Diagnosis, prognosis, and treatment of brief psychotic episodes: a review and research agenda.

Brief psychotic episodes represent an intriguing paradox in clinical psychiatry because they elude the standard knowledge that applies to the persisting psychotic disorders such as schizophrenia. This Review describes key diagnostic considerations such as conceptual foundations, current psychiatric classification versus research-based operationalisations, epidemiology, and sociocultural variations; prognostic aspects including the risk of psychosis recurrence, types of psychotic recurrences, other clinical outcomes, prognostic factors; and therapeutic issues such as treatment guidelines and unmet need of care. The advances and challenges associated with the scientific evidence are used to set a research agenda in this area. We conclude that brief psychotic episodes can be reconceptualised within a clinical staging model to promote innovative translational research and improve our understanding and treatment of psychotic disorders.

Psychosis Biotypes: Replication and Validation from the B-SNIP Consortium.

Current clinical phenomenological diagnosis in psychiatry neither captures biologically homologous disease entities nor allows for individualized treatment prescriptions based on neurobiology. In this report, we studied two large samples of cases with schizophrenia, schizoaffective, and bipolar I disorder with psychosis, presentations with clinical features of hallucinations, delusions, thought disorder, affective, or negative symptoms. A biomarker approach to subtyping psychosis cases (called psychosis Biotypes) captured neurobiological homology that was missed by conventional clinical diagnoses. Two samples (called "B-SNIP1" with 711 psychosis and 274 healthy persons, and the "replication sample" with 717 psychosis and 198 healthy persons) showed that 44 individual biomarkers, drawn from general cognition (BACS), motor inhibitory (stop signal), saccadic system (pro- and anti-saccades), and auditory EEG/ERP (paired-stimuli and oddball) tasks of psychosis-relevant brain functions were replicable (r's from .96-.99) and temporally stable (r's from .76-.95). Using numerical taxonomy (k-means clustering) with nine groups of integrated biomarker characteristics (called bio-factors) yielded three Biotypes that were virtually identical between the two samples and showed highly similar case assignments to subgroups based on cross-validations (88.5%-89%). Biotypes-1 and -2 shared poor cognition. Biotype-1 was further characterized by low neural response magnitudes, while Biotype-2 was further characterized by overactive neural responses and poor sensory motor inhibition. Biotype-3 was nearly normal on all bio-factors. Construct validation of Biotype EEG/ERP neurophysiology using measures of intrinsic neural activity and auditory steady state stimulation highlighted the robustness of these outcomes. Psychosis Biotypes may yield meaningful neurobiological targets for treatments and etiological investigations.

Subtyping based on premorbid profile: A strategy to personalize treatment in first-episode affective psychosis.

AIM: Premorbid history may have a major influence on the way patients cope with the onset of psychosis. This issue has been widely studied in the context of early intervention in schizophrenia but considerably less is known regarding affective psychosis. Our first goal was to investigate if subgroups could be identified among affective psychosis patients based on premorbid factors. Our second goal was to compare these subtypes according to the evolution of mood symptoms and outcomes at the end of the program. METHODS: We conducted a 3-year prospective study on a sample of 74 adults aged 18-35 with a first episode of affective psychosis. Latent class analysis (LCA) was used to reveal distinct exploratory subgroups within affective psychosis patients. RESULTS: Three distinct subgroups could be distinguished. One with later onset of psychosis mainly including women with more severe depressive symptoms in the first 6 months contrasting with two other subgroups with more severe manic symptoms all along the follow-up and earlier onset of psychosis, with or without many serious antecedents. The subgroup with many serious antecedents was more likely to require several hospitalizations, less likely to achieve recovery, especially regarding professional integration and return to premorbid general functioning. CONCLUSIONS: This study provides further evidence of poor functional recovery in the early phase of affective psychosis and shows that premorbid characteristics allow the identification of subgroups with distinct outcome which may require specification of treatment.

A Diagnosis and Biotype Comparison Across the Psychosis Spectrum: Investigating Volume and Shape Amygdala-Hippocampal Differences from the B-SNIP Study.

