Endogenous antagonists of N-methyl-d-aspartate receptor in schizophrenia.

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.

An overlapping pattern of cerebral cortical thinning is associated with both positive symptoms and aggression in schizophrenia via the ENIGMA consortium.

BACKGROUND: Positive 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. METHOD: To 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. RESULTS: The 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. CONCLUSION: These 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.

Unpacking Pandora From Its Box: Deciphering the Molecular Basis of the SARS-CoV-2 Coronavirus.

An enigmatic localized pneumonia escalated into a worldwide COVID-19 pandemic from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). This review aims to consolidate the extensive biological minutiae of SARS-CoV-2 which requires decipherment. Having one of the largest RNA viral genomes, the single strand contains the genes ORF1ab, S, E, M, N and ten open reading frames. Highlighting unique features such as stem-loop formation, slippery frameshifting sequences and ribosomal mimicry, SARS-CoV-2 represents a formidable cellular invader. Hijacking the hosts translational engine, it produces two polyprotein repositories (pp1a and pp1ab), armed with self-cleavage capacity for production of sixteen non-structural proteins. Novel glycosylation sites on the spike trimer reveal unique SARS-CoV-2 features for shielding and cellular internalization. Affording complexity for superior fitness and camouflage, SARS-CoV-2 challenges diagnosis and vaccine vigilance. This review serves the scientific community seeking in-depth molecular details when designing drugs to curb transmission of this biological armament.

Season of the year, vitamin D and COVID-19.

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.

Development of quality indicators for mental healthcare in the Danube region.

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.

The Comparison of Effectiveness of Various Potential Predictors of Response to Treatment With SSRIs in Patients With Depressive Disorder.

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.

Does neurogenesis relate to depression and do antidepressants affect neurogenesis?

Depression is characterized by atrophy in several brain structures, with the hippocampus seemingly particularly affected. A wide variety of cellular mechanisms have been proposed for these structural modifications, including the regression of dendritic branching. While neurogenesis alone appears inadequate to produce such marked changes, an altered rate is likely to affect hippocampal function. There is also strong evidence for neurotransmitter and glucocorticoid-mediated effects on neurogenesis, providing routes for the action of antidepressants. We aim to show how neurogenesis relates to the 'conventional monoaminergic theory of depression' and its modulation by antidepressants.

Deinstitutionalised patients, homelessness and imprisonment: systematic review.

BACKGROUND: Reports linking the deinstitutionalisation of psychiatric care with homelessness and imprisonment have been published widely. AIMS: To identify cohort studies that followed up or traced back long-term psychiatric hospital residents who had been discharged as a consequence of deinstitutionalisation. METHOD: A broad search strategy was used and 9435 titles and abstracts were screened, 416 full articles reviewed and 171 articles from cohort studies of deinstitutionalised patients were examined in detail. RESULTS: Twenty-three studies of unique populations assessed homelessness and imprisonment among patients discharged from long-term care. Homelessness and imprisonment occurred sporadically; in the majority of studies no single case of homelessness or imprisonment was reported. CONCLUSIONS: Our results contradict the findings of ecological studies which indicated a strong correlation between the decreasing number of psychiatric beds and an increasing number of people with mental health problems who were homeless or in prison.

Relationship of suicide rates with climate and economic variables in Europe during 2000-2012.

