Search

Abstract Smooth pursuit eye movements are considered a well-established and quantifiable biomarker of sensorimotor function in psychosis research. Identifying psychotic syndromes on an individual level based on neurobiological markers is limited by heterogeneity and requires comprehensive external validation to avoid overestimation of prediction models. Here, we studied quantifiable sensorimotor measures derived from smooth pursuit eye movements in a large sample of psychosis probands (N = 674) and healthy controls (N = 305) using multivariate pattern analysis. Balanced accuracies of 64% for the prediction of psychosis status are in line with recent results from other large heterogenous psychiatric samples. They are confirmed by external validation in independent large samples including probands with (1) psychosis (N = 727) versus healthy controls (N = 292), (2) psychotic (N = 49) and non-psychotic bipolar disorder (N = 36), and (3) non-psychotic affective disorders (N = 119) and psychosis (N = 51) yielding accuracies of 65%, 66% and 58%, respectively, albeit slightly different psychosis syndromes. Our findings make a significant contribution to the identification of biologically defined profiles of heterogeneous psychosis syndromes on an individual level underlining the impact of sensorimotor dysfunction in psychosis.

IntroductionIn 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.MethodsMedication 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’.Results325 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

Abstract 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.

Metabolic perturbation has been associated with depression. An untargeted metabolomics approach using liquid chromatography-high resolution mass spectrometry was employed to detect and measure the rat serum metabolic changes following chronic social isolation (CSIS), an animal model of depression, and effective antidepressant fluoxetine (Flx) treatment. Univariate and multivariate statistics were used for metabolic data analysis and differentially expressed metabolites (DEMs) determination. Potential markers and predictive metabolites of CSIS-induced depressive-like behavior and Flx efficacy in CSIS were evaluated by the receiver operating characteristic (ROC) curve, and machine learning (ML) algorithms, such as support vector machine with linear kernel (SVM–LK) and random forest (RF). Upregulated choline following CSIS may represent a potential marker of depressive-like behavior. Succinate, stachydrine, guanidinoacetate, kynurenic acid, and 7-methylguanine were revealed as potential markers of effective Flx treatment in CSIS rats. RF yielded better accuracy than SVM–LK (98.50% vs. 85.70%, respectively) in predicting Flx efficacy in CSIS vs. CSIS, however, it performed almost identically in classifying CSIS vs. control (75.83% and 75%, respectively). Obtained DEMs combined with ROC curve and ML algorithms provide a research strategy for assessing potential markers or predictive metabolites for the designation or classification of stress-induced depressive phenotype and mode of drug action.

IntroductionAssociative 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.MethodsWe 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.ResultsAccording 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.DiscussionIn 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.

Paranoid delusions or unfounded beliefs that others intend to deliberately cause harm are a frequent and burdensome symptom in early psychosis, but their emergence and consolidation still remains opaque. Recent theories suggest that overly precise prediction errors lead to an unstable model of the world providing a breeding ground for delusions. Here, we employ a Bayesian approach to test for such an unstable model of the world and investigate the computational mechanisms underlying emerging paranoia. We modelled behaviour of 18 first-episode psychosis patients (FEP), 19 individuals at clinical high risk for psychosis (CHR-P), and 19 healthy controls (HC) during an advice-taking task designed to probe learning about others’ changing intentions. We formulated competing hypotheses comparing the standard Hierarchical Gaussian Filter (HGF), a Bayesian belief updating scheme, with a mean-reverting HGF to model an altered perception of volatility. There was a significant group-by-volatility interaction on advice-taking suggesting that CHR-P and FEP displayed reduced adaptability to environmental volatility. Model comparison favored the standard HGF in HC, but the mean-reverting HGF in CHR-P and FEP in line with perceiving increased volatility, although model attributions in CHR-P were heterogeneous. We observed correlations between perceiving increased volatility and positive symptoms generally as well as with frequency of paranoid delusions specifically. Our results suggest that FEP are characterised by a different computational mechanism – perceiving the environment as increasingly volatile – in line with Bayesian accounts of psychosis. This approach may prove useful to investigate heterogeneity in CHR-P and identify vulnerability for transition to psychosis.

Abstract 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.

Deficits in memory performance have been linked to a wide range of neurological and neuropsychiatric conditions. While many studies have assessed the memory impacts of individual conditions, this study considers a broader perspective by evaluating how memory recall is differentially associated with nine common neuropsychiatric conditions using data drawn from 55 international studies, aggregating 15,883 unique participants aged 15–90. The effects of dementia, mild cognitive impairment, Parkinson’s disease, traumatic brain injury, stroke, depression, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder on immediate, short-, and long-delay verbal learning and memory (VLM) scores were estimated relative to matched healthy individuals. Random forest models identified age, years of education, and site as important VLM covariates. A Bayesian harmonization approach was used to isolate and remove site effects. Regression estimated the adjusted association of each clinical group with VLM scores. Memory deficits were strongly associated with dementia and schizophrenia (p < 0.001), while neither depression nor ADHD showed consistent associations with VLM scores (p > 0.05). Differences associated with clinical conditions were larger for longer delayed recall duration items. By comparing VLM across clinical conditions, this study provides a foundation for enhanced diagnostic precision and offers new insights into disease management of comorbid disorders.

Abstract Acute caffeine intake has been found to increase working memory (WM)-related brain activity in healthy adults without improving behavioral performances. The impact of daily caffeine intake—a ritual shared by 80% of the population worldwide—and of its discontinuation on working memory and its neural correlates remained unknown. In this double-blind, randomized, crossover study, we examined working memory functions in 20 young healthy non-smokers (age: 26.4 ± 4.0 years; body mass index: 22.7 ± 1.4 kg/m2; and habitual caffeine intake: 474.1 ± 107.5 mg/day) in a 10-day caffeine (150 mg × 3 times/day), a 10-day placebo (3 times/day), and a withdrawal condition (9-day caffeine followed by 1-day placebo). Throughout the 10th day of each condition, participants performed four times a working memory task (N-Back, comprising 3- and 0-back), and task-related blood-oxygen-level-dependent (BOLD) activity was measured in the last session with functional magnetic resonance imaging. Compared to placebo, participants showed a higher error rate and a longer reaction time in 3- against 0-back trials in the caffeine condition; also, in the withdrawal condition we observed a higher error rate compared to placebo. However, task-related BOLD activity, i.e., an increased attention network and decreased default mode network activity in 3- versus 0-back, did not show significant differences among three conditions. Interestingly, irrespective of 3- or 0-back, BOLD activity was reduced in the right hippocampus in the caffeine condition compared to placebo. Adding to the earlier evidence showing increasing cerebral metabolic demands for WM function after acute caffeine intake, our data suggest that such demands might be impeded over daily intake and therefore result in a worse performance. Finally, the reduced hippocampal activity may reflect caffeine-associated hippocampal grey matter plasticity reported in the previous analysis. The findings of this study reveal an adapted neurocognitive response to daily caffeine exposure and highlight the importance of classifying impacts of caffeine on clinical and healthy populations.

