Olfactory and gustatory dysfunctions in SARS-CoV-2 infection: A systematic review.

BACKGROUND: Among Coronavirus Disease 2019 (COVID-19) manifestations, Olfactory (OD) and Gustatory (GD) Dysfunctions (OGD) have drawn considerable attention, becoming a sort of hallmark of the disease. Many have speculated on the pathogenesis and clinical characteristics of these disturbances; however, no definite answers have been produced on the topic. With this systematic review, we aimed to collect all the available evidence regarding the prevalence of OGD, the timing of their onset and their resolution, their rate of recovery and their role as diagnostic and prognostic tools for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. METHODS: A systematic review comprising all the observational studies that reported the prevalence and/or the longitudinal trajectories of OGD in COVID-19 patients, as self-reported by patients or measured through objective psychophysical tests. RESULTS: After the selection process, 155 studies were included, with a total of 70,920 patients and 105,291 not-infected individuals. Prevalence reports were extremely variable across studies, with wide ranges for OD (0%-98%) and GD (0-89%) prevalence. OGD occurred early during the disease course and only rarely preceded other symptoms; out of 30 studies with a follow-up time of at least 20 days, only in 5 studies OGD fully resolved in more than 90% of patients. OGD had low sensitivity and high specificity for SARS-CoV-2 infection; accuracy of OD and GD for infection identification was higher than 80% in 10 out of 33 studies and in 8 out of 22 studies considered, respectively. 28 out of 30 studies that studied the association between OGD and disease severity found how OGD were associated with lower rates of severe pneumonia, hospitalization and mortality. CONCLUSIONS: OGD seem to be highly prevalent in SARS-CoV-2 infection. They occur early, concomitantly with other symptoms and often persist after recovery, in some cases for months; whether a full recovery eventually occurs in all cases is not clear yet. OGD are good predictors of SARS-CoV-2 infection and are associated with a milder disease course.

Suicide, self-harm and thoughts of suicide or self-harm in infectious disease epidemics: a systematic review and meta-analysis.

AIMS: Suicide accounts for 2.2% of all years of life lost worldwide. We aimed to establish whether infectious epidemics are associated with any changes in the incidence of suicide or the period prevalence of self-harm, or thoughts of suicide or self-harm, with a secondary objective of establishing the frequency of these outcomes. METHODS: In this systematic review and meta-analysis, MEDLINE, Embase, PsycINFO and AMED were searched from inception to 9 September 2020. Studies of infectious epidemics reporting outcomes of (a) death by suicide, (b) self-harm or (c) thoughts of suicide or self-harm were identified. A random-effects model meta-analysis for the period prevalence of thoughts of suicide or self-harm was conducted. RESULTS: In total, 1354 studies were screened with 57 meeting eligibility criteria, of which 7 described death by suicide, 9 by self-harm, and 45 thoughts of suicide or self-harm. The observation period ranged from 1910 to 2020 and included epidemics of Spanish Flu, severe acute respiratory syndrome, human monkeypox, Ebola virus disease and coronavirus disease 2019 (COVID-19). Regarding death by suicide, data with a clear longitudinal comparison group were available for only two epidemics: SARS in Hong Kong, finding an increase in suicides among the elderly, and COVID-19 in Japan, finding no change in suicides among children and adolescents. In terms of self-harm, five studies examined emergency department attendances in epidemic and non-epidemic periods, of which four found no difference and one showed a reduction during the epidemic. In studies of thoughts of suicide or self-harm, one large survey showed a substantial increase in period prevalence compared to non-epidemic periods, but smaller studies showed no difference. As a secondary objective, a meta-analysis of thoughts of suicide and self-harm found that the pooled prevalence was 8.0% overall (95% confidence interval (CI) 5.2-12.0%; 14 820 of 99 238 cases in 24 studies) over a time period of between seven days and six months. The quality assessment found 42 studies were of high quality, nine of moderate quality and six of high quality. CONCLUSIONS: There is little robust evidence on the association of infectious epidemics with suicide, self-harm and thoughts of suicide or self-harm. There was an increase in suicides among the elderly in Hong Kong during SARS and no change in suicides among young people in Japan during COVID-19, but it is unclear how far these findings may be generalised. The development of up-to-date self-harm and suicide statistics to monitor the effect of the current pandemic is an urgent priority.

