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.

Why we need to pursue both universal and targeted prevention to reduce the incidence of affective and psychotic disorders: Systematic review and meta-analysis.

The effectiveness of universal preventive approaches in reducing the incidence of affective/psychotic disorders is unclear. We therefore aimed to synthesise the available evidence from randomised controlled trials. For studies reporting change in prevalence, we simulated all possible scenarios for the proportion of individuals with the disorder at baseline and at follow-up to exclude them. We then combined these data with studies directly measuring incidence and conducted random effects meta-analysis with relative risk (RR) to estimate the incidence in the intervention group compared to the control group. Eighteen studies (k=21 samples) were included investigating the universal prevention of depression in 66,625 individuals. No studies were available investigating universal prevention on the incidence of bipolar/psychotic disorders. 63 % of simulated scenarios showed a significant preventive effect on reducing the incidence of depression (k=9 - 19, RR=0.75-0.94, 95 %CIs=0.55-0.87,0.93-1.15, p=0.007-0.246) but did not survive sensitivity analyses. There is some limited evidence for the effectiveness of universal interventions for reducing the incidence of depression but not for bipolar/psychotic disorders.

Assessing Cannabis Use in People with Psychosis.

Introduction: Cannabis use is common in people with psychotic disorders and is associated with the exacerbation of symptoms, poor treatment adherence, and an increased risk of relapse. Accurate assessment of cannabis use is thus critical to the clinical management of psychosis. Discussion: Cannabis use is usually assessed with self-report questionnaires that were originally developed for healthy individuals or people with a cannabis use disorder. Compared to these groups, the pattern of cannabis use and the associated harms in patients with psychosis are quite different. Moreover, in people with psychosis, the accuracy of self-reported use may be impaired by psychotic symptoms, cognitive deficits, and a desire to conceal use when clinicians have advised against it. Although urinary screening for delta-9-tetrahydrocannabinol is sometimes used in the assessment of acute psychotic episodes, it is not used in routinely. Cannabis use could be assessed by measuring the concentration of cannabinoids in urine and blood, but this is rarely done in either clinical settings or research. Conclusion: Using quantitative biological measures could provide a more accurate guide to the effects of use on the disorder than asking patients or using questionnaires.

Cannabidiol does not attenuate acute delta-9-tetrahydrocannabinol-induced attentional bias in healthy volunteers: A randomised, double-blind, cross-over study.

AIMS: To test how attentional bias and explicit liking are influenced by delta-9-tetrahydrocannabinol (THC) and whether these effects are moderated by cannabidiol (CBD). DESIGN: Double-blind, randomised, within-subjects cross-over study. SETTING: NIHR Wellcome Trust Clinical Research Facility at King's College Hospital, London, United Kingdom. PARTICIPANTS/CASES: Forty-six infrequent cannabis users (cannabis use <1 per week). INTERVENTION(S): Across four sessions, participants inhaled vaporised cannabis containing 10 mg of THC and either 0 mg (0:1 CBD:THC), 10 mg (1:1), 20 mg (2:1) or 30 mg (3:1) of CBD, administered in a randomised order and counter-balanced across participants (a total of 24 order groups). MEASUREMENTS: Participants completed two tasks: (1) Attentional Bias (AB), comparing reaction times toward visual probes presented behind 28 target stimuli (cannabis/food) compared with probes behind corresponding non-target (neutral) stimuli. Participants responding more quickly to probes behind target than non-target stimuli would indicate greater attentional bias to cannabis/food; (2) Picture Rating (PR), where all AB stimuli were rated on a 7-point pleasantness scale, measuring explicit liking. FINDINGS: During the AB task, participants were more biased toward cannabis stimuli in the 0:1 condition compared with baseline (mean difference = 12.2, 95% confidence intervals [CIs] = 1.20-23.3, d = 0.41, P = 0.03). No other significant AB or PR differences were found between cannabis and food stimuli between baseline and 0:1 condition (P > 0.05). No significant CBD effect was found on AB or PR task performance at any dose (P > 0.05). There was additionally no cumulative effect of THC exposure on AB or PR outcomes (P > 0.05). CONCLUSIONS: A double-blind, randomised, cross-over study among infrequent cannabis users found that inhaled delta-9-tetrahydrocannabinol increased attentional bias toward cannabis in the absence of explicit liking, a marker of liability toward cannabis use disorder. At the concentrations normally found in legal and illegal cannabis, cannabidiol had no influence on this effect.

