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Can We Reduce the Duration of Untreated Psychosis? A Systematic Review and Meta-Analysis of Controlled Interventional Studies.
Reduction of duration of untreated psychosis (DUP) is the key strategy of early interventions for improving the outcomes of first-episode psychosis. Although several controlled interventional studies have been conducted with the aim of reducing DUP, the results are highly inconsistent and conflicting. The current study systematically searches Web of Science and Ovid for English original articles investigating interventions adopted to reduce DUP, compared to a control intervention, up to April 6, 2017. Sixteen controlled interventional studies were retrieved, including 1964 patients in the intervention arm and 1358 in the control arm. The controlled intervention studies were characterized by standalone first episode psychosis services, standalone clinical high risk services, community interventions, healthcare professional training, and multifocus interventions. Random effects meta-analyses were conducted. There was no summary evidence that available interventions are successful in reducing DUP during the first episode of psychosis (Hedges' g = -0.12, 95% CI = -0.25 to 0.01). Subgroup analyses showed no differences within each subgroup, with the exception of clinical high risk services (Hedges' g = -0.386, 95% CI = -0.726 to -0.045). These negative findings may reflect a parceled research base in the area, lack of prospective randomized controlled trials (only 2 randomized cluster designed studies were present) and small sample sizes. There was substantial heterogeneity (I2 = 66.4%), most of which was accounted by different definitions of DUP onset (R2 = .88). Psychometric standardization of DUP definition, improvement of study design, and implementation of preventative strategies seem the most promising avenues for reducing DUP and improving outcomes of first-episode psychosis.
Long term outcomes of acute and transient psychotic disorders: The missed opportunity of preventive interventions.
BACKGROUND: Acute and transient psychotic disorders (ATPD) are characterized by an acute onset and a remitting course, and overlap with subgroups of the clinical high-risk state for psychosis. The long-term course and outcomes of ATPD are not completely clear. METHODS: Electronic health record-based retrospective cohort study, including all patients who received a first index diagnosis of ATPD (F23, ICD-10) within the South London and Maudsley (SLaM) National Health Service Trust, between 1 st April 2006 and 15th June 2017. The primary outcome was risk of developing persistent psychotic disorders, defined as the development of any ICD-10 diagnoses of non-organic psychotic disorders. Cumulative risk of psychosis onset was estimated through Kaplan-Meier failure functions (non-competing risks) and Greenwood confidence intervals. RESULTS: A total of 3074 patients receiving a first index diagnosis of ATPD (F23, ICD-10) within SLaM were included. The mean follow-up was 1495 days. After 8-year, 1883 cases (61.26%) retained the index diagnosis of ATPD; the remaining developed psychosis. The cumulative incidence (Kaplan-Meier failure function) of risk of developing any ICD-10 non-organic psychotic disorder was 16.10% at 1-year (95%CI 14.83-17.47%), 28.41% at 2-year (95%CI 26.80-30.09%), 33.96% at 3-year (95% CI 32.25-35.75%), 36.85% at 4-year (95%CI 35.07-38.69%), 40.99% at 5-year (95% CI 39.12-42.92%), 42.58% at 6-year (95%CI 40.67-44.55%), 44.65% at 7-year (95% CI 42.66-46.69%), and 46.25% at 8-year (95% CI 44.17-48.37%). The cumulative risk of schizophrenia-spectrum disorder at 8-year was 36.14% (95% CI 34.09-38.27%). CONCLUSIONS: Individuals with ATPD have a very high risk of developing persistent psychotic disorders and may benefit from early detection and preventive treatments to improve their outcomes.
A systematic review and meta-analysis of mental health service use in people who report psychotic experiences
Background: Self-reported psychotic experiences (PEs) are associated with psychopathology of all kinds, not just psychoses. However, systematic reviews on the relevance of this for health services are unavailable. Furthermore, whether association with service use is confounded by other psychopathology is unknown, and is relevant to prevention and treatment. Objectives: Literature examining associations between PEs and service use was systematically reviewed. Study quality and the direction and extent of any associations were assessed, and meta-analysis conducted. Methods: Systematic review and meta-analysis was carried out as per PRISMA guidelines. A search of electronic databases was performed based on free-text and structured terms. Included studies were evaluated by two raters using a structured tool and estimates extracted for reporting. Results: Thirteen studies were returned. We found two prospective studies, and a minority of studies accounted for concurrent psychopathology, limiting our ability to test our main hypotheses. Five studies reported associations by different types of service use. Almost all studies assessed service use by self-report. Meta-analysis suggested that people who reported PEs were around twice as likely to report service use compared to those who did not (pooled OR for all included studies: 2.20,95% confidence intervals (95%CI): 1.66,2.91). Conclusions: There was consistent evidence of association between PEs and mental health service use at the general population level. However, evidence for causation was poor due to a limited number of studies. Whether increased service use in this group is solely attributable to PEs, and therefore whether interventions aimed at limiting/preventing PEs might be effective, requires studies focusing on the relationships between PEs, psychopathology and service use.
