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Background and Hypothesis Exercise therapy has been shown to be an effective complementary treatment for patients with psychotic disorders. However, the specific impacts of different training modalities remain poorly understood. This article aims to quantitatively review the moderating influence of different exercise modalities, hypothesizing that higher exercise intensity as well as utilization of mindfulness-based exercise (MBE) components, will improve intervention outcomes. Study Design PubMed, Web of Science, and PsycINFO were searched from 2010 to March 2022 for randomized controlled trials investigating exercise interventions in patients with psychotic disorders (preregistration: https://doi.org/10.17605/OSF.IO/J8QNS). Outcomes considered were positive/negative symptoms, Positive and Negative Syndrome Scale (PANSS) General Psychopathology/Total scores, depressive symptoms, psychosocial functioning, quality of life, cardiorespiratory fitness, and body mass index. Separate meta-analyses, including moderator analyses, were performed to evaluate the moderating influence of different training modalities. Study Results Of 6653 studies, 40 (n  = 2111 patients) were included in the meta-analysis. The effects of moderate-intensity exercise exceed low-intensity approaches for PANSS Total scores (P  = .02) and depressive symptoms (P  = .04). The presence of MBE components was associated with improvements in positive symptoms (P  = .04) and PANSS General Psychopathology subscores (P  = .04) but also with higher error and between-study heterogeneity. Our analysis also shows improved intervention effects on depression in younger patients (P  = .012) and improved psychosocial functioning scores following more frequent sessions (P  < .01). Conclusions A minimum of moderate intensity should be considered. More frequent training sessions per week also seem to be beneficial. While adding mindfulness elements is promising, it increases heterogeneity and requires caution in terms of generalization. [ABSTRACT FROM AUTHOR]

Diagnostic heterogeneity within and across psychotic and affective disorders challenges accurate treatment selection, particularly in the early stages. Delineation of shared and distinct illness features at the phenotypic and brain levels may inform the development of more precise differential diagnostic tools. We aimed to identify prototypes of depression and psychosis to investigate their heterogeneity, with common, comorbid transdiagnostic symptoms. Analyzing clinical/neurocognitive and grey matter volume (GMV) data from the PRONIA database, we generated prototypic models of recent-onset depression (ROD) vs. recent-onset psychosis (ROP) by training support-vector machines to separate patients with ROD from patients with ROP, who were selected for absent comorbid features (pure groups). Then, models were applied to patients with comorbidity, ie, ROP with depressive symptoms (ROP+D) and ROD participants with sub-threshold psychosis-like features (ROD+P), to measure their positions within the affective-psychotic continuum. All models were independently validated in a replication sample. Comorbid patients were positioned between pure groups, with ROP+D patients being more frequently classified as ROD compared to pure ROP patients (clinical/neurocognitive model: χ 2 = 14.874; P <.001; GMV model: χ 2 = 4.933; P =.026). ROD+P patient classification did not differ from ROD (clinical/neurocognitive model: χ 2 = 1.956; P = 0.162; GMV model: χ 2 = 0.005; P =.943). Clinical/neurocognitive and neuroanatomical models demonstrated separability of prototypic depression from psychosis. The shift of comorbid patients toward the depression prototype, observed at the clinical and biological levels, suggests that psychosis with affective comorbidity aligns more strongly to depressive rather than psychotic disease processes. Future studies should assess how these quantitative measures of comorbidity predict outcomes and individual responses to stratified therapeutic interventions. [ABSTRACT FROM AUTHOR]

Depression frequently occurs in first-episode psychosis (FEP) and predicts longer-term negative outcomes. It is possible that this depression is seen primarily in a distinct subgroup, which if identified could allow targeted treatments. We hypothesize that patients with recent-onset psychosis (ROP) and comorbid depression would be identifiable by symptoms and neuroanatomical features similar to those seen in recent-onset depression (ROD). Data were extracted from the multisite PRONIA study: 154 ROP patients (FEP within 3 months of treatment onset), of whom 83 were depressed (ROP+D) and 71 who were not depressed (ROP−D), 146 ROD patients, and 265 healthy controls (HC). Analyses included a (1) principal component analysis that established the similar symptom structure of depression in ROD and ROP+D, (2) supervised machine learning (ML) classification with repeated nested cross-validation based on depressive symptoms separating ROD vs ROP+D, which achieved a balanced accuracy (BAC) of 51%, and (3) neuroanatomical ML-based classification, using regions of interest generated from ROD subjects, which identified BAC of 50% (no better than chance) for separation of ROP+D vs ROP−D. We conclude that depression at a symptom level is broadly similar with or without psychosis status in recent-onset disorders; however, this is not driven by a separable depressed subgroup in FEP. Depression may be intrinsic to early stages of psychotic disorder, and thus treating depression could produce widespread benefit. [ABSTRACT FROM AUTHOR]

