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Informal caregivers of individuals affected by psychotic disorder can play a key role in the recovery process. However, little research has been conducted on the lived experiences of carers and family members. We conducted a bottom-up (from lived experience to theory) review of first-person accounts, co-written between academics and experts by experience, to identify key experiential themes. First-person accounts of carers, relatives, and individuals with psychosis were screened and discussed in collaborative workshops involving individuals with lived experiences of psychosis, family members, and carers, representing various organizations. The lived experiences of family members and carers were characterized by experiential themes related to dealing with the unexpected news, the search for a reason behind the disorder, living with difficult and negative emotions, dealing with loss, feeling lost in fragmented healthcare systems, feeling invisible and wanting to be active partners in care, struggling to communicate with the affected person, fighting stigma and isolation, dealing with an uncertain future, and learning from one’s mistakes and building resilience and hope. Our findings bring forth the voices of relatives and informal carers of people with psychosis, by highlighting some of the common themes of their lived experiences from the time of the initial diagnosis and throughout the different clinical stages of the disorder. Informal carers are key stakeholders who can play a strategic role, and their contributions in the recovery process merit recognition and active support by mental health professionals.

Preclinical models propose that increased hippocampal activity drives subcortical dopaminergic dysfunction and leads to psychosis-like symptoms and behaviors. Here, we used multimodal neuroimaging to examine the relationship between hippocampal regional cerebral blood flow (rCBF) and striatal dopamine synthesis capacity in people at clinical high risk (CHR) for psychosis and investigated its association with subsequent clinical and functional outcomes. Ninety-five participants (67 CHR and 28 healthy controls) underwent arterial spin labeling MRI and 18F-DOPA PET imaging at baseline. CHR participants were followed up for a median of 15 months to determine functional outcomes with the global assessment of function (GAF) scale and clinical outcomes using the comprehensive assessment of at-risk mental states (CAARMS). CHR participants with poor functional outcomes (follow-up GAF n = 25) showed higher rCBF in the right hippocampus compared to CHRs with good functional outcomes (GAF ≥ 65, n = 25) (pfwe = 0.026). The relationship between rCBF in this right hippocampal region and striatal dopamine synthesis capacity was also significantly different between groups (pfwe = 0.035); the association was negative in CHR with poor outcomes (pfwe = 0.012), but non-significant in CHR with good outcomes. Furthermore, the correlation between right hippocampal rCBF and striatal dopamine function predicted a longitudinal increase in the severity of positive psychotic symptoms within the total CHR group (p = 0.041). There were no differences in rCBF, dopamine, or their associations in the total CHR group relative to controls. These findings indicate that altered interactions between the hippocampus and the subcortical dopamine system are implicated in the pathophysiology of adverse outcomes in the CHR state.

Much is not known about the efficacy of interventions to prevent poor mental health outcomes in young people by targeting either the general population (universal prevention) or asymptomatic individuals with high risk of developing a mental disorder (selective prevention).We conducted a PRISMA/MOOSE-compliant systematic review and meta-analysis of Web of Science to identify studies comparing post-test efficacy (effect size [ES]; Hedges' g) of universal or selective interventions for poor mental health outcomes versus control groups, in samples with mean age35 years (PROSPERO: CRD42018102143). Measurements included random-effects models, I2 statistics, publication bias, meta-regression, sensitivity analyses, quality assessments, number needed to treat, and population impact number.295 articles (447,206 individuals; mean age = 15.4) appraising 17 poor mental health outcomes were included. Compared to control conditions, universal and selective interventions improved (in descending magnitude order) interpersonal violence, general psychological distress, alcohol use, anxiety features, affective symptoms, other emotional and behavioral problems, consequences of alcohol use, posttraumatic stress disorder features, conduct problems, tobacco use, externalizing behaviors, attention-deficit/hyperactivity disorder features, and cannabis use, but not eating-related problems, impaired functioning, internalizing behavior, or sleep-related problems. Psychoeducation had the highest effect size for ADHD features, affective symptoms, and interpersonal violence. Psychotherapy had the highest effect size for anxiety features.Universal and selective preventive interventions for young individuals are feasible and can improve poor mental health outcomes.

The ability to identify biomarkers of psychosis risk is essential in defining effective preventive measures to potentially circumvent the transition to psychosis. Using samples of people at clinical high risk for psychosis (CHR) and Healthy controls (HC) who were administered a task fMRI paradigm, we used a framework for labelling time windows of fMRI scans as ‘integrated’ FC networks to provide a granular representation of functional connectivity (FC). Periods of integration were defined using the ‘cartographic profile’ of time windows and k‐means clustering, and sub‐network discovery was carried out using Network Based Statistics (NBS). There were no network differences between CHR and HC groups. Within the CHR group, using integrated FC networks, we identified a sub‐network negatively associated with longitudinal changes in the severity of psychotic symptoms. This sub‐network comprised brain areas implicated in bottom‐up sensory processing and in integration with motor control, suggesting it may be related to the demands of the fMRI task. These data suggest that extracting integrated FC networks may be useful in the investigation of biomarkers of psychosis risk., A framework for extracting epochs of integrated functional connectivity was used to test network differences between healthy control and clinical high‐risk (CHR) groups, as well as associations with longitudinal changes in symptom and functioning scores in CHR participants. A sub‐network suggestive of bottom‐up sensory processing was found to be associated with changes in positive psychotic symptoms in the CHR group. We suggest this to be a useful approach in searching for network‐based biomarkers of psychosis risk.

