Tobacco use is common in subjects with schizophrenia (SZ) and has sometimes been associated with better functioning in short-term studies. Only few studies embrace an extensive examination of tobacco influence on clinical, cognitive and therapeutic characteristics in stabilized SZ outpatients. The objective of the present study was to assess the association between cognitive performances and smoking status in SZ subjects.

In total, 1233 SZ participants (73.9% men, mean age 31.5) were included and tested with a comprehensive battery. Tobacco status was self-declared (never-, ex-, or current smokers). Multivariable analyses including principal component analyses (PCA) were used.

In total, 53.7% were smokers with 33.7% of them nicotine-dependent. Multiple factor analysis revealed that current tobacco smoking was associated with impaired general intellectual ability and abstract reasoning (aOR 0.60, 95% IC 0.41–0.88, p = 0.01) and with a lifetime alcohol use disorder (p = 0.026) and a lifetime cannabis use disorder (p < 0.001). Ex- and never-smokers differed for age, mean outcome, cannabis history and medication [ex-smokers being older (p = 0.047), likely to have higher income (p = 0.026), a lifetime cannabis use disorder (p < 0.001) and higher CPZeq doses (p = 0.005)]. Premorbid IQ in the three groups significantly differed with, from higher to lower: ex-smokers, never-smoker, current smokers (all p < 0.001).

This study is the largest to date providing strong evidence that chronic smoking is associated with cognitive impairment in SZ, arguing against the self-medication hypothesis as a contributor to the high prevalence of smoking in SZ. Ex-smokers may also represent a specific subgroup. Longitudinal studies are warranted to determine the developmental impact of tobacco on neurocognition.

Clozapine is the only drug licensed for treatment-resistant schizophrenia (TRS) but the real-world clinical and cost-effectiveness of community initiation of clozapine is unclear.

The aim was to assess the feasibility and cost-effectiveness of community initiation of clozapine.

This was a naturalistic study of community patients recommended for clozapine treatment.

Of 158 patients recommended for clozapine treatment, 88 (56%) patients agreed to clozapine initiation and, of these, 58 (66%) were successfully established on clozapine. The success rate for community initiation was 65.4%; which was not significantly different from that for in-patient initiation (58.82%, χ2(1,88) = 0.47, P = 0.49). Following clozapine initiation, there was a significant reduction in median out-patient visits over 1 year (from 24.00 (interquartile range (IQR) = 14.00–41.00) to 13.00 visits (IQR = 5.00–24.00), P < 0.001), and 2 years (from 47.50 visits (IQR = 24.75–71.00) to 22.00 (IQR = 11.00–42.00), P < 0.001), and a 74.71% decrease in psychiatric hospital bed days (z = −2.50, P = 0.01). Service-use costs decreased (1 year: –£963/patient (P < 0.001); 2 years: –£1598.10/patient (P < 0.001). Subanalyses for community-only initiation also showed significant cost reductions (1 year: –£827.40/patient (P < 0.001); 2 year: –£1668.50/patient (P < 0.001) relative to costs prior to starting clozapine. Relative to before initiation, symptom severity was improved in patients taking clozapine at discharge (median Positive and Negative Syndrome Scale total score: initial visit: 80 (IQR = 71.00–104.00); discharge visit 50.5 (IQR = 44.75–75.00), P < 0.001) and at 2 year follow-up (Health of Nation Outcome Scales total score median initial visit: 13.00 (IQR = 9.00–15.00); 2 year follow-up: 8.00 (IQR = 3.00–13.00), P = 0.023).

These findings indicate that community initiation of clozapine is feasible and is associated with significant reductions in costs, service use and symptom severity.

Coronavirus disease 2019 (COVID-19) has been associated with various neurological and atypical head/eyes/ears/nose/throat (HEENT) manifestations. We sought to review the evidence for these manifestations.

In this systematic review and meta-analysis, we compiled studies published until March 31, 2021 that examined non-respiratory HEENT, central, and peripheral nervous system presentations in COVID-19 patients. We included 477 studies for qualitative synthesis and 59 studies for meta-analyses.