Life expectancy, mortality risks and cause of death in patients with serious mental illness in South East London: a comparison between 2008-2012 and 2013-2017.

BACKGROUND: People with serious mental illness (SMI) have a significantly shorter life expectancy than the general population. This study investigates whether the mortality rate in this group has changed over the last decade. METHODS: Using Clinical Record Interactive Search software, we extracted data from a large electronic database of patients in South East London. All patients with schizophrenia, schizoaffective disorder or bipolar disorder from 2008 to 2012 and/or 2013 to 2017 were included. Estimates of life expectancy at birth, standardised mortality ratios and causes of death were obtained for each cohort according to diagnosis and gender. Comparisons were made between cohorts and with the general population using data obtained from the UK Office of National Statistics. RESULTS: In total, 26 005 patients were included. In men, life expectancy was greater in 2013-2017 (64.9 years; 95% CI 63.6-66.3) than in 2008-2012 (63.2 years; 95% CI 61.5-64.9). Similarly, in women, life expectancy was greater in 2013-2017 (69.1 years; 95% CI 67.5-70.7) than in 2008-2012 (68.1 years; 95% CI 66.2-69.9). The difference with general population life expectancy fell by 0.9 years between cohorts in men, and 0.5 years in women. In the 2013-2017 cohorts, cancer accounted for a similar proportion of deaths as cardiovascular disease. CONCLUSIONS: Relative to the general population, life expectancy for people with SMI is still much worse, though it appears to be improving. The increased cancer-related mortality suggests that physical health monitoring should consider including cancer as well.

Point of care assay for blood aripiprazole concentrations: development, validation and utility.

BACKGROUND: The antipsychotic aripiprazole is often used in the treatment of first-episode psychosis. Measuring aripiprazole blood levels provides an objective measure of treatment adherence, but this currently involves taking a venous blood sample and sending to a laboratory for analysis. AIMS: To detail the development, validation and utility of a new point of care (POC) test for finger-stick capillary blood concentrations of aripiprazole. METHOD: Analytical performance (sensitivity, precision, recovery and linearity) of the assay were established using spiked whole blood and control samples of varying aripiprazole concentration. Assay validation was performed over a 14-month period starting in July 2021. Eligible patients were asked to provide a finger-stick capillary sample in addition to their usual venous blood sample. Capillary blood samples were tested by the MyCare™ Insite POC analyser, which provided measurement of aripiprazole concentration in 6 min, and the venous blood sample was tested by the standard laboratory method. RESULTS: A total of 101 patients agreed to measurements by the two methods. Venous blood aripiprazole concentrations as assessed by the laboratory method ranged from 17 to 909 ng/mL, and from 1 to 791 ng/mL using POC testing. The correlation coefficient between the two methods (r) was 0.96 and there was minimal bias (slope 0.91, intercept 4 ng/ml). CONCLUSIONS: The MyCare Insite POC analyser is sufficiently accurate and reliable for clinical use. The availability of this technology will improve the assessment of adherence to aripiprazole and the optimising of aripiprazole dosing.

Influence of cannabis use on incidence of psychosis in people at clinical high risk.