BACKGROUND: It is well known that suicidal rates vary considerably among European countries and the reasons for this are unknown, although several theories have been proposed. The effect of economic variables has been extensively studied but not that of climate. METHODS: Data from 29 European countries covering the years 2000-2012 and concerning male and female standardized suicidal rates (according to WHO), economic variables (according World Bank) and climate variables were gathered. The statistical analysis included cluster and principal component analysis and categorical regression. RESULTS: The derived models explained 62.4 % of the variability of male suicidal rates. Economic variables alone explained 26.9 % and climate variables 37.6 %. For females, the respective figures were 41.7, 11.5 and 28.1 %. Male suicides correlated with high unemployment rate in the frame of high growth rate and high inflation and low GDP per capita, while female suicides correlated negatively with inflation. Both male and female suicides correlated with low temperature. DISCUSSION: The current study reports that the climatic effect (cold climate) is stronger than the economic one, but both are present. It seems that in Europe suicidality follows the climate/temperature cline which interestingly is not from south to north but from south to north-east. This raises concerns that climate change could lead to an increase in suicide rates. The current study is essentially the first successful attempt to explain the differences across countries in Europe; however, it is an observational analysis based on aggregate data and thus there is a lack of control for confounders.

[Mind as an immunomodulator]. / Duse jako imunomodulátor.

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.

Using structural MRI to identify individuals at genetic risk for bipolar disorders: a 2-cohort, machine learning study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. LIMITATIONS: Although we recruited 126 participants, ML benefits from even larger samples. CONCLUSION: 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.

Sad mood induction has an opposite effect on amygdala response to emotional stimuli in euthymic patients with bipolar disorder and healthy controls.

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.

The effectiveness of prefrontal theta cordance and early reduction of depressive symptoms in the prediction of antidepressant treatment outcome in patients with resistant depression: analysis of naturalistic data.

Current studies suggest that an early improvement of depressive symptoms and the reduction of prefrontal theta cordance value predict the subsequent response to antidepressants. The aim of our study was (1) to compare the predictive abilities of early clinical improvement defined as ≥ 20 % reduction in Montgomery and Åsberg Depression Rating Scale (MADRS) total score at week 1 and 2, and the decrease of prefrontal theta cordance at week 1 in resistant depressive patients and (2) to assess whether the combination of individual predictors yields more robust predictive power than either predictor alone. Eighty-seven subjects were treated (≥ 4 weeks) with various antidepressants chosen according to the judgment of attending psychiatrists. Areas under curve (AUC) were calculated to compare predictive effect of defined single predictors (≥ 20 % reduction in MADRS total score at week 1 and 2, and the decrease of cordance at week 1) and combined prediction models. AUCs of all three predictors were not statistically different (pair-wise comparison). The model combining all predictors yielded an AUC value 0.91 that was significantly higher than AUCs of each individual predictor. The results indicate that the combined predictor model may be a useful and clinically meaningful tool for the prediction of antidepressant response in patients with resistant depression.

Relationship of suicide rates to economic variables in Europe: 2000-2011.

BACKGROUND: It is unclear whether there is a direct link between economic crises and changes in suicide rates. AIMS: The Lopez-Ibor Foundation launched an initiative to study the possible impact of the economic crisis on European suicide rates. METHOD: Data was gathered and analysed from 29 European countries and included the number of deaths by suicide in men and women, the unemployment rate, the gross domestic product (GDP) per capita, the annual economic growth rate and inflation. RESULTS: There was a strong correlation between suicide rates and all economic indices except GPD per capita in men but only a correlation with unemployment in women. However, the increase in suicide rates occurred several months before the economic crisis emerged. CONCLUSIONS: Overall, this study confirms a general relationship between the economic environment and suicide rates; however, it does not support there being a clear causal relationship between the current economic crisis and an increase in the suicide rate.

Individualized rTMS neuronavigated according to regional brain metabolism ((18)FGD PET) has better treatment effects on auditory hallucinations than standard positioning of rTMS: a double-blind, sham-controlled study.

