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Background Clozapine is the only effective medication for treatment-resistant schizophrenia; however, its mechanism of action remains unclear. The present study explored whether its effectiveness is related to changes in hematological measures after clozapine initiation. Methods Patients with treatment-resistant schizophrenia commenced on clozapine between January 2007 and December 2014 by the United Kingdom’s largest mental health trust were identified from electronic patient records. Hematological data from these patients were obtained from a monitoring registry. White blood cell, neutrophil, and platelet count were assessed at baseline and during the early phase of clozapine treatment. Clozapine response at 3 months was defined as “much,” or “very much” improved on the seven-point Clinical Global Impression—Improvement (CGI-I) subscale. Results In the total sample (n = 188), clozapine initiation was associated with a significant transient increase (peaking in weeks 3 to 4) in white blood cell, neutrophil, and platelet count (P < 0.001). There were 112 (59.6%) patients that responded to treatment; however, none of the hematological factors assessed at baseline, nor changes in these factors, were directly associated with treatment response. Implications Clozapine treatment is associated with transient hematological changes during the first month of treatment; however, there was no evidence that these were related to the therapeutic response.

Posterior reversible encephalopathy syndrome (PRES) is a clinically and radiologically diagnosed disorder distinguished by subcortical vasogenic cerebral edema. To date, its presentation has been described through summarized neurological categories, such as seizures, headaches, "confusion," and "altered mental function." This retrospective case series identified all cases of clinically confirmed, radiologically diagnosed PRES resulting in treatment in a large teaching hospital from 2010 to 2019. The authors conducted a search for the term "reversible encephalopathy" in the hospital clinical radiology information system, followed by an audit of scan reports and clinical records. The most common reasons for psychiatric referral were addictions, acute psychosis, depression, suicidality, and treatment refusal. Multidisciplinary staff should consider PRES as a rare, organic differential diagnosis for acute mental state changes. Physicians should be aware of elevated rates of post-PRES psychiatric symptoms and consider whether psychiatric consultation may enhance recovery.

Introduction A proportion of patients admitted to acute-stroke settings have not had a stroke, but have conditions mimicking a stroke. Approximately 25% of suspected stroke cases are “stroke mimics” and 2% are patients with functional symptoms — “functional stroke mimics”. This study aimed to explore experiences and illness perceptions of patients with functional symptoms admitted to hyperacute stroke wards. Methods This study used mixed methods. Patients with functional stroke symptoms participated in semistructured qualitative interviews immediately after admission to one of two acute-stroke units in London and again 2 months after hospital discharge. Qualitative data were assessed using thematic analysis. The Brief Illness Perception Questionnaire (Brief-IPQ) measured illness perceptions at admission and at 2-month follow-up. Results A total of 36 participants completed baseline interviews and 25 completed follow-up. Six themes emerged: physical symptom experience, emotional and coping responses, symptom causes, hospital experiences, views on the future, and uncertainty after hospital discharge. Mean Brief-IPQ score at admission was 49.3 (SD: 9.9), indicating a moderate–high level of perceived illness threat. Participants presented with a range of functional symptoms. At baseline, participants were highly concerned about their symptoms, but this had decreased at 2-month follow-up. Two months later, many were confused as to the cause of their admission. Conclusion This is the first study to examine functional stroke patients’ experiences of acute-stroke admission. At admission, patients expressed confusion regarding their diagnosis, experienced high levels of emotional distress, and were concerned they were perceived as time wasting by stroke clinicians. While most participants experienced symptom recovery, there was a significant subgroup for whom symptoms persisted or worsened. A lack of care guidelines on the management of functional stroke patients may perpetuate functional symptoms.

