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Introduction: Machine learning models have shown promising potential in individual-level outcome prediction for patients with psychosis, but also have several limitations. To address some of these limitations, we present a model that predicts multiple outcomes, based on longitudinal patient data, while integrating prediction uncertainty to facilitate more reliable clinical decision-making., Material and Methods: We devised a recurrent neural network architecture incorporating long short-term memory (LSTM) units to facilitate outcome prediction by leveraging multimodal baseline variables and clinical data collected at multiple time points. To account for model uncertainty, we employed a novel fuzzy logic approach to integrate the level of uncertainty into individual predictions. We predicted antipsychotic treatment outcomes in 446 first-episode psychosis patients in the OPTiMiSE study, for six different clinical scenarios. The treatment outcome measures assessed at both week 4 and week 10 encompassed symptomatic remission, clinical global remission, and functional remission., Results: Using only baseline predictors to predict different outcomes at week 4, leave-one-site-out validation AUC ranged from 0.62 to 0.66; performance improved when clinical data from week 1 was added (AUC = 0.66-0.71). For outcome at week 10, using only baseline variables, the models achieved AUC = 0.56-0.64; using data from more time points (weeks 1, 4, and 6) improved the performance to AUC = 0.72-0.74. After incorporating prediction uncertainties and stratifying the model decisions based on model confidence, we could achieve accuracies above 0.8 for ~50% of patients in five out of the six clinical scenarios., Conclusion: We constructed prediction models utilizing a recurrent neural network architecture tailored to clinical scenarios derived from a time series dataset. One crucial aspect we incorporated was the consideration of uncertainty in individual predictions, which enhances the reliability of decision-making based on the model's output. We provided evidence showcasing the significance of leveraging time series data for achieving more accurate treatment outcome prediction in the field of psychiatry., (© 2024 The Author(s). Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Background and Hypotheses: In the past 2 decades, substantial effort has been put into research on therapeutic options for people at ultra-high risk (UHR) for developing a first episode of psychosis (FEP), focusing on omega-3 polyunsaturated fatty acids (PUFAs) in preventing transition to psychosis. Despite an initial positive finding, subsequent studies failed to find a beneficial effect. The current study aimed to further investigate the effect of omega-3 PUFAs in UHR, to determine whether this line of research is worth pursuing., Study Design: A double-blind, randomized, placebo-controlled study testing the efficacy of 6-month treatment with omega-3 PUFAs in 135 subjects at UHR for FEP, aged 13 to 20 years on the prevention of a transition to psychosis, followed up for 18 months post-treatment. The trial was conducted at 16 general hospitals and psychiatric specialty centers located in 8 European countries and Israel., Study Results: There was no beneficial effect of treatment with omega-3 PUFAs compared to placebo; the rate of transition over 2 years did not differ between treatment arms nor was there a difference in change in symptom severity after 6-month treatment. Dropout rates and serious adverse events were similar across the groups., Conclusions: This is the third study that fails to replicate the original finding on the protective effect of omega-3 PUFAs in UHR subjects for transition to psychosis. The accumulating evidence therefore suggests that omega-3 PUFAs do not reduce transition rates to psychosis in those at increased risk at 2 years follow-up., Clinical Trials: This trial is registered with ClinicalTrials.gov (NCT02597439; Study Details | Placebo-controlled Trial in Subjects at Ultra-high Risk for Psychosis With Omega-3 Fatty Acids in Europe | ClinicalTrials.gov)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Several multivariate prognostic models have been published to predict outcomes in patients with first episode psychosis (FEP), but it remains unclear whether those predictions generalize to independent populations. Using a subset of demographic and clinical baseline predictors, we aimed to develop and externally validate different models predicting functional outcome after a FEP in the context of a schizophrenia-spectrum disorder (FES), based on a previously published cross-validation and machine learning pipeline. A crossover validation approach was adopted in two large, international cohorts (EUFEST, n = 338, and the PSYSCAN FES cohort, n = 226). Scores on the Global Assessment of Functioning scale (GAF) at 12 month follow-up were dichotomized to differentiate between poor (GAF current < 65) and good outcome (GAF current ≥ 65). Pooled non-linear support vector machine (SVM) classifiers trained on the separate cohorts identified patients with a poor outcome with cross-validated balanced accuracies (BAC) of 65-66%, but BAC dropped substantially when the models were applied to patients from a different FES cohort (BAC = 50-56%). A leave-site-out analysis on the merged sample yielded better performance (BAC = 72%), highlighting the effect of combining data from different study designs to overcome calibration issues and improve model transportability. In conclusion, our results indicate that validation of prediction models in an independent sample is essential in assessing the true value of the model. Future external validation studies, as well as attempts to harmonize data collection across studies, are recommended., (© 2024. The Author(s).)

