decades of research, there is a lack of understanding of how general anesthetics induce a reversible coma-like state. Emerging evidence suggests that even brief exposure to general anesthesia may have a lasting impact on mature and especially developing brains. Commonly used anesthetics have been shown to destabilize dendritic spines and induce an enhanced plasticity state, with effects on cognition, motor functions, mood, and social behavior. Herein, we review the effects of the most widely used general anesthetics on dendritic spine dynamics and discuss functional and molecular correlates with action mechanisms. We consider the impact of neurodevelopment, anatomical location of neurons, and their neurochemical profile on neuroplasticity induction, and review the putative signaling pathways. It emerges that in addition to possible adverse effects, the stimulation of synaptic remodeling with the formation of new connections by general anesthetics may present tremendous opportunities for translational research and neurorehabilitation.

Aim: The purpose of this paper is to establish measurement properties of the Quality of Life Enjoyment and Satisfaction Questionnaire short form (Q-LES-Q-SF) employing the Rasch Masters Partial Credit Model. Patients and methods: Consecutive patients with neuropathy (N = 1,301) were interviewed by 86 out patient care neurologists. The physicians recorded patient's gender, age, education, main and associated diagnosis, length of main disease, the Clinical Global Impression (CGI)-Severity scale, and patients filled in the Q-LES-Q-SF questionnaire. Results: The findings establish that a) the instrument is unidimensional; b) 5-point scale categories progress monotonically; c) the construct "quality of life" was adequately operationalized; d) there was neither floor nor ceiling effect; e) the scale is adequately well targeted; f) there was no differential item functioning found from the viewpoint of gender, age and CGI with exception of the item reflecting sexual drive, interest and/or performance - older patients were less satisfied with their sexual life. Conclusions: Our analysis brought reliable evidence that the Q-LES-Q-SF questionnaire satisfactorily approximates resemblance between theoretical expectations of the Rasch model and our data, and that the instrument appears to be a reliable instrument for assessment of wellbeing in patients with neuropathy.

The reinstatement and revision of abandoned therapeutic ventures of the past has been an integral part of medical research and advancement. In psychiatry, much interest was generated recently by emerging data on the use of faecal supplements for restoring the neurochemical balance in the brain, and on the ingestion of placenta to stabilize neural circuits disrupted by childbirth-related hormonal changes. Herein, we consider the emerging scientific evidence and socio-cultural prerequisites favouring the re-entry of these heterodox customs, which are reminiscent of widespread instinctive behaviours in wildlife, into modern healthcare. We explore their evolutionary background and adaptive significance, and consider mechanisms of therapeutic benefits. Finally, we reflect on emerging opportunities and challenges, which present clues towards better prevention and treatment of major neuropsychiatric disorders.

Vitamin D supplementation reduced the risk of acute respiratory tract infection in two meta-analyses. Mendelian randomization shows a causal effect of low vitamin D on bacterial pneumonias risk. These studies involved patients before COVID-19 pandemic. Several association studies found higher incidence of SARS-CoV-2 positivity, greater COVID-19 severity and higher risk of mortality in vitamin D deficient subjects compared to vitamin D non-deficient controls. We draw attention to the trend of inverse relative COVID-19 mortality in Europe versus the states of the Southern Hemisphere (Australia, Brazil, South Africa) in dependence on season, which may be associated with intensity of ultraviolet radiation and consequent seasonal fluctuation of serum vitamin D levels. Although we cannot yet confirm causal role of vitamin D in SARS-CoV-2 positivity or COVID-19, we recommend consumption of vitamin D rich food or vitamin D supplementation in the non-sunny season to prevent vitamin D deficiency.

Overdose with medications is a common method of suicide. Reviews of suicide prevention strategies confirmed that restricting access to lethal means is effective in preventing suicides. Nevertheless, there have not been any randomized controlled trials, proving that restriction of the access to toxic medications decreases suicide rates. Existing evidence is based mainly on observational, ecological, and cohort studies. Factors such as better mental health conditions, effective treatment of depression, and improvement in socioeconomic status, may also contribute to decreasing suicide rates. Restrictive measures will have a large effect if the respective method is frequent and lethal. Although there are some concerns about substitution of suicide methods if access to a specific drug is restricted, many studies suggest a life-saving potential. Restrictive measures represent an effective and feasible public health strategy for suicide prevention, particularly in individuals that carry out briefly planned impulsive acts, and in combination with other interventions.

Tuberous sclerosis complex (TSC) is a dominant autosomal genetic disorder caused by loss-of-function mutations in TSC1 and TSC2, which lead to constitutive activation of the mammalian target of rapamycin C1 (mTORC1) with its decoupling from regulatory inputs. Because mTORC1 integrates an array of molecular signals controlling protein synthesis and energy metabolism, its unrestrained activation inflates cell growth and division, resulting in the development of benign tumors in the brain and other organs. In humans, brain malformations typically manifest through a range of neuropsychiatric symptoms, among which mental retardation, intellectual disabilities with signs of autism, and refractory seizures, which are the most prominent. TSC in the rat brain presents the first-rate approximation of cellular and molecular pathology of the human brain, showing many instructive characteristics. Nevertheless, the developmental profile and distribution of lesions in the rat brain, with neurophysiological and behavioral manifestation, deviate considerably from humans, raising numerous research and translational questions. In this study, we revisit brain TSC in human and Eker rats to relate their histopathological, electrophysiological, and neurobehavioral characteristics. We discuss shared and distinct aspects of the pathology and consider factors contributing to phenotypic discrepancies. Given the shared genetic cause and molecular pathology, phenotypic deviations suggest an incomplete understanding of the disease. Narrowing the knowledge gap in the future should not only improve the characterization of the TSC rat model but also explain considerable variability in the clinical manifestation of the disease in humans. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-020-01000-7.

