Exploring causal mechanisms of psychosis risk.

Robust epidemiological evidence of risk and protective factors for psychosis is essential to inform preventive interventions. Previous evidence syntheses have classified these risk and protective factors according to their strength of association with psychosis. In this critical review we appraise the distinct and overlapping mechanisms of 25 key environmental risk factors for psychosis, and link these to mechanistic pathways that may contribute to neurochemical alterations hypothesised to underlie psychotic symptoms. We then discuss the implications of our findings for future research, specifically considering interactions between factors, exploring universal and subgroup-specific factors, improving understanding of temporality and risk dynamics, standardising operationalisation and measurement of risk and protective factors, and developing preventive interventions targeting risk and protective factors.

Connectome dysfunction in patients at clinical high risk for psychosis and modulation by oxytocin.

Abnormalities in functional brain networks (functional connectome) are increasingly implicated in people at Clinical High Risk for Psychosis (CHR-P). Intranasal oxytocin, a potential novel treatment for the CHR-P state, modulates network topology in healthy individuals. However, its connectomic effects in people at CHR-P remain unknown. Forty-seven men (30 CHR-P and 17 healthy controls) received acute challenges of both intranasal oxytocin 40 IU and placebo in two parallel randomised, double-blind, placebo-controlled cross-over studies which had similar but not identical designs. Multi-echo resting-state fMRI data was acquired at approximately 1 h post-dosing. Using a graph theoretical approach, the effects of group (CHR-P vs healthy control), treatment (oxytocin vs placebo) and respective interactions were tested on graph metrics describing the topology of the functional connectome. Group effects were observed in 12 regions (all pFDR < 0.05) most localised to the frontoparietal network. Treatment effects were found in 7 regions (all pFDR < 0.05) predominantly within the ventral attention network. Our major finding was that many effects of oxytocin on network topology differ across CHR-P and healthy individuals, with significant interaction effects observed in numerous subcortical regions strongly implicated in psychosis onset, such as the thalamus, pallidum and nucleus accumbens, and cortical regions which localised primarily to the default mode network (12 regions, all pFDR < 0.05). Collectively, our findings provide new insights on aberrant functional brain network organisation associated with psychosis risk and demonstrate, for the first time, that oxytocin modulates network topology in brain regions implicated in the pathophysiology of psychosis in a clinical status (CHR-P vs healthy control) specific manner.

Increased hippocampal blood flow in people at clinical high risk for psychosis and effects of cannabidiol.

BACKGROUND: Hippocampal hyperperfusion has been observed in people at Clinical High Risk for Psychosis (CHR), is associated with adverse longitudinal outcomes and represents a potential treatment target for novel pharmacotherapies. Whether cannabidiol (CBD) has ameliorative effects on hippocampal blood flow (rCBF) in CHR patients remains unknown. METHODS: Using a double-blind, parallel-group design, 33 CHR patients were randomized to a single oral 600 mg dose of CBD or placebo; 19 healthy controls did not receive any drug. Hippocampal rCBF was measured using Arterial Spin Labeling. We examined differences relating to CHR status (controls v. placebo), effects of CBD in CHR (placebo v. CBD) and linear between-group relationships, such that placebo > CBD > controls or controls > CBD > placebo, using a combination of hypothesis-driven and exploratory wholebrain analyses. RESULTS: Placebo-treated patients had significantly higher hippocampal rCBF bilaterally (all pFWE<0.01) compared to healthy controls. There were no suprathreshold effects in the CBD v. placebo contrast. However, we found a significant linear relationship in the right hippocampus (pFWE = 0.035) such that rCBF was highest in the placebo group, lowest in controls and intermediate in the CBD group. Exploratory wholebrain results replicated previous findings of hyperperfusion in the hippocampus, striatum and midbrain in CHR patients, and provided novel evidence of increased rCBF in inferior-temporal and lateral-occipital regions in patients under CBD compared to placebo. CONCLUSIONS: These findings suggest that hippocampal blood flow is elevated in the CHR state and may be partially normalized by a single dose of CBD. CBD therefore merits further investigation as a potential novel treatment for this population.