Background: Antibodies against the N-methyl-D-aspartate receptor (NMDAR) have been described in the serum of people with schizophrenia spectrum disorders (schizophrenia). However, the prevalence and clinical relevance of these antibodies in schizophrenia is unclear. This knowledge gap includes the possibility of such antibodies being associated with a distinct clinical profile, which in turn might warrant a distinct treatment approach. We aimed to assess the seroprevalence of anti-NMDAR antibodies in schizophrenia, and compare symptoms and psychosocial functioning between patients with schizophrenia who were seropositive and seronegative for these antibodies., Methods: In this case-control comparison, by combining new and existing studies, we included patients diagnosed with schizophrenia from four independent cohorts for whom anti-NMDAR serostatus had been assessed (or could be assessed by us) with live cell-based assays. Included cohorts were from the EULAST study (a trial conducted across 15 European countries and Israel), the OPTiMiSE study (an interventional study in Europe), and the PPiP1 and PPiP2 studies (conducted in the UK). Patients from these cohorts were analysed if they had complete Positive and Negative Syndrome Scale (PANSS) data. No participant had been diagnosed with autoimmune encephalitis or received treatment for this condition. After calculating the prevalence of serum anti-NMDAR antibodies, we examined possible differences in PANSS scores (negative, positive, and general symptom subscales, and total score) between anti-NMDAR-seropositive and anti-NMDAR-seronegative patients. Psychosocial functioning as measured by Personal Social Performance (PSP) score was also compared. All analyses were exploratory and no adjustment was done for multiple testing. People with lived experience were not involved in the conduct of this study., Findings: We collected individual patient data from 1114 patients with schizophrenia across the four cohorts. The study population had a mean age of 28·6 years (SD 7·6) and comprised 382 (34·3%) women and 732 (65·7%) men, including patients of White (929 [83·4%]), Asian (54 [4·8%]), Black (68 [6·1%]), and other (62 [5·6%]) ethnicities. Overall, 41 (3·7%) participants (range 3·1-4·0% across cohorts) tested positive for serum anti-NMDAR antibodies. Lower symptom severity on the negative symptoms PANSS subscale was observed for anti-NMDAR-seropositive patients (mean score 15·8 [SD 6·4]) than for anti-NMDAR-seronegative patients (18·2 [6·8]; Cohen's d=0·36; p=0·026), as well as on the general symptoms PANSS subscale (32·9 [8·9] vs 36·1 [10·1]; d=0·33; p=0·029) and total PANSS score (65·5 [18·5] vs 72·6 [19·3]; d=0·37; p=0·013). Mean PSP score was better in anti-NMDAR-positive patients (62·0 [17·0]) than in anti-NMDAR-negative patients (53·5 [16·3]; d=0·52; p=0·014)., Interpretation: Serum NMDAR antibodies are present in 3-4% of patients with schizophrenia and are associated with relatively low severity of negative symptoms and relatively good psychosocial functioning. Thus, although the findings await replication in cohorts from other geographical regions, serum anti-NMDAR antibodies might be associated with a different form of psychotic illness. These findings could inform future prognostic and interventional studies examining whether anti-NMDAR antibodies are associated with a specific course of illness or with treatment response., Funding: None., Competing Interests: Declaration of interests AH is an editor of the German Association for Psychiatry, Psychotherapy and Psychosomatics schizophrenia treatment guidelines, and first author of the World Federation of Societies of Biological Psychiatry schizophrenia treatment guidelines; has been on the advisory boards of and received speakers fees from Janssen, Lundbeck, Recordati, Rovi, Boeringer-Ingelheim, and Otsuka; and has received speakers fees from AbbVie and Advanz. WWF has received grants from Otsuka and Lundbeck and speakers fees from Sumitomo Pharma. MD is CMO of Minerva Neurosciences, a biotech company developing CNS drugs. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Recently the 1/f signal of human electroencephalography has attracted attention, as it could potentially reveal a quantitative measure of neural excitation and inhibition in the brain, that may be relevant in a clinical setting. The purpose of this short article is to show that the 1/f signal depends on the vigilance state of the brain in both humans and mice. Therefore, proper labelling of the EEG signal is important as improper labelling may obscure disease-related changes in the 1/f signal. We demonstrate this by comparing EEG results from a longitudinal study in a genetic mouse model for synaptic dysfunction in schizophrenia and autism spectrum disorders to results from a large European cohort study with schizophrenia and mild Alzheimer's disease patients. The comparison shows when the 1/f is corrected for vigilance state there is a difference between groups, and this effect disappears when vigilance state is not corrected for. In conclusion, more attention should be paid to the vigilance state during analysis of EEG signals regardless of the species., Competing Interests: Neetha Das, Hugh Marston and Gerard R. Dawson worked for a company during the data collection of the PRISM1 study. The companies provided support in the form of salaries for authors, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the current manuscript which was performed as a secondary analysis using the PRISM1 data set. The specific roles of these authors are articulated in the ‘author contributions’ section.’ Dr. Arango has been a consultant to or has received honoraria or grants from Acadia, Angelini, Biogen, Boehringer, Gedeon Richter, Janssen Cilag, Lundbeck, Medscape, Menarini, Minerva, Otsuka, Pfizer, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion, Takeda and Teva. The other authors have declared that no competing interests exist., (Copyright: © 2024 Østergaard et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The current neuropsychiatric nosological categories underlie pragmatic treatment choice, regulation and clinical research but does not encompass biological rationale. However, subgroups of patients suffering from schizophrenia or Alzheimer's disease have more in common than the neuropsychiatric nature of their condition, such as the expression of social dysfunction. The PRISM project presents here initial quantitative biological insights allowing the first steps toward a novel trans-diagnostic classification of psychiatric and neurological symptomatology intended to reinvigorate drug discovery in this area. In this study, we applied spectral clustering on digital behavioural endpoints