Background: Functional deficits associated with the Clinical High Risk (CHR) status very often lead to inability to attend school, unemployment, as well as social isolation, thus calling for predictors of individual functional outcomes which may facilitate the identification of people requiring care irrespective of transition to psychosis. Studies have revealed that a pattern of cortical and subcortical gray matter volumes (GMV) anomalies measured at baseline in CHR individuals could predict their functional abilities at follow up. Furthermore, literature is consistent in revealing the crucial role of several environmental adverse events in increasing the risk of developing either transition to psychosis, or a worse overall personal functioning. Therefore, the aim of this study is to employ machine learning to test the individual and combined ability of baseline GMV data and of history of environmental adverse events in predicting good vs. poor social and occupational outcome in CHR individuals at follow up. Methods: 92 CHR individuals recruited from the 7 discovery PRONIA sites were included in this project. Social and occupational impairment at follow up (9–12 months) were respectively measured through the Global Functioning: Social (GF:S) and Role (GF:R) scale, and CHR with a follow up rating of 7 or below were labeled as having a poor functional outcome. This way, we could separate our cohort in 52 poor outcome CHR and 40 good outcome CHR. GMV data were preprocessed following published procedures which allowed also to correct for site effects. The environmental classifier was built based on Childhood Trauma Questionnaire, Bullying Scale, and Premorbid Adjustment Scale (childhood, early adolescence, late adolescence and adulthood) scores. Raw scores have been normalized according to the psychometric properties of the healthy samples used for validating these questionnaires and scale, in order to obtain individual scores of deviation from the normative occurrence of adverse environmental events. GMV and environmental-based predictive models were independently trained and tested within a leave-site-out cross validation framework using a Support Vector Machine algorithm (LIBSVM) through the NeuroMiner software, and their predictions were subsequently combined through stacked generalization procedures. Results: Our GMV-based model could predict follow up social outcome with 67.4% Balanced Accuracy (BAC) and significance (p=0.01), while it could not predict occupational outcome (46.6% BAC). On the other hand, our environmental-based model could discriminate both poor vs. good social and occupational outcomes at follow up with, respectively, 71% and 66.4% BACs, and significance (both p=0.0001). Specifically, the most reliable features in the environmental classifier were scores reflecting deviations from the normative values in childhood trauma and adult premorbid adjustment, for social outcome prediction, and in bullying experiences and late adolescence premorbid adjustment, for occupational outcome prediction. Only for social outcome prediction, stacked models outperformed individual classifiers’ predictions (74.3% BAC, p=0.0001). Discussion: Environmental features seem to be more accurate than GMV in predicting both social and occupational outcomes in CHR. Interestingly, the predictions of follow up social and occupational outcomes rely on different patterns of occurrence of specific environmental adverse events, thus providing novel insights about how environmental adjustment disabilities, bullying and traumatic premorbid experiences may impact on different bad outcomes associated with the CHR status. [ABSTRACT FROM AUTHOR]

Background: Evidence exists that cannabis consumption is associated with the development of psychosis. Further, continued cannabis use in individuals with recent onset psychosis (ROP) increases the risk for rehospitalization, high symptom severity and low general functioning. Clear inter-individual differences in the vulnerability to the harmful effects of the drug have been pointed out. These findings emphasize the importance of investigating the inter-individual variability in the role of cannabis use in ROP and to understand how cannabis use relates to subclinical conditions that predate the full-blown disease in clinical high-risk (CHR). Specific symptoms have been linked with continued cannabis consume, still research is lacking on how different factors contribute together to an elevated risk of cannabis relapse. Multivariate techniques have the capacity to extract complex patterns from high dimensional data and apply generalized rules to unseen cases. The aim of the study is therefore to assess the predictability of cannabis relapse in ROP and CHR by applying machine learning to clinical and environmental data. Methods: All participants were recruited within the multi-site, longitudinal PRONIA study (www.pronia.eu). 