OBJECTIVE: Brain-based Biotypes for psychotic disorders have been developed as part of the B-SNIP consortium to create neurobiologically distinct subgroups within idiopathic psychosis, independent from traditional phenomenological diagnostic methods. In the current study, we aimed to validate the Biotype model by assessing differences in volume and shape of the amygdala and hippocampus contrasting traditional clinical diagnoses with Biotype classification. METHODS: A total of 811 participants from 6 sites were included: probands with schizophrenia (n = 199), schizoaffective disorder (n = 122), psychotic bipolar disorder with psychosis (n = 160), and healthy controls (n = 330). Biotype classification, previously developed using cognitive and electrophysiological data and K-means clustering, was used to categorize psychosis probands into 3 Biotypes, with Biotype-1 (B-1) showing reduced neural salience and severe cognitive impairment. MAGeT-Brain segmentation was used to determine amygdala and hippocampal volumetric data and shape deformations. RESULTS: When using Biotype classification, B-1 showed the strongest reductions in amygdala-hippocampal volume and the most widespread shape abnormalities. Using clinical diagnosis, probands with schizophrenia and schizoaffective disorder showed the most significant reductions of amygdala and hippocampal volumes and the most abnormal hippocampal shape compared with healthy controls. Biotype classification provided the strongest neuroanatomical differences compared with conventional DSM diagnoses, with the best discrimination seen using bilateral amygdala and right hippocampal volumes in B-1. CONCLUSION: These findings characterize amygdala and hippocampal volumetric and shape abnormalities across the psychosis spectrum. Grouping individuals by Biotype showed greater between-group discrimination, suggesting a promising approach and a favorable target for characterizing biological heterogeneity across the psychosis spectrum.

Classification of Psychoses Based on Immunological Features: A Machine Learning Study in a Large Cohort of First-Episode and Chronic Patients.

For several years, the role of immune system in the pathophysiology of psychosis has been well-recognized, showing differences from the onset to chronic phases. Our study aims to implement a biomarker-based classification model suitable for the clinical management of psychotic patients. A machine learning algorithm was used to classify a cohort of 362 subjects, including 160 first-episode psychosis patients (FEP), 70 patients affected by chronic psychiatric disorders (schizophrenia, bipolar disorder, and major depressive disorder) with psychosis (CRO) and 132 health controls (HC), based on mRNA transcript levels of 56 immune genes. Models distinguished between FEP, CRO, and HC and between the subgroup of drug-free FEP and HC with a mean accuracy of 80.8% and 90.4%, respectively. Interestingly, by using the feature importance method, we identified some immune gene transcripts that contribute most to the classification accuracy, possibly giving new insights on the immunopathogenesis of psychosis. Therefore, our results suggest that our classification model has a high translational potential, which may pave the way for a personalized management of psychosis.

Heterogeneity and Classification of Recent Onset Psychosis and Depression: A Multimodal Machine Learning Approach.

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: χ2 = 14.874; P < .001; GMV model: χ2 = 4.933; P = .026). ROD+P patient classification did not differ from ROD (clinical/neurocognitive model: χ2 = 1.956; P = 0.162; GMV model: χ2 = 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.

The 12-month prevalence of psychotic experiences and their association with clinical outcomes in Hong Kong: an epidemiological and a 2-year follow up studies.

BACKGROUND: The relationship between the subtypes of psychotic experiences (PEs) and common mental health symptoms remains unclear. The current study aims to establish the 12-month prevalence of PEs in a representative sample of community-dwelling Chinese population in Hong Kong and explore the relationship of types of PEs and common mental health symptoms. METHOD: This is a population-based two-phase household survey of Chinese population in Hong Kong aged 16-75 (N = 5719) conducted between 2010 and 2013 and a 2-year follow-up study of PEs positive subjects (N = 152). PEs were measured with Psychosis Screening Questionnaire (PSQ) and subjects who endorsed any item on the PSQ without a clinical diagnosis of psychotic disorder were considered as PE-positive. Types of PEs were characterized using a number of PEs (single v. multiple) and latent class analysis. All PE-positive subjects were assessed with common mental health symptoms and suicidal ideations at baseline and 2-year follow-up. PE status was also assessed at 2-year follow-up. RESULTS: The 12-month prevalence of PEs in Hong Kong was 2.7% with 21.1% had multiple PEs. Three latent classes of PEs were identified: hallucination, paranoia and mixed. Multiple PEs and hallucination latent class of PEs were associated with higher levels of common mental health symptoms. PE persistent rate at 2-year follow-up was 15.1%. Multiple PEs was associated with poorer mental health at 2-year follow-up. CONCLUSIONS: Results highlighted the transient and heterogeneous nature of PEs, and that multiple PEs and hallucination subtype of PEs may be specific indices of poorer common mental health.

