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As early detection of symptoms in the subclinical to clinical psychosis spectrum may improve health outcomes, knowing the probabilistic susceptibility of developing a disorder could guide mitigation measures and clinical intervention. In this context, polygenic risk scores (PRSs) quantifying the additive effects of multiple common genetic variants hold the potential to predict complex diseases and index severity gradients. PRSs for schizophrenia (SZ) and bipolar disorder (BD) were computed using Bayesian regression and continuous shrinkage priors based on the latest SZ and BD genome-wide association studies (Psychiatric Genomics Consortium, third release). Eight well-phenotyped groups (n = 1580; 56% males) were assessed: control (n = 305), lower (n = 117) and higher (n = 113) schizotypy (both groups of healthy individuals), at-risk for psychosis (n = 120), BD type-I (n = 359), BD type-II (n = 96), schizoaffective disorder (n = 86), and SZ groups (n = 384). PRS differences were investigated for binary traits and the quantitative Positive and Negative Syndrome Scale. Both BD-PRS and SZ-PRS significantly differentiated controls from at-risk and clinical groups (Nagelkerke’s pseudo-R2: 1.3–7.7%), except for BD type-II for SZ-PRS. Out of 28 pairwise comparisons for SZ-PRS and BD-PRS, 9 and 12, respectively, reached the Bonferroni-corrected significance. BD-PRS differed between control and at-risk groups, but not between at-risk and BD type-I groups. There was no difference between controls and schizotypy. SZ-PRSs, but not BD-PRSs, were positively associated with transdiagnostic symptomology. Overall, PRSs support the continuum model across the psychosis spectrum at the genomic level with possible irregularities for schizotypy. The at-risk state demands heightened clinical attention and research addressing symptom course specifiers. Continued efforts are needed to refine the diagnostic and prognostic accuracy of PRSs in mental healthcare.

Research concerning the spatial orientation in patients with schizophrenia has demonstrated a state independent deficit in inhibition of return (IOR), which has been discussed as a vulnerability marker for schizophrenia. Other recent investigations on brain structure and cognitive processing have revealed less deficits in schizophrenia patients with comorbid cannabis use (SCH + CUD) compared to abstinent schizophrenia patients (SCH). It was hypothesized that these results may reflect a premorbid lower vulnerability in at least a subgroup of comorbid patients. The aim of the present study is to extend previous work by investigating IOR functioning in patients with schizophrenia and cannabis use. This in turn should supplement the existing studies on the vulnerability of this patient group. Therefore, we compared IOR functioning in four groups: 62 patients with schizophrenia and 46 healthy controls, both with and without cannabis use. Participants underwent a covert orienting of attention task (COVAT) with peripheral cues and three stimulus onset asynchronies (SOAs: 200 ms, 400 ms and 800 ms). Both schizophrenia groups displayed delayed IOR with a more pronounced IOR effect in SCH + CUD compared to SCH. In healthy controls, IOR did not seem to be significantly affected by cannabis use. Significant IOR-differences between groups were only seen between SCH patients without cannabis use and both healthy groups at SOA 400 ms. Patterns of cannabis use as well as clinical parameters of psychoses did not affect IOR. Our results may support the hypothesis of IOR as a vulnerability marker for schizophrenia and of a lower biological vulnerability in at least a subgroup of SCH + CUD.

Currently, the metabotropic glutamate receptor 5 (mGluR5) is the subject of several lines of research in the context of neurology and is of high interest as a target for positron-emission tomography (PET). Here, we assessed the feasibility of using [11C]ABP688, a specific antagonist radiotracer for an allosteric site on the mGluR5, to evaluate changes in glutamatergic neurotransmission through a mismatch-negativity (MMN) task as a part of a simultaneous and synchronized multimodal PET/MR-EEG study. We analyzed the effect of MMN by comparing the changes in nondisplaceable binding potential (BPND) prior to (baseline) and during the task in 17 healthy subjects by applying a bolus/infusion protocol. Anatomical and functional regions were analyzed. A small change in BPND was observed in anatomical regions (posterior cingulate cortex and thalamus) and in a functional network (precuneus) after the start of the task. The effect size was quantified using Kendall’s W value and was 0.3. The motor cortex was used as a control region for the task and did not show any significant BPND changes. There was a significant ΔBPND between acquisition conditions. On average, the reductions in binding across the regions were - 8.6 ± 3.2% in anatomical and - 6.4 ± 0.5% in the functional network (p ≤ 0.001). Correlations between ΔBPND and EEG latency for both anatomical (p = 0.008) and functional (p = 0.022) regions were found. Exploratory analyses suggest that the MMN task played a role in the glutamatergic neurotransmission, and mGluR5 may be indirectly modulated by these changes.