Altres ajuts: SRB: The Australian Schizophrenia Research Bank (ASRB) was supported by the National Health and Medical Research Council of Australia (NHMRC) (Enabling Grant, ID 386500), the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation and the Schizophrenia Research Institute. Chief Investigators for ASRB were Carr, V., Schall, U., Scott, R., Jablensky, A., Mowry, B., Michie, P., Catts, S., Henskens, F., Pantelis, C. We thank Loughland, C., the ASRB Manager, and acknowledge the help of Jason Bridge for ASRB database queries. CP was supported by NHMRC Senior Principal Research Fellowships (IDs: 628386 & 1105825); GC was supported by the Schizophrenia Research Institute utilizing infrastructure funding from the New South Wales Ministry of Health and New South Wales Ministry of Trade and Investment (Australia); JMF was supported by NHMRC project grant (1063960) and the Janette Mary O'Neil Research Fellowship; MJG was supported by NHMRC as an R.D. Wright Biomedical Career Development Fellow (1061875). MJC was supported by NHMRC Senior Research Fellowship (1121474). CASSI: CSW is funded by the NSW Ministry of Health, Office of Health and Medical Research. CSW is a recipient of a National Health and Medical Research Council (Australia) Principal Research Fellowship (PRF) (#1117079). CIAM: The CIAM study (FMH - PI) was supported by the University Research Committee, University of Cape Town and South African funding bodies National Research Foundation and Medical Research Council. COBRE: The COBRE dataset and investigators were supported by NIH grants R01EB006841 & P20GM103472, as well as NSF grant 1539067. JT (senior author) and VDC are supported by 5R01MH094524. JMS is supported by R01 AA021771 and P50 AA022534. EONCKS: This work was supported by a New Partnership for Africa's Development (NEPAD) grant through the Department of Science and Technology of South Africa, the Medical Research Council of South Africa (grant number 65174). ESO: The ESO study was funded by NPU I - LO1611 and Ministry of Health, Czech Republic - Conceptual Development of Research Organization 00023001 (IKEM). FIDMAG/Project: This work was supported by the Catalan Government and several grants from the Instituto de Salud Carlos III and co-funded by European Union (ERDF/ESF, 'Investing in your future'): Miguel Servet Research Contracts and Research Project Grants. FOR2107 Marburg: The FOR2107 Marburg study was funded by the German Research Foundation (DFG), Tilo Kircher (speaker FOR2107; DFG grant numbers KI588/14-1, KI588/14-2), Axel Krug (KR 3822/5-1, KR 3822/7-2), Igor Nenadic (NE 2254/1-2), Carsten Konrad (KO 4291/3-1). FOR2107 Muenster: The FOR2107 Muenster study was funded by the German Research Foundation (DFG, grant FOR2107 DA1151/5-1 and DA1151/5-2 to UD) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 to UD). TH was supported by grants from the German Research Foundation (DFG grants HA7070/2-2, HA7070/3, HA7070/4). Frankfurt: MRI was performed at the Frankfurt Brain Imaging Center, supported by the German Research Council (DFG) and the German Ministry for Education and Research (BMBF; Brain Imaging Center Frankfurt/Main, DLR 01GO0203). GIPSI: This study was supported by Colciencias PRISMA-U.T. Huilong1 & Huilong2: This study was funded by the National Natural Science Foundation of China (81761128021; 31671145; 81401115; 81401133), Beijing Municipal Science and Technology Commission grant (Z141107002514016) and Beijing Natural Science Foundation(7162087, Beijing Municipal Administration of Hospitals Clinical medicine Development of special funding (XMLX201609; zylx201409). IGP: This study was funded by Project Grants from the Australian National Health and Medical Research Council of Australia (NHMRC; APP630471 and APP1081603), the Macquarie University's Australian Research Council Centre of Excellence in Cognition and its Disorders (CE110001021). Johns Hopkins: Supported by National Institutes of Health Grant Nos. MH-092443, MH-094268 (Silvio O. Conte Center), MH-105660, and MH-107730; foundation grants from Stanley, RUSK/S-R, and NARSAD/Brain and Behavior Research Foundation. Madrid: Supported by the Spanish Ministry of Science, Innovation and Universities, Instituto de Salud Carlos III, co-financed by ERDF Funds from the European Commission, "A way of making Europe", CIBERSAM. Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds and European Union Seventh Framework Program and H2020 Program; Fundación Familia Alonso, Fundación Alicia Koplowitz and Fundación Mutua Madrileña. MPRC1 & MPRC2: Support was received from NIH grants U01MH108148, 2R01EB015611, R01MH112180, R01DA027680, R01MH085646, P50MH103222 and T32MH067533, a State of Maryland contract (M00B6400091) and NSF grant (1620457). OLIN: The Olin study was supported by NIH grants R37MH43375 and R01MH074797. Oxford: The Oxford study MRC G0500092. SLF Rome: Support from the Italian Ministry of Health grants RC-12-13-14-15-16-17-18-19/A. RSCZ: RSCZ data collection was supported by RFBR 15-06-05758 grant. SCORE: This study was supported in part by grant 3232BO_119382 from the Swiss National Science Foundation. We thank the FePsy (Frueherkennung von Psychosen; early detection of psychosis) Study Group from the University of Basel, Department of Psychiatry, Switzerland, for the recruitment of the study participants. The FePsy Study was supported in part by grant No. SNF 3200-057216/1, ext./2, ext./3. Singapore: This study was supported by research grants from the National Healthcare Group, Singapore (SIG/05004; SIG/11003), and the Singapore Bioimaging Consortium (RP C-009/2006) research grants awarded to KS. SNUH: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (Grant no. 2013R1A2A1A03071089 and 2017M3C7A1029610). UCISZ: The UCISZ study was supported by the National Institutes of Mental Health grant number R21MH097196 to TGMvE. UCISZ data were processed by the UCI High Performance Computing cluster supported by Joseph Farran, Harry Mangalam, and Adam Brenner and the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1 TR000153. UNIBA: The UNIBA study was supported by grant funding from the Italian Ministry of Health (PE-2011-02347951). UNIMAAS: The study was supported by Dutch Organization for Health Research and Development (ZonMw 91112002) and a personal grant to Thérèse van Amelsvoort (ZonMw-VIDI: 91712394). The data was collected in a clinical trial registered in the Dutch clinical trial registry under ID: NTR5094 (http://www.trialregister.nl). UPenn: This study was supported by the National Institute of Mental Health grants MH064045, MH 60722, MH019112, MH085096 (DHW), and R01MH112847 (RTS and TDS). Zurich: This study was supported by the Swiss National Science Foundation (105314_140351 to S.K.). Matthias Kirschner acknowledges support from the National Bank Fellowship (McGill University) and the Swiss National Foundation (P2SKP3_178175). Research reported in this publication was also supported by the following National Institutes of Health grants: U54 EB020403 to PMT, R01 MH116147, U24 RR21992, R21MH097196, and TR000153 to TGMvE, S10 OD023696 and R01EB015611 to PK, T32 AG058507and 5T32 MH073526 to CRKC, R01 MH117601 to NJ, ENIGMA's NIH Big Data to Knowledge (BD2K) initiative U54 EB020403, ENIGMA Sex Differences R01MH116147, and ENIGMA-COINSTAC: Advanced World-wide Transdiagnostic Analysis of Valence System Brain Circuits R01MH121246. A common limitation of neuroimaging studies is their small sample sizes. To overcome this hurdle, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium combines neuroimaging data from many institutions worldwide. However, this introduces heterogeneity due to different scanning devices and sequences. ENIGMA projects commonly address this heterogeneity with random-effects meta-analysis or mixed-effects mega-analysis. Here we tested whether the batch adjustment method, ComBat, can further reduce site-related heterogeneity and thus increase statistical power. We conducted random-effects meta-analyses, mixed-effects mega-analyses and ComBat mega-analyses to compare cortical thickness, surface area and subcortical volumes between 2897 individuals with a diagnosis of schizophrenia and 3141 healthy controls from 33 sites. Specifically, we compared the imaging data between individuals with schizophrenia and healthy controls, covarying for age and sex. The use of ComBat substantially increased the statistical significance of the findings as compared to random-effects meta-analyses. The findings were more similar when comparing ComBat with mixed-effects mega-analysis, although ComBat still slightly increased the statistical significance. ComBat also showed increased statistical power when we repeated the analyses with fewer sites. Results were nearly identical when we applied the ComBat harmonization separately for cortical thickness, cortical surface area and subcortical volumes. Therefore, we recommend applying the ComBat function to attenuate potential effects of site in ENIGMA projects and other multi-site structural imaging work. We provide easy-to-use functions in R that work even if imaging data are partially missing in some brain regions, and they can be trained with one data set and then applied to another (a requirement for some analyses such as machine learning).

