Distinct multimodal biological and functional profiles of symptom-based subgroups in recent-onset psychosis.

Symptom heterogeneity characterizes psychotic disorders and hinders the delineation of underlying biomarkers. Here, we identify symptom-based subtypes of recent-onset psychosis (ROP) patients from the multi-center PRONIA (Personalized Prognostic Tools for Early Psychosis Management) database and explore their multimodal biological and functional signatures. We clustered N = 328 ROP patients based on their maximum factor scores in an exploratory factor analysis on the Positive and Negative Syndrome Scale items. We assessed inter-subgroup differences and compared to N = 464 healthy control (HC) individuals regarding gray matter volume (GMV), neurocognition, polygenic risk scores, and longitudinal functioning trajectories. Finally, we evaluated factor stability at 9- and 18-month follow-ups. A 4-factor solution optimally explained symptom heterogeneity, showing moderate longitudinal stability. The ROP-MOTCOG (Motor/Cognition) subgroup was characterized by GMV reductions within salience, control and default mode networks, predominantly throughout cingulate regions, relative to HC individuals, had the most impaired neurocognition and the highest genetic liability for schizophrenia. ROP-SOCWD (Social Withdrawal) patients showed GMV reductions within medial fronto-temporal regions of the control, default mode, and salience networks, and had the lowest social functioning across time points. ROP-POS (Positive) evidenced GMV decreases in salience, limbic and frontal regions of the control and default mode networks. The ROP-AFF (Affective) subgroup showed GMV reductions in the salience, limbic, and posterior default-mode and control networks, thalamus and cerebellum. GMV reductions in fronto-temporal regions of the salience and control networks were shared across subgroups. Our results highlight the existence of behavioral subgroups with distinct neurobiological and functional profiles in early psychosis, emphasizing the need for refined symptom-based diagnosis and prognosis frameworks.

Distinct Volume Alterations of Thalamic Nuclei Across the Schizophrenia Spectrum.

BACKGROUND AND HYPOTHESIS: Abnormal thalamic nuclei volumes and their link to cognitive impairments have been observed in schizophrenia. However, whether and how this finding extends to the schizophrenia spectrum is unknown. We hypothesized a distinct pattern of aberrant thalamic nuclei volume across the spectrum and examined its potential associations with cognitive symptoms. STUDY DESIGN: We performed a FreeSurfer-based volumetry of T1-weighted brain MRIs from 137 healthy controls, 66 at-risk mental state (ARMS) subjects, 89 first-episode psychosis (FEP) individuals, and 126 patients with schizophrenia to estimate thalamic nuclei volumes of six nuclei groups (anterior, lateral, ventral, intralaminar, medial, and pulvinar). We used linear regression models, controlling for sex, age, and estimated total intracranial volume, both to compare thalamic nuclei volumes across groups and to investigate their associations with positive, negative, and cognitive symptoms. STUDY RESULTS: We observed significant volume alterations in medial and lateral thalamic nuclei. Medial nuclei displayed consistently reduced volumes across the spectrum compared to controls, while lower lateral nuclei volumes were only observed in schizophrenia. Whereas positive and negative symptoms were not associated with reduced nuclei volumes across all groups, higher cognitive scores were linked to lower volumes of medial nuclei in ARMS. In FEP, cognition was not linked to nuclei volumes. In schizophrenia, lower cognitive performance was associated with lower medial volumes. CONCLUSIONS: Results demonstrate distinct thalamic nuclei volume reductions across the schizophrenia spectrum, with lower medial nuclei volumes linked to cognitive deficits in ARMS and schizophrenia. Data suggest a distinctive trajectory of thalamic nuclei abnormalities along the course of schizophrenia.

Reduced prevalence of drug-related problems in psychiatric inpatients after implementation of a pharmacist-supported computerized physician order entry system - a retrospective cohort study.

