Physical Health and Transition to Psychosis in People at Clinical High Risk.

BACKGROUND: The clinical high risk for psychosis (CHR-P) construct represents an opportunity for prevention and early intervention in young adults, but the relationship between risk for psychosis and physical health in these patients remains unclear. METHODS: We conducted a RECORD-compliant clinical register-based cohort study, selecting the long-term cumulative risk of developing a persistent psychotic disorder as the primary outcome. We investigated associations between primary outcome and physical health data with Electronic Health Records at the South London and Maudsley (SLaM) NHS Trust, UK (January 2013-October 2020). We performed survival analyses using Kaplan-Meier curves, log-rank tests, and Cox proportional hazard models. RESULTS: The database included 137 CHR-P subjects; 21 CHR-P developed psychosis during follow-up, and the cumulative incidence of psychosis risk was 4.9% at 1 year and 56.3% at 7 years. Log-rank tests suggested that psychosis risk might change between different levels of nicotine and alcohol dependence. Kaplan-Meier curve analyses indicated that non-hazardous drinkers may have a lower psychosis risk than non-drinkers. In the Cox proportional hazard model, nicotine dependence presented a hazard ratio of 1.34 (95% CI: 1.1-1.64) (p = 0.01), indicating a 34% increase in psychosis risk for every additional point on the Fagerström Test for Nicotine Dependence. CONCLUSIONS: Our findings suggest that a comprehensive assessment of tobacco and alcohol use, diet, and physical activity in CHR-P subjects is key to understanding how physical health contributes to psychosis risk.

A naturalistic cohort study of first-episode schizophrenia spectrum disorder: A description of the early phase of illness in the PSYSCAN cohort.

BACKGROUND: We examined the course of illness over a 12-month period in a large, international multi-center cohort of people with a first-episode schizophrenia spectrum disorder (FES) in a naturalistic, prospective study (PSYSCAN). METHOD: Patients with a first episode of schizophrenia, schizoaffective disorder (depressive type) or schizophreniform disorder were recruited at 16 institutions in Europe, Israel and Australia. Participants (N = 304) received clinical treatment as usual throughout the study. RESULTS: The mean age of the cohort was 24.3 years (SD = 5.6), and 67 % were male. At baseline, participants presented with a range of intensities of psychotic symptoms, 80 % were taking antipsychotic medication, 68 % were receiving psychological treatment, with 46.5 % in symptomatic remission. The mean duration of untreated psychosis was 6.2 months (SD = 17.0). After one year, 67 % were in symptomatic remission and 61 % were in functional remission, but 31 % had been readmitted to hospital at some time after baseline. In the cohort as a whole, depressive symptoms remained stable over the follow-up period. In patients with a current depressive episode at baseline, depressive symptoms slightly improved. Alcohol, tobacco and cannabis were the most commonly used substances, with daily users of cannabis ranging between 9 and 11 % throughout the follow-up period. CONCLUSIONS: This study provides valuable insight into the early course of a broad range of clinical and functional aspects of illness in FES patients in routine clinical practice.

Prevalence of Neuroradiological Abnormalities in First-Episode Psychosis: A Systematic Review and Meta-analysis.