Schizophrenia is a chronic neuropsychiatric brain disorder that has devastating personal impact and rising healthcare costs. Dysregulation of glutamatergic neurotransmission has been implicated in the pathobiology of the disease, attributed largely to the hypofunction of the N-methyl-d-aspartate (NMDA) receptor. Currently, there is a major gap in mechanistic analysis as to how endogenous modulators of the NMDA receptors contribute to the onset and progression of the disease. We present a systematic review of the neurobiology and the role of endogenous NMDA receptor antagonists in animal models of schizophrenia, and in patients. We discuss their neurochemical origin, release from neurons and glia with action mechanisms, and functional effects, which might contribute toward the impairment of neuronal processes underlying this complex pathological state. We consider clinical evidence suggesting dysregulations of endogenous NMDA receptor in schizophrenia, and highlight the pressing need in future studies and emerging directions, to restore the NMDA receptor functions for therapeutic benefits.

One of the major neuropeptide groups in insects is adipokinetic hormone/red pigment-concentrating hormone (AKH/RPCH) family of peptides. AKH had improving effects on depression and anxiety in animal models and it may be a new treatment choice in these disorders. Aim of this study was to investigate effects of Anax imperator AKH (Ani-AKH), Libellula auripennis AKH (Lia-AKH) and Phormia-Terra hypertrehalosemic hormone (Pht-HrTH) on animal behavior in olfactory bulbectomy (OBX) model and in posttraumatic stress disorder (PTSD) model of Wistar-albino rats. Lia-AKH and Pht-HrTH significantly increased time spent in escape platform's quadrant compared to sham control while Lia-AKH significantly increased time spent in escape platform's quadrant compared to OBX controls in probe trial of Morris water maze (MWM). Ani-AKH, Lia-AKH and Pht-HrTH significantly decreased immobility time compared to OBX controls in forced swimming test (FST). Pht-HrTH significantly increased %open arm time compared to OBX controls in elevated plus maze (EPM) test. Ani-AKH significantly increased %open arm entry compared to sham control while Ani-AKH and Pht-HrTH significantly increased %open arm entry compared to OBX controls in EPM. In PTSD study Ani-AKH and Lia-AKH significantly decreased immobility time compared to traumatized controls in FST. In acoustic startle reflex test, Ani-AKH, Lia-AKH and Pht-HrTH significantly decreased average startle amplitude compared to non-traumatized controls in PTSD study. Metabolomic studies showed that AKH may affect glutamatergic and dopaminergic system and neurochemistry. In conclusion, AKH peptides had wide ranging effects on behavior and improved performance in OBX and PTSD models in rats.

OBJECTIVESchizophrenia has recently been associated with widespread white matter microstructural abnormalities, but the functional effects of these abnormalities remain unclear. Widespread heterogeneity of results from studies published to date preclude any definitive characterization of the relationship between white matter and cognitive performance in schizophrenia. Given the relevance of deficits in cognitive function to predicting social and functional outcomes in schizophrenia, the authors carried out a meta-analysis of available data through the ENIGMA Consortium, using a common analysis pipeline, to elucidate the relationship between white matter microstructure and a measure of general cognitive performance, IQ, in patients with schizophrenia and healthy participants.METHODSThe meta-analysis included 760 patients with schizophrenia and 957 healthy participants from 11 participating ENIGMA Consortium sites. For each site, principal component analysis was used to calculate both a global fractional anisotropy component (gFA) and a fractional anisotropy component for six long association tracts (LA-gFA) previously associated with cognition.RESULTSMeta-analyses of regression results indicated that gFA accounted for a significant amount of variation in cognition in the full sample (effect size [Hedges' g]=0.27, CI=0.17-0.36), with similar effects sizes observed for both the patient (effect size=0.20, CI=0.05-0.35) and healthy participant groups (effect size=0.32, CI=0.18-0.45). Comparable patterns of association were also observed between LA-gFA and cognition for the full sample (effect size=0.28, CI=0.18-0.37), the patient group (effect size=0.23, CI=0.09-0.38), and the healthy participant group (effect size=0.31, CI=0.18-0.44).CONCLUSIONSThis study provides robust evidence that cognitive ability is associated with global structural connectivity, with higher fractional anisotropy associated with higher IQ. This association was independent of diagnosis; while schizophrenia patients tended to have lower fractional anisotropy and lower IQ than healthy participants, the comparable size of effect in each group suggested a more general, rather than disease-specific, pattern of association.

BackgroundThe aim of the current study was to explore the changing interrelationships among clinical variables through the stages of schizophrenia in order to assemble a comprehensive and meaningful disease model.MethodsTwenty-nine centers from 25 countries participated and included 2358 patients aged 37.21 ± 11.87 years with schizophrenia. Multiple linear regression analysis and visual inspection of plots were performed.ResultsThe results suggest that with progression stages, there are changing correlations among Positive and Negative Syndrome Scale factors at each stage and each factor correlates with all the others in that particular stage, in which this factor is dominant. This internal structure further supports the validity of an already proposed four stages model, with positive symptoms dominating the first stage, excitement/hostility the second, depression the third, and neurocognitive decline the last stage.ConclusionsThe current study investigated the mental organization and functioning in patients with schizophrenia in relation to different stages of illness progression. It revealed two distinct “cores” of schizophrenia, the “Positive” and the “Negative,” while neurocognitive decline escalates during the later stages. Future research should focus on the therapeutic implications of such a model. Stopping the progress of the illness could demand to stop the succession of stages. This could be achieved not only by both halting the triggering effect of positive and negative symptoms, but also by stopping the sensitization effect on the neural pathways responsible for the development of hostility, excitement, anxiety, and depression as well as the deleterious effect on neural networks responsible for neurocognition.

The disproportionate evolutionary expansion of the human cerebral cortex with reinforcement of cholinergic innervations warranted a major rise in the functional and metabolic load of the conserved basal forebrain (BF) cholinergic system. Given that acetylcholine (ACh) regulates properties of the microtubule-associated protein (MAP) tau and promotes non-amyloidogenic processing of amyloid precursor protein (APP), growing neocortex predicts higher demands for ACh, while the emerging role of BF cholinergic projections in Aβ clearance infers greater exposure of source neurons and their innervation fields to amyloid pathology. The higher exposure of evolutionary most recent cortical areas to the amyloid pathology of Alzheimer's disease (AD) with synaptic impairments and atrophy, therefore, might involve attenuated homeostatic effects of BF cholinergic projections, in addition to fall-outs of inherent processes of expanding association areas. This unifying model, thus, views amyloid pathology and loss of cholinergic cells as a quid pro quo of the allometric evolution of the human brain, which in combination with an increase in life expectancy overwhelm the fine homeostatic balance and trigger the disease process.

