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Background: Evidence has been accumulating regarding alterations in components of the endocannabinoid system in patients with psychosis. Of all the putative risk factors associated with psychosis, being at clinical high-risk for psychosis (CHR) has the strongest association with the onset of psychosis, and exposure to childhood trauma has been linked to an increased risk of development of psychotic disorder. We aimed to investigate whether being at-risk for psychosis and exposure to childhood trauma were associated with altered endocannabinoid levels. Method: We compared 33 CHR participants with 58 healthy controls (HC) and collected information about previous exposure to childhood trauma as well as plasma samples to analyse endocannabinoid levels. Results: Individuals with both CHR and experience of childhood trauma had higher N-palmitoylethanolamine (p < 0.001) and anandamide (p < 0.001) levels in peripheral blood compared to HC and those with no childhood trauma. There was also a significant correlation between N-palmitoylethanolamine levels and symptoms as well as childhood trauma. Conclusions: Our results suggest an association between CHR and/or childhood maltreatment and elevated endocannabinoid levels in peripheral blood, with a greater alteration in those with both CHR status and history of childhood maltreatment compared to those with either of those risks alone. Furthermore, endocannabinoid levels increased linearly with the number of risk factors and elevated endocannabinoid levels correlated with the severity of CHR symptoms and extent of childhood maltreatment. Further studies in larger cohorts, employing longitudinal designs are needed to confirm these findings and delineate the precise role of endocannabinoid alterations in the pathophysiology of psychosis. [ABSTRACT FROM AUTHOR]

Background: A range of endophenotypes characterise psychosis, however there has been limited work understanding if and how they are inter-related. Methods: This multi-centre study includes 8754 participants: 2212 people with a psychotic disorder, 1487 unaffected relatives of probands, and 5055 healthy controls. We investigated cognition [digit span (N = 3127), block design (N = 5491), and the Rey Auditory Verbal Learning Test (N = 3543)], electrophysiology [P300 amplitude and latency (N = 1102)], and neuroanatomy [lateral ventricular volume (N = 1721)]. We used linear regression to assess the interrelationships between endophenotypes. Results: The P300 amplitude and latency were not associated (regression coef. −0.06, 95% CI −0.12 to 0.01, p = 0.060), and P300 amplitude was positively associated with block design (coef. 0.19, 95% CI 0.10–0.28, p < 0.001). There was no evidence of associations between lateral ventricular volume and the other measures (all p > 0.38). All the cognitive endophenotypes were associated with each other in the expected directions (all p < 0.001). Lastly, the relationships between pairs of endophenotypes were consistent in all three participant groups, differing for some of the cognitive pairings only in the strengths of the relationships. Conclusions: The P300 amplitude and latency are independent endophenotypes; the former indexing spatial visualisation and working memory, and the latter is hypothesised to index basic processing speed. Individuals with psychotic illnesses, their unaffected relatives, and healthy controls all show similar patterns of associations between endophenotypes, endorsing the theory of a continuum of psychosis liability across the population. [ABSTRACT FROM AUTHOR]

Background: Recent evidence suggests that cannabidiol (CBD), a non-intoxicating ingredient present in cannabis extract, has an antipsychotic effect in people with established psychosis. However, the effect of CBD on the neurocognitive mechanisms underlying psychosis is unknown., Methods: Patients with established psychosis on standard antipsychotic treatment were studied on separate days at least one week apart, to investigate the effects of a single dose of orally administered CBD (600 mg) compared to a matched placebo (PLB), using a double-blind, randomized, PLB-controlled, repeated-measures, within-subject cross-over design. Three hours after taking the study drug participants were scanned using a block design functional magnetic resonance imaging (fMRI) paradigm, while performing a verbal paired associate learning task. Fifteen psychosis patients completed both study days, 13 completed both scanning sessions. Nineteen healthy controls (HC) were also scanned using the same fMRI paradigm under identical conditions, but without any drug administration. Effects of CBD on brain activation measured using the blood oxygen level-dependent hemodynamic response fMRI signal were studied in the mediotemporal, prefrontal, and striatal regions of interest., Results: Compared to HC, psychosis patients under PLB had altered prefrontal activation during verbal encoding, as well as altered mediotemporal and prefrontal activation and greater mediotemporal-striatal functional connectivity during verbal recall. CBD attenuated dysfunction in these regions such that activation under its influence was intermediate between the PLB condition and HC. CBD also attenuated hippocampal-striatal functional connectivity and caused trend-level symptom reduction in psychosis patients., Conclusions: This suggests that normalization of mediotemporal and prefrontal dysfunction and mediotemporal-striatal functional connectivity may underlie the antipsychotic effects of CBD.