IMPORTANCE The ENIGMA clinical high risk (CHR) for psychosis initiative, the largest pooled neuroimaging sample of individuals at CHR to date, aims to discover robust neurobiological markers of psychosis risk.OBJECTIVE To investigate baseline structural neuroimaging differences between individuals at CHR and healthy controls as well as between participants at CHR who later developed a psychotic disorder (CHR-PS+) and those who did not (CHR-PS-).DESIGN, SETTING, AND PARTICIPANTS In this case-control study, baseline T1-weighted magnetic resonance imaging (MRI) data were pooled from 31 international sites participating in the ENIGMA Clinical High Risk for Psychosis Working Group. CHR status was assessed using the Comprehensive Assessment of At-Risk Mental States or Structured Interview for Prodromal Syndromes. MRI scans were processed using harmonized protocols and analyzed within a mega-analysis and meta-analysis framework from January to October 2020.MAIN OUTCOMES AND MEASURES Measures of regional cortical thickness (CT), surface area, and subcortical volumes were extracted from T1-weighted MRI scans. Independent variables were group (CHR group vs control group) and conversion status (CHR-PS+ group vs CHR-PS- group vs control group).RESULTS Of the 3169 included participants, 1428 (45.1%) were female, and the mean (SD; range) age was 21.1 (4.9; 9.5-39.9) years. This study included 1792 individuals at CHR and 1377 healthy controls. Using longitudinal clinical information, 253 in the CHR-PS+ group, 1234 in the CHR-PS- group, and 305 at CHR without follow-up data were identified. Compared with healthy controls, individuals at CHR exhibited widespread lower CT measures (mean [range] Cohen d = -0.13 [-0.17 to -0.09]), but not surface area or subcortical volume. Lower CT measures in the fusiform, superior temporal, and paracentral regions were associated with psychosis conversion (mean Cohen d = -0.22; 95% CI, -0.35 to 0.10). Among healthy controls, compared with those in the CHR-PS+ group, age showed a stronger negative association with left fusiform CT measures (F = 9.8; P < .001; q < .001) and left paracentral CT measures (F = 5.9; P = .005; q = .02). Effect sizes representing lower CT associated with psychosis conversion resembled patterns of CT differences observed in ENIGMA studies of schizophrenia (rho = 0.35; 95% CI, 0.12 to 0.55; P = .004) and individuals with 22q11.2 microdeletion syndrome and a psychotic disorder diagnosis (rho = 0.43; 95% CI, 0.20 to 0.61; P = .001).CONCLUSIONS AND RELEVANCE This study provides evidence for widespread subtle, lower CT measures in individuals at CHR. The pattern of CT measure differences in those in the CHR-PS+ group was similar to those reported in other large-scale investigations of psychosis. Additionally, a subset of these regions displayed abnormal age associations. Widespread disruptions in CT coupled with abnormal age associations in those at CHR may point to disruptions in postnatal brain developmental processes.Question How are brain morphometric features associated with later psychosis conversion in individuals at clinical high risk (CHR) for developing psychosis?Findings In this case-control study including 3169 participants, lower cortical thickness, but not cortical surface area or subcortical volume, was more pronounced in individuals at CHR in a manner highly consistent with thinner cortex in individuals with established psychosis. Regions that displayed lower cortical thickness in individuals at CHR who later developed a psychotic disorder additionally displayed abnormal associations with age.Meaning In this study, CHR status and later transition to psychosis was robustly associated with lower cortical thickness; abnormal age associations and specificity to cortical thickness may point to aberrant postnatal brain development in individuals at CHR, including pruning and myelination.This case-control study investigates baseline structural magnetic resonance imaging (MRI) differences between individuals at clinical high risk and healthy controls as well as between participants at clinical high risk who later developed a psychotic disorder and those who did not.

ImportanceThe ENIGMA clinical high risk for psychosis (CHR) initiative, the largest pooled CHR-neuroimaging sample to date, aims to discover robust neurobiological markers of psychosis risk in a sample with known heterogeneous outcomes.ObjectiveWe investigated baseline structural neuroimaging differences between CHR subjects and healthy controls (HC), and between CHR participants who later developed a psychotic disorder (CHR-PS+) and those who did not (CHR-PS-). We assessed associations with age by group and conversion status, and similarities between the patterns of effect size maps for psychosis conversion and those found in other large-scale psychosis studies.Design, Setting, and ParticipantsBaseline T1-weighted MRI data were pooled from 31 international sites participating in the ENIGMA CHR Working Group. MRI scans were processed using harmonized protocols and analyzed within a mega- and meta-analysis framework from January-October 2020.Main Outcome(s) and Measure(s)Measures of regional cortical thickness (CT), surface area (SA), and subcortical volumes were extracted from T1-weighted MRI scans. Independent variables were group (CHR, HC) and conversion status (CHR-PS+, CHR-PS-, HC).ResultsThe final dataset consisted of 3,169 participants (CHR=1,792, HC=1,377, age range: 9.5 to 39.8 years, 45% female). Using longitudinal clinical information, we identified CHR-PS+ (N=253) and CHR-PS- (N=1,234). CHR exhibited widespread thinner cortex compared to HC (average d=-0.125, range: -0.09 to -0.17), but not SA or subcortical volume. Thinner cortex in the fusiform, superior temporal, and paracentral regions was associated with psychosis conversion (average d=-0.22). Age showed a stronger negative association with left fusiform and left paracentral CT in HC, compared to CHR-PS+. Regional CT psychosis conversion effect sizes resembled patterns of CT alterations observed in other ENIGMA studies of psychosis.Conclusions and RelevanceWe provide evidence for widespread subtle CT reductions in CHR. The pattern of regions displaying greater CT alterations in CHR-PS+ were similar to those reported in other large-scale investigations of psychosis. Additionally, a subset of these regions displayed abnormal age associations. Widespread CT disruptions coupled with abnormal age associations in CHR may point to disruptions in postnatal brain developmental processes.Key PointsQuestionHow do baseline brain morphometric features relate to later psychosis conversion in individuals at clinical high risk (CHR)?FindingsIn the largest coordinated international analysis to date, reduced baseline cortical thickness, but not cortical surface area or subcortical volume, was more pronounced in CHR, in a manner highly consistent with thinner cortex in established psychosis. Regions that displayed greater cortical thinning in future psychosis converters additionally displayed abnormal associations with age.MeaningCHR status and later transition to psychosis is robustly associated with reduced cortical thickness. Abnormal age associations and specificity to cortical thickness may point to aberrant postnatal brain development in CHR, including pruning and myelination.