Empirical assessment of biases in cerebrospinal fluid biomarkers of Alzheimer's disease: an umbrella review and re-analysis of data from meta-analyses.

OBJECTIVE: Alzheimer's disease (AD) is a leading cause of years lived with disability in older age, and several cerebrospinal fluid (CSF) markers have been proposed in individual meta-analyses to be associated with AD but field-wide evaluation and scrutiny of the literature is not available. MATERIALS AND METHODS: We performed an umbrella review for the reported associations between CSF biomarkers and AD. Data from available meta-analyses were reanalyzed using both random and fixed effects models. We also estimated between-study heterogeneity, small-study effects, excess significance, and prediction interval. RESULTS: A total of 38 meta-analyses on CSF markers from 11 eligible articles were identified and reanalyzed. In 14 (36%) of the meta-analyses, the summary estimate and the results of the largest study showed non-concordant results in terms of statistical significance. Large heterogeneity (I2≥75%) was observed in 73% and small-study effects under Egger's test were shown in 28% of CSF biomarkers. CONCLUSIONS: Our results suggest that there is an excess of statistically significant results and significant biases in the literature of CSF biomarkers for AD. Therefore, the results of CSF biomarkers should be interpreted with caution.

Clinical outcomes in brief psychotic episodes: a systematic review and meta-analysis.

AIMS: Patients with brief psychotic episodes (BPE) have variable and fluctuating clinical outcomes which challenge psychiatric care. Our meta-analysis aims at providing a comprehensive summary of several clinical outcomes in this patient group. METHODS: A multistep systematic PRISMA/MOOSE-compliant literature search was performed for articles published from inception until 1st March 2021. Web of Science database was searched, complemented by manual search of original articles reporting relevant outcomes (psychotic recurrence, prospective diagnostic change or stability, remission, quality of life, functional status, mortality and their predictors) for patients diagnosed with acute and transient psychotic disorders (ATPD), brief psychotic disorders (BPD), brief intermittent psychotic symptoms (BIPS) and brief limited intermittent psychotic symptoms (BLIPS). Random-effects methods and Q-statistics were employed, quality assessment with Newcastle-Ottawa Scale, assessment of heterogeneity with I2 index, sensitivity analyses (acute polymorphic psychotic disorders, APPD) and multiple meta-regressions, assessment of publication bias with funnel plot, Egger's test and meta-regression (psychotic recurrence and sample size). RESULTS: A total of 91 independent articles (n = 94 samples) encompassed 37 ATPD, 24 BPD, 19 BLIPS and 14 BIPS samples, totalling 15 729 individuals (mean age: 30.89 ± 7.33 years, mean female ratio: 60%, 59% conducted in Europe). Meta-analytical risk of psychotic recurrence for all BPE increased from 15% (95% confidence interval (CI) 12-18) at 6 months, 25% (95% CI 22-30) at 12 months, 30% (95% CI 27-33) at 24 months and 33% (95% CI 30-37) at ⩾36 months follow-up, with no differences between ATPD, BPD, BLIPS and BIPS after 2 years of follow-up. Across all BPE, meta-analytical proportion of prospective diagnostic stability (average follow-up 47 months) was 49% (95% CI 42-56); meta-analytical proportion of diagnostic change (average follow-up 47 months) to schizophrenia spectrum psychoses was 19% (95% CI 16-23), affective spectrum psychoses 5% (95% CI 3-7), other psychotic disorders 7% (95% CI 5-9) and other (non-psychotic) mental disorders 14% (95% CI 11-17). Prospective diagnostic change within APPD without symptoms of schizophrenia was 34% (95% CI 24-46) at a mean follow-up of 51 months: 18% (95% CI 11-30) for schizophrenia spectrum psychoses and 17% (95% CI 10-26) for other (non-psychotic) mental disorders. Meta-analytical proportion of baseline employment was 48% (95% CI 38-58), whereas there were not enough data to explore the other outcomes. Heterogeneity was high; female ratio and study quality were negatively and positively associated with risk of psychotic recurrence, respectively. There were no consistent factor predicting clinical outcomes. CONCLUSIONS: Short-lived psychotic episodes are associated with a high risk of psychotic recurrences, in particular schizophrenia spectrum disorders. Other clinical outcomes remain relatively underinvestigated. There are no consistent prognostic/predictive factors.