Low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) of the left temporo-parietal cortex (LTPC) has been proposed as a useful therapeutic method for auditory hallucinations (AHs). Stereotactic neuronavigation enables the magnetic coil to be targeted according to the individual parameters obtained from neuroimaging. Individualized rTMS neuronavigated according to 18-fluorodeoxyglucose positron emission tomography ((18)FDG PET) allows us to focus the coil explicitly on a given area with detected maxima of specific abnormalities, thus presuming a higher therapeutic effect of the method. The objective of this study is to test clinical efficacy of neuronavigated LF-rTMS administered according to the local maxima of (18)FDG PET uptake of LTPC and to compare it with treatment effects of standard and sham rTMS. In a double-blind, sham-controlled design, patients with AHs underwent a 10-day series of LF-rTMS using (1) (18)FDG PET-guided "neuronavigation," (2) "standard" anatomically guided positioning, and (3) sham coil. The effect of different rTMS conditions was assessed by the Auditory Hallucinations Rating Scale (AHRS) and the Positive and Negative Syndrome Scale (PANSS). Fifteen patients were randomized to a treatment sequence and ten of them completed all three treatment conditions. The intention-to-treat analysis of AHRS score change revealed superiority of the (18)FDG PET-guided rTMS over both the standard and the sham rTMS. The analyses of the PANSS scores failed to detect significant difference among the treatments. Our data showed acute efficacy of (18)FDG PET-guided rTMS in the treatment of AHs. Neuronavigated rTMS was found to be more effective than standard, anatomically guided rTMS.

The media and intellectuals' response to medical publications: the antidepressants' case.

During the last decade, there was a debate concerning the true efficacy of antidepressants. Several papers were published in scientific journals, but many articles were also published in the lay press and the internet both by medical scientists and academics from other disciplines or representatives of societies or initiatives. The current paper analyzes the articles authored by three representative opinion makers: one academic in medicine, one academic in philosophical studies, and a representative of an activists' group against the use of antidepressants. All three articles share similar gaps in knowledge and understanding of the scientific data and also are driven by an 'existential-like' ideology. In our opinion, these articles have misinterpreted the scientific data, and they as such may misinform or mislead the general public and policy makers, which could have a potential impact upon public health. It seems that this line of thought represents another aspect of the stigma attached to people suffering from mental illness.

Antidepressant monotherapy compared with combinations of antidepressants in the treatment of resistant depressive patients: a randomized, open-label study.

OBJECTIVE: This randomized, 6-week, open-label study compared efficacy of CAD and antidepressant monotherapies (ADM) that had been chosen according to clinical judgment of the attending psychiatrist. METHODS: A total of 60 inpatients (intent-to-treat analysis) with depressive disorder (≥ 1 unsuccessful antidepressant treatment) were randomly assigned to the interventions. The responders who completed the acute phase of study, were evaluated for relapse within 2 months of follow-up treatment. The primary outcome measure was change in the Montgomery-Åsberg Depression Rating Scale (MADRS) and response was defined as a ≥ 50% reduction of MADRS score. RESULTS: Mean changes in total MADRS score from baseline to week 6 for patients in both treatment modalities were not different (ADM = 13.2 ± 8.6 points; CAD = 14.5 ± 9.5 points; P = 0.58). The analysis of covariance performed for significantly higher value of imipramine equivalent dose in CAD group showed only a non-significant between-group difference for total MADRS change (P = 0.17). There were also no differences between groups in response rate (ADM = 48%; CAD = 58%) and number of drop-outs in acute treatment as well as proportion of responders' relapses in the follow-up. CONCLUSION: Both treatment modalities produced clinically relevant reduction of depressive symptomatology in acute treatment of patients with resistant depression and their effect was comparable.

Hippocampal volumes in bipolar disorders: opposing effects of illness burden and lithium treatment.