Background The clinical high-risk state for psychosis (CHR-P) paradigm has facilitated the implementation of psychosis prevention into clinical practice; however, advancements in adolescent CHR-P populations are less established. Methods We performed a PRISMA/MOOSE-compliant systematic review of the Web of Science database, from inception until 7 October 2019, to identify original studies conducted in CHR-P children and adolescents (mean age = 36 months.Interventions: There was not enough evidence to recommend one specific treatment (including cognitive behavioural therapy) over the others (including control conditions) to prevent the transition to psychosis in this population. Randomised controlled trials suggested that family interventions, cognitive remediation and fish oil supplementation may improve cognition, symptoms and functioning. At baseline, 30% of CHR-P adolescents were prescribed antipsychotics and 60% received psychotherapy. Conclusions It is possible to detect and formulate a group-level prognosis in adolescents at risk for psychosis. Future interventional research is required. G.S.d.P. and J.V.S. are supported by the Alicia Koplowitz Foundation. The study has been supported by the Spanish Ministry of Science, Innovation, and Universities, Instituto de Salud Carlos III, European Regional Development Fund 'A way of making Europe,' Centro de Investigacion Biomedica en Red Salud Mental, Madrid Regional Government; and Fundacion Mutua Madrilena. A.C. has received personal fees from Janssen and grant support from the Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitiveness. C.A. has been a consultant to or has received honoraria or grants from Acadia, Angelini, Gedeon Richter, Janssen Cilag, Lundbeck, Otsuka, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. C.M. has acted as consultant or participated in DMC for Janssen, Servier, Lundbeck, Nuvelution, Angelini and Otsuka and has received grant support from European Union Funds and Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitiviness. C.U.C. has been a consultant and/or adviser to or has received honoraria from: Alkermes, Allergan, Angelini, Boehringer-Ingelheim, Gedeon Richter, Gerson Lehrman Group, Indivior, IntraCellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase, Medscape, Merck, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Servier, Sumitomo Dainippon, Sunovion, Supernus, Takeda and Teva. He has provided expert testimony for Bristol-Myers Squibb, Janssen and Otsuka. He served on a Data Safety Monitoring Board for Boehringer-Ingelheim, Lundbeck, Rovi, Supernus, and Teva. He received royalties from UpToDate and grant support from Janssen and Takeda. He is also a shareholder of LB Pharma. P.F-P. has been a consultant to and received research funds from Lundbeck and received honoraria from Menarini and Angelini

Psychosis is the most ineffable experience of mental disorder. We provide here the first co‐written bottom‐up review of the lived experience of psychosis, whereby experts by experience primarily selected the subjective themes, that were subsequently enriched by phenomenologically‐informed perspectives. First‐person accounts within and outside the medical field were screened and discussed in collaborative workshops involving numerous individuals with lived experience of psychosis as well as family members and carers, representing a global network of organizations. The material was complemented by semantic analyses and shared across all collaborators in a cloud‐based system. The early phases of psychosis (i.e., premorbid and prodromal stages) were found to be characterized by core existential themes including loss of common sense, perplexity and lack of immersion in the world with compromised vital contact with reality, heightened salience and a feeling that something important is about to happen, perturbation of the sense of self, and need to hide the tumultuous inner experiences. The first episode stage was found to be denoted by some transitory relief associated with the onset of delusions, intense self‐referentiality and permeated self‐world boundaries, tumultuous internal noise, and dissolution of the sense of self with social withdrawal. Core lived experiences of the later stages (i.e., relapsing and chronic) involved grieving personal losses, feeling split, and struggling to accept the constant inner chaos, the new self, the diagnosis and an uncertain future. The experience of receiving psychiatric treatments, such as inpatient and outpatient care, social interventions, psychological treatments and medications, included both positive and negative aspects, and was determined by the hope of achieving recovery, understood as an enduring journey of reconstructing the sense of personhood and re‐establishing the lost bonds with others towards meaningful goals. These findings can inform clinical practice, research and education. Psychosis is one of the most painful and upsetting existential experiences, so dizzyingly alien to our usual patterns of life and so unspeakably enigmatic and human.

A leading hypothesis for schizophrenia and related psychotic disorders proposes that cortical brain disruption leads to subcortical dopaminergic dysfunction, which underlies psychosis in the majority of patients who respond to treatment. Although supported by preclinical findings that prefrontal cortical lesions lead to striatal dopamine dysregulation, the relationship between prefrontal structural volume and striatal dopamine function has not been tested in people with psychosis. We therefore investigated the in vivo relationship between striatal dopamine synthesis capacity and prefrontal grey matter volume in treatment-responsive patients with psychosis, and compared them to treatment non-responsive patients, where dopaminergic mechanisms are not thought to be central. Forty patients with psychosis across two independent cohorts underwent 18F-DOPA PET scans to measure dopamine synthesis capacity (indexed as the influx rate constant Kicer) and structural 3T MRI. The PET, but not MR, data have been reported previously. Structural images were processed using DARTEL-VBM. GLM analyses were performed in SPM12 to test the relationship between prefrontal grey matter volume and striatal Kicer. Treatment responders showed a negative correlation between prefrontal grey matter and striatal dopamine synthesis capacity, but this was not evident in treatment non-responders. Specifically, we found an interaction between treatment response, whole striatal dopamine synthesis capacity and grey matter volume in left (pFWE corr. = 0.017) and right (pFWE corr. = 0.042) prefrontal cortex. We replicated the finding in right prefrontal cortex in the independent sample (pFWE corr. = 0.031). The summary effect size was 0.82. Our findings are consistent with the long-standing hypothesis of dysregulation of the striatal dopaminergic system being related to prefrontal cortex pathology in schizophrenia, but critically also extend the hypothesis to indicate it can be applied to treatment-responsive schizophrenia only. This suggests that different mechanisms underlie the pathophysiology of treatment-responsive and treatment-resistant schizophrenia.