Parsing neurobiological heterogeneity of the clinical high-risk state for psychosis: A pseudo-continuous arterial spin labelling study.

Introduction: The impact of the clinical high-risk for psychosis (CHR-P) construct is dependent on accurately predicting outcomes. Individuals with brief limited intermittent psychotic symptoms (BLIPS) have higher risk of developing a first episode of psychosis (FEP) compared to individuals with attenuated psychotic symptoms (APS). Supplementing subgroup stratification with information from candidate biomarkers based on neurobiological parameters, such as resting-state, regional cerebral blood flow (rCBF), may help refine risk estimates. Based on previous evidence, we hypothesized that individuals with BLIPS would exhibit increased rCBF compared to APS in key regions linked to dopaminergic pathways. Methods: Data from four studies were combined using ComBat (to account for between-study differences) to analyse rCBF in 150 age- and sex-matched subjects (n = 30 healthy controls [HCs], n = 80 APS, n = 20 BLIPS and n = 20 FEP). Global gray matter (GM) rCBF was examined in addition to region-of-interest (ROI) analyses in bilateral/left/right frontal cortex, hippocampus and striatum. Group differences were assessed using general linear models: (i) alone; (ii) with global GM rCBF as a covariate; (iii) with global GM rCBF and smoking status as covariates. Significance was set at p < 0.05. Results: Whole-brain voxel-wise analyses and Bayesian ROI analyses were also conducted. No significant group differences were found in global [F(3,143) = 1,41, p = 0.24], bilateral frontal cortex [F(3,143) = 1.01, p = 0.39], hippocampus [F(3,143) = 0.63, p = 0.60] or striatum [F(3,143) = 0.52, p = 0.57] rCBF. Similar null findings were observed in lateralized ROIs (p > 0.05). All results were robust to addition of covariates (p > 0.05). No significant clusters were identified in whole-brain voxel-wise analyses (p > 0.05FWE). Weak-to-moderate evidence was found for an absence of rCBF differences between APS and BLIPS in Bayesian ROI analyses. Conclusion: On this evidence, APS and BLIPS are unlikely to be neurobiologically distinct. Due to this and the weak-to-moderate evidence for the null hypothesis, future research should investigate larger samples of APS and BLIPS through collaboration across large-scale international consortia.

Erbb4 Deletion From Inhibitory Interneurons Causes Psychosis-Relevant Neuroimaging Phenotypes.

BACKGROUND AND HYPOTHESIS: Converging lines of evidence suggest that dysfunction of cortical GABAergic inhibitory interneurons is a core feature of psychosis. This dysfunction is thought to underlie neuroimaging abnormalities commonly found in patients with psychosis, particularly in the hippocampus. These include increases in resting cerebral blood flow (CBF) and glutamatergic metabolite levels, and decreases in ligand binding to GABAA α5 receptors and to the synaptic density marker synaptic vesicle glycoprotein 2A (SV2A). However, direct links between inhibitory interneuron dysfunction and these neuroimaging readouts are yet to be established. Conditional deletion of a schizophrenia susceptibility gene, the tyrosine kinase receptor Erbb4, from cortical and hippocampal inhibitory interneurons leads to synaptic defects, and behavioral and cognitive phenotypes relevant to psychosis in mice. STUDY DESIGN: Here, we investigated how this inhibitory interneuron disruption affects hippocampal in vivo neuroimaging readouts. Adult Erbb4 conditional mutant mice (Lhx6-Cre;Erbb4F/F, n = 12) and their wild-type littermates (Erbb4F/F, n = 12) were scanned in a 9.4T magnetic resonance scanner to quantify CBF and glutamatergic metabolite levels (glutamine, glutamate, GABA). Subsequently, we assessed GABAA receptors and SV2A density using quantitative autoradiography. RESULTS: Erbb4 mutant mice showed significantly elevated ventral hippccampus CBF and glutamine levels, and decreased SV2A density across hippocampus sub-regions compared to wild-type littermates. No significant GABAA receptor density differences were identified. CONCLUSIONS: These findings demonstrate that specific disruption of cortical inhibitory interneurons in mice recapitulate some of the key neuroimaging findings in patients with psychosis, and link inhibitory interneuron deficits to non-invasive measures of brain function and neurochemistry that can be used across species.

