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.

Biobehavioral Interactions between Endocannabinoid and Hypothalamicpituitary- adrenal Systems in Psychosis: A Systematic Review.

BACKGROUND: The diathesis-stress paradigm and the cannabinoid-hypothesis have been proposed as possible pathophysiological models of schizophrenia. However, they have historically been studied independently of each other. OBJECTIVE: This PRISMA 2020-compliant systematic review aimed at reappraising the interplay between the hypothalamic-pituitary-adrenal (HPA) axis and the endocannabinoid (eCB) system in psychosis- spectrum disorder risk and outcome. METHODS: All pathophysiological and outcome clinical studies, concomitantly evaluating the two systems in psychosis-spectrum disorder risk and different stages of illness, were gathered from electronic databases (Pubmed, Web of Science, and Scopus), and discussed. RESULTS: 41 eligible outputs were extracted, focusing on at least a biological measure (9 HPA-related studies: 4 eCB-interventional, 1 HPA-interventional, 1 both HPA-interventional and non-interventional, 3 non-interventional; 2 eCB-related studies: non-interventional), environmental measures only (29 studies: 1 eCB- interventional, 28 non-interventional), and genetic measures (1 study: non-interventional). Independent contributions of aberrancies in the two systems to the physiopathology and outcome of psychosis were confirmed. Also, concomitant alterations in the two systems, either genetically defined (e.g., CNR1 genetic variation), biologically determined (e.g., dysfunctional HPA axis or endocannabinoid signaling), or behaviorally imputed (e.g., cannabis use, stress exposure, and response), were consistently reported in psychosis. Further, a complex biobehavioral perturbation was revealed not only within each system (e.g., cannabis use affecting the eCB tone, stress exposure affecting the HPA axis), but also across the two systems (e.g., THC affecting the HPA axis, childhood trauma affecting the endocannabinoid signaling). CONCLUSION: There is a need to concomitantly study the two systems' mechanistic contribution to psychosis in order to establish more refined biological relevance.

Cognitive and executive impairments in Parkinson's disease psychosis: a Bayesian meta-analysis.

BACKGROUND: Cognitive and executive deficits lead to worsening of quality of life and are a risk factor for developing dementia in people with Parkinson's disease (PD) with psychosis (PDP). However, which key cognitive domains are differentially affected in PDP compared with those without (PDnP), remains unclear. Here, we examined this using a Bayesian meta-analytical approach. METHODS: Searches were conducted on PubMed, Web of Science, SCOPUS, Medline and PsycINFO. Hedges' g effect-size estimates were extracted from eligible studies as a measure of standard mean differences between PDP and PDnP participants. Meta-analyses were conducted separately for each cognitive domain and subdomain, we examined the effect of age, PD medications, PD duration and severity, depression and psychosis severity for all major domains with meta-regressions. RESULTS: Effect-size estimates suggest worse performance on all major domains (k=105 studies) in PDP compared with PDnP participants, with global cognition (k=103 studies, g=-0.57), processing speed (k=29 studies, g=-0.58), executive functions (k=33, g=-0.56), episodic memory (k=30 studies, g=-0.58) and perception (k=34 studies, g=-0.55) as the most likely affected domains. Age, depression and PD duration had moderating effects on task-related performance across most of the major nine domains. CONCLUSIONS: We report extensive deficits across nine domains as well as subdomains in PD psychosis, with global cognition, processing speed and executive functions as the most likely impaired. The presence of depression may influence task-related performance in PDP, alongside age and PD duration, but not dose of dopamine replacement treatments.

A systematic evidence map of the association between cannabis use and psychosis-related outcomes across the psychosis continuum: An umbrella review of systematic reviews and meta-analyses.