Dopaminergic dysregulation is one of the leading hypotheses for the pathoetiology underlying psychotic disorders such as schizophrenia. Molecular imaging studies have shown increased striatal dopamine synthesis capacity (DSC) in schizophrenia and people in the prodrome of psychosis. However, it is unclear if genetic risk for psychosis is associated with altered DSC. To investigate this, we recruited healthy controls and two antipsychotic naive groups of individuals with copy number variants, one with a genetic deletion at chromosome 22q11.2, and the other with a duplication at the same locus, who are at increased and decreased risk for psychosis, respectively. Fifty-nine individuals (21 with 22q11.2 deletion, 12 with the reciprocal duplication and 26 healthy controls) received clinical measures and [18F]-DOPA PET imaging to index striatal Kicer. There was an inverse linear effect of copy number variant number on striatal Kicer value (B = −1.2 × 10−3, SE = 2 × 10−4, p cer was significantly higher in the 22q11.2 deletion group compared to the healthy control (p d = 1.44) and 22q11.2 duplication (p d = 2) groups. Moreover, Kicer was positively correlated with the severity of psychosis-risk symptoms (B = 730.5, SE = 310.2, p

BackgroundPreclinical models propose that the onset of psychosis involves increased hippocampal activity which drives subcortical dopaminergic dysfunction. We used multi-modal neuroimaging to examine the relationship between hippocampal regional cerebral blood flow (rCBF) and striatal dopamine synthesis capacity in people at clinical high risk (CHR) for psychosis, and investigated its association with subsequent clinical outcomes.MethodsNinety-five participants (67 CHR and 28 healthy controls) underwent pseudo-continuous arterial spin labelling and 18F-DOPA PET imaging at baseline. Clinical outcomes in CHR participants were determined after a median of 15 months follow-up, using the Comprehensive Assessment of At Risk Mental States (CAARMS) and the Global Assessment of Function (GAF) scale.ResultsCHR participants with a poor functional outcome (follow-up GAFInterpretationThese findings indicate that altered interactions between the hippocampus and the subcortical dopamine system are implicated in the pathophysiology of psychosis-related outcomes.

Promotion of good mental health in young people is important. Our aim was to evaluate the consistency and magnitude of the efficacy of universal/selective interventions to promote good mental health. A systematic PRISMA/RIGHT-compliant meta-analysis (PROSPERO: CRD42018088708) search of Web of Science until 04/31/2019 identified original studies comparing the efficacy of universal/selective interventions for good mental health vs a control group, in samples with a mean age < 35 years. Meta-analytical random-effects model, heterogeneity statistics, assessment of publication bias, study quality and sensitivity analyses investigated the efficacy (Hedges' g = effect size, ES) of universal/selective interventions to promote 14 good mental health outcomes defined a-priori. 276 studies were included (total participants: 159,508, 79,142 interventions and 80,366 controls), mean age = 15.0 (SD = 7.4); female = 56.0%. There was a significant overall improvement in 10/13 good mental health outcome categories that could be meta-analysed: compared to controls, interventions significantly improved (in descending order of magnitude) mental health literacy (ES = 0.685, p < 0.001), emotions (ES = 0.541, p < 0.001), self-perceptions and values (ES = 0.49, p < 0.001), quality of life (ES = 0.457, p = 0.001), cognitive skills (ES = 0.428, p < 0.001), social skills (ES = 0.371, p < 0.001), physical health (ES = 0.285, p < 0.001), sexual health (ES = 0.257, p = 0.017), academic/occupational performance (ES = 0.211, p < 0.001) and attitude towards mental disorders (ES = 0.177, p = 0.006). Psychoeducation was the most effective intervention for promoting mental health literacy (ES = 0.774, p < 0.001) and cognitive skills (ES = 1.153, p = 0.03). Physical therapy, exercise and relaxation were more effective than psychoeducation and psychotherapy for promoting physical health (ES= 0.498, p

Psychosis has been proposed to develop from dysfunction in a hippocampal-striatal-midbrain circuit, leading to aberrant salience processing. Here, we used functional magnetic resonance imaging (fMRI) during novelty salience processing to investigate this model in people at clinical high risk (CHR) for psychosis according to their subsequent clinical outcomes. Seventy-six CHR participants as defined using the Comprehensive Assessment of At-Risk Mental States (CAARMS) and 31 healthy controls (HC) were studied while performing a novelty salience fMRI task that engaged an a priori hippocampal-striatal-midbrain circuit of interest. The CHR sample was then followed clinically for a mean of 59.7 months (~5 y), when clinical outcomes were assessed in terms of transition (CHR-T) or non-transition (CHR-NT) to psychosis (CAARMS criteria): during this period, 13 individuals (17%) developed a psychotic disorder (CHR-T) and 63 did not. Functional activation and effective connectivity within a hippocampal-striatal-midbrain circuit were compared between groups. In CHR individuals compared to HC, hippocampal response to novel stimuli was significantly attenuated (P = .041 family-wise error corrected). Dynamic Causal Modelling revealed that stimulus novelty modulated effective connectivity from the hippocampus to the striatum, and from the midbrain to the hippocampus, significantly more in CHR participants than in HC. Conversely, stimulus novelty modulated connectivity from the midbrain to the striatum significantly less in CHR participants than in HC, and less in CHR participants who subsequently developed psychosis than in CHR individuals who did not become psychotic. Our findings are consistent with preclinical evidence implicating hippocampal-striatal-midbrain circuit dysfunction in altered salience processing and the onset of psychosis.

Preclinical models of psychosis propose that hippocampal glutamatergic neuron hyperactivity drives increased striatal dopaminergic activity, which underlies the development of psychotic symptoms. The aim of this study was to examine the relationship between hippocampal glutamate and subcortical dopaminergic function in people at clinical high risk for psychosis, and to assess the association with the development of psychotic symptoms. 1H-MRS was used to measure hippocampal glutamate concentrations, and 18F-DOPA PET was used to measure dopamine synthesis capacity in 70 subjects (51 people at clinical high risk for psychosis and 19 healthy controls). Clinical assessments were undertaken at baseline and follow-up (median 15 months). Striatal dopamine synthesis capacity predicted the worsening of psychotic symptoms at follow-up (r = 0.35; p p = 0.13). There were no differences in either glutamate (p = 0.5) or dopamine (p = 0.5) measures in the total patient group relative to controls. Striatal dopamine synthesis capacity at presentation predicts the subsequent worsening of sub-clinical total and psychotic symptoms, consistent with a role for dopamine in the development of psychotic symptoms, but is not strongly linked to hippocampal glutamate concentrations.

