Search

Psychosis risk prediction is one of the leading challenges in psychiatry. Previous investigations have suggested that plasma proteomic data may be useful in accurately predicting transition to psychosis in individuals at clinical high risk (CHR). We hypothesized that an a priori-specified proteomic prediction model would have strong predictive accuracy for psychosis risk and aimed to replicate longitudinal associations between plasma proteins and transition to psychosis. This study used plasma samples from participants in 3 CHR cohorts: the North American Prodrome Longitudinal Studies 2 and 3, and the NEURAPRO randomized control trial (total n = 754). Plasma proteomic data were quantified using mass spectrometry. The primary outcome was transition to psychosis over the study follow-up period. Logistic regression models were internally validated, and optimism-corrected performance metrics derived with a bootstrap procedure. In the overall sample of CHR participants (age: 18.5, SD: 3.9; 51.9% male), 20.4% (n = 154) developed psychosis within 4.4 years. The a priori-specified model showed poor risk-prediction accuracy for the development of psychosis (C-statistic: 0.51 [95% CI: 0.50, 0.59], calibration slope: 0.45). At a group level, Complement C8B, C4B, C5, and leucine-rich α-2 glycoprotein 1 (LRG1) were associated with transition to psychosis but did not surpass correction for multiple comparisons. This study did not confirm the findings from a previous proteomic prediction model of transition from CHR to psychosis. Certain complement proteins may be weakly associated with transition at a group level. Previous findings, derived from small samples, should be interpreted with caution.

This article describes the rationale, aims, and methodology of the Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ). This is the largest international collaboration to date that will develop algorithms to predict trajectories and outcomes of individuals at clinical high risk (CHR) for psychosis and to advance the development and use of novel pharmacological interventions for CHR individuals. We present a description of the participating research networks and the data processing analysis and coordination center, their processes for data harmonization across 43 sites from 13 participating countries (recruitment across North America, Australia, Europe, Asia, and South America), data flow and quality assessment processes, data analyses, and the transfer of data to the National Institute of Mental Health (NIMH) Data Archive (NDA) for use by the research community. In an expected sample of approximately 2000 CHR individuals and 640 matched healthy controls, AMP SCZ will collect clinical, environmental, and cognitive data along with multimodal biomarkers, including neuroimaging, electrophysiology, fluid biospecimens, speech and facial expression samples, novel measures derived from digital health technologies including smartphone-based daily surveys, and passive sensing as well as actigraphy. The study will investigate a range of clinical outcomes over a 2-year period, including transition to psychosis, remission or persistence of CHR status, attenuated positive symptoms, persistent negative symptoms, mood and anxiety symptoms, and psychosocial functioning. The global reach of AMP SCZ and its harmonized innovative methods promise to catalyze the development of new treatments to address critical unmet clinical and public health needs in CHR individuals.

Psychotic experiences (PE) are common in the general population, in particular in childhood, adolescence and young adulthood. PE have been shown to be associated with an increased risk for later psychotic disorders, mental disorders, and poorer functioning. Recent findings have highlighted the relevance of PE to many fields of healthcare, including treatment response in clinical services for anxiety & depression treatment, healthcare costs and service use. Despite PE relevance to many areas of mental health, and healthcare research, there remains a gap of information between PE researchers and experts in other fields. With this review, we aim to bridge this gap by providing a broad overview of the current state of PE research, and future directions. This narrative review aims to provide an broad overview of the literature on psychotic experiences, under the following headings: (1) Definition and Measurement of PE; (2) Risk Factors for PE; (3) PE and Health; (4) PE and Psychosocial Functioning; (5) Interventions for PE, (6) Future Directions. [ABSTRACT FROM AUTHOR]

Background: No biological treatment has been firmly established for the at‐risk stage of psychotic disorder. In this study we aim to test if subthreshold psychotic symptoms can be effectively treated with cannabidiol (CBD), a non‐psychoactive compound of the plant Cannabis sativa. The question has taken on increased importance in the wake of evidence questioning both the need and efficacy of specific pharmacological interventions in the ultra‐high risk (UHR) for psychosis group. Methods: Three‐arm randomized controlled trial of 405 patients (135 per arm) aged 12–25 years who meet UHR for psychosis criteria. The study includes a 6‐week lead‐in phase during which 10% of UHR individuals are expected to experience symptom remission. Participants will receive CBD (per oral) at doses 600 or 1000 mg per day (fixed schedule) for 12 weeks. Participants in the third arm of the trial will receive matching placebo capsules. Primary outcome is severity of positive psychotic symptoms as measured by the Comprehensive Assessment of At‐Risk Mental States at 12 weeks. We hypothesize that CBD will be significantly more effective than placebo in improving positive psychotic symptoms in UHR patients. All participants will also be followed up 6 months post baseline to evaluate if treatment effects are sustained. Conclusion: This paper reports on the rationale and protocol of the Cannabidiol for At Risk for psychosis Youth (CanARY) study. This study will test CBD for the first time in the UHR phase of psychotic disorder. [ABSTRACT FROM AUTHOR]