Antipsychotic use and risk of life-threatening medical events: umbrella review of observational studies.

OBJECTIVE: To quantify the risk of hip fracture, thromboembolism, stroke, myocardial infarction, pneumonia and sudden cardiac death associated with exposure to antipsychotics. METHODS: Systematic searches were conducted in Medline, Embase and PsycINFO from inception until 30/07/2018 for systematic reviews of observational studies. AMSTAR-2 was used for the quality assessment of systematic reviews, while the strength of associations was measured using GRADE and quantitative umbrella review criteria (URC). RESULTS: Sixty-eight observational studies from six systematic reviews were included. The association between antipsychotic exposure and pneumonia was the strongest [URC = class I; GRADE = low quality; odds ratio (OR) = 1.84, 95% confidence interval (CI) = 1.62-2.09; participants = 28 726; age = 76.2 ± 12.3 years], followed by the association with hip fracture (URC = class II; GRADE = low quality; OR = 1.57, 95% CI = 1.42-1.74; participants = 5 288 118; age = 55.4 ± 12.5 years), and thromboembolism (URC = class II; GRADE = very low quality; OR = 1.55, 95% CI = 1.31-1.83; participants = 31 417 175; age = 55.5 ± 3.2 years). The association was weak for stroke (URC = class III; GRADE = very low quality; OR = 1.45, 95% CI = 1.24-1.70; participants = 65 700; age = 68.7 ± 13.8 years), sudden cardiac death (URC = class III; GRADE = very low quality; OR = 2.24, 95% CI = 1.45-3.46; participants = 77 488; age = 52.2 ± 6.2 years) and myocardial infarction (URC = class III; GRADE = very low quality; OR = 2.21, 95% CI = 1.41-3.46; participants = 399 868; age = 74.1 ± 9.3 years). CONCLUSION: The most robust results were found for the risk of pneumonia, followed by the risk of hip fracture and thromboembolism. For stroke, sudden cardiac death and myocardial infarction, the strength of association was weak. The observational nature of the primary studies may represent a source of bias.

Correction: Altered activation and connectivity in a hippocampal-basal ganglia-midbrain circuit during salience processing in subjects at ultra high risk for psychosis.

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Meta-analytical prognostic accuracy of the Comprehensive Assessment of at Risk Mental States (CAARMS): The need for refined prediction.

Primary indicated prevention is reliant on accurate tools to predict the onset of psychosis. The gold standard assessment for detecting individuals at clinical high risk (CHR-P) for psychosis in the UK and many other countries is the Comprehensive Assessment for At Risk Mental States (CAARMS). While the prognostic accuracy of CHR-P instruments has been assessed in general, this is the first study to specifically analyse that of the CAARMS. As such, the CAARMS was used as the index test, with the reference index being psychosis onset within 2 years. Six independent studies were analysed using MIDAS (STATA 14), with a total of 1876 help-seeking subjects referred to high risk services (CHR-P+: n=892; CHR-P-: n=984). Area under the curve (AUC), summary receiver operating characteristic curves (SROC), quality assessment, likelihood ratios, and probability modified plots were computed, along with sensitivity analyses and meta-regressions. The current meta-analysis confirmed that the 2-year prognostic accuracy of the CAARMS is only acceptable (AUC=0.79 95% CI: 0.75-0.83) and not outstanding as previously reported. In particular, specificity was poor. Sensitivity of the CAARMS is inferior compared to the SIPS, while specificity is comparably low. However, due to the difficulties in performing these types of studies, power in this meta-analysis was low. These results indicate that refining and improving the prognostic accuracy of the CAARMS should be the mainstream area of research for the next era. Avenues of prediction improvement are critically discussed and presented to better benefit patients and improve outcomes of first episode psychosis.

Why transition risk to psychosis is not declining at the OASIS ultra high risk service: The hidden role of stable pretest risk enrichment.