Background People with psychotic disorders have reduced life expectancy largely because of physical health problems, especially cardiovascular disease, that are complicated by the use of tobacco and cannabis. Objectives We set out to (1) chart lifestyle and substance use choices and the emergence of cardiometabolic risk from the earliest presentation with psychosis, (2) develop a pragmatic health promotion intervention integrated within the clinical teams to improve the lifestyle choices and health outcomes of people with psychosis and (3) evaluate the clinical effectiveness and cost-effectiveness of that health promotion intervention. Design We performed a longitudinal cohort study of people presenting with their first episode of psychosis in three mental health trusts and followed up participants for 1 year [work package 1, physical health and substance use measures in first episode of psychosis (PUMP)]. We used an iterative Delphi methodology to develop and refine a modular health promotion intervention, improving physical health and reducing substance use in psychosis (IMPaCT) therapy, which was to be delivered by the patient’s usual care co-ordinator and used motivational interviewing techniques and cognitive–behavioural therapy to improve health choices of people with psychosis (work package 2). We then conducted a multicentre, two-arm, parallel-cluster, randomised controlled trial to determine the clinical effectiveness and cost-effectiveness of using the intervention with people with established psychosis (work package 3: IMPaCT randomised controlled trial) in five UK mental health trusts. The work took place between 2008 and 2014. Participants All people aged between 16 and 65 years within 6 months of their first presentation with a non-organic psychosis and who were proficient in English were eligible for inclusion in the PUMP study. Participants in the work package 2 training development were staff selected from a range of settings, working with psychosis. Participants in the phase 3 Delphi consensus and manual development comprised three expert groups of (1) therapists/researchers recruited from the local and national community, (2) clinicians and (3) service users, each of whom took part in two iterative review and feedback sessions. For work package 3, IMPaCT randomised controlled trial, care co-ordinators in participating community mental health teams who were permanently employed and had a minimum of four eligible patients (i.e. aged between 18 and 65 years with a diagnosis of a psychotic disorder) on their caseload were eligible to participate. In studies 1 and 3, patient participants were ineligible if they were pregnant or had a major illness that would have had an impact on their metabolic status or if they had a significant learning disability. All participants were included in the study only after giving written confirmed consent. Main outcome measures Cardiometabolic risk markers, including rates of obesity and central obesity, and levels of glycated haemoglobin (HbA1c) and lipids, were the main outcomes in work package 1 (PUMP), with descriptive data presented on substance use. Our primary outcome measure for the IMPaCT randomised controlled trial was the physical or mental health component Short Form questionnaire-36 items quality-of-life scores at 12 months. Results Obesity rates rose from 18% at first presentation with psychosis to 24% by 1 year, but cardiometabolic risk was not associated with baseline lifestyle and substance use choices. Patterns of increase in the levels of HbA1c over the year following first presentation showed variation by ethnic group. We recruited 104 care co-ordinators, of whom 52 (with 213 patients) were randomised to deliver IMPaCT therapy and 52 (with 193 patients) were randomised to deliver treatment as usual, in keeping with our power calculations. Of these 406 participants with established psychosis, 318 (78%) and 301 (74%) participants, respectively, attended the 12- and 15-month follow-ups. We found no significant effect of IMPaCT therapy compared with treatment as usual on the physical or mental health component Short Form questionnaire-36 items scores at either time point in an intention-to-treat analysis [physical health score (‘d’) –0.17 at 12 months and –0.09 at 15 months; mental health score (‘d’) 0.03 at 12 months and –0.05 at 15 months] or on costs. Nor did we find an effect on other cardiovascular risk indicators, including diabetes, except in the case of high-density lipoprotein cholesterol, which showed a trend for greater benefit with IMPaCT therapy than with treatment as usual (treatment effect 0.085, 95% confidence interval 0.007 to 0.16; p = 0.034). Limitations Follow-up in work package 1 was challenging, with 127 out of 293 participants attending; however, there was no difference in cardiometabolic measures or demographic factors at baseline between those who attended for follow-up and those who did not. In work package 3, the IMPaCT randomised controlled trial, care co-ordinators struggled to provide additional time to their patients that was devoted to the health promotion intervention on top of their usual clinical care contact with them. Conclusions Cardiometabolic risk is prominent even soon after first presentation with psychosis and increases over time. Lifestyle choices and substance use habits at first presentation do not predict those who will be most cardiometabolically compromised 1 year later. Training and supervising care co-ordinators to deliver a health promotion intervention to their own patients on top of routine care is not effective in the NHS for improving quality of life or reducing cardiometabolic risk. Future work Further work is needed to develop and evaluate effective, cost-effective and affordable ways of preventing the emergence of and reversing existing cardiometabolic risk indicators in people with psychosis. Trial registration Current Controlled Trials ISRCTN58667926. Funding This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 8, No. 1. See the NIHR Journals Library website for further project information.