Introduction: In 2021, a computerized physician order entry (CPOE) system with an integrated clinical decision support system (CDSS) was implemented at a tertiary care center for the treatment of mental health conditions in Lübeck, Germany. To date, no study has been reported on the types and prevalence of drug-related problems (DRPs) before and after CPOE implementation in a psychiatric inpatient setting. The aim of this retrospective before-and-after cohort study was to investigate whether the implementation of a CPOE system with CDSS accompanied by the introduction of regular medication plausibility checks by a pharmacist led to a decrease of DRPs during hospitalization and unsolved DRPs at discharge in psychiatric inpatients. Methods: Medication charts and electronic patient records of 54 patients before (cohort I) and 65 patients after (cohort II) CPOE implementation were reviewed retrospectively by a clinical pharmacist. All identified DRPs were collected and classified based on 'The PCNE Classification V9.1', the German database DokuPIK, and the 'NCC MERP Taxonomy of Medication Errors'. Results: 325 DRPs were identified in 54 patients with a mean of 6 DRPs per patient and 151.9 DRPs per 1000 patient days in cohort I. In cohort II, 214 DRPs were identified in 65 patients with a mean of 3.3 DRPs per patient and 81.3 DRPs per 1000 patient days. The odds of having a DRP were significantly lower in cohort II (OR=0.545, 95% CI 0.412-0.721, p<0.001). The most frequent DRP in cohort I was an erroneous prescription (n=113, 34.8%), which was significantly reduced in cohort II (n=12, 5.6%, p<0.001). During the retrospective in-depth review, more DRPs were identified than during the daily plausibility analyses. At hospital discharge, patients had significantly less unsolved DRPs in cohort II than in cohort I. Discussion: The implementation of a CPOE system with an integrated CDSS reduced the overall prevalence of DRPs, especially of prescription errors, and led to a smaller rate of unsolved DRPs in psychiatric inpatients at hospital discharge. Not all DRPs were found by plausibility analyses based on the medication charts. A more interactive and interdisciplinary patient-oriented approach might result in the resolution of more DRPs.

Aging effects on the encoding/retrieval flip in associative memory: fMRI evidence from incidental contingency learning.

Introduction: Associative memory is arguably the most basic memory function and therein constitutes the foundation of all episodic and semantic memory processes. At the same time, the decline of associative memory represents a core feature of age-related cognitive decline in both, healthy and pathological (i.e., dementia-related) aging. The neural mechanisms underlying age-related impairments in associative memory are still not fully understood, especially regarding incidental (i.e., non-intentional) learning. Methods: We investigated the impact of age on the incidental learning and memory retrieval of face-name combinations in a total sample of 46 young (N = 23; mean age = 23.39 years) and elderly (N = 22, mean age = 69.05 years) participants. More specifically, particular interest was placed in age-related changes in encoding/retrieval (E/R) flips, which denote a neural antagonism of opposed activation patterns in the same brain region during memory encoding and retrieval, which were assessed using fMRI. Results: According to our hypothesis, the results showed a significant age-related decline in the retrieval performance in the old group. Additionally, at the neural level, we discovered an abolished E/R flip in the right anterior insula and a joint but reduced E/R flip activation magnitude in the posterior middle cingulate cortex in older subjects. Discussion: In conclusion, the present findings suggest that the impaired neural modulation of the E/R flip in the right aIC might be a sensitive marker in the early detection of neural aging.

Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study.

Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2439 adults with schizophrenia and 2867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n = 207), we evaluated structural alterations of schizophrenia against two network susceptibility models: (i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; (ii) epicenter mapping, which identifies regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Our findings show schizophrenia-related cortical thinning is spatially associated with functional and structural hubs, suggesting that highly interconnected regions are more vulnerable to morphological alterations. Predominantly temporo-paralimbic and frontal regions emerged as epicenters with connectivity profiles linked to schizophrenia's alteration patterns. Findings were robust across sites, disease stages, and related to individual symptoms. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, suggestive of a pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters at both the level of the group and the individual. Subtle variations of epicenters across disease stages suggest interacting pathological processes, while associations with patient-specific symptoms support additional inter-individual variability of hub vulnerability and epicenters in schizophrenia. Our work outlines potential pathways to better understand macroscale structural alterations, and inter- individual variability in schizophrenia.

[Management of treatment resistance-Treatment-resistant schizophrenia]. / Management von Therapieresistenzen ­ therapieresistente Schizophrenie.