112 individuals (58 ROP and 54 CHR) from 8 different European research centres reported lifetime cannabis consume at baseline and were abstinent for at least 4 weeks. We defined cannabis relapse as any cannabis consume between baseline and 9 months follow-up reported by the individual. To predict cannabis relapse, we trained a random forest algorithm implemented in the mlr package, R version 3.5.2. on 183 baseline variables including clinical symptoms, general functioning, demographics and consume patterns within a repeated-nested cross-validation framework. The data underwent pre-processing through pruning of non-informative variables and median-imputation for missing values. The number of trees was set to 500, while the number of nodes, sample fraction and mtry were optimized. All hyperparameters were tuned with the model-based optimization implemented in the mlrMBO R package. Results: After 9 months 50 individuals (48 % ROP, 52 % CHR) have relapsed on cannabis use. Relapse was over all timepoints associated with more severe psychotic symptoms measured by PANSS positive and PANSS general (p<0.05) and a significant interaction between positive symptoms and time of measurement (p<0.05). Our random forest classifier could predict cannabis relapse with a balanced accuracy, sensitivity, and specificity of, respectively, 66.5 %, 66.0 % and 67.0 %. The most predictive variables were a higher cumulative frequency of cannabis consumption in the last 3 months, worse general functioning in the last month, higher density of place of living, younger age and a shorter interval time since the last consumption. Discussion: Our results using a state-of-the-art machine learning approach suggest that the multivariate signature of baseline demographic and clinical data could predict follow up cannabis relapse above chance level in CHR and ROP. Our findings revealing that cannabis relapse is associated with more severe symptoms is in line with previous literature and emphasizes the need for targeted treatment towards abstinence from cannabis. The information of demographic and clinical patterns might be useful in order to specifically address therapeutic strategies in individuals at higher risk for relapse. This might include special programs for younger patients and taking model in an independent sample. [ABSTRACT FROM AUTHOR]

Background: Precise prognosis of clinical outcomes in individuals at clinical high-risk (CHR) of developing psychosis is imperative to guide treatment selection. While much effort has been put into the prediction of transition to psychosis in CHR individuals, prognostic models focusing on negative symptom progression in this population are widely missing. This is a major oversight bearing in mind that 82% of CHR individuals exhibit at least one negative symptom in the moderate to severe range at first clinical presentation, whereas 54% still meet this criteria after 12 months. Negative symptoms are strong predictors of poor functional outcome irrespective of other symptoms such as depression or anxiety. Prognostic tools are therefore urgently required to track negative symptom progression in CHR individuals in order to guide early personalized interventions. Here, we applied machine-learning to multi-site data from five European countries with the aim of predicting negative symptoms of at least moderate severity 9-month after study inclusion. Methods: We analyzed data from the ‘Personalized Prognostic Tools for Early Psychosis Management’ (PRONIA; www.pronia.eu) study, which consisted of 94 individuals at clinical high-risk of developing psychosis (CHR). Predictive models either included baseline level of negative symptoms, measured with the Structured Interview for Prodromal Syndromes, whole-brain gyrification pattern, or both to forecast negative symptoms of moderate severity or above in CHR individuals. Using data from the clinical and gyrification model, further sequential testing simulations were conducted to stratify CHR individuals into different risk groups. Lastly, we assessed the models’ ability to predict functional outcomes in CHR individuals. Results: Baseline negative symptom severity alone predicted moderate to severe negative symptoms with a balanced accuracy (BAC) of 68%, whereas predictive models trained on gyrification measures achieved a BAC of 64%. Stacking the two modalities allowed for an increased BAC of 72%. Additional sequential testing simulations suggested, that CHR patients could be stratified into a high risk group with 83% probability of experiencing at least moderate negative symptoms at follow-up and a medium/low risk group with a risk ranging from 25 to 38%, when using the two models sequentially. Furthermore, the models trained to predict negative symptom severity from baseline symptoms were less predictive of role (60% BAC) and social (62% BAC) functioning at follow-up. However, the model trained on gyrification data also predicted role (74% BAC) and social (73% BAC) functioning later on. The stacking model predicted role, and social functioning with 64% BAC and 66% BAC respectively. Discussion: To the best of our knowledge this is the first study using stateof-the-art predictive modelling to prospectively identify CHR subjects with negative symptoms in the moderate to above moderate severity range who potentially require further therapeutic consideration. While the predictive performance will need to be validated in other samples and may be improved by expanding the models with additional predictors, we believe that this pragmatic approach will help to stratify individual risk profiles and optimize personal interventions in the future. [ABSTRACT FROM AUTHOR]