Task-independent acute effects of delta-9-tetrahydrocannabinol on human brain function and its relationship with cannabinoid receptor gene expression: A neuroimaging meta-regression analysis.

The neurobiological mechanisms underlying the effects of delta-9-tetrahydrocannabinol (THC) remain unclear. Here, we examined the spatial acute effect of THC on human regional brain activation or blood flow (hereafter called 'activation signal') in a 'core' network of brain regions from 372 participants, tested using a within-subject repeated measures design under experimental conditions. We also investigated whether the neuromodulatory effects of THC are related to the local expression of the cannabinoid-type-1 (CB1R) and type-2 (CB2R) receptors. Finally, we investigated the dose-response relationship between THC and key brain substrates. These meta-analytic findings shed new light on the localisation of the effects of THC in the human brain, suggesting that THC has neuromodulatory effects in regions central to many cognitive tasks and processes, related to dose, with greater effects in regions with higher levels of CB1R expression.

Altered relationship between cortisol response to social stress and mediotemporal function during fear processing in people at clinical high risk for psychosis: a preliminary report.

Evidence suggests that people at Clinical High Risk for Psychosis (CHR) have a blunted cortisol response to stress and altered mediotemporal activation during fear processing, which may be neuroendocrine-neuronal signatures of maladaptive threat responses. However, whether these facets are associated with each other and how this relationship is affected by cannabidiol treatment is unknown. We examined the relationship between cortisol response to social stress and mediotemporal function during fear processing in healthy people and in CHR patients. In exploratory analyses, we investigated whether treatment with cannabidiol in CHR individuals could normalise any putative alterations in cortisol-mediotemporal coupling. 33 CHR patients were randomised to 600 mg cannabidiol or placebo treatment. Healthy controls (n = 19) did not receive any drug. Mediotemporal function was assessed using a fearful face-processing functional magnetic resonance imaging paradigm. Serum cortisol and anxiety were measured immediately following the Trier Social Stress Test. The relationship between cortisol and mediotemporal blood-oxygen-level-dependent haemodynamic response was investigated using linear regression. In healthy controls, there was a significant negative relationship between cortisol and parahippocampal activation (p = 0.023), such that the higher the cortisol levels induced by social stress, the lower the parahippocampal activation (greater deactivation) during fear processing. This relationship differed significantly between the control and placebo groups (p = 0.033), but not between the placebo and cannabidiol groups (p = 0.67). Our preliminary findings suggest that the parahippocampal response to fear processing may be associated with the neuroendocrine (cortisol) response to experimentally induced social stress, and that this relationship may be altered in patients at clinical high risk for psychosis.

GABAA and NMDA receptor density alterations and their behavioral correlates in the gestational methylazoxymethanol acetate model for schizophrenia.