Despite a very high prevalence and substantial impairments among affected individuals, treatment-resistant schizophrenia (TRS) has not been sufficiently researched in clinical research in the field of psychiatric disorders and the pathophysiology is still poorly understood. A better clinical and pathophysiological understanding of this heterogeneous and severely affected population of people with persistent symptoms in different domains is necessary in order not only to be able to intervene early but also to develop novel therapeutic strategies or individualized treatment approaches. This review article presents the state of the art criteria of the pharmacological TRS, neurobiological disease models and predictive factors for TRS as well as the phenomenon of pseudo-treatment resistance and the clinical management of TRS. In the future, not only the use of operationalized criteria and definitions of TRS in longitudinal studies and randomized-controlled trials (RCTs) are paramount, but also the observation of trajectories with the integration of multimodal longitudinal phenotyping and the longitudinal collection of clinical routine data in academic research, which will be possible in the newly created German Center for Mental Health (DZPG).

Algorithmic fairness in precision psychiatry: analysis of prediction models in individuals at clinical high risk for psychosis.

BACKGROUND: Computational models offer promising potential for personalised treatment of psychiatric diseases. For their clinical deployment, fairness must be evaluated alongside accuracy. Fairness requires predictive models to not unfairly disadvantage specific demographic groups. Failure to assess model fairness prior to use risks perpetuating healthcare inequalities. Despite its importance, empirical investigation of fairness in predictive models for psychiatry remains scarce. AIMS: To evaluate fairness in prediction models for development of psychosis and functional outcome. METHOD: Using data from the PRONIA study, we examined fairness in 13 published models for prediction of transition to psychosis (n = 11) and functional outcome (n = 2) in people at clinical high risk for psychosis or with recent-onset depression. Using accuracy equality, predictive parity, false-positive error rate balance and false-negative error rate balance, we evaluated relevant fairness aspects for the demographic attributes 'gender' and 'educational attainment' and compared them with the fairness of clinicians' judgements. RESULTS: Our findings indicate systematic bias towards assigning less favourable outcomes to individuals with lower educational attainment in both prediction models and clinicians' judgements, resulting in higher false-positive rates in 7 of 11 models for transition to psychosis. Interestingly, the bias patterns observed in algorithmic predictions were not significantly more pronounced than those in clinicians' predictions. CONCLUSIONS: Educational bias was present in algorithmic and clinicians' predictions, assuming more favourable outcomes for individuals with higher educational level (years of education). This bias might lead to increased stigma and psychosocial burden in patients with lower educational attainment and suboptimal psychosis prevention in those with higher educational attainment.

Transdiagnostic subgroups of cognitive impairment in early affective and psychotic illness.

Cognitively impaired and spared patient subgroups were identified in psychosis and depression, and in clinical high-risk for psychosis (CHR). Studies suggest differences in underlying brain structural and functional characteristics. It is unclear whether cognitive subgroups are transdiagnostic phenomena in early stages of psychotic and affective disorder which can be validated on the neural level. Patients with recent-onset psychosis (ROP; N = 140; female = 54), recent-onset depression (ROD; N = 130; female = 73), CHR (N = 128; female = 61) and healthy controls (HC; N = 270; female = 165) were recruited through the multi-site study PRONIA. The transdiagnostic sample and individual study groups were clustered into subgroups based on their performance in eight cognitive domains and characterized by gray matter volume (sMRI) and resting-state functional connectivity (rsFC) using support vector machine (SVM) classification. We identified an impaired subgroup (NROP = 79, NROD = 30, NCHR = 37) showing cognitive impairment in executive functioning, working memory, processing speed and verbal learning (all p < 0.001). A spared subgroup (NROP = 61, NROD = 100, NCHR = 91) performed comparable to HC. Single-disease subgroups indicated that cognitive impairment is stronger pronounced in impaired ROP compared to impaired ROD and CHR. Subgroups in ROP and ROD showed specific symptom- and functioning-patterns. rsFC showed superior accuracy compared to sMRI in differentiating transdiagnostic subgroups from HC (BACimpaired = 58.5%; BACspared = 61.7%, both: p < 0.01). Cognitive findings were validated in the PRONIA replication sample (N = 409). Individual cognitive subgroups in ROP, ROD and CHR are more informative than transdiagnostic subgroups as they map onto individual cognitive impairment and specific functioning- and symptom-patterns which show limited overlap in sMRI and rsFC. CLINICAL TRIAL REGISTRY NAME: German Clinical Trials Register (DRKS). Clinical trial registry URL: https://www.drks.de/drks_web/ . Clinical trial registry number: DRKS00005042.