BACKGROUND: The reason for declining risk to psychosis across individuals assessed and meeting Ultra High Risk (UHR) criteria is still unclear. No studies have investigated the potential substantial role of the underlying risk enrichment across all the individuals undergoing an UHR assessment. METHODS: Cohort study including all non-psychotic subjects who were assessed on suspicion of psychosis risk by the OASIS UHR service in the period 2001 to 2015. Posttest (after UHR assessment) and pretest risk (before UHR assessment) of psychosis were stratified and compared across three time periods (2001-2005, 2006-2010, 2011-2015) with Cox analysis and modulating factors were investigated. RESULTS: The posttest risk of psychosis at the OASIS service has increased from the initial pilot years of the service (2001-2005) and then stabilised and not declined over the following decade (2006-2010 and 2011-2015). This was paralleled by a similar course of pretest risk for psychosis. Stability of pretest risk for psychosis over the past decade was associated with a lack of change in ethnicity and to counterweighting changes in the type of referral sources over different time periods. CONCLUSIONS: The time course of transition risk to psychosis in UHR services is strictly associated with the time course of pretest risk enrichment. If the latter remains stable over time, as for the OASIS service, no declining transition risk is observed over the most recent years. Pretest risk enrichment is determined by recruitment and sampling strategies. This study confirms the need to control these factors in the UHR field.

Neighbourhood deprivation is positively associated with detection of the ultra-high risk (UHR) state for psychosis in South East London.

BACKGROUND: Individuals are defined as being at ultra-high risk (UHR) for psychosis based on a combination of attenuated psychotic symptoms, help-seeking behaviour, genetic risk, and social/occupational deterioration. Limited evidence is available on whether UHR detection differs by neighbourhood, and potential explanations. AIMS: To examine neighbourhood distribution of detected UHR using cases from the OASIS service in South East London, investigating neighbourhood deprivation as an explanatory variable. METHODS: Geographic data were collected on patients who met UHR criteria over a fourteen-year period, at the neighbourhood (lower super output area, LSOA) level. Rates were calculated based on cases and age-specific population estimates. Poisson regression assessed associations between UHR rate and neighbourhood deprivation, and with particular deprivation domains, adjusting for referrals for UHR assessment, population density, and proportions of non-White people, and young single people. RESULTS: Rate of UHR detection was statistically related to neighbourhood deprivation, but referral rate was not: compared to the least deprived neighbourhoods, the most deprived neighbourhoods had a greater than two-fold increase in incidence rate of detected UHR (adjusted incidence rate ratio (IRR): 2.11, 95% confidence interval (CI): 1.21,3.67). In contrast, a small, imprecise association was observed for referral for assessment for UHR (adjusted IRR: 1.26 (95%CI: 0.84,1.89)). Evidence was also found for associations of UHR detection rate with domains of deprivation pertaining to health and barriers to services. CONCLUSIONS: The distribution of UHR detection rates by neighbourhood is not random and may be explained in part by differences in the social environment between neighbourhoods.

Altered activation and connectivity in a hippocampal-basal ganglia-midbrain circuit during salience processing in subjects at ultra high risk for psychosis.

Animal models of psychosis propose that abnormal hippocampal activity drives increased subcortical dopamine function, which is thought to contribute to aberrant salience processing and psychotic symptoms. These effects appear to be mediated through connections between the hippocampus, ventral striatum/pallidum and the midbrain. The aim of the present study was to examine the activity and connectivity in this pathway in people at ultra high risk (UHR) for psychosis. Functional magnetic resonance imaging was used to compare neural responses in a hippocampal-basal ganglia-midbrain network during reward, novelty and aversion processing between 29 UHR subjects and 32 healthy controls. We then investigated whether effective connectivity within this network is perturbed in UHR subjects, using dynamic causal modelling (DCM). Finally, we examined the relationship between alterations in activation and connectivity in the UHR subjects and the severity of their psychotic symptoms. During reward anticipation, UHR subjects showed greater activation than controls in the ventral pallidum bilaterally. There were no differences in activation during novelty or aversion processing. DCM revealed that reward-induced modulation of connectivity from the ventral striatum/pallidum to the midbrain was greater in UHR subjects than controls, and that in UHR subjects, the strength of connectivity in this pathway was correlated with the severity of their abnormal beliefs. In conclusion, ventral striatal/pallidal function is altered in people at UHR for psychosis and this is related to the level of their psychotic symptoms.