Background: Formal thought disorder (FThD) has been associated with more severe illness courses and functional deficits in psychosis patients. Given these associations, it remains unclear whether the presence of FThD accounts for the heterogeneous presentation of psychoses, and whether it characterises a specific subgroup of patients showing prominent differential illness severity, neurocognitive and functional impairments already in the early stages of psychosis. Thus, our aim is 1) to evaluate whether there are stable subtypes of patients with Recent-Onset Psychosis (ROP) that are characterized by distinct FThD patterns, 2) to investigate whether this FThD-related stratification is associated with clinical, and neurocognitive phenotypes at an early stage of the disease, and 3) to explore correlation patterns among the FThD-related symptoms, functioning and neurocognition through network analysis. Methods: 279 individuals experiencing ROP were recruited for this project as part of multi-site European PRONIA study. In the present study, FThD was assessed with conceptual disorganization, difficulty in abstract thinking, poverty of content of speech, increased latency of response and poverty of speech items from the Positive and Negative Symptom Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS). We first applied a multi-step clustering protocol comparing three clustering algorithms: (i) k-means, (ii) hierarchical clustering, and (iii) partitioning around medoids with the number of clusters ranging from 2 to 10. Our protocol runs following four checkpoints; (i) validity [ClValid package], (ii) re-evaluation of validity results and unbiased determination of the winning algorithm [NbClust package], (iii) stability test [ClusterStability package] and (iv) generalizability [predict.strength package] testing for the most optimal clustering solution. Thereafter, we investigated whether the identified FThD subgrouping solution was associated with neurocognitive performance, social and occupational functioning by using Welch’s two-sample t-test or Mann-Whitney-U test based on the distribution of data, and explored the interrelation of these domains with network analysis by using qgraph package with the spearman correlation matrix among variables. All analyses and univariate statistical comparisons were conducted with R version 3.5.2. We used the False Discovery Rate (FDR)37 to correct all P-values for the multiple comparisons. Results: The k-means algorithm-based on two-cluster solution (FThD high vs. low) surviving these validity, stability and generalizability tests was chosen for further association tests and network analysis with core disease phenotypes. Patients in FThD high subgroup had lower scores in global (pfdr = 0.0001), social (pfdr < 0.0001) and role (pfdr < 0.0001) functioning, in semantic (pfdr < 0.0001) and phonological verbal fluency (pfdr = 0.0004), verbal short-term memory (pfdr = 0.0018) and abstract thinking (pfdr = 0.0099). Cluster assignment was not informed by the global disease severity (pfdr = 0.7786) but was associated with more pronounced negative symptoms (pfdr = 0.0001) in the FThD high subgroup. Discussion: Our findings highlight how the combination of unsupervised machine learning algorithms with network analysis techniques may provide novel insight about the mappings between psychopathology, neurocognition and functioning. Furthermore, they point how FThD may represent a target variable for individualized psycho-, socio-, logotherapeutic interventions aimed at improving neurocognition abilities and functioning. Prospective studies should further test this promising perspective. [ABSTRACT FROM AUTHOR]

Background It is important to decompose the clinical heterogeneity of affective and non-affective psychoses into transdiagnostic subgroups that disentangle prognostic outcomes and inform aetiological understanding. Research thus far has predominantly focused on symptoms, but there is a need to consider a wider range of clinical variables with prognostic and genetic validation. We aimed to detect psychosis subgroups using a novel unsupervised machine learning method taken from cancer genomics and used on a clinical battery of demographics, medical history, symptoms, quality of life, general functioning, and cognition. We validated the subgroups by examining their: a) illness course over 1.5-years; and b) schizophrenia polygenic risk scores (SCZ-PRS). Methods Ongoing multicenter, naturalistic, longitudinal study beginning in 2011 with three follow-up time-points collected at 6-month intervals across 18 sites. Convenience and referred sample of 765 cases (n=411 at