Normative tDCS over V5 and FEF reveals practice-induced modulation of extraretinal smooth pursuit mechanisms, but no specific stimulation effect.

The neural networks subserving smooth pursuit eye movements (SPEM) provide an ideal model for investigating the interaction of sensory processing and motor control during ongoing movements. To better understand core plasticity aspects of sensorimotor processing for SPEM, normative sham, anodal or cathodal transcranial direct current stimulation (tDCS) was applied over visual area V5 and frontal eye fields (FEF) in sixty healthy participants. The identical within-subject paradigm was used to assess SPEM modulations by practice. While no specific tDCS effects were revealed, within- and between-session practice effects indicate plasticity of top-down extraretinal mechanisms that mainly affect SPEM in the absence of visual input and during SPEM initiation. To explore the potential of tDCS effects, individual electric field simulations were computed based on calibrated finite element head models and individual functional localization of V5 and FEF location (using functional MRI) and orientation (using combined EEG/MEG) was conducted. Simulations revealed only limited electric field target intensities induced by the applied normative tDCS montages but indicate the potential efficacy of personalized tDCS for the modulation of SPEM. In sum, results indicate the potential susceptibility of extraretinal SPEM control to targeted external neuromodulation (e.g., personalized tDCS) and intrinsic learning protocols.

Normative Modeling of Brain Morphometry Across the Lifespan Using CentileBrain: Algorithm Benchmarking and Model Optimization.

We present an empirically benchmarked framework for sex-specific normative modeling of brain morphometry that can inform about the biological and behavioral significance of deviations from typical age-related neuroanatomical changes and support future study designs. This framework was developed using regional morphometric data from 37,407 healthy individuals (53% female; aged 3-90 years) following a comparative evaluation of eight algorithms and multiple covariate combinations pertaining to image acquisition and quality, parcellation software versions, global neuroimaging measures, and longitudinal stability. The Multivariate Factorial Polynomial Regression (MFPR) emerged as the preferred algorithm optimized using nonlinear polynomials for age and linear effects of global measures as covariates. The MFPR models showed excellent accuracy across the lifespan and within distinct age-bins, and longitudinal stability over a 2-year period. The performance of all MFPR models plateaued at sample sizes exceeding 3,000 study participants. The model and scripts described here are freely available through CentileBrain (https://centilebrain.org/).

Olanzapine Effects on Parvalbumin/GAD67 Cell Numbers in Layers/Subregions of Dorsal Hippocampus of Chronically Socially Isolated Rats.

Depression is linked to changes in GABAergic inhibitory neurons, especially parvalbumin (PV) interneurons, which are susceptible to redox dysregulation. Olanzapine (Olz) is an atypical antipsychotic whose mode of action remains unclear. We determined the effect of Olz on PV-positive (+) and glutamate decarboxylase 67 (GAD67) + cell numbers in the layers of dorsal hippocampus (dHIPP) cornu ammonis (CA1-CA3) and dentate gyrus (DG) subregions in rats exposed to chronic social isolation (CSIS), which is an animal model of depression. Antioxidative enzymes and proinflammatory cytokine levels were also examined. CSIS decreased the PV+ cell numbers in the Stratum Oriens (SO) and Stratum Pyramidale (SP) of dCA1 and dDG. It increased interleukin-6 (IL-6), suppressor of cytokine signaling 3 (SOCS3), and copper-zinc superoxide dismutase (CuZnSOD) levels, and it decreased catalase (CAT) protein levels. Olz in CSIS increased the number of GAD67+ cells in the SO and SP layers of dCA1 with no effect on PV+ cells. It reduced the PV+ and GAD67+ cell numbers in the Stratum Radiatum of dCA3 in CSIS. Olz antagonizes the CSIS-induced increase in CuZnSOD, CAT and SOCS3 protein levels with no effect on IL-6. Data suggest that the protective Olz effects in CSIS may be mediated by altering the number of PV+ and GAD67+ cells in dHIPP subregional layers.