AIMS: Evidence for case-control studies suggests that cannabis use is a risk factor for the development of psychosis. However, there have been limited prospective studies and the direction of this association remains controversial. The primary aim of the present study was to examine the association between cannabis use and the incidence of psychotic disorders in people at clinical high risk of psychosis. Secondary aims were to assess associations between cannabis use and the persistence of psychotic symptoms, and with functional outcome. METHODS: Current and previous cannabis use were assessed in individuals at clinical high risk of psychosis (n = 334) and healthy controls (n = 67), using a modified version of the Cannabis Experience Questionnaire. Participants were assessed at baseline and followed up for 2 years. Transition to psychosis and persistence of psychotic symptoms were assessed using the Comprehensive Assessment of At-Risk Mental States criteria. Level of functioning at follow up was assessed using the Global Assessment of Functioning disability scale. RESULTS: During follow up, 16.2% of the clinical high-risk sample developed psychosis. Of those who did not become psychotic, 51.4% had persistent symptoms and 48.6% were in remission. There was no significant association between any measure of cannabis use at baseline and either transition to psychosis, the persistence of symptoms, or functional outcome. CONCLUSIONS: These findings contrast with epidemiological data that suggest that cannabis use increases the risk of psychotic disorder.

The acute effects of cannabis with and without cannabidiol in adults and adolescents: A randomised, double-blind, placebo-controlled, crossover experiment.

BACKGROUND AND AIMS: Long-term harms of cannabis may be exacerbated in adolescence, but little is known about the acute effects of cannabis in adolescents. We aimed to (i) compare the acute effects of cannabis in adolescent and adult cannabis users and (ii) determine if cannabidiol (CBD) acutely modulates the effects of delta-9-tetrahydocannabinol (THC). DESIGN: Randomised, double-blind, placebo-controlled, crossover experiment. The experiment was registered on ClinicalTrials.gov (NCT04851392). SETTING: Laboratory in London, United Kingdom. PARTICIPANTS: Twenty-four adolescents (12 women, 16- to 17-year-olds) and 24 adults (12 women, 26- to 29-year-olds) who used cannabis 0.5-3 days/week and were matched on cannabis use frequency (mean = 1.5 days/week). INTERVENTION: We administered three weight-adjusted vaporised cannabis flower preparations: 'THC' (8 mg THC for 75 kg person); 'THC + CBD' (8 mg THC and 24 mg CBD for 75 kg person); and 'PLA' (matched placebo). MEASUREMENTS: Primary outcomes were (i) subjective 'feel drug effect'; (ii) verbal episodic memory (delayed prose recall); and (iii) psychotomimetic effect (Psychotomimetic States Inventory). FINDINGS: Compared with 'PLA', 'THC' and 'THC + CBD' significantly (P < 0.001) increased 'feel drug effect' (mean difference [MD] = 6.3, 95% CI = 5.3-7.2; MD = 6.8, 95% CI = 6.0-7.7), impaired verbal episodic memory (MD = -2.7, 95% CI = -4.1 to -1.4; MD = -2.9, 95% CI = -4.1 to -1.7) and increased psychotomimetic effects (MD = 7.8, 95% CI = 2.8-12.7; MD = 10.8, 95% CI = 6.2-15.4). There was no evidence that adolescents differed from adults in their responses to cannabis (interaction P ≥ 0.4). Bayesian analyses supported equivalent effects of cannabis in adolescents and adults (Bayes factor [BF01 ] >3). There was no evidence that CBD significantly modulated the acute effects of THC. CONCLUSIONS: Adolescent cannabis users are neither more resilient nor more vulnerable than adult cannabis users to the acute psychotomimetic, verbal memory-impairing or subjective effects of cannabis. Furthermore, in adolescents and adults, vaporised cannabidiol does not mitigate the acute harms caused by delta-9-tetrahydocannabinol.

Does cannabidiol make cannabis safer? A randomised, double-blind, cross-over trial of cannabis with four different CBD:THC ratios.