IntroductionThe 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.MethodA 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.ResultWe 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.ConclusionPsychosis-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.

Abstract Structural MRI studies in first-episode psychosis and the clinical high-risk state have consistently shown volumetric abnormalities. Aim of the present study was to introduce radiomics texture features in identification of psychosis. Radiomics texture features describe the interrelationship between voxel intensities across multiple spatial scales capturing the hidden information of underlying disease dynamics in addition to volumetric changes. Structural MR images were acquired from 77 first-episode psychosis (FEP) patients, 58 clinical high-risk subjects with no later transition to psychosis (CHR_NT), 15 clinical high-risk subjects with later transition (CHR_T), and 44 healthy controls (HC). Radiomics texture features were extracted from non-segmented images, and two-classification schemas were performed for the identification of FEP vs. HC and FEP vs. CHR_NT. The group of CHR_T was used as external validation in both schemas. The classification of a subject’s clinical status was predicted by importing separately (a) the difference of entropy feature map and (b) the contrast feature map, resulting in classification balanced accuracy above 72% in both analyses. The proposed framework enhances the classification decision for FEP, CHR_NT, and HC subjects, verifies diagnosis-relevant features and may potentially contribute to identification of structural biomarkers for psychosis, beyond and above volumetric brain changes.

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.

Abstract A promising new treatment approach for major depressive disorder (MDD) targets the microbiota-gut-brain (MGB) axis, which is linked to physiological and behavioral functions affected in MDD. This is the first randomized controlled trial to determine whether short-term, high-dose probiotic supplementation reduces depressive symptoms along with gut microbial and neural changes in depressed patients. Patients with current depressive episodes took either a multi-strain probiotic supplement or placebo over 31 days additionally to treatment-as-usual. Assessments took place before, immediately after and again four weeks after the intervention. The Hamilton Depression Rating Sale (HAM-D) was assessed as primary outcome. Quantitative microbiome profiling and neuroimaging was used to detect changes along the MGB axis. In the sample that completed the intervention (probiotics N = 21, placebo N = 26), HAM-D scores decreased over time and interactions between time and group indicated a stronger decrease in the probiotics relative to the placebo group. Probiotics maintained microbial diversity and increased the abundance of the genus Lactobacillus, indicating the effectivity of the probiotics to increase specific taxa. The increase of the Lactobacillus was associated with decreased depressive symptoms in the probiotics group. Finally, putamen activation in response to neutral faces was significantly decreased after the probiotic intervention. Our data imply that an add-on probiotic treatment ameliorates depressive symptoms (HAM-D) along with changes in the gut microbiota and brain, which highlights the role of the MGB axis in MDD and emphasizes the potential of microbiota-related treatment approaches as accessible, pragmatic, and non-stigmatizing therapies in MDD. Trial Registration: www.clinicaltrials.gov , identifier: NCT02957591.

Abstract To investigate the longitudinal latent state-trait structure of the different dimensions of psychosis symptoms in clinical high-risk state (CHRS) and first episode psychosis (FEP) individuals over a one year time-span. This paper examines if the symptom clusters Positive Symptoms, Negative Symptoms, Affectivity, Resistance, Activation, and Excitement according to the Brief Psychiatric Rating Scale (BPRS) differ in their trait and state characters in 196 CHRS and 131 FEP individuals. Statistical analysis was performed using latent state-trait analysis. On average, trait differences accounted for 72.2% of Positive Symptoms, 81.1% of Negative Symptoms, 57.0% of Affectivity, and 69.2% of Activation, whereas 15.0% of the variance of Resistance and 13.2% of the variance of Excitement were explained by trait differences. Explorative analyses showed a trait components’ increase of 0.408 in Positive Symptoms from baseline up to the 9th month and an increase of 0.521 in Affectivity from baseline up to the 6th month. Negative Symptoms had the highest trait component levels of all subscales between baseline and 6 months. The finding that an increasing proportion of psychosis symptoms is persisting over time underlines the importance of early intervention programs in individuals with psychotic disorders.

Abstract Continued cannabis use (CCu) is an important predictor for poor long-term outcomes in psychosis and clinically high-risk patients, but no generalizable model has hitherto been tested for its ability to predict CCu in these vulnerable patient groups. In the current study, we investigated how structured clinical and cognitive assessments and structural magnetic resonance imaging (sMRI) contributed to the prediction of CCu in a group of 109 patients with recent-onset psychosis (ROP). We tested the generalizability of our predictors in 73 patients at clinical high-risk for psychosis (CHR). Here, CCu was defined as any cannabis consumption between baseline and 9-month follow-up, as assessed in structured interviews. All patients reported lifetime cannabis use at baseline. Data from clinical assessment alone correctly classified 73% (p 0.093), and their addition to the interview-based predictor via stacking did not improve prediction significantly, either in the ROP or CHR groups (ps > 0.065). Lower functioning, specific substance use patterns, urbanicity and a lack of other coping strategies contributed reliably to the prediction of CCu and might thus represent important factors for guiding preventative efforts. Our results suggest that it may be possible to identify by clinical measures those psychosis-spectrum patients at high risk for CCu, potentially allowing to improve clinical care through targeted interventions. However, our model needs further testing in larger samples including more diverse clinical populations before being transferred into clinical practice.