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.

Preclinical models propose that the onset of psychosis is associated with hippocampal hyperactivity, thought to be driven by cortical GABAergic interneuron dysfunction and disinhibition of pyramidal neurons. Recent neuroimaging studies suggest that resting hippocampal perfusion is increased in subjects at ultra-high risk (UHR) for psychosis, but how this may be related to GABA concentrations is unknown. The present study used a multimodal neuroimaging approach to address this issue in UHR subjects. Proton magnetic resonance spectroscopy and pulsed-continuous arterial spin labeling imaging were acquired to investigate the relationship between medial prefrontal (MPFC) GABA+ levels (including some contribution from macromolecules) and hippocampal regional cerebral blood flow (rCBF) in 36 individuals at UHR of psychosis, based on preclinical evidence that MPFC dysfunction is involved in hippocampal hyperactivity. The subjects were then clinically monitored for 2 years: during this period, 7 developed a psychotic disorder and 29 did not. At baseline, MPFC GABA+ levels were positively correlated with rCBF in the left hippocampus (region of interest analysis, p = 0.044 family-wise error corrected, FWE). This correlation in the left hippocampus was significantly different in UHR subjects who went on to develop psychosis relative to those who did not (p = 0.022 FWE), suggesting the absence of a correlation in the latter subgroup. These findings provide the first human evidence that MPFC GABA+ concentrations are related to resting hippocampal perfusion in the UHR state, and offer some support for a link between GABA levels and hippocampal function in the development of psychosis.

Introduction. With biomedical imaging research increasingly using large datasets, it becomes critical to find operator-free methods to quality control the data collected and the associated analysis. Attempts to use artificial intelligence (AI) to perform automated quality control (QC) for both single-site and multi-site datasets have been explored in some neuroimaging techniques (e.g. EEG or MRI), although these methods struggle to find replication in other domains. The aim of this study is to test the feasibility of an automated QC pipeline for brain [18F]-FDOPA PET imaging as a biomarker for the dopamine system. Methods. Two different Convolutional Neural Networks (CNNs) were used and combined to assess spatial misalignment to a standard template and the signal-to-noise ratio (SNR) relative to 200 static [18F]-FDOPA PET images that had been manually quality controlled from three different PET/CT scanners. The scans were combined with an additional 400 scans, in which misalignment (200 scans) and low SNR (200 scans) were simulated. A cross-validation was performed, where 80% of the data were used for training and 20% for validation. Two additional datasets of [18F]-FDOPA PET images (50 and 100 scans respectively with at least 80% of good quality images) were used for out-of-sample validation. Results. The CNN performance was excellent in the training dataset (accuracy for motion: 0.86 ± 0.01, accuracy for SNR: 0.69 ± 0.01), leading to 100% accurate QC classification when applied to the two out-of-sample datasets. Data dimensionality reduction affected the generalizability of the CNNs, especially when the classifiers were applied to the out-of-sample data from 3D to 1D datasets. Conclusions. This feasibility study shows that it is possible to perform automatic QC of [18F]-FDOPA PET imaging with CNNs. The approach has the potential to be extended to other PET tracers in both brain and non-brain applications, but it is dependent on the availability of large datasets necessary for the algorithm training.

Background Brief Limited Intermittent Psychotic Symptoms (BLIPS) are key inclusion criteria to define individuals at ultra high risk for psychosis (UHR). Their diagnostic and prognostic significance is unclear. Objectives To address the baseline diagnostic relationship between BLIPS and the ICD-10 categories and examine the longitudinal prognostic impact of clinical and sociodemographic factors. Methods Prospective long-term study in UHR individuals meeting BLIPS criteria. Sociodemographic and clinical data, including ICD-10 diagnoses, were automatically drawn from electronic health records and analyzed using Kaplan–Meier failure function (1-survival), Cox regression models, bootstrapping methods, and Receiver Operating Characteristics (ROC) curve. Results Eighty BLIPS were included. At baseline, two-thirds (68%) of BLIPS met the diagnostic criteria for ICD-10 Acute and Transient Psychotic Disorder (ATPD), most featuring schizophrenic symptoms. The remaining individuals met ICD-10 diagnostic criteria for unspecified nonorganic psychosis (15%), mental and behavioral disorders due to use of cannabinoids (11%), and mania with psychotic symptoms (6%). The overall 5-year risk of psychosis was 0.54. Recurrent episodes of BLIPS were relatively rare (11%) but associated with a higher risk of psychosis (hazard ratio [HR] 3.98) than mono-episodic BLIPS at the univariate analysis. Multivariate analysis revealed that seriously disorganizing or dangerous features increased greatly (HR = 4.39) the risk of psychosis (0.89 at 5-year). Bootstrapping confirmed the robustness of this predictor (area under the ROC = 0.74). Conclusions BLIPS are most likely to fulfill the ATPD criteria, mainly acute schizophrenic subtypes. About half of BLIPS cases develops a psychotic disorder during follow-up. Recurrent BLIPS are relatively rare but tend to develop into psychosis. BLIPS with seriously disorganizing or dangerous features have an extreme high risk of psychosis.

Predicting the onset of psychosis in individuals at-risk is based on robust prognostic model building methods including a priori clinical knowledge (also termed clinical-learning) to preselect predictors or machine-learning methods to select predictors automatically. To date, there is no empirical research comparing the prognostic accuracy of these two methods for the prediction of psychosis onset. In a first experiment, no improved performance was observed when machine-learning methods (LASSO and RIDGE) were applied—using the same predictors—to an individualised, transdiagnostic, clinically based, risk calculator previously developed on the basis of clinical-learning (predictors: age, gender, age by gender, ethnicity, ICD-10 diagnostic spectrum), and externally validated twice. In a second experiment, two refined versions of the published model which expanded the granularity of the ICD-10 diagnosis were introduced: ICD-10 diagnostic categories and ICD-10 diagnostic subdivisions. Although these refined versions showed an increase in apparent performance, their external performance was similar to the original model. In a third experiment, the three refined models were analysed under machine-learning and clinical-learning with a variable event per variable ratio (EPV). The best performing model under low EPVs was obtained through machine-learning approaches. The development of prognostic models on the basis of a priori clinical knowledge, large samples and adequate events per variable is a robust clinical prediction method to forecast psychosis onset in patients at-risk, and is comparable to machine-learning methods, which are more difficult to interpret and implement. Machine-learning methods should be preferred for high dimensional data when no a priori knowledge is available.