derived from passive smartphone monitoring data in a subgroup of Schizophrenia and Alzheimer's disease patients, as well as age matched healthy controls, as part of the PRISM clinical study. This analysis provided an objective social functioning characterization with three differential clusters that transcended initial diagnostic classification and was shown to be linked to quantitative neurobiological parameters assessed. This emerging quantitative framework will both offer new ways to classify individuals in biologically homogenous clusters irrespective of their initial diagnosis, and also offer insights into the pathophysiological mechanisms underlying these clusters., Competing Interests: Conflict of interest MK has received (non-related) research funding from Novartis during the conduct of the study. MM is employee and CFB is director and shareholder of SBGneuro Ltd. CA has been a consultant to or has received honoraria or grants from Acadia, Angelini, Gedeon Richter, Janssen Cilag, Lundbeck, Minerva, Otsuka, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. BP has received (non-related) research funding from Jansen Research and Boehringer Ingelheim during the conduct of the study. ACB and GRD were fully employed by P1Vital during the conduct of the study. BS was fully employed by Boehringer Ingelheim during the conduct of the study. HM was fully employed by Eli Lilly and Company during the conduct of the study. All other authors declare no conflict of interests., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

There is currently no quantifiable method to predict long-term clinical outcomes in patients presenting with a first episode of psychosis. A major barrier to developing useful markers for this is biological heterogeneity, where many different pathological mechanisms may underly the same set of symptoms in different individuals. Normative modelling has been used to quantify this heterogeneity in established psychotic disorders by identifying regions of the cortex which are thinner than expected based on a normative healthy population range. These brain atypicalities are measured at the individual level and therefore potentially useful in a clinical setting. However, it is still unclear whether alterations in individual brain structure can be detected at the time of the first psychotic episode, and whether they are associated with subsequent clinical outcomes. We applied normative modelling of cortical thickness to a sample of first-episode psychosis patients, with the aim of quantifying heterogeneity and to use any pattern of cortical atypicality to predict symptoms and response to antipsychotic medication at timepoints from baseline up to 95 weeks (median follow-ups = 4). T1-weighted brain magnetic resonance images from the GAP and OPTiMiSE samples were processed with Freesurfer V6.0.0 yielding 148 cortical thickness features. An existing normative model of cortical thickness (n = 37,126) was adapted to integrate data from each clinical site and account for effects of gender and site. Our test sample consisted of control participants (n = 149, mean age = 26, SD = 6.7) and patient data (n = 295, mean age = 26, SD = 6.7), this sample was used for estimating deviations from the normative model and subsequent statistical analysis. For each individual, the 148 cortical thickness features were mapped to centiles of the normative distribution and converted to z-scores reflecting the distance from the population mean. Individual cortical thickness metrics of +/- 2.6 standard deviations from the mean were considered extreme deviations from the norm. We found that no more than 6.4% of psychosis patients had extreme deviations in a single brain region (regional overlap) demonstrating a high degree of heterogeneity. Mann-Whitney U tests were run on z-scores for each region and significantly lower z-scores were observed in FEP patients in the frontal, temporal, parietal and occipital lobes. Finally, linear mixed-effects modelling showed that negative deviations in cortical thickness in parietal and temporal regions at baseline are related to more severe negative symptoms over the medium-term. This study shows that even at the early stage of symptom onset normative modelling provides a framework to identify individualised cortical markers which can be used for early personalised intervention and stratification., (© 2023. The Author(s).)

Introduction: Psychiatric comorbidities have a significant impact on the course of illness in patients with schizophrenia spectrum disorders. To accurately predict outcomes for individual patients using computerized prognostic models, it is essential to consider these comorbidities and their influence., Methods: In our study, we utilized a multi-modal deep learning architecture to forecast symptomatic remission, focusing on a multicenter sample of patients with first-episode psychosis from the OPTiMiSE study. Additionally, we introduced a counterfactual model explanation technique to examine how scores on the Mini International Neuropsychiatric Interview (MINI) affected the likelihood of remission, both at the group level and for individual patients., Results: Our findings at the group level revealed that most comorbidities had a negative association with remission. Among them, current and recurrent depressive disorders consistently exerted the greatest negative impact on the probability of remission across patients. However, we made an interesting observation: current suicidality within the past month and substance abuse within the past 12 months were associated with an increased chance of remission in patients. We found a high degree of variability among patients at the individual level. Through hierarchical clustering analysis, we identified two subgroups: one in which comorbidities had a relatively limited effect on remission (approximately 45% of patients), and another in which comorbidities more strongly influenced remission. By incorporating comorbidities into individualized prognostic prediction models, we determined which specific comorbidities had the greatest impact on remission at both the group level and for individual patients., Discussion: These results highlight the importance of identifying and including relevant comorbidities in prediction models, providing valuable insights for improving the treatment and prognosis of patients with psychotic disorders. Furthermore, they open avenues for further research into the efficacy of treating these comorbidities to enhance overall patient outcomes., Competing Interests: RK reports consulting fees from Alkermes, Sunovion, Gedeon-Richter, and Otsuka. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 van Dee, Kia, Winter-van Rossum, Kahn, Cahn and Schnack.)