follow-up) collected from secondary and tertiary care centers with DSM-IV diagnoses of schizophrenia, bipolar affective (I/II), schizoaffective, schizophreniform, and brief psychotic disorder (45% female; mean age (yrs; SD) = 42.7(12.9)). A clinical battery of 188 variables assessing the domains listed in the objectives was decomposed using sparse non-negative matrix factorization consensus clustering. Subgroups were validated with mixed models and supervised machine learning analyses of illness course. SCZ-PRS was compared between the subgroups using analysis of variance and supervised machine learning. Results Five subgroups were found (permutation-based p<0.001), four of which were transdiagnostic and labelled as later-onset affective psychosis, suicidal psychosis, depressive psychosis, and male, high functioning psychosis. The fifth group was labelled severe psychosis subgroup and predominately consisted of individuals with schizophrenia diagnoses. Subgroup differences in illness courses were found for psychosis symptoms (F(4,406)=9.6, p<0.001), depression symptoms (F(4,406)=3.9, p=0.004), general functioning (F(4,406)=5.8, p<0.001), and quality of life (F(4,406)=3.1, p=0.02). The later onset affective and the high functioning psychosis subgroups demonstrated similar levels of functioning and stable, linear illness courses. The depressive and severe psychosis subgroups exhibited the lowest functioning and quadratic illness courses. Exploratory SCZ-PRS analyses did not reveal differences, but specific tests indicated higher SCZ-PRS in the severe psychosis subgroup across all thresholds. Discussion Five subgroups were detected with distinctive illness courses that crossed traditional nosological boundaries. The study demonstrates the importance of data-driven approaches and highlights the critical importance of illness trajectories to future psychosis taxonomies. [ABSTRACT FROM AUTHOR]

Background: Childhood trauma (CT) is associated with an increased risk for psychiatric disorders like major depression and psychosis. However, the pathophysiological relationship between CT, psychiatric disease and structural brain alterations is still unknown. Methods: PRONIA (‘Personalized Prognostic Tools for Early Psychosis Mangement’) is a prospective collaboration project funded by the European Union under the 7th Framework Programme (grant agreement n° 602152). Considering a broad set of variables (sMRI, rsMRI, DTI, psychopathological, life event related and sociobiographic data, neurocognition, genomics and other blood derived parameters) as well as advanced statistical methods, PRONIA aims at developing an innovative multivariate prognostic tool enabling an individualized prediction of illness trajectories and outcome. Seven clinical centers in five European countries and in Australia participate in the evaluation of three clinical groups (subjects clinically at high risk of developing a psychosis (CHR), patients with a recent onset psychosis (ROP) and patients with a recent onset depression (ROD)) as well as healthy controls (HC). To investigate the high-dimensional patterns of CT experience, measured by the childhood trauma questionnaire (CTQ), in HC and our three patient groups (PAT) (n=643), we used a Support Vector Machine (SVM). Furthermore, we tested whether patient-specific CT exposure is associated with structural brain changes by VBM analyses. Results: We found that patients and HC could be separated very well by their CTQ pattern, whereas the different patient groups showed no specific CTQ pattern. Furthermore, an association with extensive grey matter changes suggests an impact on brain maturation which may put individuals at increased risk for mental disease. Discussion: We have demonstrated in this large multi-center cohort that adverse experiences in childhood contribute transdiagnostically to the riskr for developing a psychiatric disease. The observed association between CTQ scores and structural changes suggests an impact of adverse childhood experiences on brain development. Resulting alterations may add to a neurobiological vulnerability for depression and psychosis. A role of both features for other mental disorders could be assumed and warrants further investigation. [ABSTRACT FROM AUTHOR]

Background: A multitude of clinical models to predict transition to psychosis in individuals at clinical high risk (CHR) have been proposed. However, only limited efforts have been made to systematically compare these models and to validate their performance in independent samples. Therefore, in this study we identified psychosis risk models based on information readily obtainable in general clinical settings, such as clinical and neuropsychological data, and compared their performance in the PRONIA study (Personalised Prognostic Tools for Early Psychosis Management, www.pronia.eu) as an independent sample. Methods: Of the 278 CHR participants in the PRONIA sample, 150 had available data until month 18 and were included in the validation of eleven psychosis prediction models identified through systematic literature search. Discrimination performance was assessed with the area under the receiver operating characteristic curve (AUC), and compared to the