Diagnostic validity of ICD-10 acute and transient psychotic disorders and DSM-5 brief psychotic disorder.

BACKGROUND: Short-lived psychotic disorders are currently classified under "acute and transient psychotic disorders" (ATPDs) in ICD-10, and "brief psychotic disorder" (BPD) in DSM-5. This study's aim is to review the literature and address the validity of ATPDs and BPD. METHOD: Papers published between January 1993 and December 2016 were identified through searches in Web of Science. Reference lists in the located papers provided further sources. RESULTS: A total of 295 articles were found and 100 were included in the review. There were only a few studies about the epidemiology, vulnerability factors, neurobiological correlates and treatment of these disorders, particularly little interest seems to exist in BPD. The available evidence suggests that short-lived psychotic disorders are rare conditions and more often affect women in early to middle adulthood. They also are neither associated with premorbid dysfunctions nor characteristic family predisposition, while there seems to be greater evidence of environmental factors particularly in developing countries and migrant populations. Follow-up studies report a favourable clinical and functional outcome, but case identification has proved difficult owing to high rates of transition mainly either to schizophrenia and related disorders or, to a lesser extent, affective disorders over the short- and longer-terms. CONCLUSIONS: Although the lack of neurobiological findings and little predictive power argue against the validity of the above diagnostic categories, it is important that they are kept apart from longer-lasting psychotic disorders both for clinical practice and research. Close overlap between ATPDs and BPD could enhance the understanding of these conditions.

Long-term validity of the At Risk Mental State (ARMS) for predicting psychotic and non-psychotic mental disorders.

BACKGROUND: The long-term clinical validity of the At Risk Mental State (ARMS) for the prediction of non-psychotic mental disorders is unknown. METHODS: Clinical register-based cohort study including all non-psychotic individuals assessed by the Outreach And Support in South London (OASIS) service (2002-2015). The primary outcome was risk of developing any mental disorder (psychotic or non-psychotic). Analyses included Cox proportional hazard models, Kaplan-Meier survival/failure function and C statistics. RESULTS: A total of 710 subjects were included. A total of 411 subjects were at risk (ARMS+) and 299 not at risk (ARMS-). Relative to ARMS-, the ARMS+ was associated with an increased risk (HR=4.825) of developing psychotic disorders, and a reduced risk (HR=0.545) of developing non-psychotic disorders (mainly personality disorders). At 6-year, the ARMS designation retained high sensitivity (0.873) but only modest specificity (0.456) for the prediction of psychosis onset (AUC 0.68). The brief and limited intermittent psychotic symptoms (BLIPS) subgroup had a higher risk of developing psychosis, and a lower risk of developing non-psychotic disorders as compared to the attenuated psychotic symptoms (APS) subgroup (P<0.001). CONCLUSIONS: In the long-term, the ARMS specifically predicts the onset of psychotic disorders, with modest accuracy, but not of non-psychotic disorders. Individuals meeting BLIPS criteria have distinct clinical outcomes. SIGNIFICANT OUTCOMES: In the long-term, the ARMS designation is still significantly associated with an increased risk of developing psychotic disorders but its prognostic accuracy is only modest. There is no evidence that the ARMS is associated with an increased risk of developing non-psychotic mental disorders. The BLIPS subgroup at lower risk of developing non-psychotic disorders compared to the APS subgroup. LIMITATIONS: While incident diagnoses employed in this study are high in ecological validity they have not been subjected to formal validation with research-based criteria.

Longitudinal alterations in motivational salience processing in ultra-high-risk subjects for psychosis.