This prognostic study evaluates whether psychosis transition can be predicted in patients with clinical high-risk syndromes or recent-onset depression by multimodal machine learning that optimally integrates clinical and neurocognitive data, structural magnetic resonance imaging, and polygenic risk scores for schizophrenia., Key Points Question Can a transition to psychosis be predicted in patients with clinical high-risk states or recent-onset depression by optimally integrating clinical, neurocognitive, neuroimaging, and genetic information with clinicians’ prognostic estimates? Findings In this prognostic study of 334 patients and 334 control individuals, machine learning models sequentially combining clinical and biological data with clinicians’ estimates correctly predicted disease transitions in 85.9% of cases across geographically distinct patient populations. The clinicians’ lack of prognostic sensitivity, as measured by a false-negative rate of 38.5%, was reduced to 15.4% by the sequential prognostic model. Meaning These findings suggest that an individualized prognostic workflow integrating artificial and human intelligence may facilitate the personalized prevention of psychosis in young patients with clinical high-risk syndromes or recent-onset depression., Importance Diverse models have been developed to predict psychosis in patients with clinical high-risk (CHR) states. Whether prediction can be improved by efficiently combining clinical and biological models and by broadening the risk spectrum to young patients with depressive syndromes remains unclear. Objectives To evaluate whether psychosis transition can be predicted in patients with CHR or recent-onset depression (ROD) using multimodal machine learning that optimally integrates clinical and neurocognitive data, structural magnetic resonance imaging (sMRI), and polygenic risk scores (PRS) for schizophrenia; to assess models’ geographic generalizability; to test and integrate clinicians’ predictions; and to maximize clinical utility by building a sequential prognostic system. Design, Setting, and Participants This multisite, longitudinal prognostic study performed in 7 academic early recognition services in 5 European countries followed up patients with CHR syndromes or ROD and healthy volunteers. The referred sample of 167 patients with CHR syndromes and 167 with ROD was recruited from February 1, 2014, to May 31, 2017, of whom 26 (23 with CHR syndromes and 3 with ROD) developed psychosis. Patients with 18-month follow-up (n = 246) were used for model training and leave-one-site-out cross-validation. The remaining 88 patients with nontransition served as the validation of model specificity. Three hundred thirty-four healthy volunteers provided a normative sample for prognostic signature evaluation. Three independent Swiss projects contributed a further 45 cases with psychosis transition and 600 with nontransition for the external validation of clinical-neurocognitive, sMRI-based, and combined models. Data were analyzed from January 1, 2019, to March 31, 2020. Main Outcomes and Measures Accuracy and generalizability of prognostic systems. Results A total of 668 individuals (334 patients and 334 controls) were included in the analysis (mean [SD] age, 25.1 [5.8] years; 354 [53.0%] female and 314 [47.0%] male). Clinicians attained a balanced accuracy of 73.2% by effectively ruling out (specificity, 84.9%) but ineffectively ruling in (sensitivity, 61.5%) psychosis transition. In contrast, algorithms showed high sensitivity (76.0%-88.0%) but low specificity (53.5%-66.8%). A cybernetic risk calculator combining all algorithmic and human components predicted psychosis with a balanced accuracy of 85.5% (sensitivity, 84.6%; specificity, 86.4%). In comparison, an optimal prognostic workflow produced a balanced accuracy of 85.9% (sensitivity, 84.6%; specificity, 87.3%) at a much lower diagnostic burden by sequentially integrating clinical-neurocognitive, expert-based, PRS-based, and sMRI-based risk estimates as needed for the given patient. Findings were supported by good external validation results. Conclusions and Relevance These findings suggest that psychosis transition can be predicted in a broader risk spectrum by sequentially integrating algorithms’ and clinicians’ risk estimates. For clinical translation, the proposed workflow should undergo large-scale international validation.

Objectives: The emotional Stroop effect is defined as increased reaction times to emotional stimuli compared to neutral ones. It has been often reported in the literature, on both behavioral and neurophysiological level. The goal of this study was to investigate the frontal brain activation in individuals at risk for schizophrenic psychosis and bipolar disorder during an emotional Stroop task. We expected to observe decreased activation in the at-risk individuals compared to the healthy controls. Methods: Individuals at high risk for psychosis (HR), at ultra-high risk for psychosis (UHR), at risk for bipolar disorder (BIP) and healthy controls (HC) performed an emotional Stroop task, which included positively, negatively and neutrally valenced words. Functional near-infrared spectroscopy (fNIRS) was used to measure levels of oxygenated hemoglobin (O2Hb) representing brain activity in the dorsolateral prefrontal and frontotemporal cortex. Results: Results showed significantly decreased levels of O2Hb in the right dorsolateral prefrontal cortex (DLPFC) in the HR and UHR groups compared to the HC, indicating lower activity. Even though the decrease was independent from the valence of the words, it was the most visible for the negative ones. Moreover, significantly lower O2Hb levels in the frontotemporal cortex (FTC) were observed in all at risk groups compared to the HC. Conclusions: Lower activity in the FTC in groups at risk for psychosis and bipolar disorder reflects unspecific dysfunctions. Decreased activity in the DLPFC in the HR and UHR groups indicates that hypofrontality can be found already in individuals at risk for schizophrenic psychosis., NeuroImage: Clinical, 26, ISSN:2213-1582

Little is known about valid predictive markers for functional outcomes in an at-risk for psychosis population. In a cohort of 185 individuals (age: 13-35 years) at high risk (HR) and ultra-high risk (UHR), we assessed pan-NRG1 mRNA levels across good functional status (GFS) and poor functional status (PFS) at baseline, and good functional outcome (GFO) and poor functional outcome (PFO) at 12-month follow-up. NRG1 mRNA levels were significantly higher in individuals with PFO than individuals with GFO at 12-month follow-up. Our findings suggest that NRG1 might emerge as a predictive marker for functional outcomes in at-risk for psychosis population.