As countries adopt more permissive cannabis policies, it is increasingly important to identify strategies that can reduce the harmful effects of cannabis use. This study aimed to determine if increasing the CBD content of cannabis can reduce its harmful effects. Forty-six healthy, infrequent cannabis users participated in a double-blind, within-subject, randomised trial of cannabis preparations varying in CBD content. There was an initial baseline visit followed by four drug administration visits, in which participants inhaled vaporised cannabis containing 10 mg THC and either 0 mg (0:1 CBD:THC), 10 mg (1:1), 20 mg (2:1), or 30 mg (3:1) CBD, in a randomised, counter-balanced order. The primary outcome was change in delayed verbal recall on the Hopkins Verbal Learning Task. Secondary outcomes included change in severity of psychotic symptoms (e.g., Positive and Negative Syndrome Scale [PANSS] positive subscale), plus further cognitive, subjective, pleasurable, pharmacological and physiological effects. Serial plasma concentrations of THC and CBD were measured. THC (0:1) was associated with impaired delayed verbal recall (t(45) = 3.399, d = 0.50, p = 0.001) and induced positive psychotic symptoms on the PANSS (t(45) = -4.709, d = 0.69, p = 2.41 × 10-5). These effects were not significantly modulated by any dose of CBD. Furthermore, there was no evidence of CBD modulating the effects of THC on other cognitive, psychotic, subjective, pleasurable, and physiological measures. There was a dose-response relationship between CBD dose and plasma CBD concentration, with no effect on plasma THC concentrations. At CBD:THC ratios most common in medicinal and recreational cannabis products, we found no evidence that CBD protects against the acute adverse effects of cannabis. This should be considered in health policy and safety decisions about medicinal and recreational cannabis.

Effects of Cannabidiol and Delta-9-Tetrahydrocannabinol on Plasma Endocannabinoid Levels in Healthy Volunteers: A Randomized Double-Blind Four-Arm Crossover Study.

Background: The effects of cannabis are thought to be mediated by interactions between its constituents and the endocannabinoid system. Delta-9-tetrahydrocannabinol (THC) binds to central cannabinoid receptors, while cannabidiol (CBD) may influence endocannabinoid function without directly acting on cannabinoid receptors. We examined the effects of THC coadministered with different doses of CBD on plasma levels of endocannabinoids in healthy volunteers. Methods: In a randomized, double-blind, four-arm crossover study, healthy volunteers (n=46) inhaled cannabis vapor containing 10 mg THC plus either 0, 10, 20, or 30 mg CBD, in four experimental sessions. The median time between sessions was 14 days (IQR=20). Blood samples were taken precannabis inhalation and at 0-, 5-, 15-, and 90-min postinhalation. Plasma concentrations of THC, CBD, anandamide, 2-arachidonoylglycerol (2-AG), and related noncannabinoid lipids were measured using liquid chromatography-mass spectrometry. Results: Administration of cannabis induced acute increases in plasma concentrations of anandamide (+18.0%, 0.042 ng/mL [95%CI: 0.023-0.062]), and the noncannabinoid ethanolamides, docosatetraenylethanolamide (DEA; +35.8%, 0.012 ng/mL [95%CI: 0.008-0.016]), oleoylethanolamide (+16.1%, 0.184 ng/mL [95%CI: 0.076-0.293]), and N-arachidonoyl-L-serine (+25.1%, 0.011 ng/mL [95%CI: 0.004-0.017]) (p<0.05). CBD had no significant effect on the plasma concentration of anandamide, 2-AG or related noncannabinoid lipids at any of three doses used. Over the four sessions, there were progressive decreases in the preinhalation concentrations of anandamide and DEA, from 0.254 ng/mL [95%CI: 0.223-0.286] to 0.194 ng/mL [95%CI: 0.163-0.226], and from 0.039 ng/mL [95%CI: 0.032-0.045] to 0.027 ng/mL [95%CI: 0.020-0.034] (p<0.05), respectively. Discussion: THC induced acute increases in plasma levels of anandamide and noncannabinoid ethanolamides, but there was no evidence that these effects were influenced by the coadministration of CBD. It is possible that such effects may be evident with higher doses of CBD or after chronic administration. The progressive reduction in pretreatment anandamide and DEA levels across sessions may be related to repeated exposure to THC or participants becoming less anxious about the testing procedure and requires further investigation. The study was registered on clinicaltrials.gov (NCT05170217).

Acceptability of cannabidiol in patients with psychosis.