Importance: Individuals presenting with first-episode psychosis (FEP) may have a secondary ("organic") etiology to their symptoms that can be identified using neuroimaging. Because failure to detect such cases at an early stage can have serious clinical consequences, it has been suggested that brain magnetic resonance imaging (MRI) should be mandatory for all patients presenting with FEP. However, this remains a controversial issue, partly because the prevalence of clinically relevant MRI abnormalities in this group is unclear. Objective: To derive a meta-analytic estimate of the prevalence of clinically relevant neuroradiological abnormalities in FEP. Data Sources: Electronic databases Ovid, MEDLINE, PubMed, Embase, PsychINFO, and Global Health were searched up to July 2021. References and citations of included articles and review articles were also searched. Study Selection: Magnetic resonance imaging studies of patients with FEP were included if they reported the frequency of intracranial radiological abnormalities. Data Extraction and Synthesis: Independent extraction was undertaken by 3 researchers and a random-effects meta-analysis of pooled proportions was calculated. Moderators were tested using subgroup and meta-regression analyses. Heterogeneity was evaluated using the I2 index. The robustness of results was evaluated using sensitivity analyses. Publication bias was assessed using funnel plots and Egger tests. Main Outcomes and Measures: Proportion of patients with a clinically relevant radiological abnormality (defined as a change in clinical management or diagnosis); number of patients needed to scan to detect 1 such abnormality (number needed to assess [NNA]). Results: Twelve independent studies (13 samples) comprising 1613 patients with FEP were included. Of these patients, 26.4% (95% CI, 16.3%-37.9%; NNA of 4) had an intracranial radiological abnormality, and 5.9% (95% CI, 3.2%-9.0%) had a clinically relevant abnormality, yielding an NNA of 18. There were high degrees of heterogeneity among the studies for these outcomes, 95% to 73%, respectively. The most common type of clinically relevant finding was white matter abnormalities, with a prevalence of 0.9% (95% CI, 0%-2.8%), followed by cysts, with a prevalence of 0.5% (95% CI, 0%-1.4%). Conclusions and Relevance: This systematic review and meta-analysis found that 5.9% of patients presenting with a first episode of psychosis had a clinically relevant finding on MRI. Because the consequences of not detecting these abnormalities can be serious, these findings support the use of MRI as part of the initial clinical assessment of all patients with FEP.

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.

Inflammatory cytokines and white matter microstructure in the acute phase of first-episode psychosis: A longitudinal study.

OBJECTIVES: Schizophrenia-related psychosis is associated with abnormalities in white matter (WM) microstructure and structural brain dysconnectivity. However, the pathological process underlying such changes is unknown. We sought to investigate the potential association between peripheral cytokine levels and WM microstructure during the acute phase of first-episode psychosis (FEP) in a cohort of drug-naïve patients. METHODS: Twenty-five non-affective FEP patients and 69 healthy controls underwent MRI scanning and blood collection at study entry. After achieving clinical remission, 21 FEP were reassessed; 38 age and biological sex-matched controls also had a second assessment. We measured fractional anisotropy (FA) of selected WM regions-of-interest (ROIs) and plasma levels of four cytokines (IL-6, IL-10, IFN-γ, and TNF-α). RESULTS: At baseline (acute psychosis), the FEP group showed reduced FA relative to controls in half the examined ROIs. Within the FEP group, IL-6 levels were negatively correlated with FA values. Longitudinally, patients showed increments of FA in several ROIs affected at baseline, and such changes were associated with reductions in IL-6 levels. CONCLUSIONS: A state-dependent process involving an interplay between a pro-inflammatory cytokine and brain WM might be associated with the clinical manifestation of FEP. This association suggests a deleterious effect of IL-6 on WM tracts during the acute phase of psychosis.

Serum immune markers and transition to psychosis in individuals at clinical high risk.

Individuals at clinical high risk (CHR) for psychosis have been found to have altered cytokine levels, but whether these changes are related to clinical outcomes remains unclear. We addressed this issue by measuring serum levels of 20 immune markers in 325 participants (n = 269 CHR, n = 56 healthy controls) using multiplex immunoassays, and then followed up the CHR sample to determine their clinical outcomes. Among 269 CHR individuals, 50 (18.6 %) developed psychosis by two years. Univariate and machine learning techniques were used to compare levels of inflammatory markers in CHR subjects and healthy controls, and in CHR subjects who had (CHR-t), or had not (CHR-nt) transitioned to psychosis. An ANCOVA identified significant group differences (CHR-t, CHR-nt and controls) and post-hoc tests indicated that VEGF levels and the IL-10/IL-6 ratio were significantly higher in CHR-t than CHR-nt, after adjusting for multiple comparisons. Using a penalised logistic regression classifier, CHR participants were distinguished from controls with an area-under the curve (AUC) of 0.82, with IL-6 and IL-4 levels the most important discriminating features. Transition to psychosis was predicted with an AUC of 0.57, with higher VEGF level and IL-10/IL-6 ratio the most important discriminating features. These data suggest that alterations in the levels of peripheral immune markers are associated with the subsequent onset of psychosis. The association with increased VEGF levels could reflect altered blood-brain-barrier (BBB) permeability, while the link with an elevated IL-10/IL-6 ratio points to an imbalance between anti- and pro-inflammatory cytokines.