Simultaneous PET/MR/EEG (Positron Emission Tomography – Magnetic Resonance – Electroencephalography), a new tool for the investigation of neuronal networks in the human brain, is presented here within the framework of the European Union Project TRIMAGE. The trimodal, cost-effective PET/MR/EEG imaging tool makes use of cutting edge technology both in PET and in MR fields. A novel type of magnet (1.5T, non-cryogenic) has been built together with a PET scanner that makes use of the most advanced photodetectors (i.e., SiPM matrices), scintillators matrices (LYSO) and digital electronics. The combined PET/MR/EEG system is dedicated to brain imaging and has an inner diameter of 260 mm and an axial Field-of-View of 160 mm.It enables the acquisition and assessment of molecular metabolic information with high spatial and temporal resolution in a given brain simultaneously. The dopaminergic system and the glutamatergic system in schizophrenic patients are investigated via PET, the same physiological/pathophysiological conditions with regard to functional connectivity, via fMRI, and its electrophysiological signature via EEG. In addition to basic neuroscience questions addressing neurovascular-metabolic coupling, this new methodology lays the foundation for individual physiological and pathological fingerprints for a wide research field addressing healthy aging, gender effects, plasticity and different psychiatric and neurological diseases.The preliminary performances of two components of the imaging tool (PET and MR) are discussed. Initial results of the search of possible candidates for suitable schizophrenia biomarkers are also presented as obtained with PET/MR systems available to the collaboration.

The aim of this study was to test the validity of the CHR state by focusing on the course of psychosis spectrum symptoms, depression and global functioning in converters and non-converters. A total of 188 CHR-positive subjects (60.2% men) aged between 13 and 35 years (mean = 20.5) at study outset were assessed five times (t0-t4) over a total observation period of 36 months. Conversion to manifest psychosis was defined according to ICD-10 criteria for schizophrenia (F20) or brief psychotic disorder (F23). Measures of positive and negative symptoms were assessed with the Structured Interview for Prodromal Syndromes (SIPS), depression with the Calgary Depression Scale (CDS), and global functioning with the Global Assessment of Functioning Scale (GAF). Converters scored higher over time on all SIPS scales apart from grandiosity (Cohen's d: 0.5-0.7; all p < 0.001), higher on the CDS (d = 0.43, p = 0.001) and lower on the GAF (d = 0.69, p < 0.001) than did non-converters. Positive and negative symptoms as well as depression were most severe at study outset (t0) and then declined sharply following a linear function over the three-year observation period (t1-t4) across groups (all linear contrasts p < 0.001). In conclusion, converters showed significantly more psychopathological symptoms and poorer functioning before crossing the diagnostic threshold for manifest psychosis. CHR-subjects who convert to manifest psychosis during follow-up appear to be recovering from illness rather than becoming ill. Major issues involve the poor discrimination of CHR state and psychosis as well as the dichotomous definition of both at-risk and disease states. Further examination in other CHR-samples is warranted.

For the first time in the Swiss health care system, this evaluation study examined whether patients with acute psychiatric illness who were admitted for inpatient treatment could be treated in an acute day hospital instead. The acute day hospital is characterized by the possibility of direct admission of patients without preliminary consultation or waiting time and is open every day of the week. In addition, it was examined whether and to what extent there are cost advantages for day hospital treatment. Patients who were admitted to the hospital with a referral to an inpatient admission were treated randomly either fully inpatient or in the acute day hospital. As a pilot study, 44 patients were admitted to the study. Evidence of efficacy could be provided for both treatment settings based on significant reduction in psychopathological symptoms and improvement in functional level in the course of treatment. There were no significant differences between the two settings in terms of external assessment of symptoms, subjective symptom burden, functional level, quality of life, treatment satisfaction, and number of treatment days. Treatment in the day hospital was about 45% cheaper compared to inpatient treatment. The results show that acutely ill psychiatric patients of different symptom severity can be treated just as well in an acute day hospital instead of being admitted to the hospital. In addition, when direct treatment costs are considered, there are clear cost advantages for day hospital treatment.

Schizophrenia is a complex and chronic neuropsychiatric disorder, with a heritability of around 60-80%. Large (>100 kb) rare (

IEEE transactions on radiation and plasma medical sciences : ITRPFI 3(3), 377-385 (2019). doi:10.1109/TRPMS.2018.2886525, Published by IEEE, New York, NY

Aim Presentation of attenuated positive psychotic symptoms (APS) was reported to be modestly influenced by age, sex and education in a psychosis-risk sample. We re-examined the influence of demographic variables on APS in an independent psychosis-risk sample. Method In a clinical high-risk-sample (N = 188; 13-35 years; 60.1% men), bivariate correlations were examined with Spearman correlations. All other associations were computed with generalized linear models. Results Inter-correlations between positive symptoms were statistically significant for all but the smallest coefficient (range: r = 0.12-0.49). Age was negatively related to APS (range: OR = 0.53-0.78, all P

Rationale: The loudness dependence of the auditory evoked potential (LDAEP) is considered a noninvasive in vivo marker of central serotonergic functioning in humans. Nevertheless, results of genetic association studies point towards a modulation of this biomarker by dopaminergic neurotransmission. Objective: We examined the effect of dopaminergic modulation on the LDAEP using L-3,4-dihydroxyphenylalanine (levodopa)/benserazide (Madopar®) as a challenge agent in healthy volunteers. Methods: A double-blind placebo-controlled challenge design was chosen. Forty-two healthy participants (21 females and 21 males) underwent two LDAEP measurements, following a baseline LDAEP measurement either placebo or levodopa (levodopa 200mg/benserazide 50mg) were given orally. Changes in the amplitude and dipole source activity of the N1/P2 intensities (60, 70, 80, 90, and 100dB) were analyzed. Results: The participants of neither the levodopa nor the placebo group showed any significant LDAEP alterations compared to the baseline measurement. The test-retest reliability (Cronbachs Alpha) between baseline and intervention was 0.966 in the verum group and 0.759 in the placebo group, respectively. Conclusions: The administration of levodopa showed no effect on the LDAEP. These findings are in line with other trials using dopamine receptor agonists

