Ilaria Bonoldi

Predicting psychosis: meta-analysis of transition outcomes in individuals at high clinical risk.

CONTEXT A substantial proportion of people at clinical high risk of psychosis will develop a psychotic disorder over time. However, the risk of transition to psychosis varies between centers, and some recent work suggests that the risk of transition may be declining. OBJECTIVE To quantitatively examine the literature to date reporting the transition risk to psychosis in subjects at clinical high risk. DATA SOURCES The electronic databases were searched until January 2011. All studies reporting transition risks in patients at clinical high risk were retrieved. STUDY SELECTION Twenty-seven studies met the inclusion criteria, comprising a total of 2502 patients. DATA EXTRACTION Transition risks, as well as demographic, clinical, and methodologic variables, were extracted from each publication or obtained directly from its authors. DATA SYNTHESIS There was a consistent transition risk, independent of the psychometric instruments used, of 18% after 6 months of follow-up, 22% after 1 year, 29% after 2 years, and 36% after 3 years. Significant moderators accounting for heterogeneity across studies and influencing the transition risks were the age of participants, publication year, treatments received, and diagnostic criteria used. There was no publication bias, and a sensitivity analysis confirmed the robustness of the core findings. CONCLUSIONS The state of clinical high risk is associated with a very high risk of developing psychosis within the first 3 years of clinical presentation, and the risk progressively increases across this period. The transition risk varies with the age of the patient, the nature of the treatment provided, and the way the syndrome and transition to psychosis are defined.

The Psychosis High-Risk State A Comprehensive State-of-the-Art Review

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.

At Risk for Schizophrenic or Affective Psychoses? A Meta-Analysis of DSM/ICD Diagnostic Outcomes in Individuals at High Clinical Risk

BACKGROUND The clinical high-risk state for psychosis (HRP) is associated with an enhanced probability of developing a psychotic episode over a relatively short period of time. However, the extent to which different diagnostic types of illness develop remains unclear. METHODS A systematic review was performed to identify studies of HRP participants reporting International Classfication of Diseases/Diagnostic and Statistical Manual of Mental Disorders diagnostic outcomes at follow-up. Demographic, clinical, and methodological variables were extracted from each publication or obtained directly from its authors. A meta-analysis was performed of transition to schizophrenic (SP) or affective psychoses (AP) and to specific diagnostic categories. Statistical heterogeneity and small study bias were assessed, and meta-regressions were performed. RESULTS Twenty-three studies were retrieved, including a total of 2182 HRP participants, 560 (26%) of them developed a frank psychotic disorder over the follow-up time (mean = 2.35 y). Among HRP participants who developed psychosis, 73% were diagnosed with SP and only 11% with AP (Risk Ratio, RR = 5.43, 95% CI from 3.35 to 8.83). The specific transition risk to ICD/DSM schizophrenia was of 15.7% (over 2.35y). Heterogeneity was statistically significant and moderate in magnitude. Use of basic symptoms criteria in the baseline clinical assessment was associated with a further increase in the proportion progressing to SP vs AP (RR = 17.1). There was no evidence of publication bias and the sensitivity analysis confirmed robustness of the above results. CONCLUSIONS The HRP state is heterogeneous in term of longitudinal diagnoses; however, the current HRP diagnostic criteria appear strongly biased toward an identification of early phases of SP rather than AP.

At risk or not at risk? A meta-analysis of the prognostic accuracy of psychometric interviews for psychosis prediction

An accurate detection of individuals at clinical high risk (CHR) for psychosis is a prerequisite for effective preventive interventions. Several psychometric interviews are available, but their prognostic accuracy is unknown. We conducted a prognostic accuracy meta‐analysis of psychometric interviews used to examine referrals to high risk services. The index test was an established CHR psychometric instrument used to identify subjects with and without CHR (CHR+ and CHR−). The reference index was psychosis onset over time in both CHR+ and CHR− subjects. Data were analyzed with MIDAS (STATA13). Area under the curve (AUC), summary receiver operating characteristic curves, quality assessment, likelihood ratios, Fagans nomogram and probability modified plots were computed. Eleven independent studies were included, with a total of 2,519 help‐seeking, predominately adult subjects (CHR+: N=1,359; CHR−: N=1,160) referred to high risk services. The mean follow‐up duration was 38 months. The AUC was excellent (0.90; 95% CI: 0.87‐0.93), and comparable to other tests in preventive medicine, suggesting clinical utility in subjects referred to high risk services. Meta‐regression analyses revealed an effect for exposure to antipsychotics and no effects for type of instrument, age, gender, follow‐up time, sample size, quality assessment, proportion of CHR+ subjects in the total sample. Fagans nomogram indicated a low positive predictive value (5.74%) in the general non‐help‐seeking population. Albeit the clear need to further improve prediction of psychosis, these findings support the use of psychometric prognostic interviews for CHR as clinical tools for an indicated prevention in subjects seeking help at high risk services worldwide.