Aims: Psychotic disorders are one of the main causes of chronic disability in young people. An at-risk mental state (ARMS) is represented by subclinical symptoms that precede the first episode of psychosis (FEP). The PsyYoung project aims to optimize the detection of an ARMS while reducing unnecessary psychiatric treatments. It investigates the effects of service changes on the referrals and outcomes of young people with ARMS or a FEP. Methods: Six psychiatric outpatient clinics in three cantons (Basel-Stadt, Vaud, and Geneva) participated in the project. They passed through an implementation phase including service changes and the adaptation of a standardized stepped care model for diagnosis and assessment, in addition to measures for increasing the awareness, networking and training of local professionals. Preliminary results: All participating cantons had entered the implementation phase. By March 2023, there were 619 referrals to participating sites. A total of 163 patients (37% FEP and 31% ARMS) and 15 close relatives had participated in individual longitudinal assessments, and 26 patients participated in qualitative interviews. Conclusion: This national collaborative project addresses the issue of early intervention for emerging psychoses, and creates spaces for fruitful reflections and collaboration in Switzerland. The ultimate aim of PsyYoung is to harmonize clinical practices in early intervention of psychosis on a national level.

Introduction Excessive internet use can lead to problems for some individuals. The WHO has introduced Gaming Disorder in the International Classification of Diseases-11 (ICD-11). Previous research has shown that other internet applications can cause serious mental health problems as well. It is important to provide measures of prevention, early intervention and therapy for internet use disorders (IUDs).Methods and analysis The study ‘Stepped Care Approach for Problematic Internet use Treatment’ is a randomised, two-arm, parallel-group, observer-blind trial. The aim of the study is to investigate if a stepped care approach is effective to reduce symptom severity for IUD. The sample is primarily recruited online with a focus on employees in companies with support of health insurances. After screening, the stepped care approach depends on the success of the previous step—that is, the successful reduction of criteria—and comprise: (1) app-intervention with questionnaires and feedback, (2) two telephone counsellings (duration: 50 min) based on motivational interviewing, (3) online therapy over 17 weeks (15 weekly group sessions, eight individual sessions) based on cognitive–behavioural therapy. A follow-up is conducted after 6 months. A total of 860 participants will be randomised. Hierarchical testing procedure is used to test the coprimary endpoints number of Diagnostic and Statistical Manual of Mental Disorders, fifth edition and ICD-11 criteria. Primary analysis will be performed with a sequential logit model.Ethics and dissemination The study has been approved by the Ethics Committees of the Universities of Lübeck (file number: 21-068), Mainz (file number: 2021-15907) and Berlin (file number: 015.2021). Results will be reported in accordance to the CONSORT statement. If the approach is superior to the control condition, it may serve as part of treatment for IUD.Trial registration number DRKS00025994.

Structural MRI studies in first-episode psychosis (FEP) and in clinical high risk (CHR) patients have consistently shown volumetric abnormalities in frontal, temporal, and cingulate cortex areas. The aim of the present study was to employ chaos analysis for the identification of brain topology differences in people with psychosis. Structural MRI were acquired from 77 FEP, 73 CHR and 44 healthy controls (HC). Chaos analysis of the gray matter distribution was performed: First, the distances of each voxel from the center of mass in the gray matter image was calculated. Next, the distances multiplied by the voxel intensity were represented as a spatial-series, which then was analyzed by extracting the Largest-Lyapunov-Exponent (lambda). The lambda brain map depicts thus how the gray matter topology changes. Between-group differences were identified by (a) comparing the lambda brain maps, which resulted in statistically significant differences in FEP and CHR compared to HC; and (b) matching the lambda series with the Morlet wavelet, which resulted in statistically significant differences in the scalograms of FEP against CHR and HC. The proposed framework using spatial-series extraction enhances the between-group differences of FEP, CHR and HC subjects, verifies diagnosis-relevant features and may potentially contribute to the identification of structural biomarkers for psychosis.

Abstract Deregulation of synaptic function and neurotransmission has been linked with the development of major depression disorder (MDD). Tianeptine (Tian) has been used as antidepressant with anxiolytic properties and recently as a nootropic to improve cognitive performance, but its mechanism of action is unknown. We conducted a proteomic study on the hippocampal synaptosomal fractions of adult male Wistar rats exposed to chronic social isolation (CSIS, 6 weeks), an animal model of depression and after chronic Tian treatment in controls (nootropic effect) and CSIS-exposed rats (lasting 3 weeks of 6-week CSIS) (therapeutic effect). Increased expression of Syn1 and Camk2-related neurotransmission, vesicle transport and energy processes in Tian-treated controls were found. CSIS led to upregulation of proteins associated with actin cytoskeleton, signaling transduction and glucose metabolism. In CSIS rats, Tian up-regulated proteins involved in mitochondrial energy production, mitochondrial transport and dynamics, antioxidative defense and glutamate clearance, while attenuating the CSIS-increased glycolytic pathway and cytoskeleton organization proteins expression and decreased the expression of proteins involved in V-ATPase and vesicle endocytosis. Our overall findings revealed that synaptic vesicle dynamics, specifically exocytosis, and mitochondria-related energy processes might be key biological pathways modulated by the effective nootropic and antidepressant treatment with Tian and be a potential target for therapeutic efficacy of the stress-related mood disorders.

Objective: Social dysfunction is a major feature of clinical-high-risk states for psychosis (CHR-P). Prior research has identified a neuroanatomical pattern associated with impaired social function outcome in CHR-P. The aim of the current study was to test whether social dysfunction in CHR-P is neurobiologically distinct or in a continuum with the lower end of the normal distribution of individual differences in social functioning. Methods: We used a machine learning classifier to test for the presence of a previously validated brain structural pattern associated with impaired social outcome in CHR-P (CHR-outcome-neurosignature) in the neuroimaging profiles of individuals from two non-clinical samples (total n = 1763) and examined its association with social function, psychopathology and cognition. Results: Although the CHR-outcome-neurosignature could be detected in a subset of the non-clinical samples, it was not associated was adverse social outcomes or higher psychopathology levels. However, participants whose neuroanatomical profiles were highly aligned with the CHR-outcome-neurosignature manifested subtle disadvantage in fluid (PFDR = 0.004) and crystallized intelligence (PFDR = 0.01), cognitive flexibility (PFDR = 0.02), inhibitory control (PFDR = 0.01), working memory (PFDR = 0.0005), and processing speed (PFDR = 0.04). Conclusions: We provide evidence of divergence in brain structural underpinnings of social dysfunction derived from a psychosis-risk enriched population when applied to non-clinical samples. This approach appears promising in identifying brain mechanisms bound to psychosis through comparisons of patient populations to non-clinical samples with the same neuroanatomical profiles.

