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Importance Prognosis is a venerable component of medical knowledge introduced by Hippocrates (460-377 BC). This educational review presents a contemporary evidence-based approach for how to incorporate clinical risk prediction models in modern psychiatry. The article is organized around key methodological themes most relevant for the science of prognosis in psychiatry. Within each theme, the article highlights key challenges and makes pragmatic recommendations to improve scientific understanding of prognosis in psychiatry. Observations The initial step to building clinical risk prediction models that can affect psychiatric care involves designing the model: preparation of the protocol and definition of the outcomes and of the statistical methods (theme 1). Further initial steps involve carefully selecting the predictors, preparing the data, and developing the model in these data. A subsequent step is the validation of the model to accurately test its generalizability (theme 2). The next consideration is that the accuracy of the clinical prediction model is affected by the incidence of the psychiatric condition under investigation (theme 3). Eventually, clinical prediction models need to be implemented in real-world clinical routine, and this is usually the most challenging step (theme 4). Advanced methods such as machine learning approaches can overcome some problems that undermine the previous steps (theme 5). The relevance of each of these themes to current clinical risk prediction modeling in psychiatry is discussed and recommendations are given. Conclusions and Relevance Together, these perspectives intend to contribute to an integrative, evidence-based science of prognosis in psychiatry. By focusing on the outcome of the individuals, rather than on the disease, clinical risk prediction modeling can become the cornerstone for a scientific and personalized psychiatry.

Importance Detection, prognosis, and indicated interventions in individuals at clinical high risk for psychosis (CHR-P) are key components of preventive psychiatry. Objective To provide a comprehensive, evidence-based systematic appraisal of the advancements and limitations of detection, prognosis, and interventions for CHR-P individuals and to formulate updated recommendations. Evidence Review Web of Science, Cochrane Central Register of Reviews, and Ovid/PsychINFO were searched for articles published from January 1, 2013, to June 30, 2019, to identify meta-analyses conducted in CHR-P individuals. MEDLINE was used to search the reference lists of retrieved articles. Data obtained from each article included first author, year of publication, topic investigated, type of publication, study design and number, sample size of CHR-P population and comparison group, type of comparison group, age and sex of CHR-P individuals, type of prognostic assessment, interventions, quality assessment (using AMSTAR [Assessing the Methodological Quality of Systematic Reviews]), and key findings with their effect sizes. Findings In total, 42 meta-analyses published in the past 6 years and encompassing 81 outcomes were included. For the detection component, CHR-P individuals were young (mean [SD] age, 20.6 [3.2] years), were more frequently male (58%), and predominantly presented with attenuated psychotic symptoms lasting for more than 1 year before their presentation at specialized services. CHR-P individuals accumulated several sociodemographic risk factors compared with control participants. Substance use (33% tobacco use and 27% cannabis use), comorbid mental disorders (41% with depressive disorders and 15% with anxiety disorders), suicidal ideation (66%), and self-harm (49%) were also frequently seen in CHR-P individuals. CHR-P individuals showed impairments in work (Cohen d = 0.57) or educational functioning (Cohen d = 0.21), social functioning (Cohen d = 1.25), and quality of life (Cohen d = 1.75). Several neurobiological and neurocognitive alterations were confirmed in this study. For the prognosis component, the prognostic accuracy of CHR-P instruments was good, provided they were used in clinical samples. Overall, risk of psychosis was 22% at 3 years, and the risk was the highest in the brief and limited intermittent psychotic symptoms subgroup (38%). Baseline severity of attenuated psychotic (Cohen d = 0.35) and negative symptoms (Cohen d = 0.39) as well as low functioning (Cohen d = 0.29) were associated with an increased risk of psychosis. Controlling risk enrichment and implementing sequential risk assessments can optimize prognostic accuracy. For the intervention component, no robust evidence yet exists to favor any indicated intervention over another (including needs-based interventions and control conditions) for preventing psychosis or ameliorating any other outcome in CHR-P individuals. However, because the uncertainty of this evidence is high, needs-based and psychological interventions should still be offered. Conclusions and Relevance This review confirmed recent substantial advancements in the detection and prognosis of CHR-P individuals while suggesting that effective indicated interventions need to be identified. This evidence suggests a need for specialized services to detect CHR-P individuals in primary and secondary care settings, to formulate a prognosis with validated psychometric instruments, and to offer needs-based and psychological interventions. Question What is the status of current clinical knowledge in the detection, prognosis, and interventions for individuals at risk of psychosis? Findings In this review of 42 meta-analyses encompassing 81 outcomes, detecting individuals at risk for psychosis required knowledge of their specific sociodemographic, clinical, functional, cognitive, and neurobiological characteristics, and predicting outcomes was achieved with good accuracy provided that assessment tools were used in clinical samples. Evidence for specific effective interventions for this patient population is currently insufficient. Meaning Findings of this review suggest that, although clinical research knowledge for psychosis prevention is substantial and detecting and formulating a prognosis in individuals at risk for psychosis are possible, further research is needed to identify specific effective interventions in individuals with sufficient risk enrichment. This review synthesizes research findings from 42 meta-analyses that assessed detection, prognosis, and interventions for the prevention of psychosis and offers updated practice recommendations.