The substantial non-response rate in depressive patients indicates a continuing need to identify predictors of treatment outcome. The aim of this 6-week, open-label study was (1) to compare the efficacy of a priori defined predictors: ≥20% reduction in MADRS score at week 1, ≥20% reduction in MADRS score at week 2 (RM ≥ 20% W2), decrease of cordance (RC), and increase of serum and plasma level of brain-derived neurotrophic factor at week 1; and (2) to assess whether their combination yields higher efficacy in the prediction of response to selective serotonin re-uptake inhibitors (SSRIs) than when used singly. Twenty-one patients (55%) achieved a response to SSRIs. The RM ≥20% W2 (areas under curve-AUC = 0.83) showed better predictive efficacy compared to all other predictors with the exception of RC. The identified combined model (RM ≥ 20% W2 + RC), which predicted response with an 84% accuracy (AUC = 0.92), may be a useful tool in the prediction of response to SSRIs.

Quality indicators are vital for monitoring the transformation of institution-based mental health services towards the provision of person-centered mental healthcare. While several mental healthcare quality indicators have been identified as relevant and valid, their actual usability and utility for routine monitoring healthcare quality over time is significantly determined by the availability and trustworthiness of the underlying data. In this feasibility study, quality indicators that have been systematically identified for use in the Danube region countries of Bulgaria, the Czech Republic, Hungary, and Serbia were measured on the basis of existing mental healthcare data in the four countries. Data were collected retrospectively by means of the best available, most standardized, trustworthy, and up-to-date data in each country. Out of 21 proposed quality indicators, 18 could be measured in Hungary, 17 could be measured in Bulgaria and in the Czech Republic, and 8 could be measured in Serbia. The results demonstrate that a majority of quality indicators can be measured in most of the countries by means of already existing data, thereby demonstrating the feasibility of quality measurement and regular quality monitoring. However, data availability and usability are scattered across countries and care sectors, which leads to variations in the quality of the quality indicators themselves. Making the planning and outputs of national mental healthcare reforms more transparent and evidence-based requires (trans-)national standardization of healthcare quality data, their routine availability and standardized assessment, and the regular reporting of quality indicators.

Throughout development, neuronal progenitors undergo complex transformation into polarized nerve cells, warranting the directional flow of information in the neural grid. The majority of neuronal polarization studies have been carried out on rodent-derived precursor cells, programmed to develop into neurons. Unlike rodent neuronal cells, SH-SY5Y cells derived from human bone marrow present a sub-clone of neuroblastoma line, with their transformation into neuron-like cells showing a range of highly instructive neurobiological characteristics. We applied two-step retinoic acid (RA) and brain-derived neurotrophic factor (BDNF) protocol to monitor the conversion of undifferentiated SH-SY5Y into neuron-like cells with distinctly polarized axon-dendritic morphology and formation of bona fide synaptic connections. We show that BDNF is a key driver and regulator of the expression of axonal marker tau and dendritic microtubule-associated protein-2 (MAP2), with their sorting to distinct cellular compartments. Using selective kinase inhibitors downregulating BDNF-TrkB signaling, we demonstrate that constitutive activation of TrkB receptor is essential for the maintenance of established polarization morphology. Importantly, the proximity ligation assay applied in our preparation demonstrates that differentiating neuron-like cells develop elaborate synaptic connections enriched with hallmark pre- and postsynaptic proteins. Described herein findings highlight several fundamental processes related to neuronal polarization and synaptogenesis in human-derived cells, which are of major relevance to neurobiology and translational neuroscience.

M.B. is supported by a NHMRC Senior Principal Research Fellowship (APP1059660 and APP1156072). All authors contributed equally., Fountoulakis, K.N., Dragioti, E., Theofilidis, A.T., Wikilund, T., Atmatzidis, X., Nimatoudis, I., Thys, E., Wampers, M., Hranov, L., Hristova, T., Aptalidis, D., Milev, R., Iftene, F., Spaniel, F., Knytl, P., Furstova, P., From, T., Karlsson, H., Walta, M., Salokangas, R.K.R., Azorin, J.-M., Bouniard, J., Montant, J., Juckel, G., Haussleiter, I.S., Douzenis, A., Michopoulos, I., Ferentinos, P., Smyrnis, N., Mantonakis, L., Nemes, Z., Gonda, X., Vajda, D., Juhasz, A., Shrivastava, A., Waddington, J., Pompili, M., Comparelli, A., Corigliano, V., Rancans, E., Navickas, A., Hilbig, J., Bukelskis, L., Injac Stevovic, L., Vodopic, S., Esan, O., Oladele, O., Osunbote, C., Rybakowski, J.Κ., Wojciak, P., Domowicz, K., Figueira, M.L., Linhares, L., Crawford, J., Panfil, A.-L., Smirnova, D., Izmailova, O., Lecic-Tosevski, D., Temmingh, H., Howells, F., Bobes, J., Garcia-Portilla, M.P., García-Alvarez, L., Erzin, G., Karadaǧ, H., De Sousa, A., Bendre, A., Hoschl, C., Bredicean, C., Papava, I., Vukovic, O., Pejuskovic, B., Russell, V., Athanasiadis, L., Konsta, A., Stein, D., Berk, M., Dean, O., Tandon, R., Kasper, S., De Hert, M.