Hippocampal hyperactivity driven by GABAergic interneuron deficits and NMDA receptor hypofunction is associated with the hyperdopaminergic state often observed in schizophrenia. Furthermore, previous research in the methylazoxymethanol acetate (MAM) rat model has demonstrated that repeated peripubertal diazepam administration can prevent the emergence of adult hippocampal hyperactivity, dopamine-system hyperactivity, and associated psychosis-relevant behaviors. Here, we sought to characterize hippocampal GABAA and NMDA receptors in MAM-treated rats and to elucidate the receptor mechanisms underlying the promising effects of peripubertal diazepam exposure. Quantitative receptor autoradiography was used to measure receptor density in the dorsal hippocampus CA1, ventral hippocampus CA1, and ventral subiculum. Specifically, [3H]-Ro15-4513 was used to quantify the density of α5GABAA receptors (α5GABAAR), [3H]-flumazenil to quantify α1-3;5GABAAR, and [3H]-MK801 to quantify NMDA receptors. MAM rats exhibited anxiety and schizophrenia-relevant behaviors as measured by elevated plus maze and amphetamine-induced hyperlocomotion (AIH), although diazepam only partially rescued these behaviors. α5GABAAR density was reduced in MAM-treated rats in all hippocampal sub-regions, and negatively correlated with AIH. Ventral hippocampus CA1 α5GABAAR density was positively correlated with anxiety-like behavior. Dorsal hippocampus CA1 NMDA receptor density was increased in MAM-treated rats, and positively correlated with AIH. [3H]-flumazenil revealed no significant effects. Finally, we found no significant effect of diazepam treatment on receptor densities, potentially related to the only partial rescue of schizophrenia-relevant phenotypes. Overall, our findings provide first evidence of α5GABAAR and NMDA receptor abnormalities in the MAM model, suggesting that more selective pharmacological agents may become a novel therapeutic mechanism in schizophrenia.

Transition to psychosis in randomized clinical trials of individuals at clinical high risk of psychosis compared to observational cohorts: a systematic review and meta-analysis.

BACKGROUND: Individuals at clinical high risk of psychosis (CHR-P) recruited in randomized clinical trials (RCTs) and observational cohorts may display a different enrichment and hence risk of transition to psychosis. No meta-analysis has ever addressed this issue. METHODS: "Preferred Reporting Items for Systematic reviews and Meta-Analyses" (PRISMA) and "Meta-analysis Of Observational Studies in Epidemiology" (MOOSE)-compliant meta-analysis. PubMed and Web of Science were searched until November 2020 (PROSPERO:CRD42021229223). We included nonoverlapping longitudinal studies (RCTs-control condition and observational cohorts) reporting the transition to psychosis in CHR-P individuals. The primary effect size measure was the cumulative risk of transition at 0.5, 1, and 2 years follow-up in RCTs compared to observational cohorts. Random effects meta-analyses, heterogeneity assessment, quality assessment, and meta-regressions were conducted. RESULTS: Ninety-four independent studies (24 RCTs, 70 observational cohorts) and 9,243 individuals (mean age = 20.1 ± 3.0 years; 43.7% females) were included. The meta-analytical risk of transitioning to psychosis from a CHR-P stage was 0.091 (95% confidence intervals [CI] = 0.068-0.121) at 0.5 years, 0.140 (95% CI = 0.101-0.191) at 1 year and 0.165 (95% CI = 0.097-0.267) at 2 years follow-up in RCTs, and 0.081 (95% CI = 0.067-0.099) at 0.5 years, 0.138 (95% CI = 0.114-0.167) at 1 year, and 0.174 (95% CI = 0.156-0.193) at 2 years follow-up in observational cohorts. There were no between-group differences in transition risks (p > 0.05). The proportion of CHR-P individuals with substance use disorders (excluding alcohol and cannabis) was higher in observational cohorts (16.8, 95% CI = 13.3-21.0%) than in RCTs (3.4, 95% CI = 0.8-12.7%; p = 0.018). CONCLUSIONS: There is no meta-analytic evidence supporting sampling biases in RCTs of CHR-P individuals. Further RCTs are needed to detect effective interventions to prevent psychosis in this at-risk group.

GABA, Glutamate and Neural Activity: A Systematic Review With Meta-Analysis of Multimodal 1H-MRS-fMRI Studies.