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.

Prevalence of tobacco smoking in people at clinical high-risk for psychosis: Systematic review and meta-analysis.

Several hypotheses have been proposed to explain why individuals with psychosis consume more tobacco compared with the general population, but the reasons remain unclear. The phases predating the onset of psychosis could provide an interesting framework to clarify this association. The aim of this systematic review and meta-analysis is to provide an updated and comprehensive synthesis of the association between tobacco smoking and Clinical High Risk for Psychosis (CHRP) status. We performed a multistep systematic PRISMA/MOOSE-compliant electronic search for articles published from inception until October 1st, 2021. Web of Science was searched, complemented by a manual search of original articles reporting the outcome of tobacco consumption (defined as the number of individuals which were smoking tobacco at baseline) in a group of CHR-P patients versus healthy controls (HC). We employed quality assessment of the included studies with Newcastle Ottawa Scale (NOS). The effect size for the primary outcome was the odds ratio (OR) of smoking tobacco in CHR-P samples vs HC. We performed a random-effects model meta-analysis, assessment of heterogeneity with I2 index, sensitivity analyses excluding one study at a time for primary outcome, meta-regressions with four independent moderators (mean age, female ratio, sample size, NOS) and assessment of publication bias with funnel plot and Egger's test. We included 21 independent articles, totalling 2018 CHR-P individuals (mean age of 21.35 ± 2.91 years and average female ratio of 41 ± 7 %) and 1160 HC (mean age of 22.42 ± 3.70 years and average female ratio of 45 ± 11 %). The NOS score was 6.52 ± 1.25 (range from 0 to 9). The OR of smoking status was 2.22 (95%CI 1.74-2.84, p < 0.01). Heterogeneity (I2) was 24.09 (p = 0.16). Sensitivity analyses, removing one study at a time, revealed the robustness of our main finding. Meta-regressions did not reveal any significant association between the moderators and the main outcome. Visual inspection of the funnel plot and Egger's test did not reveal evident publication bias. Our main finding of an increased OR of smokers in the CHR-P individuals compared to healthy controls corroborates the accumulation of unhealthy lifestyles in this vulnerable group. This does not demonstrate any causal association between tobacco smoking and incidence of psychosis, which should be investigated in future prospective cohorts. In conclusion, the window of opportunity represented by CHR-P status should involve more efficient physical health screening and better investigating the aetiological impact of smoking in the development of psychosis.

Differential trajectories of tobacco smoking in people at ultra-high risk for psychosis: Associations with clinical outcomes.

Objective: People at ultra-high risk (UHR) for psychosis have a high prevalence of tobacco smoking, and rates are even higher among the subgroup that later develop a psychotic disorder. However, the longitudinal relationship between the course of tobacco smoking and clinical outcomes in UHR subjects is unknown. Methods: We investigated associations between tobacco smoking and clinical outcomes in a prospective study of UHR individuals (n = 324). Latent class mixed model analyses were used to identify trajectories of smoking severity. Mixed effects models were applied to investigate associations between smoking trajectory class and the course of attenuated psychotic symptoms (APS) and affective symptoms, as assessed using the CAARMS. Results: We identified four different classes of smoking trajectory: (i) Persistently High (n = 110), (ii) Decreasing (n = 29), (iii) Persistently Low (n = 165) and (iv) Increasing (n = 20). At two-year follow-up, there had been a greater increase in APS in the Persistently High class than for both the Persistently Low (ES = 9.77, SE = 4.87, p = 0.046) and Decreasing (ES = 18.18, SE = 7.61, p = 0.018) classes. There were no differences between smoking classes in the incidence of psychosis. There was a greater reduction in the severity of emotional disturbance and general symptoms in the Decreasing class than in the High (ES = -10.40, SE = 3.41, p = 0.003; ES = -22.36, SE = 10.07, p = 0.027), Increasing (ES = -11.35, SE = 4.55, p = 0.014; ES = -25.58, SE = 13.17, p = 0.050) and Low (ES = -11.38, SE = 3.29, p = 0.001; ES = -27.55, SE = 9.78, p = 0.005) classes, respectively. Conclusions: These findings suggests that in UHR subjects persistent tobacco smoking is associated with an unfavorable course of psychotic symptoms, whereas decrease in the number of cigarettes smoked is associated with improvement in affective symptoms. Future research into smoking cessation interventions in the early stages of psychoses is required to shine light on the potential of modifying smoking behavior and its relation to clinical outcomes.