Subtypes of Clinical High Risk for Psychosis that Predict Antipsychotic Effectiveness in Long-Term Remission.

INTRODUCTION: In a previous report, we used canonical correlation analysis to classify individuals with clinical high risk (CHR) of psychosis into the 3 subtypes: subtype-1, characterized by extensive negative symptoms and cognitive deficits, appeared to have the highest risk for conversion to psychosis; subtype-2, characterized by thought and behavioral disorganization, with moderate cognitive impairment; subtype-3, characterized by the mildest symptoms and cognitive deficits. The present study attempted to identify these subtypes' response to antipsychotic (AP) treatment. METHODS: A total of 289 individuals with CHR were identified and followed up for 2 years. Individuals with CHR were classified by subtype. Use of APs was examined at 2-month, 1-year, and 2-year follow-up interviews that inquired after the subjects' medication history since the first visit. The main outcome was remission, determined according to global assessment of function (GAF) score (i. e., functional outcome) and SIPS positive symptom score (symptomatic outcome) at the follow-up points. RESULTS: Among the 289 individuals with CHR included in the current analysis, 223 (77.2%) were treated using APs for at least 2 weeks during the follow-up period. Individuals with CHR tended to show significant improvement in both symptoms and function after 2 years, but subtypes exhibited significantly different trajectories. Subtype status can predict AP treatment outcome in terms of remission. The likelihood of remission differed significantly among the subtype groups. The remission rates for individuals with subtypes 1-3 treated using AP were 13.5%, 36.1%, and 67.0%, respectively. DISCUSSION: These subtypes may be of clinical value in AP treatment decision-making in the CHR population.

Deconstructing Negative Symptoms in Individuals at Clinical High-Risk for Psychosis: Evidence for Volitional and Diminished Emotionality Subgroups That Predict Clinical Presentation and Functional Outcome.

Negative symptoms are characteristic of schizophrenia and closely linked to numerous outcomes. A body of work has sought to identify homogenous negative symptom subgroups-a strategy that can promote mechanistic understanding and precision medicine. However, our knowledge of negative symptom subgroups among individuals at clinical high-risk (CHR) for psychosis is limited. Here, we investigated distinct negative symptom profiles in a large CHR sample (N = 244) using a cluster analysis approach. Subgroups were compared on external validators that are (1) commonly observed in the schizophrenia literature and/or (2) may be particularly relevant for CHR individuals, informing early prevention and prediction. We observed 4 distinct negative symptom subgroups, including individuals with (1) lower symptom severity, (2) deficits in emotion, (3) impairments in volition, and (4) global elevations. Analyses of external validators suggested a pattern in which individuals with global impairments and volitional deficits exhibited more clinical pathology. Furthermore, the Volition group endorsed more disorganized, anxious, and depressive symptoms and impairments in functioning compared to the Emotion group. These data suggest there are unique negative symptom profiles in CHR individuals, converging with studies in schizophrenia indicating motivational deficits may be central to this symptom dimension. Furthermore, observed differences in CHR relevant external validators may help to inform early identification and treatment efforts.

The Psychopathology and Neuroanatomical Markers of Depression in Early Psychosis.

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.

Classification and Diagnosis of Schizophrenia or Other Primary Psychotic Disorders: Changes from ICD-10 to ICD-11 and Implementation in Clinical Practice.

From January 2022, the WHO member countries shall start implementing the mortality and morbidity statistics (MMS) version of the eleventh revision of the International Classification of Diseases (ICD-11). Regarding mental, behavioural or neurodevelopmental disorders, there are substantial changes from ICD-10 to ICD-11. The subchapter for schizophrenia or other primary psychotic disorders has changed due to a revised structure, new diagnostic criteria, and the introduction of dimensional elements (i.e., course and symptom qualifiers). The aim of this manuscript is twofold. First, we review changes from ICD-10 to ICD-11 in the classification and diagnosis of schizophrenia or other primary psychotic disorders, including findings from recent field studies. Second, we provide an overview of approaches to the implementation of ICD-11 in clinical practice. Critical elements for transition from ICD-10 to ICD-11 include the use of digital tools, education and training, stakeholder involvement, national adaptations, and continuous evaluation.