performance of the prognosis of clinical raters. Psychosocial functioning was explored as an alternative outcome. Results: Discrimination performance varied considerably across models (AUC ranging from 0.42 to 0.79). High model performance was associated with the inclusion of neurocognitive variables as predictors. Low model performance was associated with predictors based on dichotomized variables. Clinical raters performed comparable to the best data-driven models (AUC = 0.75). Combining raters’ prognosis and model-based predictions improved discrimination performance (AUC = 0.84), particularly for less experienced raters. One of the tested models predicted transition to psychosis and psychosocial outcomes comparably well. Discussion: The present external validation study highlights the benefit of enriching clinical information with neuropsychological data in predicting transition to psychosis satisfactorily and with good generalizability across samples. Integration of data-driven risk models and clinical expertise may improve clinical decision-making in CHR for psychosis, particularly for less experienced raters. This external validation study provides an important step toward early intervention and the personalized treatment of psychotic disorders. [ABSTRACT FROM AUTHOR]

Background: Psychotic disorders are associated with serious deterioration in functioning even before the first psychotic episode. Also on clinical high risk (CHR) states of developing a first psychotic episode, several studies reported a decreased global functioning. In a considerable proportion of CHR individuals, functional deterioration remains even after (transient) remission of symptomatic risk indicators. Furthermore, deficits in functioning cause immense costs for the health care system and are often more debilitating for individuals than positive symptoms. However in the past, CHR research has mostly focused on clinical outcomes like transition. Prediction of functioning in CHR populations has received less attention. Therefore, the current study aims at predicting functioning in CHR individuals at a single subject level applying multi pattern recognition to clinical data. Patients with a first depressive episode who frequently have persistent functional deficits comparable to patients in the CHR state were investigated in addition. Methods: PRONIA (‘Personalized Prognostic Tools for Early Psychosis Management’) is a prospective collaboration project funded by the European Union under the 7th Framework Programme (grant agreement n°602152). Considering a broad set of variables (MRI, clinical data, neurocognition, genomics and other blood derived parameters) as well as advanced statistical methods, PRONIA aims at developing an innovative multivariate prognostic tool enabling an individualized prediction of illness trajectories and outcome. 11 university centers in five European countries and in Australia (Munich, Basel, Birmingham, Cologne, Düsseldorf, Münster, Melbourne, Milan, Udine, Bari, Turku) participate in the evaluation of three clinical groups (subjects clinically at high risk of developing a psychosis [CHR], patients with a recent onset psychosis [ROP] and patients with a recent onset depression [ROD]) as well as healthy controls. In the current study, we analysed data of 114 CHR and 106 ROD patients. Functioning was measured by the ‘Global Functioning: Social and Role’ Scales (GF S/R). In a repeated, nested cross validation framework we trained a l1-regularized SVM to predict good versus bad outcome. Multivariate pattern recognition analysis allowed to identify most predictive variables from a multitude of clinical, environmental as well as sociodemographic potential predictors assessed in PRONIA. Results: Based on the 5 to 20 identified most predictive features, prediction models revealed a balanced accuracy (BAC) up to 77/72 for social functioning in CHR/ROD patients and up to 73/69 for role functioning. These models showed satisfying performance of BACs up to 69/63 for social functioning and 67/60 for role functioning in an independent test sample. As expected, prior functioning levels were identified as main predictive factor but also distinct protective and risk factors were selected into the prediction models. Discussion: Results suggest that especially prediction of the multi-faceted construct of role functioning could benefit from inclusion of a rich set of clinical variables. To the best of our knowledge this is the first study that has validated clinical prediction models of functioning in an independent test sampleIdentification of predictive variables enables a much more efficient prognostic process. Moreover, understanding the mechanisms underlying functional decline and its illness related pattern might enable an improved definition of targets for intervention. Future research should aim at further maximisation of prediction accuracy and cross-centre generalisation capacity. In addition, other functioning outcomes as well as clinical outcomes need to be focused on. [ABSTRACT FROM AUTHOR]