Background: Cannabidiol (CBD) is a promising novel candidate treatment for psychosis. It has a more benign side effect profile than antipsychotic medications, and being treated with CBD is not perceived as being stigmatising. These observations suggest that patients with psychosis would find CBD to be a relatively acceptable treatment. Objective: This study tested the above hypothesis by assessing the views of a sample of patients. Methods: Patients with a psychotic disorder were invited to complete a survey exploring their expectations about the efficacy and side effects of CBD. Results: Seventy patients completed the survey. The majority (86%) were willing to try CBD as a treatment. Most patients believed that CBD would improve their psychotic symptoms (69%) and that it would have fewer side effects than their current medication (64%; mainly antipsychotics). A minority of patients (10%) were concerned that CBD might exacerbate their psychotic symptoms. This, however, appeared to reflect confusion between the effects of CBD and those of cannabis. Conclusion: Most patients with psychosis regard CBD as an acceptable treatment. Although CBD has not yet been approved as a treatment for psychosis, many patients are aware of it through the presence of CBD in cannabis and in health supplements. When added to the emerging evidence of its efficacy and the low risk of side effects, the high acceptability of CBD underlines its therapeutic potential.

Cannabidiol (CBD) as a novel treatment in the early phases of psychosis.

The pharmacological interventions available for individuals in the early stages of psychosis are extremely limited. For those at clinical high risk for psychosis, there is no licensed treatment available. For those with first-episode psychosis, all licensed antipsychotic medications act via dopamine D2 receptors. While treatment with antipsychotics is transformative in some patients, in others, it is ineffective. In addition, these medications can often cause adverse effects which make patients reluctant to take them. This is a particular problem in the early phases of psychosis, when patients are being treated for the first time, as unpleasant experiences may colour their future attitude towards treatment. Recent research has suggested that cannabidiol (CBD), a compound found in the Cannabis sativa plant, may have antipsychotic effects and relatively few adverse effects and could therefore be an ideal treatment for the early phases of psychosis, when minimising adverse effects is a clinical priority. In this review, we consider CBD's potential as a treatment in the clinical high risk and first-episode stages of psychosis. First, we describe the limitations of existing treatments at these two stages. We then describe what is known of CBD's mechanisms of action, effectiveness as a treatment for psychosis, adverse effects and acceptability to patients. We discuss how some of the outstanding issues about the utility of CBD in the early phases of psychosis may be resolved through ongoing clinical trials. Finally, we consider the impact of recreational cannabis use and over-the-counter cannabinoids preparations and discuss the potential therapeutic role of other compounds that modulate the endocannabinoid system in psychosis.

The impact of cigarette smoking on life expectancy in schizophrenia, schizoaffective disorder and bipolar affective disorder: An electronic case register cohort study.

Severe mental disorders are associated with a life expectancy that is 10-20 years shorter than the general population's. The prevalence of cigarette smoking in these populations is very high. We examined the effect of smoking on life expectancy and survival in patients with a diagnosis of schizophrenia, schizoaffective disorder or bipolar affective disorder from 2007 to 2018 in South East London, UK. Smoking status was determined using unstructured text data extracted from electronic health records. A total of 21,588 patients were identified of which 16,717, (77.4%) were classified as current smokers and 3438 (15.9%) as non-smokers. In female participants, life expectancy at birth was 67.6 years in current smokers (95% CI: 66.4-68.8) and 74.9 years in non-smokers (95% CI: 72.8-77.0), a difference of 7.3 years. In male participants, life expectancy at birth was 63.5 years in current smokers (95% CI: 62.5-64.5) and 68.5 years in non-smokers (95% CI, 64.4-72.6), a difference of 5.0 years. Adjusted survival models found that current smoking status was associated with an increased mortality risk for both females (aHR: 1.42, 95% CI: 1.21-1.66, p < 0.001) and males (aHR: 1.49; 95% CI: 1.25-1.79, p < 0.001). In terms of the effect sizes, these risks were similar to those associated with a diagnosis of co-morbid alcohol or opioid use disorder. Smoking may account for a substantial proportion of the reduced life expectancy in patients with psychotic disorders. Increased emphasis on reducing cigarette smoking in these populations may be the most effective way to reduce the mortality gap with the general population.