Anosmia, ageusia, and conjunctivitis may precede typical upper/lower respiratory symptoms. Central nervous system (CNS) manifestations include stroke and encephalopathy, potentially with brainstem or cranial nerve involvement. MRI studies support CNS para-/postinfectious etiologies, but direct neuroinvasion seems very rare, with few cases detecting Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in the CNS. Peripheral nervous system (PNS) manifestations include muscle damage, Guillain–Barre syndrome (GBS), and its variants. There was moderate-to-high study heterogeneity and risk of bias. In random-effects meta-analyses, anosmia/ageusia was estimated to occur in 56% of COVID-19 patients (95% CI: 0.41–0.71, I2:99.9%), more commonly than in patients without COVID-19 (OR: 14.28, 95% CI: 8.39–24.29, I2: 49.0%). Neurological symptoms were estimated to occur in 36% of hospitalized patients (95% CI: 0.31–0.42, I2: 99.8%); ischemic stroke in 3% (95% CI: 0.03–0.04, I2: 99.2%), and GBS in 0.04% (0.033%–0.047%), more commonly than in patients without COVID-19 (OR[stroke]: 2.53, 95% CI: 1.16–5.50, I2: 76.4%; OR[GBS]: 3.43,1.15–10.25, I2: 89.1%).

Current evidence is mostly from retrospective cohorts or series, largely in hospitalized or critically ill patients, not representative of typical community-dwelling patients. There remains a paucity of systematically gathered prospective data on neurological manifestations. Nevertheless, these findings support a high index of suspicion to identify HEENT/neurological presentations in patients with known COVID-19, and to test for COVID-19 in patients with such presentations at risk of infection.

The determinants of quality of life (QoL) in schizophrenia are largely debated, mainly due to methodological discrepancies and divergence about the concepts concerned. As most studies have investigated bi- or tri-variate models, a multivariate model accounting for simultaneous potential mediations is necessary to have a comprehensive view of the determinants of QOL. We sought to estimate the associations between cognitive reserve, cognition, functioning, insight, depression, schizophrenic symptoms, and QoL in schizophrenia and their potential mediation relationships.

We used structural equation modeling with mediation analyses to test a model based on existing literature in a sample of 776 patients with schizophrenia from the FondaMental Foundation FACE-SZ cohort.

Our model showed a good fit to the data. We found better functioning to be positively associated with a better QoL, whereas better cognition, better insight, higher levels of depression, and schizophrenic symptoms were associated with a lower QoL in our sample. Cognitive reserve is not directly linked to QoL, but indirectly in a negative manner via cognition. We confirm the negative relationship between cognition and subjective QoL which was previously evidenced by other studies; moreover, this relationship seems to be robust as it survived in our multivariate model. It was not explained by insight as some suggested, thus the mechanism at stake remains to be explained.

The pathways to subjective QoL in schizophrenia are complex and the determinants largely influence each other. Longitudinal studies are warranted to confirm these cross-sectional findings.

High potency cannabis has been associated with greater risk, and earlier onset of psychosis. However, its effect on brain structure, particularly white matter (WM), has never been explored.

To elucidate the interplay between cannabis potency, pattern of use (frequency and age of first use) and CC microstructure; in patients with first-episode psychosis (FEP) and healthy controls.

56 FEP and 43 healthy controls underwent Diffusion-Tensor Imaging combined with WM mapping-tractography. CC was virtually dissected and segmented to calculate Fractional Anisotropy (FA), Mean Diffusivity (MD), Axial Diffusivity (AD) and Radial Diffusivity (RD) for each CC segment.

High potency cannabis users had higher Total CC MD and Total CC AD than both low potency users and those who never used (p=0.009 and p=0.02 respectively). Daily users also had higher Total CC MD and Total CC AD than both occasional users and those who never used (p=0.02 and p=0.01 respectively). Furthermore, daily/highpotency users had higher Total CC MD than those who never used or used weekly [F(2,57)=4.7, p=0.01]. There was no effect of diagnosis or diagnosis X potency/patterns of use interactions; neither differences between users who started before the age of 15 and those who started later were detected, in any diffusivity measures.

Frequent use of high-potency cannabis significantly affects callosal microstructure, regardless of the presence of a psychotic disorder. Given the increased availability and use of high potency preparations in Europe, raising awareness about some of their detrimental effects is an important avenue to pursue.

The impact of cannabis use on brain structure, particularly white matter (WM), is poorly understood. The CC is the largest WM structure in the brain. Abnormalities revealed in the CC may underlie functional anomalies of cannabis use. This is the largest study to explore the effect of cannabis on callosal WM connectivity among first episode psychosis (FEP) and controls.

To investigate the relationship between cannabis use and WM micro-structural integrity of the CC, in FEP and healthy controls.