An overview of research activities of National Institute of Mental Health (NIMH) in Klecany, Czech republic. The institute was funded by EU operational project Research and Development for Innovation and started working in 2015. NIMH activities are organized in eight research programs including the neurobiology of the serious mental disorders, social psychiatry, brain imaging and use of information technologies in psychiatric research, epidemiology of addictions, sleep laboratory and chronobiology, electrophysiology, clinical research, and transfer of technologies. The equipment and expertise ranks NIMH Klecany among top neuroscience research institutions in central and eastern Europe.

Deinstitutionalization has not been pursued in the post-communist Europe until recently. The population of psychiatric patients institutionalized in the regional mental hospitals is, however, largely understudied. The aim of this study is to assess discharges of long-term inpatients with schizophrenia from Czech psychiatric hospitals and to analyse re-hospitalizations within this group. The nationwide register of all-cause inpatient hospitalizations was merged with the nationwide register of all-cause deaths on an individual level basis. Descriptive statistics, survival analysis and logistic regression were performed. 3601 patients with schizophrenia previously hospitalized for more than a year were discharged from Czech mental hospitals between 1998 and 2012. This included 260 patients hospitalized for > 20 years. Nearly one fifth (n = 707) of the long-term patients died during the hospitalization; and discharges of 19.36% (n =697) were only administrative in their nature. Out of 2197 truly discharged patients, 14.88% (n = 327) were re-hospitalized within 2 weeks after the discharge. The highest odds of rehospitalization were associated with being discharged against medical advice (OR 5.27, CI: 3.77–7.35, p < 0.001). These data are important for the ongoing mental health care reforms in the Czech Republic and other countries in the Central and Eastern Europe.

Content-based image retrieval method designed for noisy query images.We introduce moment-based invariant functions that are tolerant to noise.Invariant features are both on grayscale and color histograms.Image-retrieval based on invariants outperform other methods. We present a histogram-based image retrieval method which is designed specifically for noisy query images. The images are retrieved according to histogram similarity. To reach high robustness to noise, the histograms are described by newly proposed features which are insensitive to a Gaussian additive noise in the original images. The advantage of the new method is proved theoretically and demonstrated experimentally on real data.

Background: Quality indicators are quality assurance instruments for the evaluation of mental healthcare systems. Quality indicators can be used to measure the effectiveness of mental healthcare structure and process reforms. This project aims to develop quality indicators for mental healthcare systems in Bulgaria, the Czech Republic, Hungary and Serbia to provide monitoring instruments for the transformation of mental healthcare systems in these countries. Methods: Quality indicators for mental healthcare systems were developed in a systematic, multidisciplinary approach. A systematic literature study was conducted to identify quality indicators that are used internationally in mental healthcare. Retrieved quality indicators were systematically selected by means of defined inclusion and exclusion criteria. Quality indicators were subsequently rated in a two-stage Delphi study for relevance, validity and feasibility (data availability and data collection effort). The Delphi panel included 22 individuals in the first round, and 18 individuals in the second and final round. Results: Overall, mental healthcare quality indicators were rated higher in relevance than in validity (Mean relevance=7.6, SD=0.8; Mean validity=7.1, SD=0.7). There was no statistically significant difference in scores between the four countries for relevance (X2(3)=3.581, p=0.310) and validity (X2(3)=1.145, p=0.766). For data availability, the appraisal of “YES” (data are available) ranged from 6% for “assisted housing” to 94% for “total beds for mental healthcare per 100,000 population” and “availability of mental health service facilities”. Conclusion: Quality indicators were developed in a systematic and multidisciplinary development process. There was a broad consensus among mental healthcare experts from the participating countries in terms of relevance and validity of the proposed quality indicators. In a next step, the feasibility of these twenty-two indicators will be evaluated in a pilot study in the participating countries.

Objective Previous studies have demonstrated the efficacy of reduction of prefrontal theta cordance (RC) after 1week of treatment in the prediction of antidepressant response. Our study aimed to compare the ability of RC in the prediction of response to various treatments. Methods In total, 167 inpatients with MDD were treated with various antidepressants and low-frequency rTMS for 4 weeks. The primary efficacy measure was MADRS score, assessed at baseline, weeks − 1, − 2, and at the end of study. The EEG was recorded at baseline and after 1 week. Prefrontal theta cordance was calculated as an average from Fp1, Fp2 and Fz electrodes. Results Logistic regression identified RC as a predictor of response to SSRI, SNRI, NDRI and rTMS but not for NaSSA. Predictive parameters of RC for response to mentioned antidepressant classes were as follows: For SSRI (N = 58), the AUC of ROC analysis yielded value of 0.77, positive predictive value (PPV) of RC at week 1 was 0.81 and negative predictive values (NPV) of RC at week 1 was 0.73. For SNRI (N = 47), the AUC of ROC analysis yielded value of 0.77, PPV of RC at week 1 was 0.72 and NPV of RC at week 1 was 0.84. For NDRI (N = 22), the AUC of ROC analysis yielded value of 0.87, PPV of RC at week 1 was 0.91 and NPV of RC at week 1 was 0.82. For rTMS (N = 25), the AUC of ROC analysis yielded value of 0.75, PPV of RC at week 1 was 0.6 and NPV of RC at week 1 was 1.0. AUC of ROC analysis of RC were not significantly different among antidepressants. Conclusion Prefrontal QEEG cordance is a promising tool predicting the response to various antidepressive interventions. In this study, the predictive efficacy of 1-week reduction of QEEG prefrontal theta cordance for response to SSRI, SNRI, NDRI and rTMS was comparable.