Stroke services have been reconfigured in recent years to facilitate early intervention. Throughout stroke settings, some patients present with functional symptoms that cannot be attributed to a structural cause. Emphasis on fast diagnosis and treatment means that a proportion of patients entering the care pathway present with functional symptoms that mimic stroke or have functional symptoms in addition to vascular stroke. There is limited understanding of mechanisms underlying functional stroke symptoms, how the treatment of such patients should be managed, and no referral pathway or treatment. Predisposing factors vary between individuals, and symptoms are heterogeneous: onset can be acute or insidious, and duration can be short-lived or chronic in the context of new or recurrent illness cognitions and behaviors. This article proposes a conceptual model of functional symptoms identified in stroke services and some hypotheses based on a narrative review of the functional neurological disorder literature. Predisposing factors may include illness experiences, stressors, and chronic autonomic nervous system arousal. Following the onset of distressing symptoms, perpetuating factors may include implicit cognitive processes, classical and operant conditioning, illness beliefs, and behavioral responses, which could form the basis of treatment targets. The proposed model will inform the development of theory-based interventions as well as a functional stroke care pathway.

BackgroundCatatonia, a severe neuropsychiatric syndrome, has few studies of sufficient scale to clarify its epidemiology or pathophysiology. We aimed to characterise demographic associations, peripheral inflammatory markers and outcome of catatonia.MethodsElectronic healthcare records were searched for validated clinical diagnoses of catatonia. In a case–control study, demographics and inflammatory markers were compared in psychiatric inpatients with and without catatonia. In a cohort study, the two groups were compared in terms of their duration of admission and mortality.ResultsWe identified 1456 patients with catatonia (of whom 25.1% had two or more episodes) and 24 956 psychiatric inpatients without catatonia. Incidence was 10.6 episodes of catatonia per 100 000 person-years. Patients with and without catatonia were similar in sex, younger and more likely to be of Black ethnicity. Serum iron was reduced in patients with catatonia [11.6 v. 14.2 μmol/L, odds ratio (OR) 0.65 (95% confidence interval (CI) 0.45–0.95), p = 0.03] and creatine kinase was raised [2545 v. 459 IU/L, OR 1.53 (95% CI 1.29–1.81), p < 0.001], but there was no difference in C-reactive protein or white cell count. N-Methyl-d-aspartate receptor antibodies were significantly associated with catatonia, but there were small numbers of positive results. Duration of hospitalisation was greater in the catatonia group (median: 43 v. 25 days), but there was no difference in mortality after adjustment.ConclusionsIn the largest clinical study of catatonia, we found catatonia occurred in approximately 1 per 10 000 person-years. Evidence for a proinflammatory state was mixed. Catatonia was associated with prolonged inpatient admission but not with increased mortality.

BACKGROUND: To determine gender differences in rates of sexual and physical abuse in functional movement disorders compared to controls and evaluate if the gender disparity of functional movement disorders is associated with abuse history. METHODS: We performed a retrospective case-control study of self-reported trauma data from 696 patients (512 women) with functional movement disorders from six clinical sites compared to 141 controls (98 women) and population data. Chi-square was used to assess gender and disorder associations; logistic regression was used to model additive effects of abuse and calculate the attributable fraction of abuse to disorder prevalence. RESULTS: Higher rates of sexual abuse were reported by women (35.3%) and men (11.5%) with functional movement disorders compared to controls (10.6% of women; 5.6% of men). History of sexual abuse increased the likelihood of functional movement disorders among women by an odds ratio of 4.57 (95% confidence interval, 2.31–9.07; p < 0.0001) and physical abuse by an odds ratio of 2.80 (95% confidence interval, 1.53–5.12; p=0.0007). Population attributable fraction of childhood sexual abuse to functional movement disorders in women was 0.12 (0.05–0.19). No statistically significant associations were found in men, but our cohort of men was underpowered despite including multiple sites. CONCLUSIONS: Our study suggests that violence against women may account for some of the gender disparity in rates of functional movement disorders. Most people with functional movement disorders do not report a history of abuse, so it remains just one among many relevant risk factors to consider.