Prevalence of COVID-19 and Psychotropic Drug Treatment in Psychiatric In-patients in Germany in 2020: Results from a Nationwide Pilot Survey.

INTRODUCTION: In patients with a pre-existing mental disorder, an increased risk for a first manifestation of a psychiatric disorder in COVID-19 patients, a more severe course of COVID-19 and an increased mortality have been described. Conversely, observations of lower COVID-19 incidences in psychiatric in-patients suggested protective effects of psychiatric treatment and/or psychotropic drugs against COVID-19. METHODS: A retrospective multi-center study was conducted in 24 German psychiatric university hospitals. Between April and December 2020 (the first and partly second wave of COVID-19), the effects of COVID-19 were assessed on psychiatric in-patient care, the incidence and course of a SARS-CoV-2 infection, and treatment with psychotropic drugs. RESULTS: Patients (n=36,322) were admitted to the hospitals. Mandatory SARS-CoV-2 tests before/during admission were reported by 23 hospitals (95.8%), while 18 (75%) conducted regular testing during the hospital stay. Two hundred thirty-two (0.6%) patients were tested SARS-CoV-2-positive. Thirty-seven (16%) patients were receiving medical treatment for COVID-19 at the psychiatric hospital, ten (4.3%) were transferred to an intermediate/intensive care unit, and three (1.3%) died. The most common prescription for SARS-CoV-2-positive patients was for second-generation antipsychotics (n=79, 28.2%) and antidepressants (SSRIs (n=38, 13.5%), mirtazapine (n=36, 12.9%) and SNRIs (n=29, 10.4%)). DISCUSSION: Contrary to previous studies, our results showed a low number of infections and mortality in SARS-CoV-2-positive psychiatric patients. Several preventive measures seem effective to protect this vulnerable group. Our observations are compatible with the hypothesis of a protective effect of psychotropic drugs against COVID-19 as the overall mortality and need for specific medical treatment was low.

Neurocognitive skills and vulnerability for psychosis in depression and across the psychotic spectrum: findings from the PRONIA Consortium.

BACKGROUND: Neurocognitive deficits are a core feature of psychosis and depression. Despite commonalities in cognitive alterations, it remains unclear if and how the cognitive deficits in patients at clinical high risk for psychosis (CHR) and those with recent-onset psychosis (ROP) are distinct from those seen in recent-onset depression (ROD). AIMS: This study was carried out within the European project 'Personalized Prognostic Tools for Early Psychosis Management', and aimed to characterise the cognitive profiles of patients with psychosis or depression. METHOD: We examined cognitive profiles for patients with ROP (n = 105), patients with ROD (n = 123), patients at CHR (n = 116) and healthy controls (n = 372) across seven sites in five European countries. Confirmatory factor analysis identified four cognitive factors independent of gender, education and site: speed of processing, attention and working memory, verbal learning and spatial learning. RESULTS: Patients with ROP performed worse than healthy controls in all four domains (P < 0.001), whereas performance of patients with ROD was not affected (P > 0.05). Patients at CHR performed worse than healthy controls in speed of processing (P = 0.001) and spatial learning (P = 0.003), but better than patients with ROP across all cognitive domains (all P ≤ 0.01). CHR and ROD groups did not significantly differ in any cognitive domain. These findings were independent of comorbid depressive symptoms, substance consumption and illness duration. CONCLUSIONS: These results show that neurocognitive abilities are affected in CHR and ROP, whereas ROD seems spared. Although our findings may support the notion that those at CHR have a specific vulnerability to psychosis, future studies investigating broader transdiagnostic risk cohorts in longitudinal designs are needed.

Predictors of transition in patients with clinical high risk for psychosis: an umbrella review.