The adipokinetic and red pigment-concentrating hormone (AKH/RPCH) family of peptides controls fat, carbohydrate, and protein metabolism in insects. In our previous study, we showed that AKH possesses antidepressant, anxiolytic, and analgesic effects, causes hyperlocomotion, and exerts neuroprotective effects and increased brain neurotrophic factors in mice. The aim of this study was to investigate the effects of Anax imperator AKH (Ani-AKH), Libellula auripennis AKH (Lia-AKH), and Phormia-Terra hypertrehalosemic hormone (Pht-HrTH) on MK-801-induced memory deterioration in the active allothetic place avoidance test (AAPA) and MK-801-induced sensorimotor gating deficit in the prepulse inhibition test (PPI). In the AAPA task, Long-Evans rats were treated with Ani-AKH (2 mg/kg), Lia-AKH (2 mg/kg), Pht-HrTH (2 mg/kg), MK-801 (0.15 mg/kg), and the combination of MK-801 with the hormones subchronically. In the prepulse inhibition test, Wistar albino rats were treated with Ani-AKH (1 mg/kg), Lia-AKH (1 mg/kg), Pht-HrTH (1 mg/kg), MK-801 (0.1 mg/kg), or the combination of MK-801 with hormones acutely before the test. In our study, Ani-AKH (2 mg/kg), Lia-AKH (2 mg/kg), and Pht-HrTH (2 mg/kg) reversed MK-801 (0.15 mg/kg)-induced cognitive memory impairment effects in the AAPA task. Lia-AKH (1 mg/kg) significantly potentiated the MK-801-induced PPI disruption, while Ani-AKH (1 mg/kg) partially potentiated the impairment caused by MK-801, and Pht-HrTH did not modify the effect of MK-801. In conclusion, AKH had no effect in sensorimotor gating deficits in the PPI test in schizophrenia model while AKH improved memory in the schizophrenia model of MK-801.

Brain imaging is of limited diagnostic use in psychiatry owing to clinical heterogeneity and low sensitivity/specificity of between-group neuroimaging differences. Machine learning (ML) may better translate neuroimaging to the level of individual participants. Studying unaffected offspring of parents with bipolar disorders (BD) decreases clinical heterogeneity and thus increases sensitivity for detection of biomarkers. The present study used ML to identify individuals at genetic high risk (HR) for BD based on brain structure.We studied unaffected and affected relatives of BD probands recruited from 2 sites (Halifax, Canada, and Prague, Czech Republic). Each participant was individually matched by age and sex to controls without personal or family history of psychiatric disorders. We applied support vector machines (SVM) and Gaussian process classifiers (GPC) to structural MRI.We included 45 unaffected and 36 affected relatives of BD probands matched by age and sex on an individual basis to healthy controls. The SVM of white matter distinguished unaffected HR from control participants (accuracy = 68.9%, p = 0.001), with similar accuracy for the GPC (65.6%, p = 0.002) or when analyzing data from each site separately. Differentiation of the more clinically heterogeneous affected familiar group from healthy controls was less accurate (accuracy = 59.7%, p = 0.05). Machine learning applied to grey matter did not distinguish either the unaffected HR or affected familial groups from controls. The regions that most contributed to between-group discrimination included white matter of the inferior/middle frontal gyrus, inferior/middle temporal gyrus and precuneus.Although we recruited 126 participants, ML benefits from even larger samples.Machine learning applied to white but not grey matter distinguished unaffected participants at high and low genetic risk for BD based on regions previously implicated in the pathophysiology of BD.

Psychiatry is that branch of the medical profession, which deals with the origin, diagnosis, prevention, and management of mental disorders or mental illness, emotional and behavioural disturbances. Thus, a psychiatrist is a trained doctor who has received further training in the field of diagnosing and managing mental illnesses, mental disorders and emotional and behavioural disturbances. This EPA Guidance document was developed following consultation and literature searches as well as grey literature and was approved by the EPA Guidance Committee. The role and responsibilities of the psychiatrist include planning and delivering high quality services within the resources available and to advocate for the patients and the services. The European Psychiatric Association seeks to rise to the challenge of articulating these roles and responsibilities. This EPA Guidance is directed towards psychiatrists and the medical profession as a whole, towards other members of the multidisciplinary teams as well as to employers and other stakeholders such as policy makers and patients and their families.

Background Aberrant amygdala reactivity to affective stimuli represents a candidate factor predisposing patients with bipolar disorder (BD) to relapse, but it is unclear to what extent amygdala reactivity is state-dependent. We evaluated the modulatory influence of mood on amygdala reactivity and functional connectivity in patients with remitted BD and healthy controls. Methods Amygdala response to sad versus neutral faces was investigated using fMRI during periods of normal and sad mood induced by autobiographical scripts. We assessed the functional connectivity of the amygdala to characterize the influence of mood state on the network responsible for the amygdala response. Results We included 20 patients with remitted BD and 20 controls in our study. The sad and normal mood exerted opposite effects on the amygdala response to emotional faces in patients compared with controls (F1,38 = 5.85, p = 0.020). Sad mood amplified the amygdala response to sad facial stimuli in controls but attenuated the amygdala response in patients. The groups differed in functional connectivity between the amygdala and the inferior prefrontal gyrus (p ≤ 0.05, family-wise error-corrected) of ventrolateral prefrontal cortex (vlPFC) corresponding to Brodmann area 47. The sad mood challenge increased connectivity during the period of processing sad faces in patients but decreased connectivity in controls. Limitations Limitations to our study included long-term medication use in the patient group and the fact that we mapped only depressive (not manic) reactivity. Conclusion Our results support the role of the amygdala-vlPFC as the system of dysfunctional contextual affective processing in patients with BD. Opposite amygdala reactivity unmasked by the mood challenge paradigm could represent a trait marker of altered mood regulation in patients with BD.