Importance: Since the release of the DSM-5 diagnosis of attenuated psychosis syndrome (DSM-5-APS) in 2013, several research studies have investigated its clinical validity. Although critical and narrative reviews have reviewed these progresses, no systematic review has comprehensively summarized the available evidence regarding the clinical validity of DSM-5-APS. Objective: To provide current evidence on the clinical validity of DSM-5-APS, focusing on recent advances in diagnosis, prognosis, and treatment. Evidence Review: A multistep literature search using the Web of Science database, Cochrane Central Register of Reviews, Ovid/PsychINFO, conference proceedings, and trial registries from database inception to June 16, 2019, was conducted following PRISMA and MOOSE guidelines and PROSPERO protocol. Studies with original data investigating individuals diagnosed using DSM-5-APS or meeting comparable criteria were included. The results of the systematic review were summarized in tables and narratively synthesized against established evidence-based antecedent, concurrent, and prognostic validators. A quantitative meta-analysis was conducted to explore the cumulative risk of psychosis onset at 6, 12, 24, and 36 months in individuals diagnosed using DSM-5-APS criteria. Findings: The systematic review included 56 articles, which reported on 124 validators, including 15 antecedent, 55 concurrent, and 54 prognostic validators. The epidemiological prevalence of the general non-help-seeking young population meeting DSM-5-APS criteria was 0.3%; the prevalence of individuals meeting DSM-5-APS criteria was variable in clinical samples. The interrater reliability for DSM-5-APS criteria was comparable with that of other DSM-5 mental disorders and can be optimized by the use of specific psychometric instruments. DSM-5-APS criteria were associated with frequent depressive comorbid disorders, distress, suicidality, and functional impairment. The meta-analysis included 23 prospective cohort studies, including 2376 individuals. The meta-analytical risk of psychosis onset was 11% at 6 months, 15% at 12 months, 20% at 24 months, and 23% at 36 months. Research into predisposing and precipitating epidemiological factors, neurobiological correlates, and effective treatments for DSM-5-APS criteria has been limited. Conclusions and Relevance: Over recent years, DSM-5-APS criteria have received substantial concurrent and prognostic validation, mostly driven by research into the clinical high-risk state for psychosis. Precipitating and predisposing factors, neurobiological correlates, and effective treatments are undetermined to date..