BACKGROUND: Impairments in the attribution of salience are thought to be fundamental to the development of psychotic symptoms and the onset of psychotic disorders. The aim of the present study was to explore longitudinal alterations in salience processing in ultra-high-risk subjects for psychosis. METHOD: A total of 23 ultra-high-risk subjects and 13 healthy controls underwent functional magnetic resonance imaging at two time points (mean interval of 17 months) while performing the Salience Attribution Test to assess neural responses to task-relevant (adaptive salience) and task-irrelevant (aberrant salience) stimulus features. RESULTS: At presentation, high-risk subjects were less likely than controls to attribute salience to relevant features, and more likely to attribute salience to irrelevant stimulus features. These behavioural differences were no longer evident at follow-up. When attributing salience to relevant cue features, ultra-high-risk subjects showed less activation than controls in the ventral striatum at both baseline and follow-up. Within the high-risk sample, amelioration of abnormal beliefs over the follow-up period was correlated with an increase in right ventral striatum activation during the attribution of salience to relevant cue features. CONCLUSIONS: These findings confirm that salience processing is perturbed in ultra-high-risk subjects for psychosis, that this is linked to alterations in ventral striatum function, and that clinical outcomes are related to longitudinal changes in ventral striatum function during salience processing.

Deconstructing vulnerability for psychosis: Meta-analysis of environmental risk factors for psychosis in subjects at ultra high-risk.

BACKGROUND: Subjects at ultra high-risk (UHR) for psychosis have an enhanced vulnerability to develop the disorder but the risk factors accounting for this accrued risk are undetermined. METHOD: Systematic review of associations between genetic or environmental risk factors for psychosis that are widely established in the literature and UHR state, based on comparisons to controls. RESULTS: Forty-four studies encompassing 170 independent datasets and 54 risk factors were included. There were no studies on association between genetic or epigenetic risk factors and the UHR state that met the inclusion criteria. UHR subjects were more likely to show obstetric complications, tobacco use, physical inactivity, childhood trauma/emotional abuse/physical neglect, high perceived stress, childhood and adolescent low functioning, affective comorbidities, male gender, single status, unemployment and low educational level as compared to controls. CONCLUSIONS: The increased vulnerability of UHR subjects can be related to environmental risk factors like childhood trauma, adverse life events and affective dysfunction. The role of genetic and epigenetic risk factors awaits clarification.

Forty years of structural imaging in psychosis: promises and truth.

OBJECTIVE: Since the first study published in the Lancet in 1976, structural neuroimaging has been used in psychosis with the promise of imminent clinical utility. The actual impact of structural neuroimaging in psychosis is still unclear. METHOD: We present here a critical review of studies involving structural magnetic resonance imaging techniques in patients with psychosis published between 1976 and 2015 in selected journals of relevance for the field. For each study, we extracted summary descriptive variables. Additionally, we qualitatively described the main structural findings of each article in summary notes and we employed a biomarker rating system based on quality of evidence (scored 1-4) and effect size (scored 1-4). RESULTS: Eighty studies meeting the inclusion criteria were retrieved. The number of studies increased over time, reflecting an increased structural imaging research in psychosis. However, quality of evidence was generally impaired by small samples and unclear biomarker definitions. In particular, there was little attempt of replication of previous findings. The effect sizes ranged from small to modest. No diagnostic or prognostic biomarker for clinical use was identified. CONCLUSIONS: Structural neuroimaging in psychosis research has not yet delivered on the clinical applications that were envisioned.

Towards a Standard Psychometric Diagnostic Interview for Subjects at Ultra High Risk of Psychosis: CAARMS versus SIPS.

Background. Several psychometric instruments are available for the diagnostic interview of subjects at ultra high risk (UHR) of psychosis. Their diagnostic comparability is unknown. Methods. All referrals to the OASIS (London) or CAMEO (Cambridgeshire) UHR services from May 13 to Dec 14 were interviewed for a UHR state using both the CAARMS 12/2006 and the SIPS 5.0. Percent overall agreement, kappa, the McNemar-Bowker χ (2) test, equipercentile methods, and residual analyses were used to investigate diagnostic outcomes and symptoms severity or frequency. A conversion algorithm (CONVERT) was validated in an independent UHR sample from the Seoul Youth Clinic (Seoul). Results. There was overall substantial CAARMS-versus-SIPS agreement in the identification of UHR subjects (n = 212, percent overall agreement = 86%; kappa = 0.781, 95% CI from 0.684 to 0.878; McNemar-Bowker test = 0.069), with the exception of the brief limited intermittent psychotic symptoms (BLIPS) subgroup. Equipercentile-linking table linked symptoms severity and frequency across the CAARMS and SIPS. The conversion algorithm was validated in 93 UHR subjects, showing excellent diagnostic accuracy (CAARMS to SIPS: ROC area 0.929; SIPS to CAARMS: ROC area 0.903). Conclusions. This study provides initial comparability data between CAARMS and SIPS and will inform ongoing multicentre studies and clinical guidelines for the UHR psychometric diagnostic interview.