ObjectivePeople at ultra-high risk (UHR) for psychosis have a high prevalence of tobacco smoking, and rates are even higher among the subgroup that later develop a psychotic disorder. However, the longitudinal relationship between the course of tobacco smoking and clinical outcomes in UHR subjects is unknown.MethodsWe investigated associations between tobacco smoking and clinical outcomes in a prospective study of UHR individuals (n = 324). Latent class mixed model analyses were used to identify trajectories of smoking severity. Mixed effects models were applied to investigate associations between smoking trajectory class and the course of attenuated psychotic symptoms (APS) and affective symptoms, as assessed using the CAARMS.ResultsWe identified four different classes of smoking trajectory: (i) Persistently High (n = 110), (ii) Decreasing (n = 29), (iii) Persistently Low (n = 165) and (iv) Increasing (n = 20). At two-year follow-up, there had been a greater increase in APS in the Persistently High class than for both the Persistently Low (ES = 9.77, SE = 4.87, p = 0.046) and Decreasing (ES = 18.18, SE = 7.61, p = 0.018) classes. There were no differences between smoking classes in the incidence of psychosis. There was a greater reduction in the severity of emotional disturbance and general symptoms in the Decreasing class than in the High (ES = −10.40, SE = 3.41, p = 0.003; ES = −22.36, SE = 10.07, p = 0.027), Increasing (ES = −11.35, SE = 4.55, p = 0.014; ES = −25.58, SE = 13.17, p = 0.050) and Low (ES = −11.38, SE = 3.29, p = 0.001; ES = −27.55, SE = 9.78, p = 0.005) classes, respectively.ConclusionsThese findings suggests that in UHR subjects persistent tobacco smoking is associated with an unfavorable course of psychotic symptoms, whereas decrease in the number of cigarettes smoked is associated with improvement in affective symptoms. Future research into smoking cessation interventions in the early stages of psychoses is required to shine light on the potential of modifying smoking behavior and its relation to clinical outcomes.

The basal forebrain cholinergic nuclei (BFCN) provide the main cholinergic input to prefrontal cortices, the hippocampi, and amygdala. These structures are highly relevant for the regulation and maintenance of many cognitive functions, such as attention and memory. In vivo neuroimaging studies reported alterations of the cholinergic system in psychotic disorders. Particularly, a downregulation of nicotinic and muscarinic acetylcholine receptors has been found. Crucially, such alterations in neurotransmission have been associated with cognitive impairments and positive and negative symptoms. Recent pharmacological studies support these findings, as they demonstrated an association between the manipulation of cholinergic transmission and an attenuation in symptom severity. Targeting acetylcholine receptors has therefore become a focus for the development of novel psychopharmacological drugs. However, many open questions remain. For instance, it remains elusive what causes such alterations in neurotransmission. While evidence supports the idea that BFCN structural integrity is altered in schizophrenia, it remains to be determined whether this is also present in other psychotic disorders. Furthermore, it is unclear when throughout the course of the disorder these alterations make their appearance and whether they reflect changes in the BFCN alone or rather aberrant interactions between the BFCN and other brain areas. In this review, the specific role of the BFCN and their projections are discussed from a neuroimaging perspective and with a focus on psychotic disorders alongside future directions. These directions set the stage for the development of new treatment targets for psychotic disorders.

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.

Abstract Negative symptoms occur frequently in individuals at clinical high risk (CHR) for psychosis and contribute to functional impairments. The aim of this study was to predict negative symptom severity in CHR after 9 months. Predictive models either included baseline negative symptoms measured with the Structured Interview for Psychosis-Risk Syndromes (SIPS-N), whole-brain gyrification, or both to forecast negative symptoms of at least moderate severity in 94 CHR. We also conducted sequential risk stratification to stratify CHR into different risk groups based on the SIPS-N and gyrification model. Additionally, we assessed the models’ ability to predict functional outcomes in CHR and their transdiagnostic generalizability to predict negative symptoms in 96 patients with recent-onset psychosis (ROP) and 97 patients with recent-onset depression (ROD). Baseline SIPS-N and gyrification predicted moderate/severe negative symptoms with significant balanced accuracies of 68 and 62%, while the combined model achieved 73% accuracy. Sequential risk stratification stratified CHR into a high (83%), medium (40–64%), and low (19%) risk group regarding their risk of having moderate/severe negative symptoms at 9 months follow-up. The baseline SIPS-N model was also able to predict social (61%), but not role functioning (59%) at above-chance accuracies, whereas the gyrification model achieved significant accuracies in predicting both social (76%) and role (74%) functioning in CHR. Finally, only the baseline SIPS-N model showed transdiagnostic generalization to ROP (63%). This study delivers a multimodal prognostic model to identify those CHR with a clinically relevant negative symptom severity and functional impairments, potentially requiring further therapeutic consideration.

Abstract Acute caffeine intake can delay sleep initiation and reduce sleep intensity, particularly when consumed in the evening. However, it is not clear whether these sleep disturbances disappear when caffeine is continuously consumed during daytime, which is common for most coffee drinkers. To address this question, we investigated the sleep of twenty male young habitual caffeine consumers during a double-blind, randomized, crossover study including three 10-day conditions: caffeine (3 × 150 mg caffeine daily), withdrawal (3 × 150 mg caffeine for 8 days, then switch to placebo), and placebo (3 × placebo daily). After 9 days of continuous treatment, electroencephalographically (EEG)-derived sleep structure and intensity were recorded during a scheduled 8-h nighttime sleep episode starting 8 (caffeine condition) and 15 h (withdrawal condition) after the last caffeine intake. Upon scheduled wake-up time, subjective sleep quality and caffeine withdrawal symptoms were assessed. Unexpectedly, neither polysomnography-derived total sleep time, sleep latency, sleep architecture nor subjective sleep quality differed among placebo, caffeine, and withdrawal conditions. Nevertheless, EEG power density in the sigma frequencies (12–16 Hz) during non-rapid eye movement sleep was reduced in both caffeine and withdrawal conditions when compared to placebo. These results indicate that daily caffeine intake in the morning and afternoon hours does not strongly impair nighttime sleep structure nor subjective sleep quality in healthy good sleepers who regularly consume caffeine. The reduced EEG power density in the sigma range might represent early signs of overnight withdrawal from the continuous presence of the stimulant during the day.