Does mindfulness improve inhibitory control in psychotic disorders? A randomized controlled clinical trial / ¿Mejora el mindfulness el control inhibitorio en la psicosis? Un ensayo clínico aleatorizado y controlado

BACKGROUND/OBJECTIVE: Impaired Inhibitory Control (IC) is a core feature of psychotic disorders and is related with impaired social functioning in people experiencing psychosis. Despite research showing the benefits of mindfulness over IC in the general population, no study has assessed its effects on IC in psychoses. The aim of our study was to assess the effectiveness of a mindfulness-based intervention combined with integrated rehabilitation treatment in a sample of people diagnosed of psychotic disorders. METHOD: Fifty-six patients diagnosed with psychotic disorder were recruited and randomly allocated either to integrated rehabilitation treatment or integrated rehabilitation treatment enhanced with 26 mindfulness group sessions. Measures comprised PANSS interview, MAAS scale, and Stroop Color Word Test (SCWT). The primary outcome variable was the performance in the non-congruent trials of the SCWT. RESULTS: There were no differences between groups at baseline. At post-treatment patients allocated to mindfulness group increased their scores in non-congruent trials of SCWT and in MAAS. At post-treatment mindfulness group scored higher than integrated rehabilitation treatment in MAAS. CONCLUSIONS: Data suggest that mindfulness added to integrated rehabilitation treatment may improve IC in psychosis. Results are convergent with prior works about the effect of mindfulness over cognitive performance in general population

ANTECEDENTES/OBJETIVO: Los déficits en el control inhibitorio (CI) son una característica central en trastornos psicóticos y se relaciona con funcionamiento social deteriorado en personas con síntomas psicóticos. A pesar de las investigaciones que muestran los beneficios del mindfulness sobre el CI, ningún estudio ha evaluado sus efectos en las psicosis. El objetivo de este estudio fue evaluar la eficacia de una intervención basada en mindfulness combinada con tratamiento rehabilitador integrado en una muestra de personas diagnosticadas con trastorno psicótico. MÉTODO: Cincuenta y seis pacientes diagnosticados con trastorno psicótico fueron reclutados y asignados aleatoriamente a tratamiento rehabilitador integrado o a tratamiento rehabilitador integrado mejorado con 26 sesiones grupales de mindfulness. Las medidas fueron la entrevista PANSS, la escala MAAS, y el Test Stroop de Palabras y Colores (TSPC). La variable resultado principal fue el rendimiento en los ensayos no congruentes del TSPC. RESULTADOS: No hubo diferencias entre grupos antes del tratamiento. En el postratamiento los pacientes del grupo de mindfulness incrementaron sus puntuaciones en TSPC y en MAAS. El grupo de mindfulness puntuó más alto que el de tratamiento rehabilitador integrado en MAAS. CONCLUSIONES: El mindfulness añadido al tratamiento rehabilitador integrado puede mejorar el CI en las psicosis. Los resultados son convergentes con los trabajos previos sobre el efecto del mindfulness en la población general

Wernicke-Kleist-Leonhard phenotypes of endogenous psychoses: a review of their validity
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While the ICD-DSM paradigm has been a major advance in clinical psychiatry, its usefulness for biological psychiatry is debated. By defining consensus-based disorders rather than empirically driven phenotypes, consensus classifications were not an implementation of the biomedical paradigm. In the field of endogenous psychoses, the Wernicke-Kleist-Leonhard (WKL) pathway has optimized the descriptions of 35 major phenotypes using common medical heuristics on lifelong diachronic observations. Regarding their construct validity, WKL phenotypes have good reliability and predictive and face validity. WKL phenotypes come with remarkable evidence for differential validity on age of onset, familiality, pregnancy complications, precipitating factors, and treatment response. Most impressive is the replicated separation of high- and low-familiality phenotypes. Created in the purest tradition of the biomedical paradigm, the WKL phenotypes deserve to be contrasted as credible alternatives with other approaches currently under discussion.
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The DSM-5 proposal for attenuated psychosis syndrome: a history.