While the legal status and public perception of cannabis are currently changing in many countries, one of the important considerations from a public health viewpoint is its potential association with adverse health outcomes such as the development of psychosis. We conducted an umbrella review of systematic reviews and meta-analyses using the AMSTAR-2 to assess the quality of included reviews. We further created an evidence map to visualize and facilitate the overview of the published evidence synthesis on the association between cannabis use and all psychosis-related outcomes and risk moderators in healthy, high-risk, and clinical populations. Overall, we found 32 systematic reviews and meta-analyses. Based on a synthesis of current evidence, cannabis use is associated with subclinical psychosis states (psychotic-like experiences) and traits (schizotypal personality) in the healthy population, as well as earlier onset and development of psychosis. An association with the clinical-high-risk state for psychosis, attenuated psychosis symptoms and transition to psychosis in this population could not be confirmed. An association between cannabis use and psychosis outcomes in patients with psychotic disorder could solely be confirmed regarding relapse. Whether causal effects underlie those associations has not sufficiently been addressed in the evidence synthesis to date.

Risk of psychosis in autism spectrum disorder individuals exposed to psychosocial stressors: A 9-year chart review study.

Psychosocial stressors have been suggested to precipitate psychotic episodes in patients with pre-existing psychosis and otherwise healthy subjects. However, such a risk has never been formally investigated in individuals with autism spectrum disorder (ASD). Sixty-nine autistic adolescents hospitalized for psychotic/manic symptoms (PSY) and other mental health issues (NPSY) over a 9-year period were compared with reference to their previous exposure to psychosocial stressors. ASD diagnoses satisfied the International Classification of Diseases (ICD)-10 criteria. Psychotic/manic symptom assessment followed the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS). Psychosocial stressor exposure was collected separately at each admission. Preliminarily, univariate between-group comparisons were conducted. Then, a binomial model was adopted to investigate associations with previous exposure to psychosocial stressors. Results were reported with a change in AIC (ΔAIC). PSY patients presented with higher previous exposure to adverse life events (30.43% vs. 6.52%, OR = 6.079 [1.209, 40.926], p = 0.013) and school/work difficulties (30.43% vs. 8.70%, OR = 4.478 [0.984, 23.846], p = 0.034) than NPSY ones. Admissions for psychotic/manic symptoms occurred more likely in the context of family disturbances (OR = 2.275 [1.045, 5.045], p = 0.030) and adverse life events (OR = 3.489 [1.194, 11.161], p = 0.014). The fitted binomial model was found to be significant compared to the random effects model (ΔAIC = -1.962; χ2 10 = 21.96, p = 0.015), with the risk of presenting psychotic/manic symptoms being increased by family disturbances (z = +4.118) and school/work difficulties (z = +2.455). The results suggest a potential psychosis-inducing effect of psychosocial stressors in ASD, which has clinical and policy implications.

Questioning the role of palmitoylethanolamide in psychosis: a systematic review of clinical and preclinical evidence.

Introduction: The endocannabinoid (eCB) system disruption has been suggested to underpin the development of psychosis, fueling the search for novel, better-tolerated antipsychotic agents that target the eCB system. Among these, palmitoylethanolamide (PEA), an N-acylethanolamine (AE) with neuroprotective, anti-inflammatory, and analgesic properties, has drawn attention for its antipsychotic potential. Methods: This Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020-compliant systematic review aimed at reappraising all clinical and preclinical studies investigating the biobehavioral role of PEA in psychosis. Results: Overall, 13 studies were eligible for data extraction (11 human, 2 animal). Observational studies investigating PEA tone in psychosis patients converged on the evidence for increased PEA plasma (6 human) and central nervous system (CNS; 1 human) levels, as a potential early compensatory response to illness and its severity, that seems to be lost in the longer-term (CNS; 1 human), opening to the possibility of exogenously supplementing it to sustain control of the disorder. Consistently, PEA oral supplementation reduced negative psychotic and manic symptoms among psychosis patients, with no serious adverse events (3 human). No PEA changes emerged in either preclinical psychosis model (2 animal) studied. Discussion: Evidence supports PEA signaling as a potential psychosis biomarker, also indicating a therapeutic role of its supplementation in the disorder. Systematic review registration: https://doi.org/10.17605/OSF.IO/AFMTK.

Stressful life events and relapse of psychosis: analysis of causal association in a 2-year prospective observational cohort of individuals with first-episode psychosis in the UK.