Abstract Recent life events have been implicated in the onset and progression of psychosis. However, psychological processes that account for the association are yet to be fully understood. Using a network approach, we aimed to identify pathways linking recent life events and symptoms observed in psychosis. Based on previous literature, we hypothesized that general symptoms would mediate between recent life events and psychotic symptoms. We analyzed baseline data of patients at clinical high risk for psychosis and with recent-onset psychosis (n = 547) from the Personalised Prognostic Tools for Early Psychosis Management (PRONIA) study. In a network analysis, we modeled links between the burden of recent life events and all individual symptoms of the Positive and Negative Syndrome Scale before and after controlling for childhood trauma. To investigate the longitudinal associations between burden of recent life events and symptoms, we analyzed multiwave panel data from seven timepoints up to month 18. Corroborating our hypothesis, burden of recent life events was connected to positive and negative symptoms through general psychopathology, specifically depression, guilt feelings, anxiety and tension, even after controlling for childhood trauma. Longitudinal modeling indicated that on average, burden of recent life events preceded general psychopathology in the individual. In line with the theory of an affective pathway to psychosis, recent life events may lead to psychotic symptoms via heightened emotional distress. Life events may be one driving force of unspecific, general psychopathology described as characteristic of early phases of the psychosis spectrum, offering promising avenues for interventions.

Caffeine elicits widespread effects in the central nervous system and is the most frequently consumed psychostimulant worldwide. First evidence indicates that, during daily intake, the elimination of caffeine may slow down, and the primary metabolite, paraxanthine, may accumulate. The neural impact of such adaptions is virtually unexplored. In this report, we leveraged the data of a laboratory study with N = 20 participants and three within-subject conditions: caffeine (150 mg caffeine × 3/day × 10 days), placebo (150 mg mannitol × 3/day × 10 days), and acute caffeine deprivation (caffeine × 9 days, afterward placebo × 1 day). On day 10, we determined the course of salivary caffeine and paraxanthine using liquid chromatography-mass spectrometry coupled with tandem mass spectrometry. We assessed gray matter (GM) intensity and cerebral blood flow (CBF) after acute caffeine deprivation as compared to changes in the caffeine condition from our previous report. The results indicated that levels of paraxanthine and caffeine remained high and were carried overnight during daily intake, and that the levels of paraxanthine remained elevated after 24 h of caffeine deprivation compared to placebo. After 36 h of caffeine deprivation, the previously reported caffeine-induced GM reduction was partially mitigated, while CBF was elevated compared to placebo. Our findings unveil that conventional daily caffeine intake does not provide sufficient time to clear up psychoactive compounds and restore cerebral responses, even after 36 h of abstinence. They also suggest investigating the consequences of a paraxanthine accumulation during daily caffeine intake.

Depression is a debilitating disorder, and at least one third of patients do not respond to therapy. Associations between gut microbiota and depression have been observed in recent years, opening novel treatment avenues. Here, we present the first two patients with major depressive disorder ever treated with fecal microbiota transplantation as add-on therapy. Both improved their depressive symptoms 4 weeks after the transplantation. Effects lasted up to 8 weeks in one patient. Gastrointestinal symptoms, constipation in particular, were reflected in microbiome changes and improved in one patient. This report suggests further FMT studies in depression could be worth pursuing and adds to awareness as well as safety assurance, both crucial in determining the potential of FMT in depression treatment.

High utilizers (HU) are patients with an above-average use of psychiatric inpatient treatment. A precise characterization of this patient group is important when tailoring specific treatment approaches for them. While the current literature reports evidence of sociodemographic, and socio-clinical characteristics of HU, knowledge regarding their psychological characteristics is sparse. This study aimed to investigate the association between patients' psychological characteristics and their utilization of psychiatric inpatient treatment. Patients from the University Psychiatric Clinics (UPK) Basel diagnosed with schizophrenia spectrum or bipolar affective disorders participated in a survey at the end of their inpatient treatment stay. The survey included assessments of psychological characteristics such as quality of life, self-esteem, self-stigma, subjective experience and meaning of psychoses, insight into the disease, and patients' utilization of psychiatric inpatient treatment in the last 30 months. The outcome variables were two indicators of utilization of psychiatric inpatient treatment, viz. "utilization pattern" (defined as HU vs. Non-HU [NHU]) and "length of stay" (number of inpatient treatment days in the last 30 months). Statistical analyses included multiple regression models, the least absolute shrinkage and selection operator (lasso) method, and the random forest model. We included 112 inpatients, of which 50 were classified as HU and 62 as NHU. The low performance of all statistical models used after cross-validation suggests that none of the estimated psychological variables showed predictive accuracy and hence clinical relevance regarding these two outcomes. Results indicate no link between psychological characteristics and inpatient treatment utilization in patients diagnosed with schizophrenia spectrum or bipolar affective disorders. Thus, in this study, the examined psychological variables do not seem to play an important role in patients' use of psychiatric inpatient treatment; this highlights the need for additional research to further examine underlying mechanisms of high utilization of psychiatric inpatient treatment.

The genetic architecture underlying brainstem regions and how this links to common brain disorders is not well understood. Here, the authors use MRI and GWAS data from 27,034 individuals to identify genetic and morphological brainstem features that influence common brain disorders.