Effects of short-duration oil exposure on bay anchovy (Anchoa mitchilli) embryos and larvae: mortality, malformation, and foraging.

The Deepwater Horizon oil spill highlighted the need to understand the effects of oil exposure on marine eggs and larvae. To determine how short-duration exposure impacts the survivability of early life stages of the bay anchovy, Anchoa mitchilli, embryos and larvae ≤ 3-days-post-hatch (dph) were exposed to high-energy water accommodated fractions of weathered crude oil for 2 or 6 h. Lethal and sublethal effects of short-duration oil exposure were observed, including crippling malformations and altered optimal swimming and foraging behavior of larvae without malformation. The probability of mortality for larvae exposed as embryos (37.37 and 77.31 µg L-1 total polycyclic aromatic hydrocarbons or 'TPAH'), assessed 48 h after exposure, increased from 0.06 to 0.15 (2 h) and 0.10-0.23 (6 h) relative to unoiled controls. When exposed as 1-dph larvae (8.80-37.37 µg L-1 TPAH) and assessed 24 h after exposure, the probabilities increased from 0.20 to 0.76 (2 h) and 0.28-0.99 (6 h). Among surviving larvae, probabilities of yolk-sac, finfold, notochord, and cranio-facial malformations increased with exposure concentration, duration, and time after exposure by up to 0.07 immediately following exposure of 1-dph larvae and 0.55 24 h after exposure. When assessed 48 h after exposure as embryos, the probability of larval malformation reached 0.43. First-feeding (3-dph) foraging behavior was altered immediately and 24 h after 2 h exposures (8.80-77.31 µg L-1 TPAH). Time spent in motion and swim speed increased with exposure concentration by up to 331% and 189%, respectively. The number of bursts min-1 increased by 293% immediately and 152% 24 h after exposure. Burst distance decreased by 201%. Pause duration and burst speed decreased by 391% and 250% immediately and 124% and 109% 24 h after exposure. No effects were found for burst duration or tortuosity. Our results suggest potential cascading effects on fitness and trophic interactions.

Managing restricted patients in acute, non-secure in-patient services: clinical, ethical and resource implications of long waits for a response from the Ministry of Justice.

AIMS AND METHOD: In-patients subject to Section 37/41 of the Mental Health Act 1983 (MHA) require permission from the Ministry of Justice (MoJ) for leave, transfer and discharge. This study aimed to quantify the time spent waiting for the MoJ to respond to requests, using data on restricted patients recalled to a non-forensic unit over 8 years. RESULTS: Eleven admissions were identified. The mean total time waiting for response was 95 days per admission, with an estimated cost of £40 922 per admission. CLINICAL IMPLICATIONS: Current procedures may contribute to considerable increases in length of stay. This goes against the principles of the MHA, as non-secure services rarely provide the range of interventions which justify prolonged admission. We suggest several ways to resolve this issue, including broadening the guidance for the use of voluntary admissions and civil sections, and allowing clinicians to make decisions on leave and transfer where there is little risk.

Lack of evidence for the effectiveness or safety of over-the-counter cannabidiol products.

Over the past 5 years, public interest in the potential health benefits of cannabidiol (CBD) has increased exponentially, and a wide range of over-the-counter (OTC) preparations of CBD are now available. A substantial proportion of the population appears to have used these products, yet the extent to which they are effective or safe is unclear. We reviewed the evidence for whether CBD has significant pharmacological and symptomatic effects at the doses typically found in OTC preparations. We found that most of the evidence for beneficial effects is derived from studies of pure, pharmaceutical grade CBD at relatively high doses. Relatively few studies have examined the effect of OTC CBD preparations, or of CBD at low doses. Thus, at present, there is little evidence that OTC CBD products have health benefits, and their safety has not been investigated. Controlled trials of OTC and low-dose CBD preparations are needed to resolve these issues.

Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic.