Background: Cannabis use has been associated with psychosis through exposure to delta-9-tetrahydrocannabinol (Δ9-THC), its key psychoactive ingredient. Although preclinical and human evidence suggests that Δ9-THC acutely modulates glial function and hypothalamic-pituitary-adrenal (HPA) axis activity, whether differential sensitivity to the acute psychotomimetic effects of Δ9-THC is associated with differential effects of Δ9-THC on glial function and HPA-axis response has never been tested., Methods: A double-blind, randomized, placebo-controlled, crossover study investigated whether sensitivity to the psychotomimetic effects of Δ9-THC moderates the acute effects of a single Δ9-THC dose (1.19 mg/2 ml) on myo-inositol levels, a surrogate marker of glia, in the Anterior Cingulate Cortex (ACC), and circadian cortisol levels, the key neuroendocrine marker of the HPA-axis, in a set of 16 healthy participants (seven males) with modest previous cannabis exposure., Results: The Δ9-THC-induced change in ACC myo-inositol levels differed significantly between those sensitive to (Δ9-THC minus placebo; M = -0.251, s.d. = 1.242) and those not sensitive (M = 1.615, s.d. = 1.753) to the psychotomimetic effects of the drug (t(14) = 2.459, p = 0.028). Further, the Δ9-THC-induced change in cortisol levels over the study period (baseline minus 2.5 h post-drug injection) differed significantly between those sensitive to (Δ9-THC minus placebo; M = -275.4, s.d. = 207.519) and those not sensitive (M = 74.2, s.d. = 209.281) to the psychotomimetic effects of the drug (t(13) = 3.068, p = 0.009). Specifically, Δ9-THC exposure lowered ACC myo-inositol levels and disrupted the physiological diurnal cortisol decrease only in those subjects developing transient psychosis-like symptoms., Conclusions: The interindividual differences in transient psychosis-like effects of Δ9-THC are the result of its differential impact on glial function and stress response.

Background: Previous studies have provided initial evidence that people at risk for psychosis (PR) suffer from stigma and discrimination related to their condition. However, no study has systematically reviewed stigma and discrimination associated with being at PR and the potential underlying mechanisms., Methods: This work aimed to systematically review all studies addressing stigma and discrimination in PR people in order to assess: (1) the occurrence of this phenomenon and its different components (public, internalized, perceived, and labeling-related), (2) whether stigma affects outcomes of the PR state, and (3) whether other factors modulate stigma among PR individuals., Results: The reviewed studies (n = 38) widely differ in their design, methodological quality, and populations under investigation, thus limiting direct comparison of findings. However, converging evidence suggests that the general public endorses stigmatizing attitudes towards PR individuals, and that this is more frequent in people with a low educational level or with no direct experience of the PR state. PR individuals experience more internalized stigma and perceive more discrimination than healthy subjects or patients with non-psychotic disorders. Further, PR labeling is equally associated with both positive (e.g. validation and relief) and negative effects (e.g. status loss and discrimination). Moreover, stigma increases the likelihood of poor outcome, transition to full-psychosis, disengagement from services, and family stigma among PR individuals. Finally, very limited evidence awaiting replication supports the efficacy of cognitive therapies in mitigating the negative effects of stigma., Conclusions: Evidence confirms previous concerns about stigma and its negative consequences for PR individuals, thus having important public health implications.

Background: Jumping to conclusions (JTC), which is the proneness to require less information before forming beliefs or making a decision, has been related to formation and maintenance of delusions. Using data from the National Institute of Health Research Biomedical Research Centre Genetics and Psychosis (GAP) case-control study of first-episode psychosis (FEP), we set out to test whether the presence of JTC would predict poor clinical outcome at 4 years., Methods: One-hundred and twenty-three FEP patients were assessed with the Positive and Negative Syndrome Scale (PANSS), Global Assessment of Functioning (GAF) and the probabilistic reasoning 'Beads' Task at the time of recruitment. The sample was split into two groups based on the presence of JTC bias. Follow-up data over an average of 4 years were obtained concerning clinical course and outcomes (remission, intervention of police, use of involuntary treatment - the Mental Health Act (MHA) - and inpatient days)., Results: FEP who presented JTC at baseline were more likely during the follow-up period to be detained under the MHA [adjusted OR 15.62, 95% confidence interval (CI) 2.92-83.54, p = 0.001], require intervention by the police (adjusted OR 14.95, 95% CI 2.68-83.34, p = 0.002) and have longer admissions (adjusted IRR = 5.03, 95% CI 1.91-13.24, p = 0.001). These associations were not accounted for by socio-demographic variables, IQ and symptom dimensions., Conclusions: JTC in FEP is associated with poorer outcome as indicated and defined by more compulsion police intervention and longer periods of admission. Our findings raise the question of whether the implementation of specific interventions to reduce JTC, such as Metacognition Training, may be a useful addition in early psychosis intervention programmes.

Background: A range of endophenotypes characterise psychosis, however there has been limited work understanding if and how they are inter-related., Methods: This multi-centre study includes 8754 participants: 2212 people with a psychotic disorder, 1487 unaffected relatives of probands, and 5055 healthy controls. We investigated cognition [digit span (N = 3127), block design (N = 5491), and the Rey Auditory Verbal Learning Test (N = 3543)], electrophysiology [P300 amplitude and latency (N = 1102)], and neuroanatomy [lateral ventricular volume (N = 1721)]. We used linear regression to assess the interrelationships between endophenotypes., Results: The P300 amplitude and latency were not associated (regression coef. -0.06, 95% CI -0.12 to 0.01, p = 0.060), and P300 amplitude was positively associated with block design (coef. 0.19, 95% CI 0.10-0.28, p 0.38). All the cognitive endophenotypes were associated with each other in the expected directions (all p < 0.001). Lastly, the relationships between pairs of endophenotypes were consistent in all three participant groups, differing for some of the cognitive pairings only in the strengths of the relationships., Conclusions: The P300 amplitude and latency are independent endophenotypes; the former indexing spatial visualisation and working memory, and the latter is hypothesised to index basic processing speed. Individuals with psychotic illnesses, their unaffected relatives, and healthy controls all show similar patterns of associations between endophenotypes, endorsing the theory of a continuum of psychosis liability across the population.