Summary Background Many countries are developing suicide prevention strategies for which up-to-date, high-quality evidence is required. We present updated evidence for the effectiveness of suicide prevention interventions since 2005. Methods We searched PubMed and the Cochrane Library using multiple terms related to suicide prevention for studies published between Jan 1, 2005, and Dec 31, 2014. We assessed seven interventions: public and physician education, media strategies, screening, restricting access to suicide means, treatments, and internet or hotline support. Data were extracted on primary outcomes of interest, namely suicidal behaviour (suicide, attempt, or ideation), and intermediate or secondary outcomes (treatment-seeking, identification of at-risk individuals, antidepressant prescription or use rates, or referrals). 18 suicide prevention experts from 13 European countries reviewed all articles and rated the strength of evidence using the Oxford criteria. Because the heterogeneity of populations and methodology did not permit formal meta-analysis, we present a narrative analysis. Findings We identified 1797 studies, including 23 systematic reviews, 12 meta-analyses, 40 randomised controlled trials (RCTs), 67 cohort trials, and 22 ecological or population-based investigations. Evidence for restricting access to lethal means in prevention of suicide has strengthened since 2005, especially with regard to control of analgesics (overall decrease of 43% since 2005) and hot-spots for suicide by jumping (reduction of 86% since 2005, 79% to 91%). School-based awareness programmes have been shown to reduce suicide attempts (odds ratio [OR] 0·45, 95% CI 0·24–0·85; p=0·014) and suicidal ideation (0·5, 0·27–0·92; p=0·025). The anti-suicidal effects of clozapine and lithium have been substantiated, but might be less specific than previously thought. Effective pharmacological and psychological treatments of depression are important in prevention. Insufficient evidence exists to assess the possible benefits for suicide prevention of screening in primary care, in general public education and media guidelines. Other approaches that need further investigation include gatekeeper training, education of physicians, and internet and helpline support. The paucity of RCTs is a major limitation in the evaluation of preventive interventions. Interpretation In the quest for effective suicide prevention initiatives, no single strategy clearly stands above the others. Combinations of evidence-based strategies at the individual level and the population level should be assessed with robust research designs. Funding The Expert Platform on Mental Health, Focus on Depression, and the European College of Neuropsychopharmacology.

BACKGROUND Agomelatine was efficacious in reducing symptoms in a short-term placebo-controlled trial in generalized anxiety disorder (GAD) and in preventing relapse in a longer term placebo-controlled study. An additional short-term placebo-controlled study is required by regulatory agencies to confirm the efficacy of agomelatine in GAD. METHOD This 12-week, placebo-controlled, double-blind, randomized, parallel group, international, multicenter study was designed to confirm the efficacy of agomelatine 25-50 mg/d in the treatment of patients with a primary DSM-IV-TR diagnosis of GAD. The primary outcome measure was the Hamilton Anxiety Rating Scale (HARS) total score. Assay sensitivity was evaluated by including an escitalopram (10-20 mg/d) group. SETTINGS The study was undertaken in 45 clinical centers in Argentina, Czech Republic, Finland, South Korea, Poland, Russia, and Slovakia from April 2010 to July 2011. RESULTS One hundred thirty-nine outpatients were included in the agomelatine group, 131 in the placebo group, and 142 in the escitalopram group. Agomelatine significantly reduced mean (SD) HARS total score (agomelatine-placebo difference: 4.71 [1.03], P

Summary Just over 25 years have passed since the major sociopolitical changes in central and eastern Europe; our aim was to map and analyse the development of mental health-care practice for people with severe mental illnesses in this region since then. A scoping review was complemented by an expert survey in 24 countries. Mental health-care practice in the region differs greatly across as well as within individual countries. National policies often exist but reforms remain mostly in the realm of aspiration. Services are predominantly based in psychiatric hospitals. Decision making on resource allocation is not transparent, and full economic evaluations of complex interventions and rigorous epidemiological studies are lacking. Stigma seems to be higher than in other European countries, but consideration of human rights and user involvement are increasing. The region has seen respectable development, which happened because of grassroots initiatives supported by international organisations, rather than by systematic implementation of government policies.

Review paper highlights the connection between psyche and the bodys immune defense mechanisms and summarizes new findings on the relations between nervous and immune systems. The article also briefly describes the outcome of authors own original works on the relationship between infections and schizophrenia, and their notice about possible immunomodulatory effects of antipsychoticsKey words: antipsychotics - immunity - infection - inflammation - mind - pain - schizophrenia.

In this paper we propose a novel algorithm for a decomposition of 3D binary shapes to rectangular blocks. The aim is to minimize the number of blocks. Theoretically optimal brute-force algorithm is known to be NP-hard and practically infeasible. We introduce its polynomial sub-optimal approximation, which transforms the decomposition problem onto a graph-theoretical problem. We show by extensive experiments that the proposed method outperforms the the octree decomposition in terms of the number of blocks on statistically significant level. We also discuss potential applications of the method in image processing.