Multimodal neuroimaging studies combining proton magnetic resonance spectroscopy (1H-MRS) to quantify GABA and/or glutamate concentrations and functional magnetic resonance imaging (fMRI) to measure brain activity non-invasively have advanced understanding of how neurochemistry and neurophysiology may be related at a macroscopic level. The present study aimed to perform a systematic review and meta-analysis of available studies examining the relationship between 1H-MRS glutamate and/or GABA levels and task-related fMRI signal in the healthy brain. Ovid (Medline, Embase, and PsycINFO) and Pubmed databases were systematically searched to identify articles published until December 2019. The primary outcome of interest was the association between resting levels of glutamate or GABA and task-related fMRI. Fifty-five papers were identified for inclusion in the systematic review. A further 22 studies were entered into four separate meta-analyses. These meta-analyses found evidence of significant negative associations between local GABA levels and (a) fMRI activation to visual tasks in the occipital lobe, and (b) activation to emotion processing in the medial prefrontal cortex (mPFC)/anterior cingulate cortex (ACC). However, there was no significant association between mPFC/ACC glutamate levels and fMRI activation to cognitive control tasks or to emotional processing, with the relationship to emotion processing related neural activity narrowly missing significance. Moreover, our systematic review also found converging evidence of negative associations between GABA levels and local brain activity, and positive associations between glutamate levels and distal brain activity, outside of the 1H-MRS sampling region. Albeit less consistently, additional relationships between GABA levels and distal brain activity and between glutamate levels and local brain activity were found. It remains unclear if the absence of effects for other brain regions and other cognitive-emotional domains reflects study heterogeneity or potential confounding effects of age, sex, or other unknown factors. Advances in 1H-MRS methodology as well as in the integration of 1H-MRS readouts with other imaging modalities for indexing neural activity hold great potential to reveal key aspects of the pathophysiology of mental health disorders involving aberrant interactions between neurochemistry and neurophysiology such as schizophrenia.

The Yin and Yang of Cannabis: A Systematic Review of Human Neuroimaging Evidence of the Differential Effects of Δ9-Tetrahydrocannabinol and Cannabidiol.

Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) have been the most investigated cannabinoids at the human and preclinical levels, although the neurobiological mechanisms underlying their effects remain unclear. Human experimental evidence complemented by observational studies suggests that THC may have psychotogenic effects while CBD may have antipsychotic effects. However, whether their effects on brain function are consistent with their opposing behavioral effects remains unclear. To address this, here we synthesize neuroimaging evidence investigating the acute effects of THC and CBD on human brain function using a range of neuroimaging techniques, with an aim to identify the key brain substrates where THC and CBD have opposing effects. After a systematic search, a review of the available studies indicated marked heterogeneity. However, an overall pattern of opposite effect profiles of the two cannabinoids was evident with some degree of consistency, primarily attributed to the head-to-head challenge studies of THC and CBD. While head-to-head comparisons are relatively few, collectively the evidence suggests that opposite effects of THC and CBD may be present in the striatum, parahippocampus, anterior cingulate/medial prefrontal cortex, and amygdala, with opposite effects less consistently identified in other regions. Broadly, THC seems to increase brain activation and blood flow, whereas CBD seems to decrease brain activation and blood flow. Given the sparse evidence, there is a particular need to understand the mechanisms underlying their opposite behavioral effects because it may not only offer insights into the underlying pathophysiological mechanisms of psychotic disorders but also suggest potentially novel targets and biomarkers for drug discovery.

Evaluation of variability in individual response to treatments in the clinical high-risk state for psychosis: A meta-analysis.