Aim: Among different types of poly unsaturated fatty acids, omega‐3 fatty acids (FA) play a substantial role in brain development and functioning. This review was designed to evaluate and synthesize available evidence regarding omega‐3 FAs and functional outcome in the ultra‐high‐risk (UHR) population. Methods: An electronic search in PubMed, EMBASE, PSYCINFO and COCHRANE search engines has been performed for all articles published until January 2019. The studies that have data regarding omega‐3 FAs and functional outcome in UHR population were included. Results: Out of 397 nonduplicate citations, 19 articles met selection criteria. These articles were from four different primary studies, namely the Program of Rehabilitation and Therapy (PORT), the North American Prodromal Longitudinal Studies (NAPLS), Vienna High Risk study (VHR) and the NEURAPRO. The data from the NAPLS study found a positive correlation between functional improvement and frequency of dietary intake omega‐3 FA. Moreover, among the erythrocyte omega‐3 FA only eicosapentaenoic acid (EPA) showed a positive correlation with functional score. The VHR study found long‐term improvement in functional outcome in omega‐3 group compared to control, whereas such difference was noticed in the NEURAPRO. In the VHR study both omega‐3 and omega‐6 together predicted the functional improvement at 12 weeks. Conclusions: The number of studies available remains insufficient and more studies with standardized outcome measures in a clinically comparable UHR population would be of more value to understand the clinical benefits of omega‐3 FA in the UHR population. [ABSTRACT FROM AUTHOR]

An editorial is presented on the development of predictive models has progressed by including several key factors, including biomarkers. It expresses the view that low predictive capacity from clinical high risk services requires us to consider additional approaches to identifying those who will transition to psychosis. An overview of the psychotic experiences as a risk factor for later psychotic disorder distracting is presented.

Background: The identification of biomarkers of transition from the at-risk mental state (ARMS) to psychotic disorder is important because early treatment of psychosis is associated with improved outcome. Increasing evidence points to an inflammatory contribution to psychosis. We questioned whether raised levels of plasma inflammatory markers predict transition from ARMS to psychotic disorder and whether any such predictors could be reduced by omega-3 (?-3) polyunsaturated fatty acids (PUFAs). Methods: We measured the levels of 40 neuroinflammation biomarkers using a commercially available immunoassay kit. Firstly, we compared inflammatory markers in subjects in the ARMS who transitioned to psychotic disorder (n = 11) compared to subjects who did not (n = 28). Then we compared inflammatory markers in all subjects before and after ω-3 PUFA treatment (n = 40). Results: Our data provides preliminary evidence that elevations in the baseline plasma levels of the inflammatory marker IL12/IL23p40 are associated with transition from ARMS to psychotic disorder. IL12/IL23p40 levels did not change following 12 weeks administration of ω-3 PUFAs. These findings provide evidence that elevated plasma IL12/IL23p40 is a potential biomarker of increased risk for transition to psychotic disorder. Conclusion: Further studies are required to confirm and extend this finding. Our results do not provide support for the possibility that administration of ω-3 PUFAs act to reduced transition to psychotic disorder by reducing blood levels of IL12/IL23p40. [ABSTRACT FROM AUTHOR]