The dissociative disorders and germane conditions are reliably characterized by elevated responsiveness to direct verbal suggestions. However, it remains unclear whether atypical responsiveness to suggestion is similarly present in depersonalization-derealization disorder (DDD). 55 DDD patients and 36 healthy controls completed a standardised behavioural measure of direct verbal suggestibility that includes a correction for compliant responding (BSS-C), and psychometric measures of depersonalization-derealization (CDS), mindfulness (FFMQ), imagery vividness (VVIQ), and anxiety (GAD-7). Patients displayed nonsignificantly lower suggestibility than controls, (g = 0.26) but significantly lower mindfulness (g = 1.38), and imagery vividness (g = 0.63), and significantly greater anxiety (g = 1.39). Although suggestibility did not correlate with severity of depersonalization-derealization symptoms in controls, r=-.03 [95% CI: -.36, .30], there was a weak tendency for a positive association in patients, r=.25, [95% CI: -.03, .48]. Exploratory analyses revealed that patients with more severe anomalous bodily experiences were also more responsive to suggestion, an effect not seen in controls. This study demonstrates that DDD is not characterized by elevated responsiveness to direct verbal suggestions. These results have implications for the aetiology and treatment of this condition, as well as its classification as a dissociative disorder in psychiatric nosology.

Thinking about our own death and its salience in relation to decision making has become a fruitful area of multidisciplinary research across the breadth of psychological science. By bringing together experts from philosophy, cognitive and affective neuroscience, clinical and computational psychiatry we have attempted to set out the current state of the art and point to areas of further enquiry. One stimulus for doing this is the need to engage with policy makers who are now having to consider guidelines on suicide and assisted suicide so that they may be aware of their own as well as the wider populations’ cognitive processes when confronted with the ultimate truth of mortality.

Professor David is among Britain’s preeminent psychiatrists and academics. His research in recent times has focused on schizophrenia, neuropsychiatry, medically unexplained syndromes and neuroimaging. He has particular interest and expertise in the concept and nature of ‘insight’ in schizophrenia, and its relation to treatment compliance and an individual’s decision-making capacity. Professor David is Director of the UCL Institute of Mental Health.Professor David is a widely published author in influential peer-reviewed academic journals. He recently published his latest book, the acclaimed Into the Abyss: A Neuropsychiatrist’s Notes on Troubled Minds. Dr David has co-edited several books, including The Self in Neuroscience and Psychiatry and Insight and Psychosis. He is the co-editor of the journal Cognitive Neuropsychiatry.Professor David is a founding member of both the British Neuropsychological Society and the British Neuropsychiatry Association – he was Chair of the latter organization between 2004 and 2007. In 2018, he delivered the inaugural lecture as part of the Kings Lectures series.AbstractA maverick is an outsider who has rare qualities which may be highly valued in many areas of society. Empirical research has validated ‘maverickism’ as a recognisable personality type. Medicine and psychiatry have always attracted mavericks – neuropsychiatry in particular. Over the last 150 years there have been several notable examples who have a few key characteristics in common, but their contribution has been mostly negative, sometimes disastrously so. Modern mavericks continue to flourish perhaps aided by the loosening of bounds on science communication and governance but also because of the difficulty mainstream neuropsychiatry has in communicating the biopsychosocial approach in a way that satisfies some sufferers. The question is whether they can be a useful stimulus.

ObjectiveTo test whether variant connective tissue structure, as indicated by the presence of joint hypermobility, poses a developmental risk for mood disorders in adolescence.DesignCohort-based case–control study.SettingData from the Avon Longitudinal Study of Parents and Children (ALSPAC) were interrogated.Participants6105 children of the ALSPAC cohort at age 14 years old, of whom 3803 also were assessed when aged 18 years.Main outcome measuresIn a risk analysis, we examined the relationship between generalised joint hypermobility (GJH) at age 14 years with psychiatric symptoms at age 18 years. In an association analysis, we examined the relationship between presence of symptomatic joint hypermobility syndrome (JHS) and International Classification of Diseases-10 indication of depression and anxiety (Clinical Interview Schedule Revised (CIS-R), Anxiety Sensitivity Index) at age 18 years.ResultsGJH was more common in females (n=856, 28%) compared with males (n=319, 11%; OR: 3.20 (95% CI: 2.78 to 3.68); pt(3278)=3.95; pt(3442)=5.50; pConclusionsVariant collagen, indexed by joint hypermobility, is linked to the emergence of depression and anxiety in adolescence, an effect mediated by autonomic factors in males. Recognition of this association may motivate further evaluation, screening and interventions to mitigate development of psychiatric disorders and improve health outcomes.