BACKGROUND: Before the COVID-19 pandemic, coronaviruses caused two noteworthy outbreaks: severe acute respiratory syndrome (SARS), starting in 2002, and Middle East respiratory syndrome (MERS), starting in 2012. We aimed to assess the psychiatric and neuropsychiatric presentations of SARS, MERS, and COVID-19. METHODS: In this systematic review and meta-analysis, MEDLINE, Embase, PsycINFO, and the Cumulative Index to Nursing and Allied Health Literature databases (from their inception until March 18, 2020), and medRxiv, bioRxiv, and PsyArXiv (between Jan 1, 2020, and April 10, 2020) were searched by two independent researchers for all English-language studies or preprints reporting data on the psychiatric and neuropsychiatric presentations of individuals with suspected or laboratory-confirmed coronavirus infection (SARS coronavirus, MERS coronavirus, or SARS coronavirus 2). We excluded studies limited to neurological complications without specified neuropsychiatric presentations and those investigating the indirect effects of coronavirus infections on the mental health of people who are not infected, such as those mediated through physical distancing measures such as self-isolation or quarantine. Outcomes were psychiatric signs or symptoms; symptom severity; diagnoses based on ICD-10, DSM-IV, or the Chinese Classification of Mental Disorders (third edition) or psychometric scales; quality of life; and employment. Both the systematic review and the meta-analysis stratified outcomes across illness stages (acute vs post-illness) for SARS and MERS. We used a random-effects model for the meta-analysis, and the meta-analytical effect size was prevalence for relevant outcomes, I2 statistics, and assessment of study quality. FINDINGS: 1963 studies and 87 preprints were identified by the systematic search, of which 65 peer-reviewed studies and seven preprints met inclusion criteria. The number of coronavirus cases of the included studies was 3559, ranging from 1 to 997, and the mean age of participants in studies ranged from 12·2 years (SD 4·1) to 68·0 years (single case report). Studies were from China, Hong Kong, South Korea, Canada, Saudi Arabia, France, Japan, Singapore, the UK, and the USA. Follow-up time for the post-illness studies varied between 60 days and 12 years. The systematic review revealed that during the acute illness, common symptoms among patients admitted to hospital for SARS or MERS included confusion (36 [27·9%; 95% CI 20·5-36·0] of 129 patients), depressed mood (42 [32·6%; 24·7-40·9] of 129), anxiety (46 [35·7%; 27·6-44·2] of 129), impaired memory (44 [34·1%; 26·2-42·5] of 129), and insomnia (54 [41·9%; 22·5-50·5] of 129). Steroid-induced mania and psychosis were reported in 13 (0·7%) of 1744 patients with SARS in the acute stage in one study. In the post-illness stage, depressed mood (35 [10·5%; 95% CI 7·5-14·1] of 332 patients), insomnia (34 [12·1%; 8·6-16·3] of 280), anxiety (21 [12·3%; 7·7-17·7] of 171), irritability (28 [12·8%; 8·7-17·6] of 218), memory impairment (44 [18·9%; 14·1-24·2] of 233), fatigue (61 [19·3%; 15·1-23·9] of 316), and in one study traumatic memories (55 [30·4%; 23·9-37·3] of 181) and sleep disorder (14 [100·0%; 88·0-100·0] of 14) were frequently reported. The meta-analysis indicated that in the post-illness stage the point prevalence of post-traumatic stress disorder was 32·2% (95% CI 23·7-42·0; 121 of 402 cases from four studies), that of depression was 14·9% (12·1-18·2; 77 of 517 cases from five studies), and that of anxiety disorders was 14·8% (11·1-19·4; 42 of 284 cases from three studies). 446 (76·9%; 95% CI 68·1-84·6) of 580 patients from six studies had returned to work at a mean follow-up time of 35·3 months (SD 40·1). When data for patients with COVID-19 were examined (including preprint data), there was evidence for delirium (confusion in 26 [65%] of 40 intensive care unit patients and agitation in 40 [69%] of 58 intensive care unit patients in one study, and altered consciousness in 17 [21%] of 82 patients who subsequently died in another study). At discharge, 15 (33%) of 45 patients with COVID-19 who were assessed had a dysexecutive syndrome in one study. At the time of writing, there were two reports of hypoxic encephalopathy and one report of encephalitis. 68 (94%) of the 72 studies were of either low or medium quality. INTERPRETATION: If infection with SARS-CoV-2 follows a similar course to that with SARS-CoV or MERS-CoV, most patients should recover without experiencing mental illness. SARS-CoV-2 might cause delirium in a significant proportion of patients in the acute stage. Clinicians should be aware of the possibility of depression, anxiety, fatigue, post-traumatic stress disorder, and rarer neuropsychiatric syndromes in the longer term. FUNDING: Wellcome Trust, UK National Institute for Health Research (NIHR), UK Medical Research Council, NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London.