Background and Hypothesis: This analysis examined the relationship between cannabis use, compliance with antipsychotics and risk for relapse in patients in remission following a first episode of schizophrenia, schizophreniform, or schizoaffective disorder., Study Design: Analyses were performed on data from a large European study on first episode of schizophrenia, schizophreniform, or schizoaffective disorder (OPTiMiSE). After 10 weeks of antipsychotic treatment, 282/446 patients (63%) met criteria for symptomatic remission; of whom 134/282 (47.5%) then completed a 1-year follow-up. Cross-lagged models and mediation models investigated the temporal relationships between cannabis use, compliance with antipsychotics, social functioning, and symptomatic worsening/relapse., Study Results: Compared to nonusers, cannabis use increased risk for relapse, adjusted hazard ratio (HR) = 3.03 (SE = 0.32), P < .001, even in patients who were compliant with antipsychotic medication, adjusted HR = 2.89, (SE = 0.32), P < .001. Cannabis use preceded symptomatic worsening and was followed by worsening of Positive and Negative Syndrome Scale total score at the 1-year end-point (standardized β = 0.62, SE = 0.19, P = .001) and by worsening of social functioning (coef = -0.66, P ≤ .001)., Conclusions: In patients in remission from their first episode of schizophrenia, schizophreniform, or schizoaffective disorder, cannabis use increases the rate of relapse in both compliant and noncompliant individuals. Importantly, the temporal relationship between cannabis and relapse was that cannabis use preceded later relapse, noncompliance, and decrease in social functioning, and not that patients began to relapse, then used cannabis. Further research with a precision psychiatry approach might identify those patients in particular danger of relapse when using cannabis., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Hypothesis: Treatment response to specific antipsychotic medications is difficult to predict on clinical grounds alone. The current study hypothesizes that the baseline complement pathway activity predicts the treatment response and investigates the relationship between baseline plasma biomarkers with treatment response to antipsychotic medications., Study Design: Baseline plasma samples were collected from first episode of psychosis patients (n = 243) from a multi-center clinical trial. The participants were treated with amisulpride for 4 weeks. Levels of complement and coagulation proteins at baseline were measured using both data-dependent and data-independent mass spectrometry approaches. The primary outcome was remission status at 4 weeks and the secondary outcomes included change in psychotic and functional symptoms over the period of treatment. In addition, immunoassays were performed at baseline for complement C1R, as well as for activation markers C4a and sC5b-9., Study Results: The plasma level of complement variant C4A was significantly associated with remission at 4 weeks. Moreover, higher levels of several complement and coagulation pathway proteins were associated with a reduction in psychotic symptoms and an improvement in functioning. Immunoassays showed an association of baseline levels of C1R and C4a as well as complement activation marker sC5b-9 levels with treatment response., Conclusion: The results demonstrated that the response to antipsychotic treatment might be related to pre-treatment levels of plasma complement and coagulation pathway proteins. This is consistent with independent evidence associating immune dysfunction with the pathophysiology of psychosis. Moreover, these results inform the development of novel therapeutic approaches that target the complement system for psychosis., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Objective: In the majority of randomized controlled trials (RCTs) conducted in schizophrenia populations, patients suffering from a substance use disorder (SUD) or suicidality are excluded. Excluding these patients from RCTs might impact the generalizability of results. The aim of this study is to determine whether excluding patients with suicidality and/or SUD impacts RCT results on symptomatic remission, premature study discontinuation, symptom severity, and social functioning., Methods: Across Europe and Israel, 481 patients with first-episode schizophrenia, schizophreniform disorder, or schizoaffective disorder, based on DSM-IV criteria, were recruited between May 26, 2011, and May 15, 2016, for the Optimization of Treatment and Management of Schizophrenia in Europe (OPTiMiSE) trial. Baseline characteristics and follow-up assessments were compared between patients with versus without baseline SUD and/or suicidality., Results: A total of 446 patients met eligibility criteria for the OPTiMiSE trial and initiated amisulpride treatment, of whom 404 (91%) had data available on suicidality, SUD, duration of illness, and CDS score. Of the 360 eligible patients with baseline data on suicidality and SUD, 106 patients had comorbid suicidality and/or SUD while 254 patients had neither of these comorbidities. No significant differences in the likelihood to achieve symptomatic remission or to prematurely discontinue the study were found when comparing comorbid versus non-comorbid patients ( P  = .27). There were no significant differences in symptom severity and social functioning between the groups. Comorbid patients had a higher level of depressive symptoms and more impaired social functioning compared to non-comorbid patients., Discussion: Excluding first-episode schizophrenia patients with comorbidities from clinical trials unlikely affects key outcome measures. It is recommended to include patients with comorbidities in clinical trials while carefully monitoring suicidality and implementing safety plans to gain insight into efficacy and safety of treatment in this substantial patient population., Trial Registration: ClinicalTrials.gov identifier: NCT01248195., (© Copyright 2023 Physicians Postgraduate Press, Inc.)