Background: Psychotic disorders are associated with high rates of comorbid substance use disorders. Use of cannabis rich in tetrahydrocannabinol (THC) is linked to an increased risk of psychosis, worsening of psychotic symptoms, and an adverse course of psychotic disorders. Previous studies suggest oral cannabidiol (CBD) as possible novel antipsychotic agent; however, no studies evaluated the effects of smoked CBD.Objective: The main aim of the study was to clarify the antipsychotic potential of CBD used as adjunctive therapy simulating a naturalistic setting. Our trial is the first study evaluating the effects of smoked CBD-cigarettes as adjunctive therapy for psychotic symptoms.Methods: A randomized, placebo-controlled open-label trial of cigarettes containing CBD-rich cannabis (THC < 1%) as adjunctive therapy to standard psychiatric treatment was conducted (ClinicalTrials.gov identifier NCT04700930). Primary outcomes were mean scores of Positive and Negative Syndrome Scale (PANSS), Brøset Violence Checklist, the Beck's Depression Inventory (BDI), the Subjective Well-Being Under Neuroleptics Scale short form (SWN-K), and antipsychotic medication equivalent doses. Outcomes were assessed after 4 weeks of acute treatment and long-term follow-up after discontinuation of CBD-cigarettes after 25 weeks. Participants were 31 acutely psychotic patients with tobacco use disorder and a mean age of 35.1 ± 10.58 years (71% male). Comorbid cannabis use was diagnosed in 51.6%.Results: A discontinuous multilevel model revealed no significant group differences for primary outcomes. After 4 weeks of acute treatment, mean PANSS and BDI decreased in both groups, while an increase of antipsychotic medication equivalent was observed in the placebo group.Conclusions: The presented findings might suggest an antipsychotic medication sparing effect of CBD-cigarettes as adjunctive treatment of acute psychosis. However, the low number of participants did not allow for further statistical analysis. Hence, a larger study sample and a more rigorous study design (blinding of the interventional product, fixed dosing regimen) may reveal different results.Clinical Trial Registration:ClinicalTrials.gov, identifier: NCT04700930

Psychiatry has a well-established tradition of comparing drug-induced experiences to psychotic symptoms, based on shared phenomena such as altered perceptions. The present review focuses on experiences induced by classic psychedelics, which are substances capable of eliciting powerful psychoactive effects, characterized by distortions/alterations of several neurocognitive processes (e.g., hallucinations). Herein we refer to such experiences as psychedelic states. Psychosis is a clinical syndrome defined by impaired reality testing, also characterized by impaired neurocognitive processes (e.g., hallucinations and delusions). In this review we refer to acute phases of psychotic disorders as psychotic states. Neuropharmacological investigations have begun to characterize the neurobiological mechanisms underpinning the shared and distinct neurophysiological changes observed in psychedelic and psychotic states. Mounting evidence indicates changes in thalamic filtering, along with disturbances in cortico-striato-pallido-thalamo-cortical (CSPTC)-circuitry, in both altered states. Notably, alterations in thalamocortical functional connectivity were reported by functional magnetic resonance imaging (fMRI) studies. Thalamocortical dysconnectivity and its clinical relevance are well-characterized in psychotic states, particularly in schizophrenia research. Specifically, studies report hyperconnectivity between the thalamus and sensorimotor cortices and hypoconnectivity between the thalamus and prefrontal cortices, associated with patients' psychotic symptoms and cognitive disturbances, respectively. Intriguingly, studies also report hyperconnectivity between the thalamus and sensorimotor cortices in psychedelic states, correlating with altered visual and auditory perceptions. Taken together, the two altered states appear to share clinically and functionally relevant dysconnectivity patterns. In this review we discuss recent findings of thalamocortical dysconnectivity, its putative extension to CSPTC circuitry, along with its clinical implications and future directions.

Background: This study explores the association of experienced dependency in psychotherapy as measured with the CDQ (Care Dependency Questionnaire) and treatment outcome in depression. Furthermore, the course of care dependency and differences in the CDQ scores depending on the received type of treatment, MCT (metacognitive therapy), or CBASP (cognitive behavioral analysis system of psychotherapy), were investigated.Methods: The study follows a prospective, parallel group observational design. Patients suffering from depression received an 8-week intensive day clinic program, which was either CBASP or MCT. The treatment decision was made by clinicians based on the presented symptomatology and with regard to the patients' preferences. The patients reported depressive symptoms with the QIDS-SR16 (Quick Inventory of Depressive Symptomatology) and levels of experienced care dependency with the German version of the CDQ on a weekly basis. Mixed-model analyses were run to account for the repeated-measures design.Results: One hundred patients were included in the analyses. Results indicate that higher levels of care dependency might predict a less favorable outcome of depressive symptomatology. Levels of care dependency as well as depressive symptoms decreased significantly over the course of treatment. There was no significant between-group difference in care dependency between the two treatment groups.Conclusion: The results suggest that care dependency might be associated with a worse treatment outcome in depressed patients. In general, care dependency seems to be a dynamic construct, as it is changing over time, while the levels of care dependency seem to be independent from the received type of treatment. Future research should continue investigating the mechanisms of care dependency in a randomized controlled design.Clinical Trial Registration:https://www.drks.de/drks_web/, identifier: DRKS00023779.

The putative risk/protective factors for several personality disorders remain unclear. The vast majority of published studies has assessed personality characteristics/traits rather than disorders. Thus, the current umbrella review of meta-analyses (MAs) aims to systematically assess risk or protective factors associated with personality disorders. We searched PubMed–MEDLINE/PsycInfo databases, up to August 31, 2020. Quality of MAs was assessed with AMSTAR-2, while the credibility of evidence for each association was assessed through standard quantitative criteria. Out of 571 initial references, five meta-analyses met inclusion criteria, encompassing 56 associations of 26 potential environmental factors for antisocial, dependent, borderline personality disorder, with a median of five studies per association, and median 214 cases per association. Overall, 35 (62.5%) of the associations were nominally significant. Six associations met class II (i.e., highly suggestive) evidence for borderline personality disorder, with large effect sizes involving childhood emotional abuse (OR = 28.15, 95% CI 14.76–53.68), childhood emotional neglect (OR = 22.86, 95% CI 11.55–45.22), childhood any adversities (OR = 14.32, 95% CI 10.80–18.98), childhood physical abuse (OR = 9.30, 95% CI 6.57–13.17), childhood sexual abuse (OR = 7.95, 95% CI 6.21–10.17), and childhood physical neglect (OR = 5.73, 95% CI 3.21–10.21), plus 16 further associations supported by class IV evidence. No risk factor for antisocial or dependent personality disorder was supported by class I, II, and III, but six and seven met class IV evidence, respectively. Quality of included meta-analyses was rated as moderate in two, critically low in three. The large effect sizes found for a broad range of childhood adversities suggest that prevention of personality disorders should target childhood-related risk factors. However, larger cohort studies assessing multidimensional risk factors are needed in the field.