IMPORTANCE: Preclinical and human data suggest that hippocampal dysfunction plays a critical role in the onset of psychosis. Neural hyperactivity in the hippocampus is thought to drive an increase in subcortical dopamine function through glutamatergic projections to the striatum. OBJECTIVE: To examine the association between hippocampal glutamate levels in individuals at clinical high risk for psychosis and their subsequent clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study of 86 individuals at clinical high risk for psychosis and 30 healthy control individuals, with a mean follow-up of 18.5 months, was conducted between November 1, 2011, and November 1, 2017, at early detection services in London and Cambridge, United Kingdom. MAIN OUTCOMES AND MEASURES: Concentrations of glutamate and other metabolites were measured in the left hippocampus using 3-T proton magnetic resonance spectroscopy at the first clinical presentation. At follow-up, clinical outcomes were assessed in terms of transition or nontransition to psychosis using the Comprehensive Assessment of the At-Risk Mental State criteria and the level of overall functioning using the Global Assessment of Function scale. RESULTS: Of 116 total participants, 86 were at clinical high risk for psychosis (50 [58%] male; mean [SD] age, 22.4 [3.5] years) and 30 were healthy controls (14 [47%] male; mean [SD] age, 24.7 [3.8] years). At follow-up, 12 clinical high-risk individuals developed a first episode of psychosis whereas 74 clinical high-risk individuals did not; 19 clinical high-risk individuals showed good overall functioning (Global Assessment of Function ≥65), whereas 38 clinical high-risk individuals had a poor functional outcome (Global Assessment of Function

One of the most statistically significant loci to result from large-scale GWAS of schizophrenia is 10q24.32. However, it is still unclear how this locus is involved in the pathoaetiology of schizophrenia. The hypothesis that presynaptic dopamine dysfunction underlies schizophrenia is one of the leading theories of the pathophysiology of the disorder. Supporting this, molecular imaging studies show evidence for elevated dopamine synthesis and release capacity. Thus, altered dopamine function could be a potential mechanism by which this genetic variant acts to increase the risk of schizophrenia. We therefore tested the hypothesis that the 10q24.32 region confers genetic risk for schizophrenia through an effect on striatal dopamine function. To this aim we investigated the in vivo relationship between a GWAS schizophrenia-associated SNP within this locus and dopamine synthesis capacity measured using [18F]-DOPA PET in healthy controls. 92 healthy volunteers underwent [18F]-DOPA PET scans to measure striatal dopamine synthesis capacity (indexed as Ki cer) and were genotyped for the SNP rs7085104. We found a significant association between rs7085104 genotype and striatal Ki cer. Our findings indicate that the mechanism mediating the 10q24.32 risk locus for schizophrenia could involve altered dopaminergic function. Future studies are needed to clarify the neurobiological pathway implicated in this association.

A 17-year-old boy was referred from the general practitioner to the local psychosis early-detection clinic owing to a drop in functioning and social withdrawal during the previous 6 months. He began college 6 months prior but had found the workload difficult and failed his examinations. He had no family history of mental disorders, denied any current or past use of drugs, and reported no significant medical history. He was well kempt, was quiet during his interview, and provided short answers. He reported that he no longer enjoyed his former interests and could not relate to people at college or to friends, but there were no clear signs of depressive disorders. No formal thought disorders were elicited. He was 80% convinced that random people looked and talked about him when he was out in public but was able to question it. He stated that these people were probably commenting on the way he looked, but he did not believe these individuals meant him harm. He never acted on these thoughts. He also reported a vague feeling of perplexity and derealization. These experiences began when he started college and continued to occur every day for up to an hour at a time, causing significant distress. The Structured Clinical Interview for DSM did not reveal any mental disorder.

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-Bowkerχ2test, 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.

Whilst the role of the Disrupted-in-Schizophrenia 1 (DISC1) gene in the aetiology of major mental illnesses is debated, the characterization of its function lends it credibility as a candidate. A key aspect of this functional characterization is the determination of the role of common non-synonymous polymorphisms on normal variation within these functions. The common allele (A) of the DISCI single-nucleotide polymorphism (SNP) rs821616 encodes a serine (ser) at the Ser704Cys polymorphism, and has been shown to increase the phosphorylation of extracellular signal-regulated protein Kinases 1 and 2 (ERK1/2) that stimulate the phosphorylation of tyrosine hydroxylase, the rate-limiting enzyme for dopamine biosynthesis. We therefore set out to test the hypothesis that human ser (A) homozygotes would show elevated dopamine synthesis capacity compared with cysteine (cys) homozygotes and heterozygotes (TT and AT) for rs821616. [F-18]-DOPA positron emission tomography (PET) was used to index striatal dopamine synthesis capacity as the influx rate constant K-i(cer) in healthy volunteers DISC1 rs821616 ser homozygotes (N = 46) and healthy volunteers DISC1. rs821616 cys homozygotes and heterozygotes (N = 56), matched for age, gender, ethnicity and using three scanners. We found DISC1 rs821616 ser homozygotes exhibited a significantly higher striatal K-i(cer) compared with cys homozygotes and heterozygotes (P = 0.012) explaining 6.4% of the variance (partial eta(2) = 0.064). Our finding is consistent with its previous association with heightened activation of ERK1/2, which stimulates tyrosine hydroxylase activity for dopamine synthesis. This could be a potential mechanism mediating risk for psychosis, lending further credibility to the fact that DISC1. is of functional interest in the aetiology of major mental illness. info:eu-repo/semantics/acceptedVersion