Background: Schizophrenia is a severe psychiatric disorder with periods of remission and relapse. As discontinuation of antipsychotic medication is the most important reason for relapse, long-term maintenance treatment is key. Whether intramuscular long-acting (depot) antipsychotics are more efficacious than oral medication in preventing medication discontinuation is still unresolved. We aimed to compare time to all-cause discontinuation in patients randomly allocated to long-acting injectable (LAI) versus oral medication., Methods: EULAST was a pragmatic, randomised, open-label trial conducted at 50 general hospitals and psychiatric specialty clinics in 15 European countries and Israel. Patients aged 18 years and older, with DSM-IV schizophrenia (as confirmed by the Mini International Neuropsychiatric Interview 5 plus) and having experienced their first psychotic episode from 6 months to 7 years before screening, were randomly allocated (1:1:1:1) using block randomisation to LAI paliperidone, LAI aripiprazole, or the respective oral formulations of these antipsychotics. Randomisation was stratified by country and duration of illness (6 months up to 3 years vs 4 to 7 years). Patients were followed up for up to 19 months. The primary endpoint was discontinuation, regardless of the reason, during 19 months of treatment. We used survival analysis to assess the time until all-cause discontinuation in the intention-to-treat (ITT) group, and per protocol analyses were also done. This trial is registered with ClinicalTrials.gov, NCT02146547, and is complete., Findings: Between Feb 24, 2015, and Dec 15, 2018, 533 individuals were recruited and assessed for eligibility. The ITT population included 511 participants, with 171 (33%) women and 340 (67%) men, and a mean age of 30·5 (SD 9·6) years. 410 (80%) of 511 participants were White, 35 (7%) were Black, 20 (4%) were Asian, and 46 (9%) were other ethnicity. In the combined oral antipsychotics treatment group of 247 patients, 72 (29%) patients completed the study and 175 (71%) met all-cause discontinuation criteria. In the combined LAI treatment arm of 264 patients, 95 (36%) completed the study and 169 (64%) met the all-cause discontinuation criteria. Cox regression analyses showed that treatment discontinuation for any cause did not differ between the two combined treatment groups (hazard ration [HR] 1·16, 95% CI 0·94-1·43, p=0·18). No significant difference was found in the time to all-cause discontinuation between the combined oral and combined LAI treatment groups (log rank test χ 2 =1·87 [df 1]; p=0·17). During the study, 121 psychiatric hospitalisations occurred in 103 patients, and one patient from each of the LAI groups died; the death of the patient assigned to paliperidone was assessed to be unrelated to the medication, but the cause of other patient's death was not shared with the study team. 86 (25%) of 350 participants with available data met akathisia criteria and 70 (20%) met parkinsonism criteria at some point during the study., Interpretation: We found no substantial advantage for LAI antipsychotic treatment over oral treatment regarding time to discontinuation in patients with early-phase schizophrenia, indicating that there is no reason to prescribe LAIs instead of oral antipsychotics if the goal is to prevent discontinuation of antipsychotic medication in daily clinical practice., Funding: Lundbeck and Otsuka., Competing Interests: Declaration of interests SG reports consulting fees from Angelini, Janssen Pharmaceuticals, Gedeon-Richter, Recordati, and Innova Pharma; and honoraria and expenses from Angelini, Gedeon-Richter, Recordati, Janssen Pharmaceuticals, Janssen-Cilag, Lundbeck, Lundbeck Italia, and Sunovion. SL reports payments to the institution from European Group for Research In Schizophrenia for the conduct of the trial; consulting fees from Alkermes, Angelini, Lundbeck, Lundbeck Foundation, Otsuka, Recordati, Rovi, and Teva; and honoraria for lectures from Angelini, Eisai, Gedeon, Lundbeck, Medichem, Merck, Mitsubishi, Otsuka, Recordati, and Sanofi-Aventis. IB reports grants from the EU to the Semmelweise University; royalties from Oxford University for a published book (editor); consulting fees from Gedeon Richter, Janssen, Janssen Cilag; speaker fees from Hikma Janssen, Janssen Cilag, Gedeon Richter, Medichem Pharmaceuticals by Unilab, and Mitsubishi Tanabe Pharma Signapure; and leadership or fiduciary roles with European College of Neuropsychopharmacology, the European Psychiatry Association, and Clincal Pharmacological Ethics Committee and Medical Research Council (Hungary). BG has been the leader of a Lundbeck Foundation Centre of Excellence for Clinical Intervention and Neuropsychiatric Schizophrenia Research (January, 2009–December, 2021), which was partially financed by an independent grant from the Lundbeck Foundation based on international review and partially financed by the Mental Health Services in the Capital Region of Denmark, the University of Copenhagen, and other foundations; all grants are the property of the Mental Health Services in the Capital Region of Denmark and administrated by them. AH reports speaker fees from Lundbeck, Otsuka, Janssen, Recordati, and Rovi; was member of advisory boards for Lundbeck, Otsuka, Janssen, Recordati, and Rovi; and is an Editor of the German Association of Scientific Medical Societies in Germany and World Federation of Societies of Biological Psychiatry schizophrenia guidelines. GP reports honoraria from Lundbeck, Janssen, Schwabe Austria; support for attending meetings from Schwabe Austria; being president at the Austrian Society for Social Psychiatry and Gerontopsychiatry; and stock with Janssen. PR reports an advisory board role for Angelini. NS reports honoraria for lectures from Recordati Hellas, BGP Pharmaceuticals, Lundbeck Hellas, and Vianex. MD is an employee of Minerva Neurosciences with stock options. RSK reports consulting fees from Alkermes, Sunovion, Gedeon-Richter, and Otsuka. WWF reports consultant fees from Angelini, Richter, Recordati, Lundbeck, Otsuka, Teva, Boehringer-Ingelheim, Pierre Fabre, Janssen, Sunovion, Dainippon-Sumitomo, Takeda, and Pfizer; speaker fees from Janssen, Lundbeck, Otsuka, Richter, and Recordati; and grants from Janssen, Lundbeck, and Otsuka. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Social functioning is often impaired in schizophrenia (SZ) and Alzheimer's disease (AD). However, commonalities and differences in social dysfunction among these patient groups remain elusive., Materials and Methods: Using data from the PRISM study, behavioral (all subscales and total score of the Social Functioning Scale) and affective (perceived social disability and loneliness) indicators of social functioning were measured in patients with SZ (N = 56), probable AD (N = 50) and age-matched healthy controls groups (HC, N = 29 and N = 28). We examined to what extent social functioning differed between disease and age-matched HC groups, as well as between patient groups. Furthermore, we examined how severity of disease and mood were correlated with social functioning, irrespective of diagnosis., Results: As compared to HC, both behavioral and affective social functioning seemed impaired in SZ patients (Cohen's d's 0.81-1.69), whereas AD patients mainly showed impaired behavioral social function (Cohen's d's 0.65-1.14). While behavioral indices of social functioning were similar across patient