Adverse effects of cannabidiol: a systematic review and meta-analysis of randomized clinical trials.

Cannabidiol (CBD) is being investigated as a treatment for several medical disorders but there is uncertainty about its safety. We conducted the first systematic review and meta-analysis of the adverse effects of CBD across all medical indications. Double-blind randomized placebo-controlled clinical trials lasting ≥7 days were included. Twelve trials contributed data from 803 participants to the meta-analysis. Compared with placebo, CBD was associated with an increased likelihood of withdrawal for any reason (OR 2.61, 95% CI: 1.38-4.96) or due to adverse events (OR 2.65, 95% CI: 1.04-6.80), any serious adverse event (OR 2.30, 95% CI: 1.18-4.48), serious adverse events related to abnormal liver function tests (OR 11.19, 95% CI: 2.09-60.02) or pneumonia (OR 5.37, 95% CI: 1.17-24.65), any adverse event (OR 1.55, 95% CI: 1.03-2.33), adverse events due to decreased appetite (OR 3.56, 95% CI: 1.94-6.53), diarrhoea (OR 2.61, 95% CI: 1.46-4.67), somnolence (OR 2.23, 95% CI: 1.07-4.64) and sedation (OR 4.21, 95% CI: 1.18-15.01). Associations with abnormal liver function tests, somnolence, sedation and pneumonia were limited to childhood epilepsy studies, where CBD may have interacted with other medications such as clobazam and/or sodium valproate. After excluding studies in childhood epilepsy, the only adverse outcome associated with CBD treatment was diarrhoea (OR 5.03, 95% CI: 1.44-17.61). In summary, the available data from clinical trials suggest that CBD is well tolerated and has relatively few serious adverse effects, however interactions with other medications should be monitored carefully. Additional safety data from clinical trials outside of childhood epilepsy syndromes and from studies of over-the-counter CBD products are needed to assess whether the conclusions drawn from clinical trials can be applied more broadly.

Real-world digital implementation of the Psychosis Polyrisk Score (PPS): A pilot feasibility study.

BACKGROUND: The Psychosis Polyrisk Score (PPS) is a potential biomarker integrating non-purely genetic risk/protective factors for psychosis that may improve identification of individuals at risk and prediction of their outcomes at the individual subject level. Biomarkers that are easy to administer are direly needed in early psychosis to facilitate clinical implementation. This study digitally implements the PPS and pilots its feasibility of use in the real world. METHODS: The PPS was implemented digitally and prospectively piloted across individuals referred for a CHR-P assessment (n = 16) and healthy controls (n = 66). Distribution of PPS scores was further simulated in the general population. RESULTS: 98.8% of individuals referred for a CHR-P assessment and healthy controls completed the PPS assessment with only one drop-out. 96.3% of participants completed the assessment in under 15 min. Individuals referred for a CHR-P assessment had high PPS scores (mean = 6.2, SD = 7.23) than healthy controls (mean = -1.79, SD = 6.78, p < 0.001). In simulated general population data, scores were normally distributed ranging from -15 (lowest risk, RR = 0.03) to 39.5 (highest risk, RR = 8912.51). DISCUSSION: The PPS is a promising biomarker which has been implemented digitally. The PPS can be easily administered to both healthy controls and individuals at potential risk for psychosis on a range of devices. It is feasible to use the PPS in real world settings to assess individuals with emerging mental disorders. The next phase of research should be to include the PPS in large-scale international cohort studies to evaluate its ability to refine the prognostication of outcomes.