Psychosis High-Risk states are today a major field of research in psychiatry allowing early intervention (including primary prevention) of severe psychotic disorders. Psychosis High-Risk criteria select different clinical features and appear to be different center-wise and country-wise. As several of the phenomena accounting for symptoms are subjective in nature, both original and recent inputs from research in phenomenological psychopathology are great candidates for adding to the conceptual validity of High-Risk states. These subjects show a disturbed grip on reality–perplexity, derealization, and depersonalization—as well as a diminished presence in the world and involuntarily ruminating on things they previously ignored. Special sets of phenomena are presented including Truman symptoms, anomalous subjective self and world experiences, and abnormal bodily phenomena. Contemporary predictive and translational research will ultimately integrate phenomenological data with the neurocognitive and neurobiological models of mental disorders.

The external prognostic accuracy of Bipolar At Risk (BAR) criteria is undetermined and no psychometric tools are available to measure them. We present here three studies that overcome these limitations. Study 1 and 2 investigated the prognostic accuracy (Harrell's C) of the original BAR and revised Bipolar At Risk States (BARS) criteria respectively for the prediction of bipolar disorders, using a retrospective cohort of individuals at Clinical High Risk for Psychosis (CHR-P). Study 3 validated externally the prognostic accuracy of a newly developed Semistructured Interview of At Risk Bipolar States (SIBARS) in an independent prospective CHR-P cohort. In study 1 (n = 205), those meeting BAR criteria had an increased risk of developing bipolar disorders (HR = 5.30) relative to those not meeting them, but the prognostic accuracy was poor (Harrell's C = 0.659). In study 2 (n = 205), those meeting the refined BARS criteria had a higher risk of developing bipolar disorders than those not meeting them (HR = 12.364), with an adequate prognostic accuracy (Harrell's C = 0.777). Study 3 (n = 71) confirmed that SIBARS criteria had an adequate prognostic accuracy (Harrell's C = 0.742) and clinical utility. Overall, these findings suggest that the SIBARS could be used for the detection of individuals at risk of developing bipolar disorders in CHR-P services.

BackgroundThe 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.MethodsProspective 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.ResultIn 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.ConclusionsThe DSM-5-APS designation may be clinically useful in individuals accessing clinical services for psychosis prevention.

We recently reported that resting hippocampal, basal ganglia and midbrain perfusion is elevated in people at ultra high risk (UHR) for psychosis. The present study sought to replicate our previous finding in an independent UHR cohort, and examined the relationship between resting perfusion in these regions, psychosis and depression symptoms, and traumatic experiences in childhood. Pseudo-Continuous Arterial Spin Labelling (p-CASL) imaging was used to measure resting cerebral blood flow (rCBF) in 77 UHR for psychosis individuals and 25 healthy volunteers in a case-control design. UHR participants were recruited from clinical early detection services at 3 sites in the South of England. Symptoms levels were assessed using the Comprehensive Assessment of At Risk Mental States (CAARMS), the Hamilton Depression Scale (HAM-D), and childhood trauma was assessed retrospectively using the Childhood Trauma Questionnaire (CTQ). Right hippocampal and basal ganglia rCBF were significantly increased in UHR subjects compared to controls, partially replicating our previous finding in an independent cohort. In UHR participants, positive symptoms were positively correlated with rCBF in the right pallidum. CTQ scores were positively correlated with rCBF values in the bilateral hippocampus and negatively associated with rCBF in the left prefrontal cortex. Elevated resting hippocampal and basal ganglia activity appears to be a consistent finding in individuals at high risk for psychosis, consistent with data from preclinical models of the disorder. The association with childhood trauma suggests that its influence on the risk of psychosis may be mediated through an effect on hippocampal function.

The dopamine hypothesis suggests that dopamine abnormalities underlie psychosis, irrespective of diagnosis, implicating dopamine dysregulation in bipolar affective disorder and schizophrenia, in line with the research domain criteria approach. However, this hypothesis has not been directly examined in individuals diagnosed with bipolar disorder with psychosis.To test whether dopamine synthesis capacity is elevated in bipolar disorder with psychosis and how this compares with schizophrenia and matched controls and to examine whether dopamine synthesis capacity is associated with psychotic symptom severity, irrespective of diagnostic class.This cross-sectional case-control positron emission tomographic study was performed in the setting of first-episode psychosis services in an inner-city area (London, England). Sixty individuals participated in the study (22 with bipolar psychosis [18 antipsychotic naive or free], 16 with schizophrenia [14 antipsychotic naive or free], and 22 matched controls) and underwent fluorodihydroxyphenyl-l-alanine ([18F]-DOPA) positron emission tomography to examine dopamine synthesis capacity. Standardized clinical measures, including the Positive and Negative Syndrome Scale, Young Mania Rating Scale, and Global Assessment of Functioning, were administered. The study dates were March 2013 to November 2016.Dopamine synthesis capacity (Kicer) and clinical measures (Positive and Negative Syndrome Scale, Young Mania Rating Scale, and Global Assessment of Functioning).The mean (SD) ages of participants were 23.6 (3.6) years in 22 individuals with bipolar psychosis (13 male), 26.3 (4.4) years in 16 individuals with schizophrenia (14 male), and 24.5 (4.5) years in controls (14 male). There was a significant group difference in striatal dopamine synthesis capacity (Kicer) (F2,57 = 6.80, P = .002). Kicer was significantly elevated in both the bipolar group (mean [SD], 13.18 [1.08] × 10-3 min-1; P = .002) and the schizophrenia group (mean [SD], 12.94 [0.79] × 10-3 min-1; P = .04) compared with controls (mean [SD], 12.16 [0.92] × 10-3 min-1). There was no significant difference in striatal Kicer between the bipolar and schizophrenia groups. Kicer was significantly positively correlated with positive psychotic symptom severity in the combined bipolar and schizophrenia sample experiencing a current psychotic episode, explaining 27% of the variance in symptom severity (n = 32, r = 0.52, P = .003). There was a significant positive association between Kicer and positive psychotic symptom severity in individuals with bipolar disorder experiencing a current psychotic episode (n = 16, r = 0.60, P = .01), which remained significant after adjusting for manic symptom severity.These findings are consistent with a transdiagnostic role for dopamine dysfunction in the pathoetiology of psychosis and suggest dopamine synthesis capacity as a potential novel drug target for bipolar disorder and schizophrenia.