Objective: Somatosensory evoked potentials (SEPs) enable the investigation of thalamocortical and early cortical processing. Previous studies reported alterations of SEPs in patients with schizophrenia as well as in individuals in the prodromal stage. Moreover, cannabis use as an environmental risk factor for the development of schizophrenia has been demonstrated to influence SEP parameters in individuals at risk to develop psychosis. The aim of this study was to explore the course of SEP changes and the impact of concomitant cannabis use in individuals at risk to develop psychosis who sought medical help. Methods: Median nerve SEPs including high-frequency oscillations (HFOs) superimposed on the primary cortical response (N20) were investigated using multichannel EEG in individuals (n = 54 at baseline) remaining at risk to develop psychosis at follow-up after 1 year (high-risk: n = 19; ultra-high-risk: n = 27) vs. subjects with conversion to psychosis (n = 8) and a healthy control group (n = 35). Longitudinal and cross-sectional analyses of SEP components as estimated by dipole source analysis were performed. Results: The longitudinal development of the N20 strength depended on cannabis use. In cannabis non-users, a greater decrease of N20 strengths over time was associated with more negative symptoms at baseline. At baseline, converters did not differ from subjects remaining at risk. At follow-up, converters showed increased low- and high-frequency activity than at-risk subjects and did not differ from controls. Conclusion: The results of this study lead to the suggestion that the deficits in early somatosensory processing in individuals at risk to develop psychosis may not represent a marker for a genetic risk for psychosis but rather reflect state-dependent factors such as negative symptoms. On the other hand, the transition to psychosis seems to represent an interstage between reduced sensory registration from the at-risk state and gating deficits in the chronic state., Frontiers in Psychiatry, 10, ISSN:1664-0640

According to stress-vulnerability models, social stressors contribute to the onset of schizophrenia. Stigma and discrimination associated with mental illness may be a stressor for young people at risk of psychosis even prior to illness onset, but quantitative longitudinal data on this issue are lacking. We examined the cognitive appraisal of stigma-related stress as predictor of transition to schizophrenia among young people at risk of psychosis. In Zurich, Switzerland, 172 participants between 13 and 35years old and with either high or ultra-high risk of psychosis or risk of bipolar disorder were included. With 71 dropouts, transition was assessed during 12months among 101 participants of whom 13 converted to schizophrenia. At baseline, the cognitive appraisal of stigma as a stressor was measured by self-report, based on the primary appraisal of stigma as harmful and the secondary appraisal of resources to cope with stigma. Positive and negative symptoms were examined using the Positive and Negative Syndrome Scale. Compared with participants who did not convert to schizophrenia, converters had significantly more positive (p

Mental health service use is helpful but rare among young people at risk of psychosis. The label and stigma associated with mental illness may affect attitudes towards help-seeking. We examined 67 individuals at risk of psychosis over the course of 1 year. An increase of self-labelling as "mentally ill" predicted more positive attitudes towards psychiatric medication, while increased perceived stigma and the cognitive appraisal of stigma as a stressor predicted poorer attitudes towards psychotherapy after 1 year. Early intervention could improve non-stigmatizing awareness of at-risk mental state and reduce the public stigma associated with at-risk status to facilitate help-seeking.

BackgroundNeurocognitive deficits are important aspects of schizophrenic disorder because they have a strong impact on social and vocational outcomes. Previously it was assumed that cognitive abilities progressively deteriorate with illness onset. However, recent research results have contradicted this with observations of continuous or even improved performance in individuals at risk for psychosis or manifest schizophrenia. The objective of our longitudinal study was to examine neurocognitive functioning in help-seeking individuals meeting basic symptoms or ultra-high-risk criteria for schizophrenic psychosis (HRSchiz) or risk criteria for affective psychosis (HRBip). The progression of cognitive functioning in individuals converting to psychosis was compared with that of at-risk individuals who did not convert during the follow-up period.MethodData were available from 86 study participants who completed neurocognitive and clinical assessments at baseline and, on average, 12.8 (s.d. = 1.5) months later. Neurocognitive measures were grouped according to their load in factor analysis to five cognitive domains: speed, attention, fluency, learning and memory, and working memory.ResultsNeurocognitive functioning in HRSchiz and HRBip individuals generally improved over time. Subjects converting to manifest psychosis displayed a stable neurocognitive profile from baseline to follow-up. Compared with non-converters, they had already demonstrated a significantly lower level of performance during their baseline examinations.ConclusionsOur data provide no evidence for a progressive cognitive decline in individuals at risk of psychosis. In line with the neurodevelopmental model, our findings suggest that cognitive deficits are already present very early, before or during the prodromal stage of the illness.

The N400, an event-related brain potential (ERP), can be triggered by semantic or arithmetic violations in visual or auditory stimulus material. Schizophrenia patients exhibit an altered N400 presumably resulting from impaired semantic memory associative networks. The present study investigates, whether an altered N400 can also be found in semantic violations of the own self-concept. We use simple descriptive sentences to combine semantics with the self-concept in order to explore differences and possible deficits in schizophrenia patients. Schizophrenia patients and controls were shown trait adjectives in reference to themselves. Participants had to decide if the presented trait adjective was congruent or incongruent with their own self-concept. Only in controls, the N400 was significantly more negative in the incongruent compared to the congruent condition. Controls seemed to profit from a stable self-concept as they were faster in judging if a given trait was descriptive for the self than for someone else, which might result from processes related to the self-reference effect. Interestingly, in schizophrenia patients, the higher the scores for ego pathology were, the smaller the N400 effect turned out to be. The diminished N400 effect is probably associated with a disturbed self-concept in schizophrenia.