groups, SZ patients reported more perceived social disability than AD patients (Cohen's d's 0.65). Across patient groups, positive mood, lower depression and anxiety levels were strong determinants of better social functioning (p's <0.001), even more so than severity of disease., Conclusions: AD and SZ patients both exhibit poor social functioning in comparison to age- and sex matched HC participants. Social dysfunction in SZ patients may be more severe than in AD patients, though this may be due to underreporting by AD patients. Across patients, social functioning appeared as more influenced by mood states than by severity of disease., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: CA has been a consultant to or has received honoraria or grants from Acadia, Angelini, Gedeon Richter, Janssen Cilag, Lundbeck, Minerva, Otsuka, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. ACB has received salaries from P1vital Ltd. MK has received (non-related) research funding from Novartis. BP has received (non-related) research funding from Jansen Research and Boehringer Ingelheim. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Structural magnetic resonance imaging studies in individuals at clinical high risk (CHR) for psychosis have yielded conflicting results., Methods: The aims of this study were to compare intracranial and structural brain volumes and variability of CHR individuals with those of healthy control (HC) subjects and to investigate brain volume differences and variability in CHR subjects with and without transition to psychosis. The PubMed and Embase databases were searched for relevant studies published before June 1, 2020., Results: A total of 34 studies were deemed eligible, which included baseline data of 2111 CHR and 1472 HC participants. In addition, data were included for 401 CHR subjects who subsequently transitioned to psychosis and 1023 nontransitioned CHR participants. Whole-brain and left, right, and bilateral hippocampal volume were significantly smaller in CHR subjects than in HC subjects. Cerebrospinal fluid and lateral ventricle volumes were significantly larger in CHR subjects than in HC subjects. Variability was not significantly different in CHR subjects compared with HC subjects. CHR individuals with and without subsequent transition to psychosis did not show significant differences in any of the volumetric assessments or in variability., Conclusions: This meta-analysis demonstrates reduced whole-brain and hippocampal volumes and increased cerebrospinal fluid and lateral ventricle volumes in CHR individuals. However, no significant differences were observed in any of the volumetric assessments between CHR individuals with and without subsequent transition to psychosis. These findings suggest that although structural brain alterations are present before the onset of the disorder, they may not significantly contribute to the identification of CHR individuals at the highest risk for the development of psychosis., (© 2021 The Authors.)

Objective: The identification of predictors of psychosis remission could guide early clinical decision-making for treatment of first-episode schizophrenia (FES)., Methods: We analyzed two non-independent subsamples of patients with FES ages 18-40 years from the OPTiMiSE study dataset to investigate the demographic and clinical factors that might help to differentiate "late" remitters (i.e., not in remission at week 2 or 4, but achieving remission within a 10-week follow-up period) from non-remitters within the same period., Results: Subsample 1 included 216 individuals (55 females, mean age 25.9 years) treated with amisulpride in an open-label design who were not in remission at week 2. Early symptomatic response between baseline and week 2 (odds ratio (OR) = 4.186, 95% confidence interval (CI) = 2.082-8.416, p < 0.001) and older age (OR = 1.081, 95% CI = 1.026-1.138, p = 0.003) were the only variables significantly associated with a higher probability of psychosis remission at week 4. Subsample 2 was composed of the 72 participants (19 females, mean age 25.1 years) who were not in remission at week 4 and completed a 6-week double-blind randomized trial comparing continuation of amisulpride with switch to olanzapine. Depression at baseline (as measured with the Calgary Depression Scale for Schizophrenia) was significantly associated with a nearly 3-fold lower likelihood of psychosis remission during the 10-week follow-up (hazard ratio = 2.865, 95% CI = 1.187-6.916, p = 0.019)., Conclusion: Our results reinforce the importance of assessing depressive symptoms in people with FES and support the relevance of an early response (as early as 2 weeks) as a predictor of clinical outcome in this population., Clinical Trials Registration: ClinicalTrials.gov identifier: NCT01248195, https://clinicaltrials.gov/ct2/show/NCT01248195., Competing Interests: Declaration of competing interest Dr. Fraguas has been a consultant and/or has received fees from Angelini, Eisai, IE4Lab, Janssen, Lundbeck, and Otsuka. He has also received grant support from Instituto de Salud Carlos III (Spanish Ministry of Science, Innovation and Universities) and from Fundación Alicia Koplowitz. Dr. Díaz-Caneja has received honoraria from Sanofi-Aventis and Abbvie, and grant support from Instituto de Salud Carlos III (Spanish Ministry of Science, Innovation and Universities). Laura Pina-Camacho has received honoraria or grants from Rubio, Takeda, and Rovi, Instituto de Salud Carlos III (Spanish Ministry of Science, Innovation and Universities), and from Fundacion Alicia Koplowitz. Dr. Winter van Rossum reports no conflict of interest. Dr. Baandrup reports no conflict of interest. Dr. Sommer has received support from Janssen and from Sunovion. She is consultant to Gabather. Dr. Glenthøj is the leader of Lundbeck Foundation Centre of Excellence for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS), which is partially financed by an independent grant from the Lundbeck Foundation based on international review and partially financed by the Mental Health Services in the Capital Region of Denmark, the University of Copenhagen, and other foundations. Her group has also received a research grant from Lundbeck A/S for another independent investigator-initiated study. All grants are the property of the Mental Health Services in the Capital Region of Denmark and administered by them. She has no other conflicts to disclose. Dr. Kahn declares personal fees for consultancy from Alkermes, Minerva Neuroscience, Gedeon Richter, and Otsuka; and personal (speaker) fees from Otsuka/Lundbeck. Dr. Leucht has received honoraria for service as a consultant or adviser and/or for lectures from Angelini, Boehringer Ingelheim, Gedeon