Diagnosis of a clinical high-risk (CHR) state enables timely treatment of individuals at risk for a psychotic disorder, thereby contributing to improving illness outcomes. However, only a minority of patients diagnosed with CHR will make the transition to overt psychosis. To identify patients most likely to benefit from early intervention, several studies have investigated characteristics that distinguish CHR patients who will later develop a psychotic disorder from those who will not. We aimed to summarize evidence from systematic reviews and meta-analyses on predictors of transition to psychosis in CHR patients, among characteristics and biomarkers assessed at baseline. A systematic search was conducted in Pubmed, Scopus, PsychInfo and Cochrane databases to identify reviews and meta-analyses of studies that investigated specific baseline predictors or biomarkers for transition to psychosis in CHR patients using a cross-sectional or longitudinal design. Non-peer-reviewed publications, gray literature, narrative reviews and publications not written in English were excluded from analyses. We provide a narrative synthesis of results from all included reviews and meta-analyses. For each included publication, we indicate the number of studies cited in each domain and its quality rating. A total of 40 publications (21 systematic reviews and 19 meta-analyses) that reviewed a total of 272 original studies qualified for inclusion. Baseline predictors most consistently associated with later transition included clinical characteristics such as attenuated psychotic and negative symptoms and functioning, verbal memory deficits and the electrophysiological marker of mismatch negativity. Few predictors reached a level of evidence sufficient to inform clinical practice, reflecting generalizability issues in a field characterized by studies with small, heterogeneous samples and relatively few transition events. Sample pooling and harmonization of methods across sites and projects are necessary to overcome these limitations.

Basal-Forebrain Cholinergic Nuclei Alterations are Associated With Medication and Cognitive Deficits Across the Schizophrenia Spectrum.

BACKGROUND AND HYPOTHESIS: The cholinergic system is altered in schizophrenia. Particularly, patients' volumes of basal-forebrain cholinergic nuclei (BFCN) are lower and correlated with attentional deficits. It is unclear, however, if and how BFCN changes and their link to cognitive symptoms extend across the schizophrenia spectrum, including individuals with at-risk mental state for psychosis (ARMS) or during first psychotic episode (FEP). STUDY DESIGN: To address this question, we assessed voxel-based morphometry (VBM) of structural magnetic resonance imaging data of anterior and posterior BFCN subclusters as well as symptom ratings, including cognitive, positive, and negative symptoms, in a large multi-site dataset (n = 4) comprising 68 ARMS subjects, 98 FEP patients (27 unmedicated and 71 medicated), 140 patients with established schizophrenia (SCZ; medicated), and 169 healthy controls. RESULTS: In SCZ, we found lower VBM measures for the anterior BFCN, which were associated with the anticholinergic burden of medication and correlated with patients' cognitive deficits. In contrast, we found larger VBM measures for the posterior BFCN in FEP, which were driven by unmedicated patients and correlated at-trend with cognitive deficits. We found no BFCN changes in ARMS. Altered VBM measures were not correlated with positive or negative symptoms. CONCLUSIONS: Results demonstrate complex (posterior vs. anterior BFCN) and non-linear (larger vs. lower VBM) differences in BFCN across the schizophrenia spectrum, which are specifically associated both with medication, including its anticholinergic burden, and cognitive symptoms. Data suggest an altered trajectory of BFCN integrity in schizophrenia, influenced by medication and relevant for cognitive symptoms.

Effective Connectivity of Thalamocortical Interactions Following d-Amphetamine, LSD, and MDMA Administration.

BACKGROUND: While the exploration of serotonergic psychedelics as psychiatric medicines deepens, so does the pressure to better understand how these compounds act on the brain. METHODS: We used a double-blind, placebo-controlled, crossover design and administered lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA), and d-amphetamine in 25 healthy participants. By using spectral dynamic causal modeling, we mapped substance-induced changes in effective connectivity between the thalamus and different cortex types (unimodal vs. transmodal) derived from a previous study with resting-state functional magnetic resonance imaging data. Due to the distinct pharmacological modes of action of the 3 substances, we were able to investigate specific effects mainly driven by different neurotransmitter systems on thalamocortical and corticothalamic interactions. RESULTS: Compared with placebo, all 3 substances increased the effective connectivity from the thalamus to specific unimodal cortices, whereas the influence of these cortices on the thalamus was reduced. These results indicate increased bottom-up and decreased top-down information flow between the thalamus and some unimodal cortices. However, for the amphetamines, we found the opposite effects when examining the effective connectivity with transmodal cortices, including parts of the salience network. Intriguingly, LSD increased the effective connectivity from the thalamus to both unimodal and transmodal cortices, indicating a breach in the hierarchical organization of ongoing brain activity. CONCLUSIONS: The results advance our knowledge about the action of psychedelics on the brain and refine current models aiming to explain the underlying neurobiological processes.