OBJECTIVE: Hippocampal volume decrease associated with illness burden is among the most replicated findings in unipolar depression. The absence of hippocampal volume changes in most studies of individuals with bipolar disorder (BD) may reflect neuroprotective effects of lithium (Li). METHODS: We recruited 17 BD patients from specialized Li clinics, with at least two years of regularly monitored Li treatment (Li group), and compared them to 12 BD participants with < 3 months of lifetime Li exposure and no Li treatment within two years prior to the scanning (non-Li group) and 11 healthy controls. All BD patients had at least 10 years of illness and five episodes. We also recruited 13 Li-naïve, young BD participants (15-30 years of age) and 18 sex- and age-matched healthy controls. We compared hippocampal volumes obtained from 1.5-T magnetic resonance imaging (MRI) scans using optimized voxel-based morphometry with small volume correction. RESULTS: The non-Li group had smaller left hippocampal volumes than controls (corrected p < 0.05), with a trend for lower volumes than the Li group (corrected p < 0.1), which did not differ from controls. Young, Li-naïve BD patients close to the typical age of onset had comparable hippocampal volumes to controls. CONCLUSIONS: Whereas patients with limited lifetime Li exposure had significantly lower hippocampal volumes than controls, patients with comparable illness burden, but with over two years of Li treatment, or young Li-naïve BD patients, showed hippocampal volumes comparable to controls. These results provide indirect support for neuroprotective effects of Li and negative effects of illness burden on hippocampal volumes in bipolar disorders.

Smaller hippocampal volumes in patients with bipolar disorder are masked by exposure to lithium: a meta-analysis.

BACKGROUND: Smaller hippocampal volumes relative to controls are among the most replicated neuroimaging findings in individuals with unipolar but not bipolar depression. Preserved hippocampal volumes in most studies of participants with bipolar disorder may reflect potential neuroprotective effects of lithium (Li). METHODS: To investigate hippocampal volumes in patients with bipolar disorder while controlling for Li exposure, we performed a meta-analysis of neuroimaging studies that subdivided patients based on the presence or absence of current Li treatment. To achieve the best coverage of literature, we categorized studies based on whether all or a majority, or whether no or a minority of patients were treated with Li. Hippocampal volumes were compared by combining standardized differences between means (Cohen d) from individual studies using random-effects models. RESULTS: Overall, we analyzed data from 101 patients with bipolar disorder in the Li group, 245 patients in the non-Li group and 456 control participants from 16 studies. Both the left and right hippocampal volumes were significantly larger in the Li group than in controls (Cohen d = 0.53, 95% confidence interval [CI] 0.18 to 0.88; Cohen d = 0.51, 95% CI 0.21 to 0.81, respectively) or the non-Li group (Cohen d = 0.93, 95% CI 0.56 to 1.31; Cohen d = 1.07, 95% CI 0.70 to 1.45, respectively), which had smaller left and right hippocampal volumes than the control group (Cohen d = -0.36, 95% CI -0.55 to -0.17; Cohen d = -0.38, 95% CI -0.63 to -0.13, respectively). There was no evidence of publication bias. LIMITATIONS: Missing information about the illness burden or lifetime exposure to Li and polypharmacy in some studies may have contributed to statistical heterogeneity in some analyses. CONCLUSION: When exposure to Li was minimized, patients with bipolar disorder showed smaller hippocampal volumes than controls or Li-treated patients. Our findings provide indirect support for the negative effects of bipolar disorder on hippocampal volumes and are consistent with the putative neuroprotective effects of Li. The preserved hippocampal volumes among patients with bipolar disorder in most individual studies and all previous meta-analyses may have been related to the inclusion of Li-treated participants.

The state of psychiatry in the Czech Republic.

This overview of Czech psychiatry begins with a brief review of its history; outlines its social, political and economic determinants and then describes the field itself. Both epidemiological and service-related information are discussed, together with the issues for mental health personnel, education and research. The heavy burden of communist history pervades most areas and must be taken into account in the specific characteristics that influence both the current situation and future prospects of Czech psychiatry. This consideration is essential for orientation in the field and to understand Czech particularities. The greatest challenges, however, originate from the fundamental changes that are going on in the world today. These challenges reach beyond national boundaries and include such phenomena as globalization, migration, ageing population, growing burden of mental ill health, the still prevailing stigma towards psychiatry, and the psychological roots and consequences of current financial and societal crises.