Background: Neurocognitive impairment plays a central role in pathogenesis and course of psychotic disorders. Patients suffering from psychosis or psychosis-related diseases show general and specific neurocognitive impairments that often precede the onset of manifest symptoms. Neurocognitive impairments are frequently associated with reduced psychosocial functioning along with altered brain morphology and function. Quantifying neurocognitive heterogeneity in impairment in schizophrenia patients, cluster analytic approaches differentiated several cognitive subtypes, including a generally impaired and generally spared subgroup. An independent set of findings provided evidence that neurocognitive subgroups of cognitively spared and impaired SZ patients can also be differentiated based on their brain morphology. The current study aims to (1) subtype a first episode psychosis sample based on neurocognitive performance using cluster analysis and (2) investigate grey matter (GM) differences between the obtained cognitive subtypes and healthy volunteers. Methods: 121 recent onset-psychosis (ROP) patients and 201 healthy controls (HC) were recruited within the framework of the Personalized Prognostic Tool for Early Psychosis Management (PRONIA) project. Patients fulfilled DSM-IV-TR criteria of a first affective or nonaffective psychotic episode in the last 3 month with onset in the last 24 months. Cognitive subtypes of the ROP patients were derived from 83 variables of 10 neurocognitive tasks using a kmeans clustering algorithm. A resampling approach implemented in R was used to assess the statistical stability of the results. Neuropsychological and clinical cluster characteristics were assessed using t tests. GM volume of the obtained patient clusters was compared by means of intracranial volume corrected t tests with age, sex and site matched HCs using SPM. Results: The analysis reveals a stable two-cluster solution: A higher cognitive performance cluster (HCP; N=71) and a lower cognitive performance cluster (LCP; N=39). Patients assigned to HCP performed significantly (p < 0.01) worse in 4 out of 10 neuropsychological tasks. Patients assigned to LCP performed significantly (p < 0.01) worse in 9 out of 10 neuropsychological tasks. LCP patients show significantly lower premorbid IQ (p < 0.001) and General Assessment of Functioning score (GAF; p < 0.01), lower occupational functioning (p < 0.01) and higher values on the negative component of the Positive and Negative Syndrom Scale (PANSS; p < 0.05). They show no demographical differences regarding age, sex, education years and study site. LCP patients reveal widespread GM reductions in bilateral temporal, parietal and frontal brain regions as compared to healthy controls. GM reductions of the HCP cluster are more restricted and evident in temporal, occipital regions and in the anterior cingulum. Discussion: Two homogeneous, neurocognitive subgroups of patients suffering from a recent psychotic episode were identified and show distinctive psychopathological and neuroanatomical patterns. The obtained GM reductions in LCP go in line with the neuro-developmental origin of the disease affecting premorbid cognitive and occupational functioning as well as the STG which was reported to be decreased in the early course of the disease. Finding subgroups within early stage psychotic patients with minimal intake of antipsychotic medication, suggests different underlying patho(-physio)logical mechanisms predating manifest illness expression. This evidence offers the opportunity for personalizing interventions like neurocognitive trainings to enhance patients’ odds for recovery after psychosis. [ABSTRACT FROM AUTHOR]

Background: Network models of psychopathology have gained increasing ground recently. It is suggested that psychopathology arises from the reciprocal associations between symptoms and other psycho-biological factors. Given the heterogeneity in psychopathological phenomena, it seems likely that subgroups with distinct network structures may emerge given different demographic and environmental risk factors. Thus, the identification of heterogeneity in symptom networks associated with specific variables may promote an understanding of the mechanisms that underlie the relation between environmental factors and psychopathology. Methods: We took a recursive partitioning approach based on conditional inference trees that iteratively splits the sample of interest based on a predefined set of covariates to detect subgroups with significantly different network structures, resulting in a network tree. We used general population data from the 2000 and 2007 English National Survey of Psychiatric Morbidity, with a combined sample size of n = 15,983 (age range: 16–95 years, 55.9% female), to model networks of psychotic experiences (hallucinations, persecutory ideation) and affective symptoms (worry, mood instability, depression, anxiety, sleep problems). Split variables explored as sources of heterogeneity in networks were sex, age, and exposure to environmental risk factors (cannabis use in past month, lifetime sexual abuse, lifetime experience of bullying). We used a stop-splitting rule based on Bonferroniadjusted p-values to determine the final tree size (α = .01). Results: Environmental factors were the primary sources of heterogeneity in network structures, with exposure to