The Dark Side of the Moon: Meta-analytical Impact of Recruitment Strategies on Risk Enrichment in the Clinical High Risk State for Psychosis

Background: The individual risk of developing psychosis after being tested for clinical high-risk (CHR) criteria (posttest risk of psychosis) depends on the underlying risk of the disease of the population from which the person is selected (pretest risk of psychosis), and thus on recruitment strategies. Yet, the impact of recruitment strategies on pretest risk of psychosis is unknown. Methods: Meta-analysis of the pretest risk of psychosis in help-seeking patients selected to undergo CHR assessment: total transitions to psychosis over the pool of patients assessed for potential risk and deemed at risk (CHR+) or not at risk (CHR−). Recruitment strategies (number of outreach activities per study, main target of outreach campaign, and proportion of self-referrals) were the moderators examined in meta-regressions. Results: 11 independent studies met the inclusion criteria, for a total of 2519 (CHR+: n = 1359; CHR−: n = 1160) help-seeking patients undergoing CHR assessment (mean follow-up: 38 months). The overall meta-analytical pretest risk for psychosis in help-seeking patients was 15%, with high heterogeneity (95% CI: 9%–24%, I 2 = 96, P < .001). Recruitment strategies were heterogeneous and opportunistic. Heterogeneity was largely explained by intensive (n = 11, β = −.166, Q = 9.441, P = .002) outreach campaigns primarily targeting the general public (n = 11, β = −1.15, Q = 21.35, P < .001) along with higher proportions of self-referrals (n = 10, β = −.029, Q = 4.262, P = .039), which diluted pretest risk for psychosis in patients undergoing CHR assessment. Conclusions: There is meta-analytical evidence for overall risk enrichment (pretest risk for psychosis at 38monhts = 15%) in help-seeking samples selected for CHR assessment as compared to the general population (pretest risk of psychosis at 38monhts=0.1%). Intensive outreach campaigns predominantly targeting the general population and a higher proportion of self-referrals diluted the pretest risk for psychosis.

Prevalence of self-reported childhood abuse in psychosis: a meta-analysis of retrospective studies

There is extensive clinical literature reporting traumatic childhood experiences in patients with psychosis. A quantitative meta-analysis addressing the prevalence of self-reported childhood sexual (CSA), physical (CPA) and emotional abuse (CEA) in psychotic patients has yet to be done. We conducted, a systematic literature search to identify retrospective studies addressing self-reported childhood abuse in patients with DSM/ICD psychosis. Demographic, clinical, and methodological variables were extracted from each publication, or obtained directly from its authors. Quantitative meta-analysis of CSA, CPA, CEA in the sample of patients was performed. Statistical heterogeneity and publication bias were assessed and meta-regressions performed to control for different moderators. Twenty-three studies were retrieved and included a total of 2017 psychotic patients. The prevalence of self-reported CSA, CPA, CEA were respectively of 26%, 39% and 34%. Age, publication year, gender and substance abuse moderated CSA, while age, clinical setting and substance abuse moderated CPA. Results indicated that CEA was moderated by gender and publication year of the study. According to our meta-analysis, psychotic patients have a consistently high self-report of childhood traumatic events which are sexual, physical and emotional in nature. It is our opinion that clinicians should be trained and skilled to carefully investigate childhood abuse in psychosis.

Prognosis of Brief Psychotic Episodes: A Meta-analysis

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 < .02 and P < .001, respectively) compared with the other 4 groups (0.39 [0.32-0.47] at 24 months and 0.51 [0.41-0.61] at ≥ 36 months). There were no publication biases. Sex and exposure to antipsychotic medication modulated the meta-analytical estimates (.002 < P < .03). 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.

Development and Validation of a Clinically Based Risk Calculator for the Transdiagnostic Prediction of Psychosis.

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.

Speed of Psychosis Progression in People at Ultra-High Clinical Risk: A Complementary Meta-analysis

Speed of Psychosis Progression in People at Ultra-High Clinical Risk: A Complementary Meta-analysis The transition to psychosis in patients at ultra-high clinical risk (UHR; as defined elsewhere1) is most likely to occur within the first 2 years after presentation to clinical services (risk estimate, 29%; 95% CI, 23-36).2 After this phase, the speed of psychosis progression tends to plateau from the third year,2 reaching approximately 35% after 10 years.3 However, the exact speed of psychosis progression at a particular point during the critical first 2 years is unclear, preventing clinical advancements in the field.

Relationship between brain glutamate levels and clinical outcome in individuals at ultra high risk of psychosis.

Alterations in brain glutamate levels may be associated with psychosis risk, but the relationship to clinical outcome in at-risk individuals is unknown. Glutamate concentration was measured in the left thalamus and anterior cingulate cortex (ACC) using 3-Tesla proton magnetic resonance spectroscopy in 75 participants at ultra high risk (UHR) of psychosis and 56 healthy controls. The severity of attenuated positive symptoms and overall functioning were assessed. Measures were repeated in 51 UHR and 33 Control subjects after a mean of 18 months. UHR subjects were allocated to either remission (no longer meeting UHR criteria) or non-remission (meeting UHR or psychosis criteria) status on follow-up assessment. Thalamic glutamate levels at presentation were lower in the UHR non-remission (N=29) compared with the remission group (N=22) (t(49)=3.03; P=0.004), and were associated with an increase in the severity of total positive symptoms over time (r=−0.33; df=47; P=0.02), most notably abnormal thought content (r=−0.442; df=47; P=0.003). In the UHR group, ACC glutamate levels were lower at follow-up compared with baseline (F(80)=4.28; P=0.04). These findings suggest that measures of brain glutamate function may be useful as predictors of clinical outcome in individuals at high risk of psychosis.