Richter, Janssen, Johnson & Johnson, LB Pharma, LTS Lohmann, Lundbeck, MSD, Otsuka, Recordati, Sandoz, Sanofi-Aventis, Sunovion, and TEVA. Dr. Arango has been a consultant to or has received honoraria or grants from Acadia, Angelini, Gedeon Richter, Janssen-Cilag, Lundbeck, Otsuka, Roche, Sage, Servier, Shire, Schering-Plough, Sumitomo Dainippon Pharma, Sunovion, and Takeda., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aim: The aim of this paper is to determine clinical factors related to hostility and disturbing and aggressive behaviour and to examine the effect of medication on these behaviours in FEP., Methods: Data from phase I and II of the OPTiMiSE trial are used. Outcome measures are the hostility item of the Positive and Negative Syndrome Scale (PANSS P7) and the disturbing and aggressive behaviour domain of the Personal and Social Performance scale (PSP-D)., Results: Moderate, severe or extreme hostility (PANSS P7 > 3) was present in 42 patients (9.4%). The PANSS P7 and PSP-D were low to moderate but significantly associated with the selected PANSS items: delusions, hallucinatory behaviour, excitement, tension, uncooperativeness, unusual thought content, impulsivity, and lack of judgement and insight. In a subsample of 185 patients (41.5%) with baseline PANSS P7 > 1, the PANSS P7 and PSP-D scores improved in the first 4 weeks of amisulpride treatment. This effect remained significant after controlling for baseline positive symptoms (PANSS P1-P6). No significant differences were found between olanzapine and amisulpride in the second phase of the trial., Conclusion: Clinical risk factors such as poor impulse control, uncooperativeness and excitement could help clinicians in detecting and treating hostile and aggressive behaviour in FEP. Amisulpride could be an effective antipsychotic choice in the treatment of FEP patients who express hostile or aggressive behaviour. Future research is needed to compare the effects of amisulpride and olanzapine on hostility in FEP during the first weeks of treatment., Competing Interests: Declaration of competing interest CA has been a consultant to or has received honoraria or grants from Acadia, Angelini, Gedeon Richter, Janssen Cilag, Lundbeck, Otsuka, Roche, Sage, Sanofi, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. GB received honoraria from Lundbeck, Otsuka and Burgerstein, as well as funding from the Swiss National Science Foundation. SL has received honoraria as a consultant/advisor and/or for lectures from LB Pharma, Otsuka, Lundbeck, Boehringer Ingelheim, LTS Lohmann, Janssen, Johnson&Johnson, TEVA, MSD, Sandoz, SanofiAventis, Angelini, Recordati, Sunovion, Geodon Richter. JB has received research grants and served as consultant, advisor or speaker within de last 5 years for: AB-Biotics, Acadia Pharmaceuticals, Ambrosseti-Angelini, Casen Recordati, D&A Pharma, Exeltis, Gilead, Indivior, Janssen-Cilag, Lundbeck, Mundipharma, Otsuka, Pfizer, Roche, Sage Therapeutics, Servier, Schwabe Farma Ibérica, Shire, Takeda, research funding from the Spanish Ministry of Economy and Competiveness –Centro de Investigación Biomedica en Red area de Salud Mental (CIBERSAM) and Instituto de Salud Carlos III-, Spanish Ministry of Health, Social Services and Equality - Plan Nacional sobre Drogas- and the 7th Framework Program of the European Union. PAS has been a consultant to and/or has received honoraria or grants from Adamed, CIBERSAM, European Comission, GlaxoSmithKline, Instituto de Salud Carlos III, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Plan Nacional Sobre Drogas and Servier. MPGP has been a consultant to and/or has received honoraria/grants within the last 5 years from Angelini, Alianza Otsuka-Lundbeck, CIBERSAM, European Medicines Agency, Instituto de Salud Carlos III, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, and SAGE Therapeutics. The remaining authors report no competing interests related to this work., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The symptom severity of a substantial group of schizophrenia patients (30-40%) does not improve through pharmacotherapy with antipsychotic medication, indicating a clear need for new treatment options to improve schizophrenia outcome. Meta-analyses, genetic studies, randomized controlled trials, and post-mortem studies suggest that immune dysregulation plays a role in the pathophysiology of schizophrenia. Some anti-inflammatory drugs have shown beneficial effects on the symptom severity of schizophrenia patients. Corticosteroids are effective in various chronic inflammatory and autoimmune disorders. Prednisolone, a potent glucocorticosteroid, has minor mineral-corticosteroid potencies and can adequately pass the blood-brain barrier and its side effects and safety profile are well known. Therefore, the effect of prednisolone can be studied as a proof of concept for immune modulation as a treatment for schizophrenia., Methods/design: In total, 90 subjects aged 18-70 years and diagnosed with schizophrenia, schizoaffective disorder, or schizophreniform disorder (Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) 295.x) or psychosis not otherwise specified (NOS; 298.9) will be included. The time interval between the onset of psychosis and study entry should not exceed 7 years. Patients will be randomized 1:1 to either prednisolone or placebo daily for a period of 6 weeks in addition to a stable dose of antipsychotic medication. Study medication will be initiated at 40 mg for 3 days, after which it will be tapered down within 6 weeks after initiation, following inflammatory bowel diseases treatment guidelines. Primary outcome is change in symptom severity, expressed as change in total score on the Positive and Negative Symptom Scale (PANSS) from baseline to end of treatment. Cognitive functioning (measured through the Brief Assessment of Cognition in Schizophrenia (BACS)) and change in Global Assessment Functioning (GAF) and depressive symptoms as measured with the Calgary Depression Scale for Schizophrenia (CDS) will be assessed, in addition to various immunological biomarkers. Secondary outcomes are a 4- and 6-month follow-up assessment of PANSS, BACS, and GAF scores and immunological biomarkers. Additionally, a subgroup of patients will be included in the magnetic resonance imaging (MRI) part of the study where MR spectroscopy and structural, functional, and diffusion MRI will be conducted., Discussion: It is expected that prednisolone addition to current antipsychotic medication use will reduce symptom severity and will improve cognition when compared to placebo., Trial Registration: ClinicalTrials.gov, NCT02949232 and NCT03340909. Registered 31 October 2016 and 14 November 2017. EudraCT-number 2014-000520-14 and 2017-000163-32.