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.
The role of parietal cortex in overimitation: a study with fNIRS
Previous studies have shown right parietal activation in response to observing irrational actions. Behavioral studies show that people sometimes imitate irrational actions, a phenomenon called overimitation. However, limitations on movement in functional magnetic resonance imaging (fMRI) mean that the neural basis of overimitation has not been studied. To address this, our study employed a less restrictive neuroimaging technique, functional near-infrared spectroscopy (fNIRS). Measurements were taken while participants observed either rational or irrational movements before performing movements on a computerized puzzle task. Observing irrational actions produced greater activation in right anterior inferior parietal lobule (aIPL), replicating results from the fMRI literature. This is a proof of principle that fNIRS can be used as an alternative to fMRI in social cognition experiments, and that parietal cortex has a core role in responding to irrational actions.
What causes psychosis? An umbrella review of risk and protective factors.
Psychosis is a heterogeneous psychiatric condition for which a multitude of risk and protective factors have been suggested. This umbrella review aimed to classify the strength of evidence for the associations between each factor and psychotic disorders whilst controlling for several biases. The Web of Knowledge database was searched to identify systematic reviews and meta-analyses of observational studies which examined associations between socio-demographic, parental, perinatal, later factors or antecedents and psychotic disorders, and which included a comparison group of healthy controls, published from 1965 to January 31, 2017. The literature search and data extraction followed PRISMA and MOOSE guidelines. The association between each factor and ICD or DSM diagnoses of non-organic psychotic disorders was graded into convincing, highly suggestive, suggestive, weak, or non-significant according to a standardized classification based on: number of psychotic cases, random-effects p value, largest study 95% confidence interval, heterogeneity between studies, 95% prediction interval, small study effect, and excess significance bias. In order to assess evidence for temporality of association, we also conducted sensitivity analyses restricted to data from prospective studies. Fifty-five meta-analyses or systematic reviews were included in the umbrella review, corresponding to 683 individual studies and 170 putative risk or protective factors for psychotic disorders. Only the ultra-high-risk state for psychosis (odds ratio, OR=9.32, 95% CI: 4.91-17.72) and Black-Caribbean ethnicity in England (OR=4.87, 95% CI: 3.96-6.00) showed convincing evidence of association. Six factors were highly suggestive (ethnic minority in low ethnic density area, second generation immigrants, trait anhedonia, premorbid IQ, minor physical anomalies, and olfactory identification ability), and nine were suggestive (urbanicity, ethnic minority in high ethnic density area, first generation immigrants, North-African immigrants in Europe, winter/spring season of birth in Northern hemisphere, childhood social withdrawal, childhood trauma, Toxoplasma gondii IgG, and non-right handedness). When only prospective studies were considered, the evidence was convincing for ultra-high-risk state and suggestive for urbanicity only. In summary, this umbrella review found several factors to be associated with psychotic disorders with different levels of evidence. These risk or protective factors represent a starting point for further etiopathological research and for the improvement of the prediction of 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.
Diagnostic and Prognostic Significance of DSM-5 Attenuated Psychosis Syndrome in Services for Individuals at Ultra High Risk for Psychosis.