BACKGROUND: Individuals at Clinical High Risk for Psychosis (CHR-P) may differ considerably in their response to indicated preventive interventions. No studies have tested this. METHOD: PRISMA-compliant systematic review of the Web of Science (MEDLINE), PsycInfo, CENTRAL and unpublished/gray literature up to 1 September 2019. RCTs in CHR-P individuals, reporting on attenuated positive psychotic symptoms were included. The primary outcome was the variability ratio between the variance of the severity of attenuated positive psychotic symptoms in the indicated intervention condition vs the control condition (needs-based interventions, NBI) at 6 and 12 months. Random effect models, C statistics, meta-regressions/sensitivity analyses and Cochrane Risk of Bias assessment were performed. RESULTS: Overall, 1707 individuals from 14 RCTs (57% male, mean age = 20) reporting on the impact of preventive interventions on attenuated positive psychotic symptoms were included. At 6 months, the variability ratio was 1 (95% CI 0.89-1.12). At 12 months, the variability ratio was higher in the indicated intervention compared to the NBI condition but not statistically different: 1.09 (95% CI 0.94-1.25). Between-study heterogeneity was serious (I2 = 51% and 68%, respectively), but sensitivity analysis suggested it may be related to two outlying studies or larger variability in the response to treatment in small studies. CONCLUSIONS: There is no evidence for individual differences in CHR-P response to preventive treatments. Although the study cannot exclude that subsets of CHR-P individuals may respond differently to preventive treatments, it indicates that the average effect of preventive interventions is a reasonable estimate for the CHR-P individual.

A single dose of cannabidiol modulates medial temporal and striatal function during fear processing in people at clinical high risk for psychosis.

Emotional dysregulation and anxiety are common in people at clinical high risk for psychosis (CHR) and are associated with altered neural responses to emotional stimuli in the striatum and medial temporal lobe. Using a randomised, double-blind, parallel-group design, 33 CHR patients were randomised to a single oral dose of CBD (600 mg) or placebo. Healthy controls (n = 19) were studied under identical conditions but did not receive any drug. Participants were scanned with functional magnetic resonance imaging (fMRI) during a fearful face-processing paradigm. Activation related to the CHR state and to the effects of CBD was examined using a region-of-interest approach. During fear processing, CHR participants receiving placebo (n = 15) showed greater activation than controls (n = 19) in the parahippocampal gyrus but less activation in the striatum. Within these regions, activation in the CHR group that received CBD (n = 15) was intermediate between that of the CHR placebo and control groups. These findings suggest that in CHR patients, CBD modulates brain function in regions implicated in psychosis risk and emotion processing. These findings are similar to those previously evident using a memory paradigm, suggesting that the effects of CBD on medial temporal and striatal function may be task independent.

Intranasal oxytocin increases heart-rate variability in men at clinical high risk for psychosis: a proof-of-concept study.

Autonomic nervous system (ANS) dysfunction (i.e., increased sympathetic and/or decreased parasympathetic activity) has been proposed to contribute to psychosis vulnerability. Yet, we still lack directed therapeutic strategies that improve ANS regulation in psychosis or at-risk states. The oxytocin system constitutes a potential therapeutic target, given its role in ANS regulation. However, whether intranasal oxytocin ameliorates autonomic regulation during emerging psychosis is currently unknown. We pooled together two datasets, one of 30 men at clinical high risk for psychosis (CHR-P), and another of 17 healthy men, who had participated in two double-blinded, placebo-controlled, randomised, crossover MRI studies with similar protocols. All participants self-administered 40 IU of intranasal oxytocin or placebo using a nasal spray. We recorded pulse plethysmography during a period of 8 min at about 1 h post dosing and estimated heart rate (HR) and high-frequency HR variability (HF-HRV), an index of cardio-parasympathetic activity. CHR-P and healthy men did not differ at resting HR or HF-HRV under placebo. We found a significant condition × treatment effect for HF-HRV, showing that intranasal oxytocin, compared with placebo, increased HF-HRV in CHR-P but not in healthy men. The main effects of treatment and condition were not significant. In this proof-of-concept study, we show that intranasal oxytocin increases cardio-parasympathetic activity in CHR-P men, highlighting its therapeutic potential to improve autonomic regulation in this clinical group. Our findings support the need for further research on the preventive and therapeutic potential of intranasal oxytocin during emerging psychosis, where we lack effective treatments.