BACKGROUND: Despite accumulating evidence of an association between stressful life events and psychosis relapse, the extent to which this is a causal relationship remains unclear. We aimed to examine the association between exposure to, and number of, stressful life events after initial psychosis onset and psychosis relapse. METHODS: In this 2-year prospective observational study, we recruited individuals with first-episode psychosis, aged 18-65 years, who presented to psychiatric services in south London, UK. Participants were assessed via interview, with additional data obtained from electronic clinical records. Stressful life events were recorded at psychosis onset and during the 2-year follow-up using a brief questionnaire that assesses 12 major life events. Psychosis relapse was defined as inpatient admission because of symptom exacerbation within 2 years from psychosis onset. We examined the time to first psychosis relapse and the number and length of relapses using survival and binomial regression analyses. We used fixed-effects regression and cross-lagged path analysis to examine the directionality of effects and control for unmeasured confounders. FINDINGS: Between April 12, 2002, and July 26, 2013, 256 individuals with first-episode psychosis (100 [39%] female and 156 [61%] male; 16 [6%] Asian, 140 [55%] Black African or Caribbean, 86 [34%] White, and 14 [6%] mixed ethnicity) were recruited, with a mean age of onset of psychosis of 28·06 years (SD 8·03; range 17·21-56·03). 93 (36%) participants experienced at least one relapse during the 2-year follow-up. 253 individuals had all relevant data and were included in analyses. For people exposed to stressful life events after the onset of psychosis, the adjusted hazard (hazard ratio [HR] 2·60, 95% CI 1·63-4·16, p<0·0001), incidence (incidence rate ratio [IRR] 1·87, 1·24-2·80, p=0·0026), and length (IRR 2·53, 1·40-4·67, p=0·0011) of relapse were greater than for those who were unexposed. These relationships were dose dependent (HR 1·36; 1·09-1·69, p=0·0054; incidence IRR 1·26, 1·02-1·53, p=0·023; length IRR 1·52, 1·12-2·12, p=0·0028). Adjusted fixed-effects models showed a higher (odds ratio [OR] 3·82, 1·82-8·00, p=0·0004) and dose-dependent (OR 1·62, 1·18-2·21, p=0·0028) risk of relapse when stressful life events preceded relapse compared with the period when they did not. Cross-lagged path analysis confirmed an effect of stressful life events on the number of subsequent relapses (ß=0·66, p=0·0055) that was dose dependent (ß=0·29, p=0·029), but it did not show an effect of relapses on subsequent risk or number of stressful life events. INTERPRETATION: These results provide converging evidence of a causal effect of stressful life events on the risk of relapse in psychosis. They suggest that there is a need to develop interventions at the individual and health-service level that could mitigate the harmful effects of stressful life events. FUNDING: National Institute for Health Research, UK.

Grey matter volume loss in Parkinson's disease psychosis and its relationship with serotonergic gene expression: A meta-analysis.

BACKGROUND: Neuroanatomical alterations underlying psychosis in Parkinson's Disease (PDP) remain unclear. We carried out a meta-analysis of MRI studies investigating the neural correlates of PDP and examined its relation with dopaminergic and serotonergic receptor gene expression. METHODS: PubMed, Web of Science and Embase were searched for MRI studies (k studies = 10) of PDP compared to PD patients without psychosis (PDnP). Seed-based d Mapping with Permutation of Subject Images and multiple linear regression analyses was used to examine the relationship between pooled estimates of grey matter volume (GMV) loss in PDP and D1/D2 and 5-HT1a/5-HT2a receptor gene expression estimates from Allen Human Brain Atlas. RESULTS: We observed lower grey matter volume in parietal-temporo-occipital regions (PDP n = 211, PDnP, n = 298). GMV loss in PDP was associated with local expression of 5-HT1a (b = 0.109, p = 0.012) and 5-HT2a receptors (b= -0.106, p = 0.002) but not dopaminergic receptors. CONCLUSION: Widespread GMV loss in the parieto-temporo-occipital regions may underlie PDP. Association between grey matter volume and local expression of serotonergic receptor genes may suggest a role for serotonergic receptors in PDP.