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.

Association between tobacco use and symptomatology in individuals at ultra-high risk to develop a psychosis: A longitudinal study.

BACKGROUND: The high prevalence rates and impact of tobacco smoking in individuals with a psychotic disorder have become an increasing interest. Little is known about tobacco smoking in individuals at ultra-high risk of psychosis (UHR). METHODS: We studied 345 UHR individuals of the high-risk study of the European network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI). Smoking status and the number of cigarettes per day were assessed at multiple moments using the CIDI. Symptom severity at each time point was assessed using CAARMS. Linear mixed-effects analyses were conducted to examine the multi-cross-sectional and prospective associations between (change in) smoking behaviour and symptomatology. FINDINGS: At baseline, 175 individuals (53%) smoked tobacco with an average of 12.4 (SD = 9.0) cigarettes per day. Smokers did not significantly differ in symptom severity from non-smokers on general, positive, negative, emotional, cognitive, behavioural, or motor symptoms across time. However, associations were found between the number of cigarettes and the severity of general psychopathology (estimate 0.349, SE 0.146, p = 0.017). Change in the number of cigarettes had no significant effect on change in general symptom severity (estimate 0.330, SE 0.285, p = 0.248). INTERPRETATION: Smoking prevalence in UHR individuals is high. Cigarette consumption was associated with higher levels of general symptoms. However, we observed no association between change in number of cigarettes and symptom severity. Given the fact that smoking is associated with poorer health and worse outcomes in people with psychosis, the clinical high-risk phase offers a window of opportunity for prevention and cessation interventions.

Cannabis use in patients with early psychosis is associated with alterations in putamen and thalamic shape.

Around half of patients with early psychosis have a history of cannabis use. We aimed to determine if there are neurobiological differences in these the subgroups of persons with psychosis with and without a history of cannabis use. We expected to see regional deflations in hippocampus as a neurotoxic effect and regional inflations in striatal regions implicated in addictive processes. Volumetric, T1w MRIs were acquired from people with a diagnosis psychosis with (PwP + C = 28) or without (PwP - C = 26) a history of cannabis use; and Controls with (C + C = 16) or without (C - C = 22) cannabis use. We undertook vertex-based shape analysis of the brainstem, amygdala, hippocampus, globus pallidus, nucleus accumbens, caudate, putamen, thalamus using FSL FIRST. Clusters were defined through Threshold Free Cluster Enhancement and Family Wise Error was set at p < .05. We adjusted analyses for age, sex, tobacco and alcohol use. The putamen (bilaterally) and the right thalamus showed regional enlargement in PwP + C versus PwP - C. There were no areas of regional deflation. There were no significant differences between C + C and C - C. Cannabis use in participants with psychosis is associated with morphological alterations in subcortical structures. Putamen and thalamic enlargement may be related to compulsivity in patients with a history of cannabis use.

Association of cannabis with glutamatergic levels in patients with early psychosis: Evidence for altered volume striatal glutamate relationships in patients with a history of cannabis use in early psychosis.