Some, but not all, studies have found longer duration of untreated psychosis (DUP) to be associated with poor response to treatment and more severe negative symptoms in schizophrenia. The aim of the current analysis was to investigate these parameters in a large cohort of patients in their first psychotic episode. The OPTiMiSE cohort included 446 patients with DUP up to two years, who were administered amisulpride for 4 weeks (Phase I). Patients who did not meet Andreasen remission criteria were randomized to double-blind continuation of amisulpride or olanzapine for 6 additional weeks in a blinded study (Phase II). Analyses showed that shorter DUP was associated with lower baseline CGI scores (p<0.001, r = 0.184), PANSS total (p = 0.025, r = 0.106) and PANSS negative subscale scores (p = 0.023, r = 0.107). Remitters had a significantly shorter mean DUP compared to non-remitters both in Phase I (24.5 weeks ±24.3 vs. 35 weeks ± 32.2, p = 0.01, t=-2.521) and in Phase II (24.3 weeks ± 26.4 vs. 38.3 weeks ± 31.3, p = 0.031, t=-2.194). Logistic regression analyses showed a significant effect of DUP on treatment response both in phase I (p = 0.008) and phase II (p = 0.041). Linear regression analyses found that DUP significantly affects PANSS Total change at the end of phase I (p = 0.028) but not at the end of phase II (p = 0.236). Based on these findings, it is possible to conclude that shorter DUP is associated with better response to treatment, particularly during the first weeks after treatment initiation. These findings highlight the need for early identification of the first psychotic episode., Competing Interests: Conflict of interest Michael Davidson MD is an employee of Minerva Neurosciences Inc. a biotech company developing drugs for CNS indications. Renè Kahn is a consultant for Alkermes, Otsuka, Janssen-Cilag, Luye Pharma and Sunovion since September 2019. All other authors do not have any conflicts of interest to declare, according to the Journal's requirements., (Copyright © 2020 Elsevier B.V. and ECNP. All rights reserved.)

In the last 2 decades, several neuroimaging studies investigated brain abnormalities associated with the early stages of psychosis in the hope that these could aid the prediction of onset and clinical outcome. Despite advancements in the field, neuroimaging has yet to deliver. This is in part explained by the use of univariate analytical techniques, small samples and lack of statistical power, lack of external validation of potential biomarkers, and lack of integration of nonimaging measures (eg, genetic, clinical, cognitive data). PSYSCAN is an international, longitudinal, multicenter study on the early stages of psychosis which uses machine learning techniques to analyze imaging, clinical, cognitive, and biological data with the aim of facilitating the prediction of psychosis onset and outcome. In this article, we provide an overview of the PSYSCAN protocol and we discuss benefits and methodological challenges of large multicenter studies that employ neuroimaging measures., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Trans-diagnostic, domain- or symptom-focused approaches have been heralded as advancing psychiatric research, but relatively few clinical research programmes have been undertaken to leverage their potential. In this manuscript we describe the approach and protocol for an exploratory study, PRISM (Psychiatric Ratings using Intermediate Stratified Markers), that will be conducted to explore the biomarkers in schizophrenia (SZ) and Alzheimer's Disease (AD) that may be related to a common symptom, social withdrawal. Patient participants (N = 72 SZ and N = 72 AD study completers), will complete a series of fMRI, EEG, and behavioural paradigms, as well as contributing blood-derived (e.g. epigenetic) and smartphone data related to social behaviour. Self- as well as caregiver- and researcher-reported assessments will be provided to characterise social withdrawal. Normative data will also be collected from a group of healthy controls (N = 48 study completers), half of whom will be matched in terms of age and gender distribution to the SZ and AD group, respectively. Thus we will explore both differentiation and cross-diagnostic overlap in the biomarkers associated with different levels of social withdrawal in SZ and AD. In this way we aim to provide a deeper understanding of the biological underpinnings of symptomatology common to both disorders, and provide insights into novel treatment targets and future drug development approaches., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: An insight into preferences, satisfaction and treatment goals of patients is important for reaching treatment alliance and may increase the success of initiated treatment., Methods: Participants from the Netherlands,with at least one psychotic episode, were asked to fill in an online questionnaire. Participants ranked their priorities in treatment content, stated whether they were satisfied on these items and ranked a list of treatment goals., Results: 462 respondents ranked their treatment preferences regarding treatment content(mean age: 40.3 years; mean duration of illness: 13.5 years). Items ranked most important: “prompt assistance, preferably in own environment”, “attention for medication”, “appropriate attitude of the professional caregiver”. More than 50 % rated “unsatisfied” or “very unsatisfied” for: “practical help in resocialization”, “aid to acquire autonomy” and “help with physical health”. 345 participants ranked treatment goals (mean age: 40.4 years; mean duration of illness: 13.7 years). Items ranked most important: “reducing apathy and lack of initiative”, “reducing disturbing or unusual experiences”, “reducing confusion and concentration problems”., Conclusion: Psychiatric services should pay great attention to early outpatient intervention with supportive counseling and an appropriate attitude of the caregiver with attention for medication use. Improvement is warranted for practical assistance, help in regaining autonomy and help with physical health., (© Georg Thieme Verlag KG Stuttgart · New York.)