Background: Interpersonal skills deficits and dysfunctional metacognitive beliefs have been implicated in the etiology and maintenance of depression. This study aimed to investigate the association between changes in these skills deficits and change in depressive symptoms over the course of treatment with Cognitive Behavioral Analysis System of Psychotherapy (CBASP) and Metacognitive Therapy (MCT).Methods: In this prospective, parallel group observational study, data was collected at baseline and after 8 weeks of an intensive day clinic psychotherapy program. Based on a shared decision between patients and clinicians, patients received either CBASP or MCT. Ninety patients were included in the analyses (CBASP: age M = 38.7, 40.5% female, MCT: age M = 44.7, 43.3% female). Interpersonal deficits were assessed with the short-form of the Luebeck Questionnaire for Recording Preoperational Thinking (LQPT-SF) and the Impact Message Inventory (IMI-R). Metacognitive beliefs were assessed with the Metacognition Questionnaire-30 (MCQ-30). The Quick Inventory of Depressive Symptomatology (QIDS-SR16) was utilized to assess depressive symptoms. A regression analysis was conducted to assess variables associated with outcome. ANCOVAs were utilized to investigate whether improvement in skills deficits is dependent on type of treatment received.Results: Improvements in preoperational thinking and increases in friendly-dominant behavior were associated with change in depressive symptoms. There was no association between reductions in dysfunctional metacognitive beliefs and a decrease in depressive symptoms. While both treatment groups showed significant improvements in interpersonal and metacognitive skills, there was no significant between-group difference in the change scores for either of these skills.Conclusion: Our findings suggest that changes in interpersonal skills seem to be of particular relevance in the treatment of depression. These results have to be replicated in a randomized-controlled design before firm conclusions can be drawn.

The treatment of patients with schizophrenia and substance use disorder poses a challenge for clinicians. Continued use of cannabis and cocaine can exacerbate psychotic symptoms and worsen the course of disease. To date, no pharmacotherapy is available for patients with cannabis use disorder (CUD). Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are the main active constituents in Cannabis sativa, with the latter being linked to an increased risk of psychosis. We describe a clinical case of a male patient diagnosed with schizophrenia, combined personality disorder, CUD and cocaine use disorder. Over the course of 8 years, he was hospitalized 30 times due to psychotic relapses and continued substance use. Consequently, CBD cigarettes with a low THC content (

Schizophrenia has a prodromal phase of several years in most patients, making it possible to identify patients at clinical high risk (CHR) for developing the disorder. So far, these individuals are identified based on clinical criteria alone, and there is no reliable biomarker for predicting the transition to psychosis. It is well-established that reductions in brain volume, especially in the hippocampus, are associated with schizophrenia. Therefore, hippocampal volume may serve as a biomarker for psychosis. Several studies have already investigated hippocampal volume in CHR groups. Based on these studies, the present meta-analysis compares the baseline left and right hippocampal volume of CHR patients who developed a psychosis with that of CHR patients without such a transition. Our results show no statistically significant effect of the hippocampal volume on the transition risk for psychosis.

Distress Tolerance Skills (DTS) are an important component of Dialectical Behavioral Therapy (DBT), a therapy method frequently used for treating patients with Borderline Personality Disorder (BPD). However, little is known about how DTS-training is experienced by individuals with BPD. The aim of this study was to explore BPD patients' experiences with receiving DTS-training. Qualitative data were collected through semi-structured interviews with 24 individuals (87.5% females) with a primary diagnosis of BPD who received DTS-training in the context of 18 months of DBT treatment. Interview data were analyzed following the procedures of qualitative content analysis. Participants reported various effects of DTS including an immediate reduction of tension. Patients perceived DTS as a tool to cope with difficult interpersonal situations and emergencies and stated that this helped them to feel stable, safe and self-confident. Patients reported difficulties during the initial engagement, the learning process and the application of DTS as well as various facilitating factors. Implications of the findings for further research and for optimizing DTS-training in clinical practice are discussed.

Anhedonia has been associated with abnormal reward-related striatal dopamine functioning in patients with different psychiatric disorders. Here, we tested whether anhedonia expression mapped onto striatal volume across several psychiatric diagnoses.T1-weighted images from 313 participants including 89 healthy controls (HC), 22 patients with opioid use disorder (OUD), 50 patients with major depressive disorder (MDD), 45 patients with borderline personality disorder (BPD), 49 patients with first-episode psychosis (FEP), 43 patients with cocaine use disorder (CUD) and 15 patients with schizophrenia (SZ) were included. Anhedonia was assessed with subscores of the Beck Depression Inventory (BDI) and/or the Scale for the Assessment of Negative Symptoms (SANS). Voxel-based morphometry (VBM) was conducted for identifying dimensional symptom-structure associations using region of interest (ROI, dorsal and ventral striatum) and whole-brain analyses, as well as for group comparisons of striatal volume.ROI analyses revealed significant negative relationships between putamen volume and BDI and SANS anhedonia scores across OUD, MDD, BPD, CUD and SZ patients (n = 175) and MDD, FEP and SZ patients (n = 114), respectively. Whole-brain VBM analyses confirmed these associations and further showed negative relationships between anhedonia severity and volume of the bilateral cerebellum. There were group differences in right accumbens volume, which however were not related to anhedonia expression across the different diagnoses.Our findings indicate volumetric abnormalities in the putamen and cerebellum as a common neural substrate of anhedonia severity that cut across psychiatric entities.