these factors being linked to more densely connected networks. Globally, cannabis use was associated with particularly strong connections between hallucinations and persecutory ideation, depression and persecutory ideation, and depression and mood instability. In those participants with cannabis use and experiences of sexual abuse, the association between depression and persecutory ideation was particularly strong, and further, strong connections were present between the affective symptoms. Similarly, those with exposure to both cannabis and bullying showed stronger associations involving sleep problems than participants exposed to either bullying or cannabis alone. Exposure to either bullying or sexual abuse without concurrent cannabis use was linked to a strongly connected cluster of worry, anxiety, and depression, with only weak associations to other symptoms. Lastly, the sample was split at 60 years of age. The younger group was divided further by age, with participants younger than 26 years showing stronger associations between hallucinations and persecutory ideation and worry and depression than those older than 26 years. In participants older than 60 years, another split was made by gender: women showed a more densely connected network than men. Discussion: Findings from this exploratory analysis document substantial heterogeneity in symptom network structures in a large general population sample. Exposure to risk factors is linked to more strongly connected, probably less resilient symptom networks, with evidence for additive vulnerability given the presence of several risk factors. Exposure to sexual abuse or bullying mainly seems to relate to higher connectivity of affective symptoms, while cannabis use links to higher connection of psychotic symptoms with each other, but also with affective symptoms. The analysis also highlights demographic variables as sources of heterogeneity in symptom networks, pointing to specifically relevant symptom interactions in subgroups of age and gender. [ABSTRACT FROM AUTHOR]

Background: Childhood maltreatment (CM) is a major psychiatric risk factor and leads to long-lasting physical and mental health implications throughout the affected individual’s lifespan. Nonetheless, the neuroanatomical correlates of CM and their specific clinical impact remain elusive. This might be attributed to the complex, multidimensional nature of CM as well as to the restrictions of traditional analysis pipelines using nosological grouping, univariate analysis and region-of-interest approaches. To overcome these issues, we present a novel transdiagnostic and naturalistic machine learning approach towards a better and more comprehensive understanding of the clinical and neuroanatomical complexity of CM. Methods: We acquired our dataset from the multi-center European PRONIA cohort (www.pronia.eu). Specifically, we selected 649 male and female individuals, comprising young, minimally medicated patients with clinical high-risk states for psychosis as well as recent-onset of depression or psychosis and healthy volunteers. As part of our analysis approach, we created a new Matlab Toolbox, which performs multivariate Sparse Partial Least Squares Analysis in a robust machine learning framework. We employed this algorithm to detect multi-layered associations between combinations of items from the Childhood Trauma Questionnaire (CTQ) and grey matter volume (GMV) and assessed their generalizability via nested cross-validation. The clinical relevance of these CM signatures was assessed by correlating them to a wide range of clinical measurements, including current functioning (GAF, GF), depressivity (BDI), quality of life (WHOQOL-BREF) and personality traits (NEO-FFI). Results: Overall, we detected three distinct signatures of sexual, physical and emotional maltreatment. The first signature consisted of an agedependent sexual abuse pattern and a corresponding GMV pattern along the prefronto-thalamo-cerebellar axis. The second signature yielded a sexdependent physical and sexual abuse pattern with a corresponding GMV pattern in parietal, occipital and subcortical regions. The third signature was a global emotional trauma signature, independent of age or sex, and projected to a brain structural pattern in sensory and limbic brain regions. Regarding the clinical impact of these signatures, the emotional trauma signature was most strongly associated with massively impaired state- and trait-level characteristics. Both on a phenomenological and on a brain structural level, the emotional trauma pattern was significantly correlated with lower levels of functioning, higher depression scores, decreased quality of life and maladaptive personality traits. Discussion: Our findings deliver multimodal, data-driven evidence for a differential impact of sexual, physical and emotional trauma on brain structure and clinical state- and trait-level phenotypes. They also highlight the multidimensional nature of CM, which consists of multiple layers of highly complex trauma-brain patterns. In broader terms, our study emphasizes the potential of machine learning approaches in generating novel insights into long-standing psychiatric topics. [ABSTRACT FROM AUTHOR]