This article narrates a consensus history of the proposal to include diagnostic criteria for a psychosis risk syndrome in the DSM-5, in part, to document what happened, but also to potentially help focus future efforts at clinically useful early detection. The purpose of diagnosing a risk state would be to slow and ideally prevent the development of the full disorder. Concerns about diagnosing a psychosis risk state included a high false positive rate, potentially harmful use of anti-psychotic medication with people who would not transition to psychosis, and stigmatization. Others argued that educating professionals about what 'risk' entails could reduce inappropriate treatments. During the revision, the proposal shifted from diagnosing risk to emphasizing current clinical need associated with attenuated psychotic symptoms. Within the community of researchers who studied psychosis risk, people disagreed about whether risk and/or attenuated symptoms should be an official DSM-5 diagnosis. Once it became clear that the DSM-5 field trials did not include enough cases to establish the reliability of the proposed criteria, everyone agreed that the criteria should be put in a section on conditions for further study rather the main section of the DSM-5. We close with recommendations about some practical benchmarks that should be met for including criteria for early detection in the classification system.

Corticolimbic brain anomalies are associated with cognitive subtypes in psychosis: A longitudinal study.

BACKGROUND: Earlier studies examining structural brain abnormalities associated with cognitively derived subgroups were mainly cross-sectional in design and had mixed findings. Thus, we obtained cross-sectional and longitudinal data to characterize the extent and trajectory of brain structure abnormalities underlying distinct cognitive subtypes ("preserved," "deteriorated," and "compromised") seen in psychotic spectrum disorders. METHODS: Data from 364 subjects (225 patients with psychotic conditions and 139 healthy controls) were first used to determine the relationship of cognitive subtypes with cross-sectional measures of subcortical volume and cortical thickness. To probe neurodevelopmental abnormalities, brain structure laterality was examined. To examine whether neuroprogressive abnormalities persist, longitudinal brain structural changes over 5 years were examined within a subset of 101 subjects. Subsequent discriminant analysis using the identified brain measures was performed on an independent subject group. RESULTS: Cross-sectional comparisons showed that cortical thinning and limbic volume reductions were most widespread in "deteriorated" cognitive subtype. Laterality comparisons showed more rightward amygdala lateralization in "compromised" than "preserved" subtype. Longitudinal comparisons revealed progressive hippocampal shrinkage in "deteriorated" compared with healthy controls and "preserved" subtype, which correlated with worse negative symptoms, cognitive and psychosocial functioning. Post-hoc discrimination analysis on an independent group of 52 subjects using the identified brain structures found an overall accuracy of 71% for classification of cognitive subtypes. CONCLUSION: These findings point toward distinct extent and trajectory of corticolimbic abnormalities associated with cognitive subtypes in psychosis, which can allow further understanding of the biological course of cognitive functioning over illness course and with treatment.

Functional somatic disorders: discussion paper for a new common classification for research and clinical use.

BACKGROUND: Functional somatic symptoms and disorders are common and complex phenomena involving both bodily and brain processes. They pose major challenges across medical specialties. These disorders are common and have significant impacts on patients' quality of life and healthcare costs. MAIN BODY: We outline five problems pointing to the need for a new classification: (1) developments in understanding aetiological mechanisms; (2) the current division of disorders according to the treating specialist; (3) failure of current classifications to cover the variety of disorders and their severity (for example, patients with symptoms from multiple organs systems); (4) the need to find acceptable categories and labels for patients that promote therapeutic partnership; and (5) the need to develop clinical services and research for people with severe disorders. We propose 'functional somatic disorders' (FSD) as an umbrella term for various conditions characterised by persistent and troublesome physical symptoms. FSDs are diagnosed clinically, on the basis of characteristic symptom patterns. As with all diagnoses, a diagnosis of FSD should be made after considering other possible somatic and mental differential diagnoses. We propose that FSD should occupy a neutral space within disease classifications, favouring neither somatic disease aetiology, nor mental disorder. FSD should be subclassified as (a) multisystem, (b) single system, or (c) single symptom. While additional specifiers may be added to take account of psychological features or co-occurring diseases, neither of these is sufficient or necessary to make the diagnosis. We recommend that FSD criteria are written so as to harmonise with existing syndrome diagnoses. Where currently defined syndromes fall within the FSD spectrum - and also within organ system-specific chapters of a classification - they should be afforded dual parentage (for example, irritable bowel syndrome can belong to both gastrointestinal disorders and FSD). CONCLUSION: We propose a new classification, 'functional somatic disorder', which is neither purely somatic nor purely mental, but occupies a neutral space between these two historical poles. This classification reflects both emerging aetiological evidence of the complex interactions between brain and body and the need to resolve the historical split between somatic and mental disorders.