Predicting the onset of psychosis in patients at clinical high risk: practical guide to probabilistic prognostic reasoning.

Prediction of psychosis in patients at clinical high risk (CHR) has become a mainstream focus of clinical and research interest worldwide. When using CHR instruments for clinical purposes, the predicted outcome is but only a probability; and, consequently, any therapeutic action following the assessment is based on probabilistic prognostic reasoning. Yet, probabilistic reasoning makes considerable demands on the clinicians. We provide here a scholarly practical guide summarising the key concepts to support clinicians with probabilistic prognostic reasoning in the CHR state. We review risk or cumulative incidence of psychosis in, person-time rate of psychosis, Kaplan-Meier estimates of psychosis risk, measures of prognostic accuracy, sensitivity and specificity in receiver operator characteristic curves, positive and negative predictive values, Bayes' theorem, likelihood ratios, potentials and limits of real-life applications of prognostic probabilistic reasoning in the CHR state. Understanding basic measures used for prognostic probabilistic reasoning is a prerequisite for successfully implementing the early detection and prevention of psychosis in clinical practice. Future refinement of these measures for CHR patients may actually influence risk management, especially as regards initiating or withholding treatment.

Identifying children and adolescents at ultra high risk of psychosis in Italian neuropsychiatry services: a feasibility study.

The past 20 years have seen the evolution of the construct of a clinical high-risk (hereafter, HR) state for psychosis. This construct is designed to capture the pre-psychotic phase. Some aspects of this approach, such as its feasibility in children and adolescents, are still under investigation. In the present study, we address the feasibility of implementing prodrome clinics for HR individuals within the framework of Italy's national child and adolescent neuropsychiatry services and the clinical relevance of a HR diagnosis in this population. Using the Comprehensive Assessment of At-Risk Mental States (CAARMS) to identify help-seeking patients meeting at least one HR criterion at baseline (HR+), we recruited 50 subjects for a feasibility study. The results obtained show that the Italian version of the CAARMS is easily administrable, causing patients no substantial discomfort. The prevalence of HR+ in our cohort was 44 %, which increased by an additional 18 % when negative symptoms were considered as an experimental inclusion criterion (HRNeg). The HR+ subjects were significantly more impaired in their social and occupational functioning than their HR- peers (subjects not at HR). The cumulative 1-year transition risk of psychosis of the HR+ group was 26.7 %. When the HRNeg group was added, the 1-year transition risk was 17.3 %. We suggest that administration of the CAARMS to children and adolescents with putative prodromal psychosis is feasible and that this assessment can easily be integrated into existing Italian neuropsychiatry services although clinicians should interpret results with caution as results in this age group still have to be replicated.

Services for people at high risk improve outcomes in patients with first episode psychosis.

OBJECTIVE: About one-third of patients referred to services for people at high risk for psychosis may have already developed a first episode of psychosis (FEP). We compared clinical outcomes in FEP patients who presented to either high risk or conventional mental health services. METHOD: Retrospective study comparing duration of hospital admission, referral-to-diagnosis time, need for compulsory hospital admission and frequency of admission in patients with FEP who initially presented to a high-risk service (n = 164) to patients with FEP who initially presented to conventional mental health services (n = 2779). Regression models were performed, controlling for several confounders. RESULTS: FEP patients who had presented to a high-risk service spent 17 fewer days in hospital [95% CI: -33.7 to (-0.3)], had a shorter referral-to-diagnosis time [B coefficient -74.5 days, 95% CI: -101.9 to -(47.1)], a lower frequency of admission [IRR: 0.49 (95% CI: 0.39-0.61)] and a lower likelihood of compulsory admission [OR: 0.52 (95% CI: 0.34-0.81)] in the 24 months following referral, as compared to FEP patients who were first diagnosed at conventional services. CONCLUSION: Services for people at high risk for psychosis are associated with better clinical outcomes in patients who are already psychotic.