Grazia Rutigliano

Heterogeneity of Psychosis Risk Within Individuals at Clinical High Risk: A Meta-analytical Stratification

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]. The meta-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 individuals were included. The meta-analytical proportion of individuals meeting each UHR subgroup at intake was: 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. There was 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. There was no evidence that the GRD subgroup has a higher risk of psychosis than the CHR- subgroup. There were too few BS or BS and UHR studies to allow robust 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.

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.

Metabolic syndrome and major depression

Major depression is associated with a 4-fold increased risk for premature death, largely accounted by cardiovascular disease (CVD). The relationship between depression and CVD is thought to be mediated by the so-called metabolic syndrome (MeS). Epidemiological studies have consistently demonstrated a co-occurrence of depression with MeS components, ie, visceral obesity, dyslipidemia, insulin resistance, and hypertension. Although the exact mechanisms linking MeS to depression are unclear, different hypotheses have been put forward. On the one hand, MeS could be the hallmark of the unhealthy lifestyle habits of depressed patients. On the other, MeS and depression might share common alterations of the stress system, including the hypothalamus-pituitary-adrenal (HPA) axis, the autonomic nervous system, the immune system, and platelet and endothelial function. Both the conditions induce a low grade chronic inflammatory state that, in turn, leads to increased oxidative and nitrosative (O&NS) damage of neurons, pancreatic cells, and endothelium. Recently, neurobiological research revealed that peripheral hormones, such as leptin and ghrelin, which are classically involved in homeostatic energy balance, may play a role in mood regulation. Metabolic risk should be routinely assessed in depressed patients and taken into account in therapeutic decisions. Alternative targets should be considered for innovative antidepressant agents, including cytokines and their receptors, intracellular inflammatory mediators, glucocorticoids receptors, O&NS pathways, and peripheral mediators.

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.

Peripheral oxytocin and vasopressin: Biomarkers of psychiatric disorders? A comprehensive systematic review and preliminary meta-analysis

A large array of studies have investigated peripheral oxytocin (OT) and vasopressin (ADH) as potential biomarkers of psychiatric disorders, with highly conflicting and heterogenous findings. We searched Web of KnowledgeSM and Scopus® for English original articles investigating OT and/or ADH levels in different biological fluids (plasma/serum, saliva, urine and cerebrospinal fluid) across several psychiatric disorders. Sixty-four studies were included. We conducted 19 preliminary meta-analyses addressing OT alterations in plasma/serum, saliva, urine and cerebrospinal fluid of 7 psychiatric disorders and ADH alterations in plasma/serum, saliva, urine and cerebrospinal fluid of 6 psychiatric disorders compared to controls. Hedges g was used as effect size measure, together with heterogeneity analyses, test of publication biases and quality control. None of them (except serum OT in anorexia nervosa) revealed significant differences. There is no convincing evidence that peripheral ADH or OT might be reliable biomarkers in psychiatric disorders. However, the lack of significant results was associated with high methodological heterogeneity, low quality of the studies, small sample size, and scarce reliability of the methods used in previous studies, which need to be validated and standardized.

Diagnostic Stability of ICD/DSM First Episode Psychosis Diagnoses: Meta-analysis

Background: Validity of current International Classification of Disease/Diagnostic and Statistical Manual of Mental Disorders (ICD/DSM) first episode psychosis diagnoses is essential in clinical practice, research, training and public health. Method: We provide a meta-analytical estimate of prospective diagnostic stability and instability in ICD-10 or DSM-IV first episode diagnoses of functional psychoses. Independent extraction by multiple observers. Random effect meta-analysis conducted with the “metaprop,” “metaninf,” “metafunnel,” “metabias,” and “metareg” packages of STATA13.1. Moderators were tested with meta-regression analyses. Heterogeneity was assessed with the I 2 index. Sensitivity analyses tested robustness of results. Publication biases were assessed with funnel plots and Egger’s test. Findings: 42 studies and 45 samples were included, for a total of 14 484 first episode patients and an average follow-up of 4.5 years. Prospective diagnostic stability ranked: schizophrenia 0.90 (95% CI 0.85–0.95), affective spectrum psychoses 0.84 (95% CI 0.79–0.89), schizoaffective disorder 0.72 (95% CI 0.61–0.73), substance-induced psychotic disorder 0.66 (95% CI 0.51–0.81), delusional disorder 0.59 (95% CI 0.47–0.71), acute and transient psychotic disorder/brief psychotic disorder 0.56 (95% CI 0.62–0.60), psychosis not otherwise specified 0.36 (95% CI 0.27–0.45, schizophreniform disorder 0.29 (95% CI 0.22–0.38). Diagnostic stability within schizophrenia spectrum psychoses was 0.93 (95% CI 0.89–0.97); changes to affective spectrum psychoses were 0.05 (95% CI 0.01–0.08). About 0.10 (95% CI 0.05–0.15) of affective spectrum psychoses changed to schizophrenia spectrum psychosis. Across the other psychotic diagnoses there was high diagnostic instability, mostly to schizophrenia. Interpretation: There is meta-analytical evidence for high prospective diagnostic stability in schizophrenia spectrum and affective spectrum psychoses, with no significant ICD/DSM differences. These results may inform the development of new treatment guidelines for early psychosis and impact drug licensing from regulatory agencies.