BACKGROUND: The diagnostic and prognostic significance of the DSM-5-defined Attenuated Psychosis Syndrome (DSM-5-APS) in individuals undergoing an ultra high risk (UHR) clinical assessment for suspicion of psychosis risk is unknown. METHODS: Prospective cohort study including all consecutive help-seeking individuals undergoing both a DSM-5-APS and a Comprehensive Assessment of At Risk Mental States (CAARMS 12/2006) assessment for psychosis risk at the Outreach and Support in South London (OASIS) UHR service (March 2013-April 2014). The diagnostic significance of DSM-5-APS was assessed with percent overall agreement, prevalence bias adjusted kappa, Bowker's test, Stuart-Maxwell test, residual analysis; the prognostic significance with Cox regression, Kaplan-Meier failure function, time-dependent area under the curve (AUC) and net benefits analysis. The impact of specific revisions of the DSM-5-APS was further tested. RESULT: In 203 help-seeking individuals undergoing UHR assessment, the agreement between the DSM-5-APS and the CAARMS 12/2006 was only moderate (kappa 0.59). Among 142 nonpsychotic cases, those meeting DSM-5-APS criteria had a 5-fold probability (HR = 5.379) of developing psychosis compared to those not meeting DSM-5-APS criteria, with a 21-month cumulative risk of psychosis of 28.17% vs 6.49%, respectively. The DSM-5-APS prognostic accuracy was acceptable (AUC 0.76 at 24 months) and similar to the CAARMS 12/2006. The DSM-5-APS designation may be clinically useful to guide the provision of indicated interventions within a 7%-35% (2-year) range of psychosis risk. The removal of the criterion E or C of the DSM-5-APS may improve its prognostic performance and transdiagnostic value. CONCLUSIONS: The DSM-5-APS designation may be clinically useful in individuals accessing clinical services for psychosis prevention.
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.
Sample ascertainment and clinical outcome measures in the Accelerating Medicines Partnership® Schizophrenia Program.
Clinical ascertainment and clinical outcome are key features of any large multisite study. In the ProNET and PRESCIENT research networks, the Accelerating Medicines Partnership® Schizophrenia (AMP®SCZ) Clinical Ascertainment and Outcome Measures Team aimed to establish a harmonized clinical assessment protocol across these two research networks and to define ascertainment criteria and primary and secondary endpoints. In addition to developing the assessment protocol, the goals of this aspect of the AMP SCZ project were: (1) to implement and monitor clinical training, ascertainment of participants, and clinical assessments; (2) to provide expert clinical input to the Psychosis Risk Evaluation, Data Integration and Computational Technologies: Data Processing, Analysis, and Coordination Center (PREDICT-DPACC) for data collection, quality control, and preparation of data for the analysis of the clinical measures; and (3) to provide ongoing support to the collection, analysis, and reporting of clinical data. This paper describes the (1) protocol clinical endpoints and outcomes, (2) rationale for the selection of the clinical measures, (3) extensive training of clinical staff, (4) preparation of clinical measures for a multisite study which includes several sites where English is not the native language; and (5) the assessment of measure stability over time in the AMP SCZ observational study comparing clinical ratings at baseline and at the 2-month follow up. Watch Dr. Jean Addington discuss her work and this article: https://vimeo.com/1040425281 .
Digital sleep phenotype and wrist actigraphy in individuals at clinical high risk for psychosis and people with schizophrenia spectrum disorders: a systematic review and meta-analysis.
AIM: To identify sleep abnormalities in individuals at clinical high risk for psychosis (CHR-P) or with schizophrenia spectrum disorders (SSDs) compared with healthy controls (HCs) using wrist actigraphy, and to assess potential differences in the direction of effect with self-reported assessments of sleep. METHODS: We conducted a systematic review of observational studies, with the search last updated on 29 April 2024. Primary outcome was total sleep time (TST), with secondary outcomes including time in bed (TIB), sleep latency, sleep efficiency, wake after sleep onset, nighttime awakenings and self-reported sleep quality. Random-effects pairwise meta-analyses were used to summarise the effects of each outcome. RESULTS: Nineteen studies were included, with 18 contributing to the meta-analyses (202 CHR-P, 584 SSD, 582 HC). TST results were inconclusive for CHR-P (MD -4.88 min (95% CI -20.57 to 10.81)), while SSD participants showed an increase in TST compared with HC (MD 106.13 min (86.02 to 124.24)). Factors such as antipsychotic medications (pseudo-R²=88.14%), age (38.89%) and gender (26.29%) partially explained the heterogeneity between subgroups. Additionally, CHR-P individuals exhibited reduced sleep efficiency (MD -2.04% (-3.55 to 0.53)), whereas SSD participants had increased TIB (MD 121.58 min (88.16 to 155.00)) and sleep latency (MD 13.05 min (2.11 to 24.00)). The risk-of-bias assessment ranged from some concerns to high risk. CONCLUSIONS: Our analyses identified sleep abnormalities in CHR-P and SSD compared with placebo. However, observed heterogeneity and potential biases across studies may limit the interpretability of findings. These limitations underscore the need for standardised guidelines and more precise participant stratification.