Cannabidiol attenuates insular activity during motivational salience processing in patients with early psychosis.

BACKGROUND: The mechanisms underlying the antipsychotic potential of cannabidiol (CBD) remain unclear but growing evidence indicates that dysfunction in the insula, a key brain region involved in the processing of motivationally salient stimuli, may have a role in the pathophysiology of psychosis. Here, we investigate whether the antipsychotic mechanisms of CBD are underpinned by their effects on insular activation, known to be involved in salience processing. METHODS: A within-subject, crossover, double-blind, placebo-controlled investigation of 19 healthy controls and 15 participants with early psychosis was conducted. Administration of a single dose of CBD was compared with placebo in psychosis participants while performing the monetary incentive delay task, an fMRI paradigm. Anticipation of reward and loss were used to contrast motivationally salient stimuli against a neutral control condition. RESULTS: No group differences in brain activation between psychosis patients compared with healthy controls were observed. Attenuation of insula activation was observed following CBD, compared to placebo. Sensitivity analyses controlling for current cannabis use history did not affect the main results. CONCLUSION: Our findings are in accordance with existing evidence suggesting that CBD modulates brain regions involved in salience processing. Whether such effects underlie the putative antipsychotic effects of CBD remains to be investigated.

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.

Attenuated transcriptional response to pro-inflammatory cytokines in schizophrenia hiPSC-derived neural progenitor cells.

Maternal immune activation (MIA) during prenatal development is an environmental risk factor for psychiatric disorders including schizophrenia (SZ). Converging lines of evidence from human and animal model studies suggest that elevated cytokine levels in the maternal and fetal compartments are an important indication of the mechanisms driving this association. However, there is variability in susceptibility to the psychiatric risk conferred by MIA, likely influenced by genetic factors. How MIA interacts with a genetic profile susceptible to SZ is challenging to test in animal models. To address this gap, we examined whether differential gene expression responses occur in forebrain-lineage neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (hiPSC) generated from three individuals with a diagnosis of schizophrenia and three healthy controls. Following acute (24 h) treatment with either interferon-gamma (IFNγ; 25 ng/µl) or interleukin (IL)-1ß (10 ng/µl), we identified, by RNA sequencing, 3380 differentially expressed genes (DEGs) in the IFNγ-treated control lines (compared to untreated controls), and 1980 DEGs in IFNγ-treated SZ lines (compared to untreated SZ lines). Out of 4137 genes that responded significantly to IFNγ across all lines, 1223 were common to both SZ and control lines. The 2914 genes that appeared to respond differentially to IFNγ treatment in SZ lines were subjected to a further test of significance (multiple testing correction applied to the interaction effect between IFNγ treatment and SZ diagnosis), yielding 359 genes that passed the significance threshold. There were no differentially expressed genes in the IL-1ß-treatment conditions after Benjamini-Hochberg correction. Gene set enrichment analysis however showed that IL-1ß impacts immune function and neuronal differentiation. Overall, our data suggest that a) SZ NPCs show an attenuated transcriptional response to IFNγ treatment compared to controls; b) Due to low IL-1ß receptor expression in NPCs, NPC cultures appear to be less responsive to IL-1ß than IFNγ; and c) the genes differentially regulated in SZ lines - in the face of a cytokine challenge - are primarily associated with mitochondrial, "loss-of-function", pre- and post-synaptic gene sets. Our findings particularly highlight the role of early synaptic development in the association between maternal immune activation and schizophrenia risk.

The Autism-Psychosis Continuum Conundrum: Exploring the Role of the Endocannabinoid System.