We evaluated 56 FEP patients (67% current cannabis users), and 43 healthy controls (44% current cannabis users). We used Diffusion Tensor Imaging combined with a WM mapping-tractography technique to investigate the microstructural integrity of the CC.

Total CC Fractional anisotropy (FA) was lower in patients than controls (p=0.05). Cannabis-using patients had lower FA of the total CC than cannabis-using controls (p=0.04). There were no differences in FA between cannabis-using patients and those who had never used. However, cannabis-using patients had higher mean diffusivity (MD) of total CC (p= 0.02), Rostral-Body (p=0.003), Anterior Mid-Body (p=0.03) and the Splenium (p=0.06) than patients who never used cannabis. There were no differences in MD between patient users who started before the age of 16 and those who started later.

Cannabis is associated with a significant effect on callosal WM integrity only in patients with psychosis. Disturbed callosal connectivity may explain some of the abnormalities with regard to the functional and clinical outcomes in FEP cannabis users, including measures of cognitive impairment.

Neuroanatomical abnormalities in first-episode psychosis (FEP) tend to be subtle and widespread. The vast majority of previous studies have used small samples, and therefore may have been underpowered. In addition, most studies have examined participants at a single research site, and therefore the results may be specific to the local sample investigated. Consequently, the findings reported in the existing literature are highly heterogeneous. This study aimed to overcome these issues by testing for neuroanatomical abnormalities in individuals with FEP that are expressed consistently across several independent samples.

Structural Magnetic Resonance Imaging data were acquired from a total of 572 FEP and 502 age and gender comparable healthy controls at five sites. Voxel-based morphometry was used to investigate differences in grey matter volume (GMV) between the two groups. Statistical inferences were made at p < 0.05 after family-wise error correction for multiple comparisons.

FEP showed a widespread pattern of decreased GMV in fronto-temporal, insular and occipital regions bilaterally; these decreases were not dependent on anti-psychotic medication. The region with the most pronounced decrease – gyrus rectus – was negatively correlated with the severity of positive and negative symptoms.

This study identified a consistent pattern of fronto-temporal, insular and occipital abnormalities in five independent FEP samples; furthermore, the extent of these alterations is dependent on the severity of symptoms and duration of illness. This provides evidence for reliable neuroanatomical alternations in FEP, expressed above and beyond site-related differences in anti-psychotic medication, scanning parameters and recruitment criteria.

Positive symptoms are a useful predictor of aggression in schizophrenia. Although a similar pattern of abnormal brain structures related to both positive symptoms and aggression has been reported, this observation has not yet been confirmed in a single sample.

To study the association between positive symptoms and aggression in schizophrenia on a neurobiological level, a prospective meta-analytic approach was employed to analyze harmonized structural neuroimaging data from 10 research centers worldwide. We analyzed brain MRI scans from 902 individuals with a primary diagnosis of schizophrenia and 952 healthy controls.

The result identified a widespread cortical thickness reduction in schizophrenia compared to their controls. Two separate meta-regression analyses revealed that a common pattern of reduced cortical gray matter thickness within the left lateral temporal lobe and right midcingulate cortex was significantly associated with both positive symptoms and aggression.

These findings suggested that positive symptoms such as formal thought disorder and auditory misperception, combined with cognitive impairments reflecting difficulties in deploying an adaptive control toward perceived threats, could escalate the likelihood of aggression in schizophrenia.

Jumping to conclusions (JTC), which is the proneness to require less information before forming beliefs or making a decision, has been related to formation and maintenance of delusions. Using data from the National Institute of Health Research Biomedical Research Centre Genetics and Psychosis (GAP) case–control study of first-episode psychosis (FEP), we set out to test whether the presence of JTC would predict poor clinical outcome at 4 years.

One-hundred and twenty-three FEP patients were assessed with the Positive and Negative Syndrome Scale (PANSS), Global Assessment of Functioning (GAF) and the probabilistic reasoning ‘Beads’ Task at the time of recruitment. The sample was split into two groups based on the presence of JTC bias. Follow-up data over an average of 4 years were obtained concerning clinical course and outcomes (remission, intervention of police, use of involuntary treatment – the Mental Health Act (MHA) – and inpatient days).

FEP who presented JTC at baseline were more likely during the follow-up period to be detained under the MHA [adjusted OR 15.62, 95% confidence interval (CI) 2.92–83.54, p = 0.001], require intervention by the police (adjusted OR 14.95, 95% CI 2.68–83.34, p = 0.002) and have longer admissions (adjusted IRR = 5.03, 95% CI 1.91–13.24, p = 0.001). These associations were not accounted for by socio-demographic variables, IQ and symptom dimensions.