Do biological alterations precede the onset of psychosis? A systematic review and meta-analysis of immune, cardiometabolic, prolactin and HPA axis alterations in clinical high-risk for psychosis.
First episode psychosis (FEP) individuals show biological abnormalities preceding antipsychotic treatment. However, it remains unclear whether such alterations are also present before the onset of psychosis. We aim to provide estimates of standardized mean differences for immune, cardiometabolic, prolactin, and HPA axis parameters in individuals at clinical high-risk for psychosis (CHR-P) compared to healthy controls (HC) and FEP individuals, and between CHR-P transitioning to psychosis (CHR-T) compared non-transitioning (CHR-NT). A multistep literature search was performed from database inception until September 25, 2023. PRISMA/MOOSE-compliant and pre-registered (PROSPERO: CRD42024507670) systematic review identified studies reporting on immune, cardiovascular or endocrine parameters in CHR-P samples compared with HC or FEP samples or comparing CHR-T vs CHR-NT. Inter-group differences in magnitude of effect were estimated using Hedges g and estimates were pooled using random-effects meta-analysis. Heterogeneity was high for most outcomes. 37 studies were included, total sample 2509 CHR-P, 710 FEP, and 1444 HC individuals. A statistically significant elevation of pro-inflammatory proteins was found among CHR-P compared with HC (k = 12; N = 1710; g = 0.16; p
The Translational Future of Stress Neurobiology and Psychosis Vulnerability: A Review of the Evidence.
Psychosocial stress is a well-established risk factor for psychosis, yet the neurobiological mechanisms underlying this relationship have yet to be fully elucidated. Much of the research in this field has investigated hypothalamic-pituitary-adrenal (HPA) axis function and immuno-inflammatory processes among individuals with established psychotic disorders. However, as such studies are limited in their ability to provide knowledge that can be used to develop preventative interventions, it is important to shift the focus to individuals with increased vulnerability for psychosis (i.e., high-risk groups). In the present article, we provide an overview of the current methods for identifying individuals at high-risk for psychosis and review the psychosocial stressors that have been most consistently associated with psychosis risk. We then describe a network of interacting physiological systems that are hypothesised to mediate the relationship between psychosocial stress and the manifestation of psychotic illness and critically review evidence that abnormalities within these systems characterise highrisk populations. We found that studies of high-risk groups have yielded highly variable findings, likely due to (i) the heterogeneity both within and across high-risk samples, (ii) the diversity of psychosocial stressors implicated in psychosis, and (iii) that most studies examine single markers of isolated neurobiological systems. We propose that to move the field forward, we require well-designed, largescale translational studies that integrate multi-domain, putative stress-related biomarkers to determine their prognostic value in high-risk samples. We advocate that such investigations are highly warranted, given that psychosocial stress is undoubtedly a relevant risk factor for psychotic disorders.
Effects of Cannabidiol and Delta-9-Tetrahydrocannabinol on Plasma Endocannabinoid Levels in Healthy Volunteers: A Randomized Double-Blind Four-Arm Crossover Study.