Background:The aim of this study was to critically examine the prognostic validity of various clinical high-risk (CHR) criteria alone and in combination with additional clinical characteristics.Methods:A total of 188 CHR positive persons from the region of Zurich, Switzerland (mean age 20.5 years; 60.2% male), meeting ultra high-risk (UHR) and/or basic symptoms (BS) criteria, were followed over three years. The test battery included the Structured Interview for Prodromal Syndromes (SIPS), verbal IQ and many other screening tools. Conversion to psychosis was defined according to ICD-10 criteria for schizophrenia (F20) or brief psychotic disorder (F23).Results:Altogether n = 24 persons developed manifest psychosis within three years and according to Kaplan–Meier survival analysis, the projected conversion rate was 17.5%. The predictive accuracy of UHR was statistically significant but poor (area under the curve [AUC] = 0.65, P < .05), whereas BS did not predict psychosis beyond mere chance (AUC = 0.52, P = .730). Sensitivity and specificity were 0.83 and 0.47 for UHR, and 0.96 and 0.09 for BS. UHR plus BS achieved an AUC = 0.66, with sensitivity and specificity of 0.75 and 0.56. In comparison, baseline antipsychotic medication yielded a predictive accuracy of AUC = 0.62 (sensitivity = 0.42; specificity = 0.82). A multivariable prediction model comprising continuous measures of positive symptoms and verbal IQ achieved a substantially improved prognostic accuracy (AUC = 0.85; sensitivity = 0.86; specificity = 0.85; positive predictive value = 0.54; negative predictive value = 0.97).Conclusions:We showed that BS have no predictive accuracy beyond chance, while UHR criteria poorly predict conversion to psychosis. Combining BS with UHR criteria did not improve the predictive accuracy of UHR alone. In contrast, dimensional measures of both positive symptoms and verbal IQ showed excellent prognostic validity. A critical re-thinking of binary at-risk criteria is necessary in order to improve the prognosis of psychotic disorders.

Reduction in hippocampal volume is a hallmark of schizophrenia and already present in the clinical high-risk state. Nevertheless, other subcortical structures, such as the thalamus, amygdala and pallidum can differentiate schizophrenia patients from controls. We studied the role of hippocampal and subcortical structures in clinical high-risk individuals from two cohorts. High-resolution T1-weighted structural MRI brain scans of a total of 91 clinical high-risk individuals and 64 healthy controls were collected in two centers. The bilateral volume of the hippocampus, the thalamus, the caudate, the putamen, the pallidum, the amygdala, and the accumbens were automatically segmented using FSL-FIRST. A linear mixed-effects model and a prospective meta-analysis were applied to assess group-related volumetric differences. We report reduced hippocampal and thalamic volumes in clinical high-risk individuals compared to healthy controls. No volumetric alterations were detected for the caudate, the putamen, the pallidum, the amygdala, or the accumbens. Moreover, we found comparable medium effect sizes for group-related comparison of the thalamus in the two analytical methods. These findings underline the relevance of specific alterations in the hippocampal and subcortical volumes in the high-risk state. Further analyses may allow hippocampal and thalamic volumes to be used as biomarkers to predict psychosis.

Stigma may undermine the well-being of young people at risk of psychosis. We therefore measured self-labeling, stigma variables and well-being at baseline and again one year later among 77 at-risk participants. An increase in self-labeling during this period predicted heightened stigma stress after one year and a decrease in stigma stress predicted better well-being at follow-up, controlling for symptoms, psychiatric comorbidity and sociodemographic variables. Besides early intervention programmes, strategies are needed to reduce the public stigma associated with at-risk status and to support young people at risk to better cope with self-labeling and stigma stress.

Deficits in attentional functions belong to the core cognitive symptoms in schizophrenic patients. Alertness is a nonselective attention component that refers to a state of general readiness that improves stimulus processing and response initiation. The main goal of the present study was to investigate cerebral correlates of alertness in the human 5HT2A agonist and N-methyl-D-aspartic acid (NMDA) antagonist model of psychosis. Fourteen healthy volunteers participated in a randomized double-blind, cross-over event-related functional magnetic resonance imaging (fMRI) study with dimethyltryptamine (DMT) and S-ketamine. A target detection task with cued and uncued trials in both the visual and the auditory modality was used. Administration of DMT led to decreased blood oxygenation level-dependent response during performance of an alertness task, particularly in extrastriate regions during visual alerting and in temporal regions during auditory alerting. In general, the effects for the visual modality were more pronounced. In contrast, administration of S-ketamine led to increased cortical activation in the left insula and precentral gyrus in the auditory modality. The results of the present study might deliver more insight into potential differences and overlapping pathomechanisms in schizophrenia. These conclusions must remain preliminary and should be explored by further fMRI studies with schizophrenic patients performing modality-specific alertness tasks.

Passivity experiences are hallmark symptoms of schizophrenia that can be characterized by the belief that one's thoughts or actions are controlled by an external agent. It has recently been suggested that these psychotic experiences result from defective monitoring of one's own actions, i.e. disturbed comparison of actions and perceived outcomes. In this study, we examined the function of the previously characterized action monitoring network of the inferior parietal lobule (IPL), medial (mPFC) and lateral prefrontal cortices in patients with different levels of passivity symptoms with an fMRI task. The visuomotor fMRI task demanded control of visually perceived object movements by alternating button presses with the left and the right index finger. In the monitoring condition of this task subjects stopped their actions whenever they detected visuomotor incongruence. fMRI and behavioural data from 15 patients were tested for correlation with passivity symptoms using standardized Scale for Assessment of Positive Symptoms (SAPS)- and AMDP- passivity symptom ratings. Both types of data were tested for differences between the patients group and 15 healthy controls. In the patient group we found the expected correlation of passivity symptoms and visuomotor monitoring performance. There was a significant positive correlation of passivity symptoms with increased latency of incongruence detection and a negative correlation of SAPS-passivity with the number of detected events. fMRI data revealed correlations of passivity symptoms with activation in bilateral IPL, primary motor and sensory cortices in the action monitoring condition. A correlation of passivity symptoms with the main experimental effect (actions with -- actions without monitoring) was found in the posterior cingulate cortex (PCC) and in the left IPL. No group differences or group by task interactions were found within the visuomotor-action-monitoring network. Our results demonstrate the association between passivity symptoms and the dysfunction of visuomotor action monitoring and support the idea that psychotic passivity experiences result from dysfunctions of central action monitoring mechanisms: According to pre-existing concepts of parietal cortex function, IPL-hyperactivation may represent an increase in false detections of visuomotor incongruence while the correlation between passivity and the differential effect of monitoring on PCC-activation assumedly represents greater self-monitoring effort in passivity experiences.