JTC in FEP is associated with poorer outcome as indicated and defined by more compulsion police intervention and longer periods of admission. Our findings raise the question of whether the implementation of specific interventions to reduce JTC, such as Metacognition Training, may be a useful addition in early psychosis intervention programmes.

Major depressive disorder (MDD) is underdiagnosed and undertreated in schizophrenia, and has been strongly associated with impaired quality of life.

To determine the prevalence and associated factors of MDD and unremitted MDD in schizophrenia, to compare treated and non-treated MDD.

Participants were included in the FondaMental Expert Centers for Schizophrenia and received a thorough clinical assessment. MDD was defined by a Calgary score ≥6. Non-remitted MDD was defined by current antidepressant treatment (unchanged for >8 weeks) and current Calgary score ≥6.

613 patients were included and 175 (28.5%) were identified with current MDD. MDD has been significantly associated with respectively paranoid delusion (odds ratio 1.8; P = 0.01), avolition (odds ratio 1.8; P = 0.02), blunted affect (odds ratio 1.7; P = 0.04) and benzodiazepine consumption (odds ratio 1.8; P = 0.02). Antidepressants were associated with lower depressive symptoms score (5.4 v. 9.5; P < 0.0001); however, 44.1% of treated patients remained in non-remittance MDD. Nonremitters were found to have more paranoid delusion (odds ratio 2.3; P = 0.009) and more current alcohol misuse disorder (odds ratio 4.8; P = 0.04). No antidepressant class or specific antipsychotic were associated with higher or lower response to antidepressant treatment. MDD was associated with Metabolic syndrome (31.4 v. 20.2%; P = 0.006) but not with increased C-reactive protein.

Antidepressant administration is associated with lower depressive symptom level in patients with schizophrenia and MDD. Paranoid delusions and alcohol misuse disorder should be specifically explored and treated in cases of non-remission under treatment. MetS may play a role in MDD onset and/or maintenance in patients with schizophrenia.

None.

There is no consensus as to whether magnetic resonance imaging (MRI) should be used as part of the initial clinical evaluation of patients with first-episode psychosis (FEP).

(a) To assess the logistical feasibility of routine MRI; (b) to define the clinical significance of radiological abnormalities in patients with FEP.

Radiological reports from MRI scans of two FEP samples were reviewed; one comprised 108 patients and 98 healthy controls recruited to a research study and the other comprised 241 patients scanned at initial clinical presentation plus 66 healthy controls.

In the great majority of patients, MRI was logistically feasible. Radiological abnormalities were reported in 6% of the research sample and in 15% of the clinical sample (odds ratio (OR) = 3.1, 95% CI 1.26–7.57, χ2(1) = 6.63, P = 0.01). None of the findings necessitated a change in clinical management.

Rates of neuroradiological abnormalities in FEP are likely to be underestimated in research samples that often exclude patients with organic abnormalities. However, the majority of findings do not require intervention.

Clozapine remains the only evidence-based antipsychotic for treatment-resistant schizophrenia (TRS). The ability to predict which patients with their first onset of schizophrenia would subsequently meet criteria for treatment resistance (TR) could help to diminish the severe functional disability which may ensue if TR is not recognized and correctly treated.

This is a 5-year longitudinal assessment of clinical outcomes in a cohort of 246 first-episode schizophrenia spectrum patients recruited as part of the NIHR Genetics and Psychosis (GAP) study conducted in South London from 2005 to 2010. We examined the relationship between baseline demographic and clinical measures and the emergence of TR. TR status was determined from a review of electronic case records. We assessed for associations with early-, and late-onset TR, and non-TR, and differences between those TR patients treated with clozapine and those who were not.

Seventy per cent (n = 56) of TR patients, and 23% of the total study population (n = 246) were treatment resistant from illness onset. Those who met criteria for TR during the first 5 years of illness were more likely to have an early age of first contact for psychosis (<20 years) [odds ratio (OR) 2.49, 95% confidence interval (CI) 1.25–4.94] compared to those with non-TR. The relationship between an early age of first contact (<20 years) and TR was significant in patients of Black ethnicity (OR 3.71, 95% CI 1.44–9.56); and patients of male gender (OR 3.13 95% CI 1.35–7.23).

For the majority of the TR group, antipsychotic TR is present from illness onset, necessitating increased consideration for the earlier use of clozapine.