Perinatal brain injuries, including hippocampal lesions, cause lasting changes in dopamine function in rodents, but it is not known if this occurs in humans. We compared adults who were born very preterm with perinatal brain injury to those born very preterm without perinatal brain injury, and age-matched controls born at full term using [18F]-DOPA PET and structural MRI. Dopamine synthesis capacity was reduced in the perinatal brain injury group relative to those without brain injury (Cohen’s d = 1.36, p=0.02) and the control group (Cohen’s d = 1.07, p=0.01). Hippocampal volume was reduced in the perinatal brain injury group relative to controls (Cohen’s d = 1.17, p=0.01) and was positively correlated with striatal dopamine synthesis capacity (r = 0.344, p=0.03). This is the first evidence in humans linking neonatal hippocampal injury to adult dopamine dysfunction, and provides a potential mechanism linking early life risk factors to adult mental illness., eLife digest Thirteen million infants are born too early every year. Improved care allows many to survive, but these “preterm infants” still face an increased risk of death and many other complications. Infants born very early, before 32 weeks, are at risk of brain injury because the brain is normally still developing in the later stages of pregnancy. They also have an increased risk of developing mental health problems later in life. Early-life brain injuries in rats cause changes in the production of a chemical called dopamine. Dopamine is a chemical messenger in the brain that reinforces rewarding behaviour. People with schizophrenia and attention deficit hyperactivity disorder (ADHD) have abnormal levels of dopamine. Changes in brain dopamine levels may explain why early-life brain injury is linked to later mental illness. But first scientists must study whether similar changes occur in humans with an early-life brain injury. Now, Froudist-Walsh et al. use brain imaging to show that people born very early who suffered a brain injury have lower dopamine levels than other adults. Imaging techniques were used to scan the brains of 13 adults who were born before 32 weeks and who had a brain injury around birth, 13 adults born before 32 weeks without a brain injury, and 13 adults born at “full term” (around 39 to 40 weeks). Individuals with low dopamine levels reported difficulty concentrating and a lack of motivation and enjoyment in their lives. Both can be warning signs of mental health problems. People born prematurely without a brain injury had normal dopamine levels and did not report such symptoms. More studies may help scientists understand how early brain injuries may cause brain chemical differences later in life, and how these brain changes affect individual’s mental health. They may also help scientists develop treatments to prevent or treat mental illness in people who experienced a brain injury after a very early birth.

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.

Background: One of the most prevailing hypotheses of schizophrenia implicates the dopaminergic system. Positron Emission Tomography (PET) studies have consistently reported increased presynaptic dopamine synthesis capacity (DSC) in individuals with schizophrenia. Interestingly, striatal hyperdopaminergia has also been shown to precede the onset of psychosis and to be associated with symptom severity. Although current evidence suggests that dopaminergic dysregulation has at least a state component, the evidence for the trait component is still ambiguous. This highlights the need for studies in a homogenous population of individuals with shared etiological genetic risk factors. Over the last fifteen years, it has been well established that 22q11 deletion is one of the most important genetic risk factors for the development of schizophrenia. Individuals with 22q11 deletion are at increased genetic risk for psychosis, reaching a prevalence for schizophrenia spectrum disorders of 23.53% in adults between 18 and 26 years old and 41% in individuals above 26 years old 30% for psychotic disorder. This mutation accounts for 1% -2% of sporadic cases of schizophrenia. The aim of our study was to investigate dopamine (DA) function in individuals with 22q11 deletion.

Background: Some animal models propose that the onset of psychosis involves dysfunction in GABAergic interneurons, leading to excessive cortical glutamatergic activity, which then drives subcortical dopamine activity. Recent neuroimaging studies in people at ultra high risk (UHR) for psychosis have revealed the extent to which GABA, glutamate, and dopamine function are altered in this population and the relationship between these changes and the later onset of psychosis.

Background: The Ultra High Risk (UHR) state is a combination of genetic and clinical risk factors that are associated with an imminent high risk for psychotic disorder. Clinical features in UHR individuals are assessed using specialized semistructured interviews, such as the Comprehensive Assessment of At Risk Mental State (CAARMS). Previous studies have found that the range of symptoms measured by the CAARMS can be reduced to underlying symptom dimensions and these underlying psychopathological dimensions have been linked to higher risk of transition to psychosis, however neither of the two alternative factor structures in UHR have been replicated and to date there has been no investigation of the neurobiological correlates of symptom dimensions in UHR.

Little is known about the neurobiological factors that determine functional outcome in people at high risk for psychosis. We use multimodal neuroimaging to investigate whether cortical responses during a cognitive task and thalamic glutamate levels were associated with subsequent functional outcome. Sixty subjects participated: 27 healthy controls (CTRL) and 33 at ultrahigh risk (UHR) for psychosis. At baseline, cortical responses during a verbal fluency task were measured using functional Magnetic Resonance Imaging (fMRI) and proton Magnetic Resonance Spectroscopy (1H-MRS) was used to measure thalamic glutamate levels. The UHR subjects were then followed clinically for a mean duration of 18 months, and subdivided into "good" and "poor" functional outcome subgroups according to their Global Assessment of Function score at follow-up. UHR subjects with a poor functional outcome showed greater cortical and subcortical activation than UHR subjects with a good functional outcome. They also had lower levels of thalamic glutamate and showed a negative relationship between thalamic glutamate levels and prefrontal-striatal activation that was not present in the good functional outcome or control groups. In people at high risk for psychosis, their subsequent level of functioning may depend on the extent to which neurophysiological and neurochemical function is perturbed when they first present to clinical services.