Metabolic Fingerprints of Effective Fluoxetine Treatment in the Prefrontal Cortex of Chronically Socially Isolated Rats: Marker Candidates and Predictive Metabolites.

The increasing prevalence of depression requires more effective therapy and the understanding of antidepressants' mode of action. We carried out untargeted metabolomics of the prefrontal cortex of rats exposed to chronic social isolation (CSIS), a rat model of depression, and/or fluoxetine treatment using liquid chromatography-high resolution mass spectrometry. The behavioral phenotype was assessed by the forced swim test. To analyze the metabolomics data, we employed univariate and multivariate analysis and biomarker capacity assessment using the receiver operating characteristic (ROC) curve. We also identified the most predictive biomarkers using a support vector machine with linear kernel (SVM-LK). Upregulated myo-inositol following CSIS may represent a potential marker of depressive phenotype. Effective fluoxetine treatment reversed depressive-like behavior and increased sedoheptulose 7-phosphate, hypotaurine, and acetyl-L-carnitine contents, which were identified as marker candidates for fluoxetine efficacy. ROC analysis revealed 4 significant marker candidates for CSIS group discrimination, and 10 for fluoxetine efficacy. SVM-LK with accuracies of 61.50% or 93.30% identified a panel of 7 or 25 predictive metabolites for depressive-like behavior or fluoxetine effectiveness, respectively. Overall, metabolic fingerprints combined with the ROC curve and SVM-LK may represent a new approach to identifying marker candidates or predictive metabolites for ongoing disease or disease risk and treatment outcome.

The heterogeneity of attenuated and brief limited psychotic symptoms: association of contents with age, sex, country, religion, comorbidities, and functioning.

Introduction: The Attenuated Psychosis Symptoms (APS) syndrome mostly represents the ultra-high-risk state of psychosis but, as does the Brief Intermittent Psychotic Symptoms (BIPS) syndrome, shows a large variance in conversion rates. This may be due to the heterogeneity of APS/BIPS that may be related to the effects of culture, sex, age, and other psychiatric morbidities. Thus, we investigated the different thematic contents of APS and their association with sex, age, country, religion, comorbidity, and functioning to gain a better understanding of the psychosis-risk syndrome. Method: A sample of 232 clinical high-risk subjects according to the ultra-high risk and basic symptom criteria was recruited as part of a European study conducted in Germany, Italy, Switzerland, and Finland. Case vignettes, originally used for supervision of inclusion criteria, were investigated for APS/BIPS contents, which were compared for sex, age, country, religion, functioning, and comorbidities using chi-squared tests and regression analyses. Result: We extracted 109 different contents, mainly of APS (96.8%): 63 delusional, 29 hallucinatory, and 17 speech-disorganized contents. Only 20 contents (18.3%) were present in at least 5% of the sample, with paranoid and referential ideas being the most frequent. Thirty-one (28.5%) contents, in particular, bizarre ideas and perceptual abnormalities, demonstrated an association with age, country, comorbidity, or functioning, with regression models of country and obsessive-compulsive disorders explaining most of the variance: 55.8 and 38.3%, respectively. Contents did not differ between religious groups. Conclusion: Psychosis-risk patients report a wide range of different contents of APS/BIPS, underlining the psychopathological heterogeneity of this group but also revealing a potential core set of contents. Compared to earlier reports on North-American samples, our maximum prevalence rates of contents were considerably lower; this likely being related to a stricter rating of APS/BIPS and cultural influences, in particular, higher schizotypy reported in North-America. The various associations of some APS/BIPS contents with country, age, comorbidities, and functioning might moderate their clinical severity and, consequently, the related risk for psychosis and/or persistent functional disability.