Acute oxytocin effects in inferring others' beliefs and social emotions in people at clinical high risk for psychosis.

Social deficits are key hallmarks of the Clinical High Risk for Psychosis (CHR-P) state and of established psychotic disorders, and contribute to impaired social functioning, indicating a potential target for interventions. However, current treatments do not significantly ameliorate social impairments in CHR-P individuals. Given its critical role in social behaviour and cognition, the oxytocinergic (OT) system is a promising target for novel interventions in CHR-P subjects. In a double-blind, placebo-controlled, crossover design, 30 CHR-P males were studied using functional magnetic resonance imaging (fMRI) on two occasions, once after 40IU self-administered intranasal OT and once after placebo. A modified version of the Sally-Anne task was used to assess brain activation during inferring others' beliefs and social emotions. The Reading the Mind in the Eyes Test was acquired prior to the first scan to test whether OT effects were moderated by baseline social-emotional abilities. OT did not modulate behavioural performances but reduced activation in the bilateral inferior frontal gyrus compared with placebo while inferring others' social emotions. Furthermore, the relationship between brain activation and task performance after OT administration was moderated by baseline social-emotional abilities. While task accuracy during inferring others' social emotion increased with decreasing activation in the left inferior frontal gyrus in CHR-P individuals with low social-emotional abilities, there was no such relationship in CHR-P individuals with high social-emotional abilities. Our findings may suggest that acute OT administration enhances neural efficiency in the inferior frontal gyrus during inferring others' social emotions in those CHR-P subjects with low baseline social-emotional abilities.

Prenatal and perinatal risk and protective factors for psychosis: a systematic review and meta-analysis.

BACKGROUND: Prenatal and perinatal insults are implicated in the aetiopathogenesis of psychotic disorders but the consistency and magnitude of their associations with psychosis have not been updated for nearly two decades. The aim of this systematic review and meta-analysis was to provide a comprehensive and up-to-date synthesis of the evidence on the association between prenatal or perinatal risk and protective factors and psychotic disorders. METHODS: In this systematic review and meta-analysis, we searched the Web of Science database for articles published up to July 20, 2019. We identified cohort and case-control studies examining the association (odds ratio [OR]) between prenatal and perinatal factors and any International Classification of Diseases (ICD) or Diagnostic and Statistical Manual of Mental Disorders (DSM) non-organic psychotic disorder with a healthy comparison group. Other inclusion criteria were enough data available to do the analyses, and non-overlapping datasets. We excluded reviews, meta-analyses, abstracts or conference proceedings, and articles with overlapping datasets. Data were extracted according to EQUATOR and PRISMA guidelines. Extracted variables included first author, publication year, study type, sample size, type of psychotic diagnosis (non-affective psychoses or schizophrenia-spectrum disorders, affective psychoses) and diagnostic instrument (DSM or ICD and version), the risk or protective factor, and measure of association (primary outcome). We did random-effects pairwise meta-analyses, Q statistics, I2 index, sensitivity analyses, meta-regressions, and assessed study quality and publication bias. The study protocol was registered at PROSPERO, CRD42017079261. FINDINGS: 152 studies relating to 98 risk or protective factors were eligible for analysis. Significant risk factors were: maternal age younger than 20 years (OR 1·17) and 30-34 years (OR 1·05); paternal age younger than 20 years (OR 1·31) and older than 35 years (OR 1·28); any maternal (OR 4·60) or paternal (OR 2·73) psychopathology; maternal psychosis (OR 7·61) and affective disorder (OR 2·26); three or more pregnancies (OR 1·30); herpes simplex 2 (OR 1·35); maternal infections not otherwise specified (NOS; OR 1·27); suboptimal number of antenatal visits (OR 1·83); winter (OR 1·05) and winter to spring (OR 1·05) season of birth in the northern hemisphere; maternal stress NOS (OR 2·40); famine (OR 1·61); any famine or nutritional deficits in pregnancy (OR 1·40); maternal hypertension (OR 1·40); hypoxia (OR 1·63); ruptured (OR 1·86) and premature rupture (OR 2·29) of membranes; polyhydramnios (OR 3·05); definite obstetric complications NOS (OR 1·83); birthweights of less than 2000 g (OR 1·84), less than 2500 g (OR 1·53), or 2500-2999 g (OR 1·23); birth length less than 49 cm (OR 1·17); small for gestational age (OR 1·40); premature birth (OR 1·35), and congenital malformations (OR 2·35). Significant protective factors were maternal ages 20-24 years (OR 0·93) and 25-29 years (OR 0·92), nulliparity (OR 0·91), and birthweights 3500-3999 g (OR 0·90) or more than 4000 g (OR 0·86). The results were corrected for publication biases; sensitivity and meta-regression analyses confirmed the robustness of these findings for most factors. INTERPRETATION: Several prenatal and perinatal factors are associated with the later onset of psychosis. The updated knowledge emerging from this study could refine understanding of psychosis pathogenesis, enhance multivariable risk prediction, and inform preventive strategies. FUNDING: None.