Stages of recovery in psychosis: Converging qualitative research and psychoanalysis.

PURPOSE: The purpose of this study is to find common points of view between the results of qualitative studies researching stages of the recovery process in persons with psychosis and mental changes in a therapeutic relationship in psychoanalytically oriented psychotherapy. CONCLUSIONS: Both concepts correspond one to another. The added psychoanalytical perspective highlights milestones in psychic change: attainment of mental differentiation; integration of self together with the transformation of psychotic grandiosity into decentration, which implies responsibility for illness and own life. PRACTICE IMPLICATIONS: These conclusions highlight the importance of supporting relationships for people suffering from psychoses.

An Investigation of Psychosis Subgroups With Prognostic Validation and Exploration of Genetic Underpinnings: The PsyCourse Study.

Importance: Identifying psychosis subgroups could improve clinical and research precision. Research has focused on symptom subgroups, but there is a need to consider a broader clinical spectrum, disentangle illness trajectories, and investigate genetic associations. Objective: To detect psychosis subgroups using data-driven methods and examine their illness courses over 1.5 years and polygenic scores for schizophrenia, bipolar disorder, major depression disorder, and educational achievement. Design, Setting, and Participants: This ongoing multisite, naturalistic, longitudinal (6-month intervals) cohort study began in January 2012 across 18 sites. Data from a referred sample of 1223 individuals (765 in the discovery sample and 458 in the validation sample) with DSM-IV diagnoses of schizophrenia, bipolar affective disorder (I/II), schizoaffective disorder, schizophreniform disorder, and brief psychotic disorder were collected from secondary and tertiary care sites. Discovery data were extracted in September 2016 and analyzed from November 2016 to January 2018, and prospective validation data were extracted in October 2018 and analyzed from January to May 2019. Main Outcomes and Measures: A clinical battery of 188 variables measuring demographic characteristics, clinical history, symptoms, functioning, and cognition was decomposed using nonnegative matrix factorization clustering. Subtype-specific illness courses were compared with mixed models and polygenic scores with analysis of covariance. Supervised learning was used to replicate results in validation data with the most reliably discriminative 45 variables. Results: Of the 765 individuals in the discovery sample, 341 (44.6%) were women, and the mean (SD) age was 42.7 (12.9) years. Five subgroups were found and labeled as affective psychosis (n = 252), suicidal psychosis (n = 44), depressive psychosis (n = 131), high-functioning psychosis (n = 252), and severe psychosis (n = 86). Illness courses with significant quadratic interaction terms were found for psychosis symptoms (R2 = 0.41; 95% CI, 0.38-0.44), depression symptoms (R2 = 0.28; 95% CI, 0.25-0.32), global functioning (R2 = 0.16; 95% CI, 0.14-0.20), and quality of life (R2 = 0.20; 95% CI, 0.17-0.23). The depressive and severe psychosis subgroups exhibited the lowest functioning and quadratic illness courses with partial recovery followed by reoccurrence of severe illness. Differences were found for educational attainment polygenic scores (mean [SD] partial η2 = 0.014 [0.003]) but not for diagnostic polygenic risk. Results were largely replicated in the validation cohort. Conclusions and Relevance: Psychosis subgroups were detected with distinctive clinical signatures and illness courses and specificity for a nondiagnostic genetic marker. New data-driven clinical approaches are important for future psychosis taxonomies. The findings suggest a need to consider short-term to medium-term service provision to restore functioning in patients stratified into the depressive and severe psychosis subgroups.