Background: Epilepsy has long been considered to be a risk factor for psychosis. However there is a lack of consistency in findings across studies on the effect size of this risk which reflects methodological differences in studies and changing diagnostic classifications within neurology and psychiatry. The aim of this study was to assess the prevalence of psychosis in epilepsy and to estimate the risk of psychosis among individuals with epilepsy compared with controls. Methods: A systematic review and meta-analysis was conducted of all published literature pertaining to prevalence rates of psychosis in epilepsy using electronic databases PUBMED, OVIDMEDLINE, PsychINFO and Embase from their inception until September 2010 with the following search terms: prevalence, incidence, rate, rates, psychosis, schizophrenia, schizophreniform illness, epilepsy, seizures, temporal lobe epilepsy. Results: The literature search and search of reference lists yielded 215 papers. Of these, 58 (27%) had data relevant to the review and 157 were excluded following a more detailed assessment. 10% of the included studies were population based studies. The pooled odds ratio for risk of psychosis among people with epilepsy compared with controls was 7.8. The pooled estimate of prevalence of psychosis in epilepsy was found to be 5.6% (95% CI: 4.8-6.4). There was a high level of heterogeneity. The prevalence of psychosis in temporal lobe epilepsy was 7% (95% CI: 4.9-9.1). The prevalence of interictal psychosis in epilepsy was 5.2% (95% CI: 3.3-7.2). The prevalence of postictal psychosis in epilepsy was 2% (95% CI: 1.2-2.8). Conclusions: Our systematic review found that up to 6% of individuals with epilepsy have a co-morbid psychotic illness and that patients have an almost eight fold increased risk of psychosis. The prevalence rate of psychosis is higher in temporal lobe epilepsy (7%). We suggest that further investigation of this association could give clues to the aetiology of psychosis. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is known to lead to a range of adverse psychiatric sequelae but the question of whether TBI is a risk factor for psychosis and, in particular, schizophrenia remains unclear. Studies examining this issue have yielded conflicting results. We carried out a systematic review of the literature on TBI and psychosis in order to identify all population-based controlled studies which provide estimates of risk for schizophrenia following TBI. Odds ratios (ORs) were combined using random effects meta-analysis. Our literature search yielded 172 studies which were considered to be potentially relevant. From these, we identified 9 studies that could provide estimates of risk in the form of ORs. The pooled analysis revealed a significant association between TBI and schizophrenia (OR = 1.65; 95% CI = 1.17–2.32), with significant heterogeneity between the studies. Estimates from the family studies (OR = 2.8: 95% CI =1.76–4.47) were higher than those from the cohort/nested case-control studies (OR = 1.42: 95% CI = 1.02–1.97) by a factor of almost 2. There did not appear to be a dose-response relationship between severity of head injury and subsequent risk of schizophrenia. This meta-analysis supports an increased risk of schizophrenia following TBI, with a larger effect in those with a genetic predisposition to psychosis. Further epidemiological and neuroscientific studies to elucidate the mechanisms underlying this association are warranted. [ABSTRACT FROM PUBLISHER]

Cannabis use confers a two-fold increase in the risk for psychosis, with adolescent use conferring even greater risk. A high-low activity catechol-O-methyltransferase (COMT) polymorphism may modulate the effects of adolescent Δ-9-tetrahydrocannabinol (THC) exposure on the risk for adult psychosis. Mice with knockout of the COMT gene were treated chronically with THC (4.0 and 8.0 mg/kg over 20 days) during either adolescence (postnatal days (PDs) 32-52) or adulthood (PDs 70-90). The effects of THC exposure were then assessed in adulthood across behavioral phenotypes relevant for psychosis: exploratory activity, spatial working memory (spontaneous and delayed alternation), object recognition memory, social interaction (sociability and social novelty preference), and anxiety (elevated plus maze). Adolescent THC administration induced a larger increase in exploratory activity, greater impairment in spatial working memory, and a stronger anti-anxiety effect in COMT knockouts than in wild types, primarily among males. No such effects of selective adolescent THC administration were evident for other behaviors. Both object recognition memory and social novelty preference were disrupted by either adolescent or adult THC administration, independent of genotype. The COMT genotype exerts specific modulation of responsivity to chronic THC administration during adolescence in terms of exploratory activity, spatial working memory, and anxiety. These findings illuminate the interaction between genes and adverse environmental exposures over a particular stage of development in the expression of the psychosis phenotype. [ABSTRACT FROM AUTHOR]

Background: There is renewed focus on the complement system in the pathogenesis of schizophrenia. In addition to providing aetiological insights, consistently dysregulated complement proteins in serum or plasma may have clinical utility as biomarkers.Methods: We performed a systematic literature review searching PubMed, Embase and PsycINFO for studies measuring complement system activity or complement protein concentrations in serum or plasma from patients with schizophrenia compared to controls. Random-effects meta-analyses were performed to calculate pooled effect estimates (Hedges' g standardised mean difference [SMD]) for complement proteins whose concentrations were measured in three or more studies. The review was pre-registered on the PROSPERO database (CRD42018109012).Results: Database searching identified 1146 records. Fifty-eight full-text articles were assessed for eligibility and 24 studies included. Seven studies measured complement system activity. Activity of the classical pathway did not differ between cases and controls in four of six studies, and conflicting results were noted in two studies of alternative pathway activity. Twenty studies quantified complement protein concentrations of which complement components 3 (C3) and 4 (C4) were measured in more than three studies. Meta-analyses showed no evidence of significant differences between cases and controls for 11 studies of C3 (SMD 0.04, 95% confidence interval [CI] -0.29-0.36) and 10 studies of C4 (SMD 0.10, 95% CI -0.21-0.41).Conclusions: Serological studies provide mixed evidence regarding dysregulation of the complement system in schizophrenia. Larger studies of a longitudinal nature, focusing on early phenotypes, could provide further insights regarding the potential role of the complement system in psychotic disorders. [ABSTRACT FROM AUTHOR]