Deconstructing Pretest Risk Enrichment to Optimize Prediction of Psychosis in Individuals at Clinical High Risk

Importance Pretest risk estimation is routinely used in clinical medicine to inform further diagnostic testing in individuals with suspected diseases. To our knowledge, the overall characteristics and specific determinants of pretest risk of psychosis onset in individuals undergoing clinical high risk (CHR) assessment are unknown. Objectives To investigate the characteristics and determinants of pretest risk of psychosis onset in individuals undergoing CHR assessment and to develop and externally validate a pretest risk stratification model. Design, Setting, and Participants Clinical register-based cohort study. Individuals were drawn from electronic, real-world, real-time clinical records relating to routine mental health care of CHR services in South London and the Maudsley National Health Service Trust in London, United Kingdom. The study included nonpsychotic individuals referred on suspicion of psychosis risk and assessed by the Outreach and Support in South London CHR service from 2002 to 2015. Model development and validation was performed with machine-learning methods based on Least Absolute Shrinkage and Selection Operator for Cox proportional hazards model. Main Outcomes and Measures Pretest risk of psychosis onset in individuals undergoing CHR assessment. Predictors included age, sex, age × sex interaction, race/ethnicity, socioeconomic status, marital status, referral source, and referral year. Results A total of 710 nonpsychotic individuals undergoing CHR assessment were included. The mean age was 23 years. Three hundred ninety-nine individuals were men (56%), their race/ethnicity was heterogenous, and they were referred from a variety of sources. The cumulative 6-year pretest risk of psychosis was 14.55% (95% CI, 11.71% to 17.99%), confirming substantial pretest risk enrichment during the recruitment of individuals undergoing CHR assessment. Race/ethnicity and source of referral were associated with pretest risk enrichment. The predictive model based on these factors was externally validated, showing moderately good discrimination and sufficient calibration. It was used to stratify individuals undergoing CHR assessment into 4 classes of pretest risk (6-year): low, 3.39% (95% CI, 0.96% to 11.56%); moderately low, 11.58% (95% CI, 8.10% to 16.40%); moderately high, 23.69% (95% CI, 16.58% to 33.20%); and high, 53.65% (95% CI, 36.78% to 72.46%). Conclusions and Relevance Significant risk enrichment occurs before individuals are assessed for a suspected CHR state. Race/ethnicity and source of referral are associated with pretest risk enrichment in individuals undergoing CHR assessment. A stratification model can identify individuals at differential pretest risk of psychosis. Identification of these subgroups may inform outreach campaigns and subsequent testing and eventually optimize psychosis prediction.

Persistence or recurrence of non-psychotic comorbid mental disorders associated with 6-year poor functional outcomes in patients at ultra high risk for psychosis

BACKGROUND Patients at ultra-high risk for psychosis (UHR) are a highly heterogeneous group in terms of clinical and functional outcomes. Several non-psychotic mental disorders co-occur together with the UHR state. Little is known about the impact of non-psychotic comorbid mental disorders on clinical and functional outcomes of UHR patients. METHODS The sample included 154 UHR help-seeking patients (identified with the CAARMS, comprehensive assessment of the at-risk mental state), evaluated at baseline on the Ham-D, Ham-A (Hamilton depression/anxiety rating scale), and PANSS (positive and negative syndrome scale). 74 patients completed the 6-year follow-up assessment (mean=6.19, SD=1.87). Comorbid disorders at follow-up were assessed with the SCID I and II. Global functioning was rated on the global assessment of functioning (GAF) scale. RESULTS In the present sample, 6-year risk of psychosis transition was 28.4%. Among non-transitioned UHR patients, 28.3% reported attenuated psychotic symptoms (APS) and 45.3% remained functionally impaired at follow-up (GAF<60). 56.8% patients were affected by at least one comorbid disorder at follow-up. Among UHR patients who presented with some comorbid disorder at baseline, 61.5% had persistent or recurrent course. Incident comorbid disorders emerged in 45.4% of baseline UHR patients. The persistence or recurrence of non-psychotic comorbid mental disorders was associated with poorer global functional outcomes at follow-up. LIMITATIONS A substantial proportion of the initial sample was not available for follow-up interviews and some groups in the analyses had small sample size. Predictors of longitudinal outcomes were not explored. CONCLUSIONS Among UHR patients, persistence or recurrence of non-psychotic comorbid mental disorders, mostly affective disorders, is associated with 6-year poor functional outcomes.