Background: The effects of cannabis are thought to be mediated by interactions between its constituents and the endocannabinoid system. Delta-9-tetrahydrocannabinol (THC) binds to central cannabinoid receptors, while cannabidiol (CBD) may influence endocannabinoid function without directly acting on cannabinoid receptors. We examined the effects of THC coadministered with different doses of CBD on plasma levels of endocannabinoids in healthy volunteers. Methods: In a randomized, double-blind, four-arm crossover study, healthy volunteers (n=46) inhaled cannabis vapor containing 10 mg THC plus either 0, 10, 20, or 30 mg CBD, in four experimental sessions. The median time between sessions was 14 days (IQR=20). Blood samples were taken precannabis inhalation and at 0-, 5-, 15-, and 90-min postinhalation. Plasma concentrations of THC, CBD, anandamide, 2-arachidonoylglycerol (2-AG), and related noncannabinoid lipids were measured using liquid chromatography-mass spectrometry. Results: Administration of cannabis induced acute increases in plasma concentrations of anandamide (+18.0%, 0.042 ng/mL [95%CI: 0.023-0.062]), and the noncannabinoid ethanolamides, docosatetraenylethanolamide (DEA; +35.8%, 0.012 ng/mL [95%CI: 0.008-0.016]), oleoylethanolamide (+16.1%, 0.184 ng/mL [95%CI: 0.076-0.293]), and N-arachidonoyl-L-serine (+25.1%, 0.011 ng/mL [95%CI: 0.004-0.017]) (p<0.05). CBD had no significant effect on the plasma concentration of anandamide, 2-AG or related noncannabinoid lipids at any of three doses used. Over the four sessions, there were progressive decreases in the preinhalation concentrations of anandamide and DEA, from 0.254 ng/mL [95%CI: 0.223-0.286] to 0.194 ng/mL [95%CI: 0.163-0.226], and from 0.039 ng/mL [95%CI: 0.032-0.045] to 0.027 ng/mL [95%CI: 0.020-0.034] (p<0.05), respectively. Discussion: THC induced acute increases in plasma levels of anandamide and noncannabinoid ethanolamides, but there was no evidence that these effects were influenced by the coadministration of CBD. It is possible that such effects may be evident with higher doses of CBD or after chronic administration. The progressive reduction in pretreatment anandamide and DEA levels across sessions may be related to repeated exposure to THC or participants becoming less anxious about the testing procedure and requires further investigation. The study was registered on clinicaltrials.gov (NCT05170217).
PSYSCAN multi-centre study: baseline characteristics and clinical outcomes of the clinical high risk for psychosis sample.
Predicting outcomes in individuals at clinical high risk (CHR) of developing psychosis remains challenging using clinical metrics alone. The PSYSCAN project aimed to enhance predictive value by integrating data across clinical, environmental, neuroimaging, cognitive, and peripheral blood biomarkers. PSYSCAN employed a naturalistic, prospective design across 12 sites (Europe, Australia, Asia, Americas). Assessments were conducted at baseline, 3, 6, and 12 months, with follow-ups at 18 and 24 months to evaluate clinical and functional outcomes. The study included 238 CHR individuals and 134 healthy controls (HC). At baseline, CHR and HC groups differed significantly in age, education, IQ, and vocational and relationship status. Cannabis and tobacco use did not significantly differ between groups, however CHR individuals had higher proportion of moderate to high risk of tobacco abuse. A substantial portion of the CHR sample met DSM criteria for anxiety (53.4%) and/or mood disorders (52.9%), with some prescribed antidepressants (38.7%), antipsychotics (13.9%), or benzodiazepines (16.4%). Over the follow-up period, 25 CHR individuals (10.5%) transitioned to psychosis. However, the CHR group as a whole showed improvements in functioning and attenuated psychotic symptoms. Similar to other recent multi-centre studies, the CHR cohort exhibits high comorbidity rates and relatively low psychosis transition rates. These findings highlight the clinical heterogeneity within CHR populations and suggest that outcomes extend beyond psychosis onset, reinforcing the need for broader prognostic models that consider functional and transdiagnostic outcomes.
Exploring the relationship between frequent cannabis use, belief updating under uncertainty and psychotic-like symptoms.
BACKGROUND: Cannabis users present an important group for investigating putative mechanisms underlying psychosis, as cannabis-use is associated with an increased risk of psychosis. Recent work suggests that alterations in belief-updating under uncertainty underlie psychosis. We therefore compared belief updating under uncertainty between cannabis and non-cannabis users. METHODS: 49 regular cannabis users and 52 controls completed the Space Game, via an online platform used for behavioral testing. In the task, participants were asked to predict the location of the stimulus based on previous information, under different uncertainty conditions. Mixed effects models were used to identify significant predictors of mean score, confidence, performance error and learning rate. RESULTS: Both groups showed decreased confidence in high noise conditions, and increased belief updating in more volatile conditions, suggesting that they could infer the degree and sources of uncertainty. There were no significant effects of group on any of the performance indices. However, within the cannabis group, frequent users showed worse performance than less frequent users. CONCLUSION: Belief updating under uncertainty is not affected by cannabis use status but could be impaired in those who use cannabis more frequently. This finding could show a similarity between frequent cannabis use and psychosis risk, as predictors for abnormal belief-updating.