Rationale Many studies have reported deficits of mismatch negativity (MMN) in schizophrenic patients. Pharmacological challenges with hallucinogens in healthy humans are used as models for psychotic states. Previous studies reported a significant reduction of MMN after ketamine (N-methyl-d-aspartate acid [NMDA] antagonist model) but not after psilocybin (5HT2A agonist model). Objectives The aim of the present study was to directly compare the two models of psychosis using an intraindividual crossover design. Materials and methods Fifteen healthy subjects participated in a randomized, double-blind, crossover study with a low and a high dose of the 5HT2A agonist dimethyltryptamine (DMT) and the NMDA antagonist S-ketamine. During electroencephalographic recording, the subjects were performing the AX-version of a continuous performance test (AX-CPT). A source analysis of MMN was performed on the basis of a four-source model of MMN generation. Results Nine subjects completed both experimental days with the two doses of both drugs. Overall, we found blunted MMN and performance deficits in the AX-CPT after both drugs. However, the reduction in MMN activity was overall more pronounced after S-ketamine intake, and only S-ketamine had a significant impact on the frontal source of MMN. Conclusions The NDMA antagonist model and the 5HT2A agonist model of psychosis display distinct neurocognitive profiles. These findings are in line with the view of the two classes of hallucinogens modeling different aspects of psychosis.

An important aim in schizophrenia research is to optimize the prediction of psychosis and to improve strategies for early intervention. The objectives of this study were to explore neurocognitive performance in individuals at risk for psychosis and to optimize predictions through a combination of neurocognitive and psychopathological variables. Information on clinical outcomes after 24 months was available from 118 subjects who had completed an extensive assessment at baseline. Subjects who had converted to psychosis were compared with subjects who had not. Multivariate Cox regression analyses were used to determine which baseline measure best predicted a conversion to psychosis. The premorbid IQ and the neurocognitive domains of processing speed, learning/memory, working memory and verbal fluency significantly discriminated between converters and non-converters. When entered into multivariate regression analyses, the combination of PANSS positive/negative symptom severity and IQ best predicted the clinical outcomes. Our results confirm previous evidence suggesting moderate premorbid cognitive deficits in individuals developing full-blown psychosis. Overall, clinical symptoms appeared to be a more sensitive predictor than cognitive performance. Nevertheless, the two might serve as complementary predictors when assessing the risk for psychosis.

Erworben im Rahmen der Schweizer Nationallizenzen (http://www.nationallizenzen.ch), Interest in subtypes of mental disorders is growing in parallel with continuing research progress in psychiatry. The aim of this study was to examine pure animal phobia in contrast to other specific phobias and a mixed subtype. Data from three representative Swiss community samples were analysed: PsyCoLaus (n= 3720), the ZInEP Epidemiology Survey (n = 1500) and the Zurich Study (n= 591). Pure animal phobia and mixed animal/other specific phobias consistently displayed a low age at onset of first symptoms (8-12 years) and clear preponderance of females (OR > 3). Meanwhile, other specific phobias started up to 10 years later and displayed almost a balanced sex ratio. Pure animal phobia showed no associations with any included risk factors and comorbid disorders, in contrast to numerous associations found in the mixed subtype and in other specific phobias. Across the whole range of epidemiological parameters examined in three different samples, pure animal phobia seems to represent a different entity compared to other specific phobias. The etiopathogenetic mechanisms and risk factors associated with pure animal phobias appear less clear than ever.

In typical orienting of attention tasks subjects have to respond as fast as possible to targets which appear in the periphery of the visual field and are preceded by spatial cues (e.g. brightening of a peripheral box where the target may subsequently appear). Reaction times (RT) are facilitated when cue and target appear at the same location (valid cueing) and the cue target interval is short (

Suicidality is common among individuals at risk of psychosis. Emerging findings suggest that mental illness stigma contributes to suicidality. However, it is unclear whether stigma variables are associated with suicidality among young people at risk of psychosis. This longitudinal study assessed perceived public stigma and the cognitive appraisal of stigma as a stressor (stigma stress) as predictors of suicidal ideation among individuals at risk of psychosis over the period of one year. One hundred and seventy-two participants between 13 and 35 years of age were included who were at high or ultra-high risk of psychosis or at risk of bipolar disorder. At one-year follow-up, data were available from 73 completers. In multiple logistic regressions an increase of stigma stress (but not of perceived stigma) over one year was significantly associated with suicidal ideation at one-year follow-up, controlling for age, gender, symptoms, comorbid depression and suicidal ideation at baseline. Interventions to reduce public stigma and stigma stress could therefore improve suicide prevention among young people at risk of psychosis.