What Causes the Onset of Psychosis in Individuals at Clinical High Risk? A Meta-analysis of Risk and Protective Factors.

Twenty percent of individuals at clinical high risk for psychosis (CHR-P) develop the disorder within 2 years. Extensive research has explored the factors that differentiate those who develop psychosis and those who do not, but the results are conflicting. The current systematic review and meta-analysis comprehensively addresses the consistency and magnitude of evidence for non-purely genetic risk and protective factors associated with the risk of developing psychosis in CHR-P individuals. Random effects meta-analyses, standardized mean difference (SMD) and odds ratio (OR) were used, in combination with an established stratification of evidence that assesses the association of each factor and the onset of psychotic disorders (from class I, convincing evidence to class IV weak evidence), while controlling for several types of biases. A total of 128 original controlled studies relating to 26 factors were retrieved. No factors showed class I-convincing evidence. Two further factors were associated with class II-highly suggestive evidence: attenuated positive psychotic symptoms (SMD = 0.348, 95% CI: 0.280, 0.415) and global functioning (SMD = -0.291, 95% CI: -0.370, -0.211). There was class III-suggestive evidence for negative psychotic symptoms (SMD = 0.393, 95% CI: 0.317, 0.469). There was either class IV-weak or no evidence for all other factors. Our findings suggest that despite the large number of putative risk factors investigated in the literature, only attenuated positive psychotic symptoms, global functioning, and negative psychotic symptoms show suggestive evidence or greater for association with transition to psychosis. The current findings may inform the refinement of clinical prediction models and precision medicine in this field.

Cannabidiol as a potential treatment for psychosis.

Psychotic disorders such as schizophrenia are heterogeneous and often debilitating conditions that contribute substantially to the global burden of disease. The introduction of dopamine D2 receptor antagonists in the 1950s revolutionised the treatment of psychotic disorders and they remain the mainstay of our treatment arsenal for psychosis. However, traditional antipsychotics are associated with a number of side effects and a significant proportion of patients do not achieve an adequate remission of symptoms. There is therefore a need for novel interventions, particularly those with a non-D2 antagonist mechanism of action. Cannabidiol (CBD), a non-intoxicating constituent of the cannabis plant, has emerged as a potential novel class of antipsychotic with a unique mechanism of action. In this review, we set out the prospects of CBD as a potential novel treatment for psychotic disorders. We first review the evidence from the perspective of preclinical work and human experimental and neuroimaging studies. We then synthesise the current evidence regarding the clinical efficacy of CBD in terms of positive, negative and cognitive symptoms, safety and tolerability, and potential mechanisms by which CBD may have antipsychotic effects.