The associative striatum, an established substrate in psychosis, receives widespread glutamatergic projections. We sought to see if glutamatergic indices are altered between early psychosis patients with and without a history of cannabis use and characterise the relationship to grey matter. 92 participants were scanned: Early Psychosis with a history of cannabis use (EPC = 29); Early Psychosis with minimal cannabis use (EPMC = 25); Controls with a history of cannabis use (HCC = 16) and Controls with minimal use (HCMC = 22). Whole brain T1 weighted MR images and localised proton MR spectra were acquired from head of caudate, anterior cingulate and hippocampus. We examined relationships in regions with known high cannabinoid 1 receptor (CB1R) expression (grey matter, cortex, hippocampus, amygdala) and low expression (white matter, ventricles, brainstem) to caudate Glutamine+Glutamate (Glx). Patients were well matched in symptoms, function and medication. There was no significant group difference in Glx in any region. In EPC grey matter volume explained 31.9% of the variance of caudate Glx (p = 0.003) and amygdala volume explained 36.9% (p = 0.001) of caudate Glx. There was no significant relationship in EPMC. The EPC vs EPMC interaction was significant (p = 0.042). There was no such relationship in control regions. These results are the first to demonstrate association of grey matter volume and striatal glutamate in the EPC group. This may suggest a history of cannabis use leads to a conformational change in distal CB1 rich grey matter regions to influence striatal glutamatergic levels or that such connectivity predisposes to heavy cannabis use.

Prevention of Psychosis: Advances in Detection, Prognosis, and Intervention.

Importance: Detection, prognosis, and indicated interventions in individuals at clinical high risk for psychosis (CHR-P) are key components of preventive psychiatry. Objective: To provide a comprehensive, evidence-based systematic appraisal of the advancements and limitations of detection, prognosis, and interventions for CHR-P individuals and to formulate updated recommendations. Evidence Review: Web of Science, Cochrane Central Register of Reviews, and Ovid/PsychINFO were searched for articles published from January 1, 2013, to June 30, 2019, to identify meta-analyses conducted in CHR-P individuals. MEDLINE was used to search the reference lists of retrieved articles. Data obtained from each article included first author, year of publication, topic investigated, type of publication, study design and number, sample size of CHR-P population and comparison group, type of comparison group, age and sex of CHR-P individuals, type of prognostic assessment, interventions, quality assessment (using AMSTAR [Assessing the Methodological Quality of Systematic Reviews]), and key findings with their effect sizes. Findings: In total, 42 meta-analyses published in the past 6 years and encompassing 81 outcomes were included. For the detection component, CHR-P individuals were young (mean [SD] age, 20.6 [3.2] years), were more frequently male (58%), and predominantly presented with attenuated psychotic symptoms lasting for more than 1 year before their presentation at specialized services. CHR-P individuals accumulated several sociodemographic risk factors compared with control participants. Substance use (33% tobacco use and 27% cannabis use), comorbid mental disorders (41% with depressive disorders and 15% with anxiety disorders), suicidal ideation (66%), and self-harm (49%) were also frequently seen in CHR-P individuals. CHR-P individuals showed impairments in work (Cohen d = 0.57) or educational functioning (Cohen d = 0.21), social functioning (Cohen d = 1.25), and quality of life (Cohen d = 1.75). Several neurobiological and neurocognitive alterations were confirmed in this study. For the prognosis component, the prognostic accuracy of CHR-P instruments was good, provided they were used in clinical samples. Overall, risk of psychosis was 22% at 3 years, and the risk was the highest in the brief and limited intermittent psychotic symptoms subgroup (38%). Baseline severity of attenuated psychotic (Cohen d = 0.35) and negative symptoms (Cohen d = 0.39) as well as low functioning (Cohen d = 0.29) were associated with an increased risk of psychosis. Controlling risk enrichment and implementing sequential risk assessments can optimize prognostic accuracy. For the intervention component, no robust evidence yet exists to favor any indicated intervention over another (including needs-based interventions and control conditions) for preventing psychosis or ameliorating any other outcome in CHR-P individuals. However, because the uncertainty of this evidence is high, needs-based and psychological interventions should still be offered. Conclusions and Relevance: This review confirmed recent substantial advancements in the detection and prognosis of CHR-P individuals while suggesting that effective indicated interventions need to be identified. This evidence suggests a need for specialized services to detect CHR-P individuals in primary and secondary care settings, to formulate a prognosis with validated psychometric instruments, and to offer needs-based and psychological interventions.