Background: Childhood maltreatment and difficulties in emotion regulation are common in patients with Borderline Personality Disorder (BPD) and Depressive Disorders (DD). Objective: This study examines differences between patients with BPD and patients with DD, regarding childhood maltreatment and difficulties in emotion regulation as well as the mediating effect of different aspects of emotion regulation deficits on the association between childhood maltreatment and BPD-symptoms. Method: A total of 305 participants, 177 with BPD and 128 with DD completed an assessment including the Childhood Trauma Questionnaire (CTQ), the Emotion Regulation Scale (DERS), the Brief Symptom Inventory (BSI), and the Structured Clinical Interview for DSM-IV (SCID). Data was analyzed using multiple analyses of variances and mediation analyses. Results: Patients with BPD reported more childhood maltreatment and more difficulties in emotion regulation than patients with DD. When general symptom severity, age, and gender were included in the analysis as covariates only group differences regarding ‘impulse control difficulties’ (F(1,299) = 38.97, p < .001, ηp2 = .115), ‘limited access to emotion regulation strategies’ (F(1,299) = 4.66, p = .032, ηp2 = .015), and ‘lack of emotional clarity’ (F(1,299) = 9.38, p = .002, ηp2 = .030) remained statistically significant. A mediation analysis, including above-mentioned covariates, indicated an association between emotional abuse and BPD-symptoms, which was mediated by difficulties in emotion regulation (indirect effect B = .012, 95% CI [.001; .031], R2 = .429). Subscale analyses revealed ‘impulse control difficulties’ as the aspect of difficulties in emotion regulation that has the greatest impact on this association (B = .021, 95% CI [.003; .045]). Conclusions: Patients with BPD display more childhood maltreatment and difficulties in emotion regulation than patients with DD. Difficulties in emotion regulation, especially difficulties in impulse control, seem to play an important role in the association between childhood emotional abuse and BPD-symptoms.

In community studies, both attenuated psychotic symptoms (APS) and basic symptoms (BS) were more frequent but less clinically relevant in children and adolescents compared to adults. In doing so, they displayed differential age thresholds that were around age 16 for APS, around age 18 for perceptive BS, and within the early twenties for cognitive BS. Only the age effect has previously been studied and replicated in clinical samples for APS. Thus, we examined the reported age effect on and age thresholds of 14 criteria-relevant BS in a patient sample at clinical-high risk of psychosis (N = 261, age 15–40 yrs.), recruited within the European multicenter PRONIA-study. BS and the BS criteria, “Cognitive Disturbances” (COGDIS) and “Cognitive-perceptive BS” (COPER), were assessed with the “Schizophrenia Proneness Instrument, Adult version” (SPI-A). Using logistic regressions, prevalence rates of perceptive and cognitive BS, and of COGDIS and COPER, as well as the impact of social and role functioning on the association between age and BS were studied in three age groups (15–18 years, 19–23 years, 24–40 years). Most patients (91.2%) reported any BS, 55.9% any perceptive and 87.4% any cognitive BS. Furthermore, 56.3% met COGDIS and 80.5% COPER. Not exhibiting the reported differential age thresholds, both perceptive and cognitive BS, and, at trend level only, COPER were less prevalent in the oldest age group (24–40 years); COGDIS was most frequent in the youngest group (15–18 years). Functional deficits did not better explain the association with age, particularly in perceptive BS and cognitive BS meeting the frequency requirement of BS criteria. Our findings broadly confirmed an age threshold in BS and, thus, the earlier assumed link between presence of BS and brain maturation processes. Yet, age thresholds of perceptive and cognitive BS did not differ. This lack of differential age thresholds might be due to more pronounced the brain abnormalities in this clinical sample compared to earlier community samples. These might have also shown in more frequently occurring and persistent BS that, however, also resulted from a sampling toward these, i.e., toward COGDIS. Future studies should address the neurobiological basis of CHR criteria in relation to age.

There has been considerable interest in the role of synchronous brain activity abnormalities in the pathophysiology of psychotic disorders and their relevance for treatment; one index of such activity are EEG resting-state microstates. These reflect electric field configurations of the brain that persist over 60–120 ms time periods. A set of quasi-stable microstates classes A, B, C, and D have been repeatedly identified across healthy participants. Changes in microstate parameters coverage, duration and occurrence have been found in medication-naïve as well as medicated patients with psychotic disorders compared to healthy controls. However, to date, only two studies have directly compared antipsychotic medication effects on EEG microstates either pre- vs. post-treatment or between medicated and unmedicated chronic schizophrenia patients. The aim of this study was therefore to directly compare EEG resting-state microstates between medicated and medication-naïve (untreated) first-episode (FEP) psychosis patients (mFEP vs. uFEP). We used 19-channel clinical EEG recordings to compare temporal parameters of four prototypical microstate classes (A–D) within an overall sample of 47 patients (mFEP n = 17; uFEP n = 30). The results demonstrated significant decreases of microstate class A and significant increases of microstate class B in mFEP compared to uFEP. No significant differences between groups were found for microstate classes C and D. Further studies are needed to replicate these results in longitudinal designs that assess antipsychotic medication effects on neural networks at the onset of the disorder and over time during illness progression. As treatment response and compliance in FEP patients are relatively low, such studies could contribute to better understand treatment outcomes and ultimately improve treatment strategies.

A 39-year-old female patient suffering from severe, treatment-resistant depression and other symptoms associated with a complex personality disorder was admitted to our open psychiatric ward for an experimental treatment with lysergic acid diethylamide (LSD). The substance was administered in repeated weekly and ascending doses. Curiously, there were no substantial acute subjective effects of the drug despite adequate dosing, which was also confirmed by plasma drug concentration monitoring. However, the patient showed rapid and significant improvement with most notable changes in depressed mood, emotional instability, loss of energy, and suicidal ideations. Additionally, the SCL-90 questionnaire indicated significant decreases in global severity and in various psychopathological subscales. Improvements persisted for ~7 days after each administration. Due to the severe course of the illness and the resistance to previous treatment it was decided to continue this experimental approach with weekly repeated doses of LSD. The patient will be observed closely with regard to somatic and mental side effects. Two features of this case are remarkable: Firstly, administration of LSD was associated with significant improvements in various symptoms of a condition usually difficult to treat. Secondly, symptom reductions occurred in the absence of acute drug effects. Therefore, the mechanism of action seemed to deviate from the concept that improvements after administration of drugs like LSD are due to experiences during the acute drug effects. This case might indicate that LSD can induce rapid but transient beneficial effects on several psychopathological symptoms. The time course of these improvements resembled antidepressant effects seen after administration of ketamine.

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).