Importance: The overall effect of At Risk Mental State (ARMS) services for the detection of individuals who will develop psychosis in secondary mental health care is undetermined.Objective: To measure the proportion of individuals with a first episode of psychosis detected by ARMS services in secondary mental health services, and to develop and externally validate a practical web-based individualized risk calculator tool for the transdiagnostic prediction of psychosis in secondary mental health care.Design, Setting, and Participants: Clinical register-based cohort study. Patients were drawn from electronic, real-world, real-time clinical records relating to 2008 to 2015 routine secondary mental health care in the South London and the Maudsley National Health Service Foundation Trust. The study included all patients receiving a first index diagnosis of nonorganic and nonpsychotic mental disorder within the South London and the Maudsley National Health Service Foundation Trust in the period between January 1, 2008, and December 31, 2015. Data analysis began on September 1, 2016.Main Outcomes and Measures: Risk of development of nonorganic International Statistical Classification of Diseases and Related Health Problems, Tenth Revision psychotic disorders.Results: A total of 91 199 patients receiving a first index diagnosis of nonorganic and nonpsychotic mental disorder within South London and the Maudsley National Health Service Foundation Trust were included in the derivation (n = 33 820) or external validation (n = 54 716) data sets. The mean age was 32.97 years, 50.88% were men, and 61.05% were white race/ethnicity. The mean follow-up was 1588 days. The overall 6-year risk of psychosis in secondary mental health care was 3.02 (95% CI, 2.88-3.15), which is higher than the 6-year risk in the local general population (0.62). Compared with the ARMS designation, all of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnoses showed a lower risk of psychosis, with the exception of bipolar mood disorders (similar risk) and brief psychotic episodes (higher risk). The ARMS designation accounted only for a small proportion of transitions to psychosis (n = 52 of 1001; 5.19% in the derivation data set), indicating the need for transdiagnostic prediction of psychosis in secondary mental health care. A prognostic risk stratification model based on preselected variables, including index diagnosis, age, sex, age by sex, and race/ethnicity, was developed and externally validated, showing good performance and potential clinical usefulness.Conclusions and Relevance: This online individualized risk calculator can be of clinical usefulness for the transdiagnostic prediction of psychosis in secondary mental health care. The risk calculator can help to identify those patients at risk of developing psychosis who require an ARMS assessment and specialized care. The use of this calculator may eventually facilitate the implementation of an individualized provision of preventive focused interventions and improve outcomes of first episode psychosis.

IMPORTANCE: The prognostic significance of competing constructs and operationalizations for brief psychotic episodes (acute and transient psychotic disorder [ATPD], brief psychotic disorder [BPD], brief intermittent psychotic symptoms [BIPS], and brief limited intermittent psychotic symptoms [BLIPS]) is unknown.OBJECTIVE: To provide a meta-analytical prognosis of the risk of psychotic recurrence in patients with remitted first-episode ATPD, BPD, BIPS, and BLIPS and in a benchmark group of patients with remitted first-episode schizophrenia (FES). We hypothesized a differential risk: FES > ATPD > BPD > BIPS > BLIPS.DATA SOURCES: The Web of Knowledge and Scopus databases were searched up to May 18, 2015; the articles identified were reviewed as well as citations of previous publications and results of a manual search of the reference lists of retrieved articles.STUDY SELECTION: We included original articles that reported the risk of psychotic recurrence at follow-up for patients in remission from first-episode ATPD, BPD, BLIPS, BIPS, and FES.DATA EXTRACTION AND SYNTHESIS: Independent extraction by multiple observers. Random-effects meta-analysis was performed, and moderators were tested with meta-regression analyses, Bonferroni corrected. Heterogeneity was assessed with the I2 index. Sensitivity analyses tested the robustness of the results. Publication bias was assessed with funnel plots and the Egger test.MAIN OUTCOMES AND MEASURES: Proportion of patients with baseline ATPD, BPD, BLIPS, and BIPS who had any psychotic recurrence at 6, 12, 24, and 36 or more months of follow-up.RESULTS: Eighty-two independent studies comprising up to 11 133 patients were included. There was no prognostic difference in risk of psychotic recurrence between ATPD, BPD, BLIPS, and BIPS at any follow-up (P > .03). In the long-term analysis, risk of psychotic recurrence (reported as mean [95% CI]) was significantly higher in the FES group (0.78 [0.58-0.93] at 24 months and 0.84 [0.70-0.94] at ≥36 months; P CONCLUSIONS AND RELEVANCE: There are no prognostic differences in risk of psychotic recurrence between ATPD, BPD, BLIPS, and BIPS constructs of brief psychotic episodes. Conversely, there is consistent meta-analytical evidence for better long-term prognosis of brief psychotic episodes compared with remitted first-episode schizophrenia. These findings should influence the diagnostic practice and clinical services in the management of early psychosis.