Effect of single dose N-acetylcysteine administration on resting state functional connectivity in schizophrenia.

RATIONALE: There is interest in employing N-acetylcysteine (NAC) in the treatment of schizophrenia, but investigations of the functional signatures of its pharmacological action are scarce. OBJECTIVES: The aim of this study was to identify the changes in resting-state functional connectivity (rs-FC) that occur following administration of a single dose of NAC in patients with schizophrenia. A secondary aim was to examine whether differences in rs-FC between conditions were mediated by glutamate metabolites in the anterior cingulate cortex (ACC). METHODS: In a double-blind, placebo-controlled crossover design, 20 patients with schizophrenia had two MRI scans administered 7 days apart, following oral administration of either 2400 mg NAC or placebo. Resting state functional fMRI (rsfMRI) assessed the effect of NAC on rs-FC within the default mode network (DMN) and the salience network (SN). Proton magnetic resonance spectroscopy was used to measure Glx/Cr (glutamate plus glutamine, in ratio to creatine) levels in the ACC during the same scanning sessions. RESULTS: Compared to the placebo condition, the NAC condition was associated with reduced within the DMN and SN, specifically between the medial pre-frontal cortex to mid frontal gyrus, and ACC to frontal pole (all p < 0.04). There were no significant correlations between ACC Glx/Cr and rs-FC in either condition (p > 0.6). CONCLUSIONS: These findings provide preliminary evidence that NAC can reduce medial frontal rs-FC in schizophrenia. Future studies assessing the effects of NAC on rs-FC in early psychosis and on repeated administration in relation to efficacy would be of interest.

Nitrous Oxide and Methane Dynamics in Woodchip Bioreactors: Effects of Water Level Fluctuations on Partitioning into Trapped Gas Phases.

Woodchip bioreactors (WBRs) are low-cost, passive systems for nonpoint source nitrogen removal at terrestrial-aquatic interfaces. The greenhouse gases nitrous oxide (N2O) and methane (CH4) can be produced within WBRs, and efforts to reduce N2O and CH4 emissions from WBR systems require improved understanding of the biogeochemical and physical-chemical mechanisms regulating their production, transport, and release. This study evaluates the impact of trapped gas-filled void volumes as sinks of dissolved gases from water and as sources of episodic fluxes when water levels fall. Dissolved gas tracer experiments in a laboratory bioreactor were used to parameterize nonequilibrium advection-dispersion-gas transfer models and quantify trapping of gas-filled voids as a function of antecedent hydrological conditions. Experiments following a water-level rise revealed that up to 24% of the WBR pore volume was occupied by trapped gas phases, which were primarily located in pore spaces inside woodchips. This finding was confirmed with X-ray-computed microtomography. N2O (3.3-10%) and CH4 (4.3-14%) injected into the reactor following a water table rise partitioned into gas-filled voids and were released when water tables fell. In the case of N2O, partitioning into trapped gas phases makes N2O unavailable for enzymatic reduction, potentially enhancing N2O fluxes under fluctuating water levels.

Transdiagnostic Risk Calculator for the Automatic Detection of Individuals at Risk and the Prediction of Psychosis: Second Replication in an Independent National Health Service Trust.