Current diagnosis of schizophrenia relies exclusively on the potentially subjective interpretation of clinical symptoms and social functioning as more objective biological measurement and medical diagnostic tests are not presently available. The use of metabolomics in the discovery of disease biomarkers has grown in recent years. Metabolomic methods could aid in the discovery of diagnostic biomarkers of schizophrenia. This systematic review focuses on biofluid metabolites associated with schizophrenia. A systematic search of Web of Science and Ovid Medline databases was conducted and 63 studies investigating metabolite biomarkers of schizophrenia were included. A review of these studies revealed several potential metabolite signatures of schizophrenia including reduced levels of essential polyunsaturated fatty acids (EPUFAs), vitamin E and creatinine; and elevated levels of lipid peroxidation metabolites and glutamate. Further research is needed to validate these biomarkers and would benefit from large cohort studies and more homogeneous and well-defined subject groups. [ABSTRACT FROM AUTHOR]

Alterations of immune function have been reported in ultra-high risk (UHR) for psychosis patients causing expectations in terms of predictive meaningfulness and benefits of anti-inflammatory agents. According to a RCT in UHR-patients supplementation of omega-3 polyunsaturated fatty acids (PUFA) was effective in reducing transition to psychosis risk and to improve symptomatology. Based on preclinical findings, we now investigated state marker properties of and the influence of PUFA on immune markers in a RCT (clinical trials.gov Identifier: NCT00396643). In a longitudinal design we measured plasma levels of the pro-inflammatory interleukin 6 (IL-6), the soluble alpha (Tac) subunit of the interleukin 2 receptor (sIL-2r), and the circulating soluble form of the intercellular adhesion molecule one (sICAM-1), in 79 help-seeking UHR individuals (13-25years of age). Using linear mixed model (LMM) analysis, we investigated the effects of 12weeks supplementation of either 1.2g/d PUFA (n=38) or Placebo (n=41). At baseline, inflammatory markers were not altered in patients who later suffered transition to psychosis within one year (n=12; 11 PUFA-group, 1 PL-group). IL-6 was weakly inverse associated with omega-6 PUFA, and highly increased in nicotine users. In univariate tests of the LMM omega-3 PUFA caused a significant increase of sICAM-1 (p=0.022). PUFA did not significantly influence IL-6 or sIL-2r. The enhancement of sICAM-1 in the PUFA condition is suggestive for supportive effects on vascular immune response and immediate Th1 helper cell mediated immune answer, which was found disturbed in manifest schizophrenia, e.g. by facilitating the leukocyte adhesion and migration across the endothelium. [ABSTRACT FROM AUTHOR]

Background: There is emerging evidence of an etiological overlap between a range of neurodevelopmental disorders, including schizophrenia and epilepsy. Here we investigate shared familial vulnerability to psychotic illness and epilepsy in a family-based study. Methods: The study population consisted of parents and their children born in Helsinki between 1947 and 1990. The Finnish Hospital Discharge Register was used to determine psychiatric and neurological outcomes in adulthood for all offspring. Parental history of psychosis and epilepsy was determined by linking the Hospital Discharge Register and the Finnish Population Register. Results: Our total sample comprised 9653 families and 23,404 offspring. Individuals with epilepsy had a 5.5-fold increase in the risk of having a broadly defined psychotic disorder, an almost 8.5-fold increase in the risk of having schizophrenia, and a 6.3-fold increase in the risk of having bipolar disorder. There was strong evidence of clustering of the association between epilepsy and psychosis within families. Individuals with a parental history of epilepsy had a 2-fold increase in the risk of developing psychosis, compared with individuals without a parental history of epilepsy. Individuals with a parental history of psychosis had, reciprocally, a 2.7-fold increase in the risk of having a diagnosis of generalized epilepsy, compared with individuals without a parental history of psychosis. Post hoc analyses showed that these associations were not driven by the comorbidity of epilepsy and psychosis in the parents. Conclusions: These findings support recent evidence of overlapping etiological factors between epilepsy and schizophrenia, especially recent evidence of a genetic overlap between these disorders. [Copyright &y& Elsevier]