IMPORTANCE Individuals can be classified as being at clinical high risk (CHR) for psychosis if they meet at least one of the ultra-high-risk (UHR) inclusion criteria (brief limited intermittent psychotic symptoms [BLIPS] and/or attenuated psychotic symptoms [APS] and/or genetic risk and deterioration syndrome [GRD]) and/or basic symptoms [BS]. Themeta-analytical risk of psychosis of these different subgroups is still unknown. OBJECTIVE To compare the risk of psychosis in CHR individuals who met at least one of the major inclusion criteria and in individuals not at CHR for psychosis (CHR-). DATA SOURCES Electronic databases (Web of Science, MEDLINE, Scopus) were searched until June 18, 2015, along with investigation of citations of previous publications and a manual search of the reference lists of retrieved articles. STUDY SELECTION We included original follow-up studies of CHR individuals who reported the risk of psychosis classified according to the presence of any BLIPS, APS and GRD, APS alone, GRD alone, BS, and CHR-. DATA EXTRACTION AND SYNTHESIS Independent extraction by multiple observers and random-effects meta-analysis of proportions. Moderators were tested with meta-regression analyses (Bonferroni corrected). Heterogeneity was assessed with the I2 index. Sensitivity analyses tested robustness of results. Publication biases were assessed with funnel plots and the Egger test. MAIN OUTCOMES AND MEASURES The proportion of each subgroup with any psychotic disorder at 6, 12, 24, 36, and 48 or more months of follow-up. RESULTS Thirty-three independent studies comprising up to 4227 individualswere included. The meta-analytical proportion of individuals meeting each UHR subgroup at intakewas: 0.85 APS (95%CI, 0.79-0.90), 0.1 BLIPS (95%CI, 0.06-0.14), and 0.05 GRD (95%CI, 0.03-0.07). There were no significant differences in psychosis risk at any time point between the APS and GRD and the APS-alone subgroups. Therewas a higher risk of psychosis in the any BLIPS greater than APS greater than GRD-alone subgroups at 24, 36, and 48 or more months of follow-up. Therewas no evidence that the GRD subgroup has a higher risk of psychosis than the CHR- subgroup. There were too fewBS or BS and UHR studies to allowrobust conclusions. CONCLUSIONS AND RELEVANCE There is meta-analytical evidence that BLIPS represents separate risk subgroup compared with the APS. The GRD subgroup is infrequent and not associated with an increased risk of psychosis. Future studies are advised to stratify their findings across these different subgroups. The CHR guidelines should be updated to reflect these differences.

The Promises In 1995, great expectations laid aheadof the launchof the first preventive service for young people at clinical high risk (CHR) for psychosis. Researchers hoped to identify not only staterisk factors for psychosis but above all touncover “specific precursor features that predicted subsequentpsychosis in thenear futurewith ahighdegree of probability,”1(p285) by analogy defined as Koplik spot equivalentsofpsychosis,1 allowingeffectiveearlydiagnosisand treatment. Koplik spots are small white lesions on the buccal mucosa thatprecedemeaslesdiseasewithhigh sensitivity and are important inthepreventionofoutbreaks.AsforKoplikspots, earlysignsofpsychosisareclinicallydifficult todetect.Because ofthis,CHRresearchershavereliedonneuroimagingtechniques in their enduring search for the Koplik spots of psychosis.

Context: During the past 2 decades, a major transition in the clinical characterization of psychotic disorders has occurred. The construct of a clinical high-risk (HR) state for psychosis has evolved to capture the prepsychotic phase, describing people presenting with potentially prodromal symptoms. The importance of this HR state has been increasingly recognized to such an extent that a new syndrome is being considered as a diagnostic category in the DSM-5. Objective: To reframe the HR state in a comprehensive state-of-the-art review on the progress that has been made while also recognizing the challenges that remain. Data Sources: Available HR research of the past 20 years from PubMed, books, meetings, abstracts, and international conferences. Study Selection and Data Extraction: Critical review of HR studies addressing historical development, inclusion criteria, epidemiologic research, transition criteria, outcomes, clinical and functional characteristics, neurocognition, neuroimaging, predictors of psychosis development, treatment trials, socioeconomic aspects, nosography, and future challenges in the field. Data Synthesis: Relevant articles retrieved in the literature search were discussed by a large group of leading worldwide experts in the field. The core results are presented after consensus and are summarized in illustrative tables and figures. Conclusions: The relatively new field of HR research in psychosis is exciting. It has the potential to shed light on the development of major psychotic disorders and to alter their course. It also provides a rationale for service provision to those in need of help who could not previously access it and the possibility of changing trajectories for those with vulnerability to psychotic illnesses