Evidence indicates shared physiopathological mechanisms between autism and psychosis. In this regard, the endocannabinoid system has been suggested to modulate neural circuits during the early stage of neurodevelopment, with implications for both autism and psychosis. Nevertheless, such potential common markers of disease have been investigated in both autism and psychosis spectrum disorders, without considering the conundrum of differentiating the two groups of conditions in terms of diagnosis and treatment. Here, we systematically review all human and animal studies examining the endocannabinoid system and its biobehavioral correlates in the association between autism and psychosis. Studies indicate overlapping biobehavioral aberrancies between autism and schizophrenia, subject to correction by modulation of the endocannabinoid system. In addition, common cannabinoid-based pharmacological strategies have been identified, exerting epigenetic effects across genes controlling neural mechanisms shared between autism and schizophrenia. Interestingly, a developmental and transgenerational trajectory between autism and schizophrenia is supported by evidence that exogenous alteration of the endocannabinoid system promotes progression to inheritable psychosis phenotypes in the context of biobehavioral autism vulnerability. However, evidence for a diametral association between autism and psychosis is scant. Several clinical implications follow from evidence of a developmental continuum between autism and psychosis as a function of the endocannabinoid system dysregulation.

Is It Time to Test the Antiseizure Potential of Palmitoylethanolamide in Human Studies? A Systematic Review of Preclinical Evidence.

Antiseizure medications are the cornerstone pharmacotherapy for epilepsy. They are not devoid of side effects. In search for better-tolerated antiseizure agents, cannabinoid compounds and other N-acylethanolamines not directly binding cannabinoid receptors have drawn significant attention. Among these, palmitoylethanolamide (PEA) has shown neuroprotective, anti-inflammatory, and analgesic properties. All studies examining PEA's role in epilepsy and acute seizures were systematically reviewed. Preclinical studies indicated a systematically reduced PEA tone accompanied by alterations of endocannabinoid levels. PEA supplementation reduced seizure frequency and severity in animal models of epilepsy and acute seizures, in some cases, similarly to available antiseizure medications but with a better safety profile. The peripheral-brain immune system seemed to be more effectively modulated by subchronic pretreatment with PEA, with positive consequences in terms of better responding to subsequent epileptogenic insults. PEA treatment restored the endocannabinoid level changes that occur in a seizure episode, with potential preventive implications in terms of neural damage. Neurobiological mechanisms for PEA antiseizure effect seemed to include the activation of the endocannabinoid system and the modulation of neuroinflammation and excitotoxicity. Although no human study was identified, there is ground for testing the antiseizure potential of PEA and its safety profile in human studies of epilepsy.

Cannabinoids in psychiatry: they are here to stay.

Cannabinoids are commonly perceived by the public as safe and effective for improving mental health, despite limited evidence to support their use. We discuss reasons why cannabinoids may be particularly compelling for our patients and provide strategies for how psychiatrists can counsel and educate patients on the evidence regarding cannabinoids.

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.

Cannabinoids, reward processing, and psychosis.

BACKGROUND: Evidence suggests that an overlap exists between the neurobiology of psychotic disorders and the effects of cannabinoids on neurocognitive and neurochemical substrates involved in reward processing. AIMS: We investigate whether the psychotomimetic effects of delta-9-tetrahydrocannabinol (THC) and the antipsychotic potential of cannabidiol (CBD) are underpinned by their effects on the reward system and dopamine. METHODS: This narrative review focuses on the overlap between altered dopamine signalling and reward processing induced by cannabinoids, pre-clinically and in humans. A systematic search was conducted of acute cannabinoid drug-challenge studies using neuroimaging in healthy subjects and those with psychosis RESULTS: There is evidence of increased striatal presynaptic dopamine synthesis and release in psychosis, as well as abnormal engagement of the striatum during reward processing. Although, acute THC challenges have elicited a modest effect on striatal dopamine, cannabis users generally indicate impaired presynaptic dopaminergic function. Functional MRI studies have identified that a single dose of THC may modulate regions involved in reward and salience processing such as the striatum, midbrain, insular, and anterior cingulate, with some effects correlating with the severity of THC-induced psychotic symptoms. CBD may modulate brain regions involved in reward/salience processing in an opposite direction to that of THC. CONCLUSIONS: There is evidence to suggest modulation of reward processing and its neural substrates by THC and CBD. Whether such effects underlie the psychotomimetic/antipsychotic effects of these cannabinoids remains unclear. Future research should address these unanswered questions to understand the relationship between endocannabinoid dysfunction, reward processing abnormalities, and psychosis.