BACKGROUND: The benefits of indicated primary prevention among individuals at Clinical High Risk for Psychosis (CHR-P) are limited by the difficulty in detecting these individuals. To overcome this problem, a transdiagnostic, clinically based, individualized risk calculator has recently been developed and subjected to a first external validation in 2 different catchment areas of the South London and Maudsley (SLaM) NHS Trust. METHODS: Second external validation of real world, real-time electronic clinical register-based cohort study. All individuals who received a first ICD-10 index diagnosis of nonorganic and nonpsychotic mental disorder within the Camden and Islington (C&I) NHS Trust between 2009 and 2016 were included. The model previously validated included age, gender, ethnicity, age by gender, and ICD-10 index diagnosis to predict the development of any ICD-10 nonorganic psychosis. The model's performance was measured using Harrell's C-index. RESULTS: This study included a total of 13702 patients with an average age of 40 (range 16-99), 52% were female, and most were of white ethnicity (64%). There were no CHR-P or child/adolescent services in the C&I Trust. The C&I and SLaM Trust samples also differed significantly in terms of age, gender, ethnicity, and distribution of index diagnosis. Despite these significant differences, the original model retained an acceptable predictive performance (Harrell's C of 0.73), which is comparable to that of CHR-P tools currently recommended for clinical use. CONCLUSIONS: This risk calculator may pragmatically support an improved transdiagnostic detection of at-risk individuals and psychosis prediction even in NHS Trusts in the United Kingdom where CHR-P services are not provided.

A pre-post pilot study of electronic cigarettes to reduce smoking in people with severe mental illness.

BACKGROUND: Smoking is the largest single contributor to poor physical health and increased mortality in people with serious mental illnesses. The aim of the study was to investigate the utility of electronic cigarettes (e-cigarettes) as a harm reduction intervention in this population. METHOD: Fifty tobacco smokers with a psychotic disorder were enrolled onto a 24-week pilot study (ClinicalTrials.gov: NCT02212041) investigating the efficacy of a 6-week free e-cigarette intervention to reduce smoking. Cigarette and e-cigarette use was self-reported at weekly visits, and verified using carbon monoxide tests. Psychopathology, e-cigarette acceptability and adverse effects were assessed using standardised scales. RESULTS: There was a significant (⩾50%) reduction in cigarettes consumed per day between baseline and week 6 [F(2.596,116.800) = 25.878, p < 0.001], and e-cigarette use was stable during this period [F(2.932,46.504) = 2.023, p = 0.115]. These changes were verified by significant carbon monoxide reductions between these time points [F(3.335,126.633) = 5.063, p = 0.002]. CONCLUSIONS: The provision of e-cigarettes is a potentially useful harm reduction intervention in smokers with a psychotic disorder.

Effects of N-acetylcysteine on brain glutamate levels and resting perfusion in schizophrenia.

RATIONALE: N-Acetylcysteine (NAC) is currently under investigation as an adjunctive treatment for schizophrenia. The therapeutic potential of NAC may involve modulation of brain glutamate function, but its effects on brain glutamate levels in schizophrenia have not been evaluated. OBJECTIVES: The aim of this study was to examine whether a single dose of NAC can alter brain glutamate levels. A secondary aim was to characterise its effects on regional brain perfusion. METHODS: In a double-blind placebo-controlled crossover study, 19 patients with a diagnosis of schizophrenia underwent two MRI scans, following oral administration of 2400 mg NAC or matching placebo. Proton magnetic resonance spectroscopy was used to investigate the effect of NAC on glutamate and Glx (glutamate plus glutamine) levels scaled to creatine (Cr) in the anterior cingulate cortex (ACC) and in the right caudate nucleus. Pulsed continuous arterial spin labelling was used to assess the effects of NAC on resting cerebral blood flow (rCBF) in the same regions. RESULTS: Relative to the placebo condition, the NAC condition was associated with lower levels of Glx/Cr, in the ACC (P < 0.05), but not in the caudate nucleus. There were no significant differences in CBF in the NAC compared to placebo condition. CONCLUSIONS: These data provide preliminary evidence that NAC can modulate ACC glutamate in patients with schizophrenia. In contrast, physiological effects of NAC on the brain were not detectable as between session changes in rCBF. Future studies assessing the effects of a course of treatment with NAC on glutamate metabolites in schizophrenia are indicated.