BackgroundThe attenuated positive symptoms syndrome (APSS) is considered an at-risk indicator for psychosis. However, the characteristics and developmental aspects of the combined or enriched risk criteria of APSS and basic symptom (BS) criteria, including self-experienced cognitive disturbances (COGDIS) remain under-researched.MethodBased on the Structured Interview of Prodromal Syndromes (SIPS), the prevalence of APSS in 13- to 35-year-old individuals seeking help in an early recognition program for schizophrenia and bipolar-spectrum disorders was examined. BS criteria and COGDIS were rated using the Schizophrenia Proneness Instrument for Adults/Children and Youth. Participants meeting APSS criteria were compared with participants meeting only BS criteria across multiple characteristics. Co-occurrence (APSS+/BS+, APSS+/COGDIS+) was compared across 13–17, 18–22 and 23–35 years age groups.ResultsOf 175 individuals (age = 20.6 ± 5.8, female = 38.3%), 94 (53.7%) met APSS criteria. Compared to BS, APSS status was associated with suicidality, higher illness severity, lower functioning, higher SIPS positive, negative, disorganized and general symptoms scores, depression scores and younger age (18.3 ± 5.0 v. 23.2 ± 5.6 years, p < 0.0001) with age-related differences in the prevalence of APSS (ranging from 80.3% in 13- to 17-year-olds to 33.3% in 23- to 35-year-olds (odds ratio 0.21, 95% confidence interval 0.11–0.37). Within APSS+ individuals, fewer adolescents fulfilled combined risk criteria of APSS+/BS+ or APSS+/COGDIS+ compared to the older age groups.ConclusionsAPSS status was associated with greater suicidality and illness/psychophathology severity in this help-seeking cohort, emphasizing the need for clinical care. The age-related differences in the prevalence of APSS and the increasing proportion of APSS+/COGDIS+ may point to a higher proportion of non-specific/transient, rather than risk-specific attenuated positive symptoms in adolescents.

Mental illness stigma may contribute to suicidality and is associated with social isolation and low self-esteem among young people at risk of psychosis. However, it is unclear whether mental illness stigma contributes to suicidality in this population. We therefore examined the associations of self-labeling and stigma stress with suicidality among young people at risk. Self-labeling as "mentally ill", stigma stress, social isolation, self-esteem, symptoms and suicidal ideation were assessed in 172 individuals at risk of psychosis. Self-labeling and stigma stress were examined as predictors of suicidality by path analysis. Increased self-labeling as "mentally ill" was associated with suicidality, directly as well as indirectly mediated by social isolation. More stigma stress was related to social isolation which in turn was associated with low self-esteem, depression and suicidal ideation. Social isolation fully mediated the link between stigma stress and suicidal ideation. Interventions to reduce the public stigma associated with risk of psychosis as well as programs to facilitate non-stigmatizing awareness of at-risk mental state and to reduce stigma stress among young people at risk of psychosis might strengthen suicide prevention in this population.

BackgroundDeficits of mismatch negativity (MMN) in schizophrenia and individuals at risk for psychosis have been replicated many times. Several studies have also demonstrated the occurrence of subclinical psychotic symptoms within the general population. However, none has yet investigated MMN in individuals from the general population who report subclinical psychotic symptoms.MethodsThe MMN to duration-, frequency-, and intensity deviants was recorded in 217 nonclinical individuals classified into a control group (n = 72) and three subclinical groups: paranoid (n = 44), psychotic (n = 51), and mixed paranoid-psychotic (n = 50). Amplitudes of MMN at frontocentral electrodes were referenced to average. Based on a three-source model of MMN generation, we conducted an MMN source analysis and compared the amplitudes of surface electrodes and sources among groups.ResultsWe found no significant differences in MMN amplitudes of surface electrodes. However, significant differences in MMN generation among the four groups were revealed at the frontal source for duration-deviant stimuli (P = 0.01). We also detected a trend-level difference (P = 0.05) in MMN activity among those groups for frequency deviants at the frontal source.ConclusionsIndividuals from the general population who report psychotic symptoms are a heterogeneous group. However, alterations exist in their frontal MMN activity. This increased activity might be an indicator of more sensitive perception regarding changes in the environment for individuals with subclinical psychotic symptoms.

Introduction: Pharmacological challenges with hallucinogens are used as models for psychosis in experimental research. The state induced by glutamate antagonists such as phencyclidine (PCP) is often considered as a more appropriate model of psychosis than the state induced by serotonergic hallucinogens such as lysergic acid diethylamide (LSD), psilocybin and N,N-dimethyl-tryptamine (DMT). However, so far, the psychological profiles of the two types of hallucinogenic drugs have never been studied directly in an experimental within-subject design. Methods: Fifteen healthy volunteers were included in a double-blind, cross-over study with two doses of the serotonin 5-HT 2 A agonist DMT and the glutamate N-methyl-d-aspartate (NMDA) antagonist (S)-ketamine. Results: Data are reported for nine subjects who completed both experimental days with both doses of the two drugs. The intensity of global psychological effects was similar for DMT and (S)-ketamine. However, phenomena resembling positive symptoms of schizophrenia, particularly positive formal thought disorder and inappropriate affect, were stronger after DMT. Phenomena resembling negative symptoms of schizophrenia, attention deficits, body perception disturbances and catatonia-like motor phenomena were stronger after (S)-ketamine. Discussion: The present study suggests that the NMDA antagonist model of psychosis is not overall superior to the serotonin 5-HT 2 A agonist model. Rather, the two classes of drugs tend to model different aspects or types of schizophrenia. The NMDA antagonist state may be an appropriate model for psychoses with prominent negative and possibly also catatonic features, while the 5-HT 2 A agonist state may be a better model for psychoses of the paranoid type.

The role of self-labeling as 'mentally ill' and of stigma-related stress for help-seeking among young people at risk for psychosis is unknown. Stronger self-labeling and less stigma stress predicted better attitudes towards psychiatric medication and psychotherapy, controlling for clinical and sociodemographic variables. Interventions could target stigma-related stress to increase help-seeking.