All current antipsychotic drugs block dopamine (DA) receptors, but the nature of the DA dysfunction in schizophrenia has not been clear. However, consistent evidence now shows that presynaptic dopaminergic function is altered in schizophrenia, specifically in terms of increased DA synthesis capacity, baseline synaptic DA levels, and DA release. Furthermore, presynaptic dopaminergic function is already elevated in prodromal patients who later developed the disorder. Currently available antipsychotics act on postsynaptic receptors, not targeting presynaptic DA abnormalities. This has implications for understanding response and developing new treatments. The lack of normalization of the abnormal presynaptic function could explain why discontinuation is likely to lead to relapse, because the major dopaminergic function persists, meaning that once treatment stops there is nothing to oppose the dysregulated dopamine function reinstating symptoms. Furthermore, it suggests that drugs that target presynaptic dopaminergic function may constitute new treatment possibilities for schizophrenic patients, in particular, for those in whom antipsychotics are poorly effective. In addition, the longitudinal changes with the onset of psychosis indicate the potential to target a defined dynamic neurochemical abnormality to prevent the onset of psychosis.

Preliminary qualitative research has suggested that patients with early stages of psychosis and those at Ultra High Risk (UHR) may experience "Truman symptoms" (TS). This study is an exploratory investigation of TS in a sample of 26 UHR subjects and 14 matched controls (HC) recruited from three prodromal and early intervention clinics and its relation with clinical features, depersonalization and basic self-disturbances. The UHR were assessed with the Comprehensive Assessment of At-Risk Mental States (CAARMS), Social and Occupational Functioning Assessment Scale (SOFAS), the Positive and Negative Syndrome Scale (PANSS), the Cambridge Depersonalization Scale (CDS) and the Examination of Anomalous Self Experiences (EASE) checklist. In our sample, TS were specific (TS absent in HC) and highly prevalent (50%) in UHR subjects. We found a significant difference in EASE total scores across HC, UHR with TS and without TS but post-hoc analyses showed similar scores in the two latter groups. The presence of TS in our UHR sample was associated with significant higher PANSS general psychopathology but with non-significant difference in the CAARMS, CDS and SOFAS scores. This study of TS in UHR subjects suggested that they might be prevalent and specific of this population.

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

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.

Animal models suggest that the development of psychosis involves hyperactivity in the hippocampus that drives increased activity in the midbrain and basal ganglia. The authors examined this hypothesis by measuring resting perfusion in the hippocampus, basal ganglia, and midbrain in people at high risk of psychosis.Pseudo-continuous arterial spin labeling imaging was used to measure resting regional cerebral blood flow (rCBF) in 52 individuals at ultra-high risk for psychosis and in 27 healthy volunteers. The severity of psychotic symptoms was assessed using the Comprehensive Assessment of At-Risk Mental States. The ultra-high-risk subjects were reassessed after a mean of 17 months, using the same measures as at baseline.At baseline, relative to healthy volunteers, ultra-high-risk subjects showed elevated rCBF in the hippocampus, basal ganglia, and midbrain. In the ultra-high-risk sample overall, at follow-up, symptomatic improvement and reduced rCBF in the hippocampus and ventral striatum were observed. Subjects whose symptoms had resolved such that they no longer met ultra-high-risk criteria showed a longitudinal reduction in left hippocampal rCBF that was not evident in subjects who remained in a high-risk state or had become psychotic.A high risk for psychosis was associated with increased resting activity in the hippocampus, midbrain, and basal ganglia. Subsequent resolution of the high-risk state was linked to a normalization of activity in these regions. These findings are consistent with animal models that propose that psychotic symptoms may be generated when hippocampal hyperactivity drives hyperactivity in regions involved in subcortical dopamine signaling.

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Background The dopamine hypothesis of psychosis suggests that dopamine abnormalities are present in psychotic illness, irrespective of diagnostic class. Meta-analyses of Positron Emission Tomography (PET) studies of the dopamine system have shown elevated dopamine synthesis capacity in schizophrenia, though there is a dearth of studies examining this in other psychotic disorders. We therefore sought to answer the question of whether abnormalities of the presynaptic dopamine system are seen in bipolar psychosis, how this compared to schizophrenia, and whether positive psychotic symptoms were associated with dopamine synthesis capacity, irrespective of diagnostic class. Methods Cross-sectional, case-control 18F-DOPA Positron Emission Tomography (PET) study in people with first episode bipolar psychosis, schizophrenia and control subjects. Clinical measures included the Positive and Negative Syndrome Scale (PANSS), Young Mania Rating Scale and Global Assessment of Functioning (GAF). Results Mean (SD) ages were 23.6 (3.6) years in 22 people with bipolar psychosis (13 male), 26.3 (4.4) years in 16 people with schizophrenia (14 male), and 24.5 (4.5) years in controls (14 male). There was a significant group difference in striatal dopamine synthesis capacity (Kicer) (F2,57=6.80, P=.002), post-hoc tests indicating Kicer was significantly elevated in both the bipolar group (mean [SD], 13.18 [1.08]×10–3 min-1; P=.002) and the schizophrenia group (mean [SD], 12.94 [0.79]×10–3 min-1; P=.04) compared with controls (mean [SD], 12.16 [0.92]×10–3 min-1). Kicer was positively correlated with positive psychotic symptom severity in the combined bipolar and schizophrenia sample currently experiencing psychosis, explaining 27% of the variance in symptom severity (n=32, r=0.52, P=.003). Discussion This is the first study to examine the presynaptic dopamine system in bipolar psychosis, finding an elevation compared to controls, equivalent to schizophrenia, from first onset of illness. A relationship was found between dopamine synthesis capacity and positive psychotic symptoms, across diagnostic classes, indicating a transdiagnostic role for dopamine synthesis capacity and positive psychotic symptoms.