Background: Insight into illness is often used in clinical and legal contexts, for example, as evidence of decision-making capacity. However, it is unclear whether this disadvantages certain groups protected under equality legislation. To our knowledge, this question has yet to be addressed systematically. Therefore, the present study reviews empirical studies that look at the relationship between insight and sociodemographic variables. Methods: A systematic search of six bibliographic databases (CENTRAL, CINAHL, Cochrane Library of Systematic Reviews, EMBASE, MEDLINE and PsycINFO) was conducted, which yielded 6,192 results. Study characteristics and outcomes (associations between insight and socio-demographic variables) were then extracted from 207 eligible studies. This included protected characteristics under the Equality Act (2010): age, sex, ethnicity, marital status and religion. Weighted confidence estimates were calculated and relevant moderators included in a random effects meta-analysis. A study protocol was registered prospectively on PROSPERO, ID: CRD42019120117. Results: Insight was not strongly associated with any sociodemographic variable. Better insight was weakly but significantly associated with white ethnicity, being employed, younger age and more years of education. The age associations were mostly explained by relevant moderating variables. For people with schizophrenia, the associations between sociodemographic variables and insight were comparable to associations with decision making capacity. Conclusions: Our results suggest that insight is not strongly associated with any sociodemographic variables. Further research is needed to clarify potential associations, particularly with non-white ethnicity and proxies for social support.

Background: Ecological momentary assessment (EMA) tools appear to be useful interventions for collecting real-time data on patients behavior and functioning. However, concerns have been voiced regarding the acceptability of EMA among patients with schizophrenia and the factors influencing EMA acceptability. Objective: The aim of this study was to investigate the acceptability of a passive smartphone-based EMA app, evidence-based behavior (eB2), among patients with schizophrenia spectrum disorders and the putative variables underlying their acceptance. Methods: The participants in this study were from an ongoing randomized controlled trial (RCT) of metacognitive training, consisting of outpatients with schizophrenia spectrum disorders (F20-29 of 10th revision of the International Statistical Classification of Diseases and Related Health Problems), aged 18-64 years, none of whom received any financial compensation. Those who consented to installation of the eB2 app (users) were compared with those who did not (nonusers) in sociodemographic, clinical, premorbid adjustment, neurocognitive, psychopathological, insight, and metacognitive variables. A multivariable binary logistic regression tested the influence of the above (independent) variables on being user versus nonuser (acceptability), which was the main outcome measure. Results: Out of the 77 RCT participants, 24 (31%) consented to installing eB2, which remained installed till the end of the study (median follow-up 14.50 weeks) in 14 participants (70%). Users were younger and had a higher education level, better premorbid adjustment, better executive function (according to the Trail Making Test), and higher cognitive insight levels (measured with the Beck Cognitive Insight Scale) than nonusers (univariate analyses) although only age (OR 0.93, 95% CI 0.86-0.99; P=048) and early adolescence premorbid adjustment (OR 0.75, 95% CI 0.61-0.93; P=01) survived the multivariable regression model, thus predicting eB2 acceptability. Conclusions: Acceptability of a passive smartphone-based EMA app among participants with schizophrenia spectrum disorders in this RCT where no participant received financial compensation was, as expected, relatively low, and linked with being young and good premorbid adjustment. Further research should examine how to increase EMA acceptability in patients with schizophrenia spectrum disorders, in particular, older participants and those with poor premorbid adjustment. This study was supported by the Universidad Autónoma de Madrid and European Union via the Intertalentum Project Grant-Marie Skodowska Curie Actions (GA 713366) to JDLM who is the principal investigator. This grant, therefore, funds both JDLM's salary and the consumable expenses related to the study. MLB, VGRR, ASEM, PJEA, SSA, LMI, LML, and EBG's salaries come from the Hospital Universitario Fundación Jiménez Díaz, where this study is currently being carried out, which therefore provides the necessary institutional/departmental support for its development. Additional departmental support concerning the use of EMA is provided by the Instituto de Salud Carlos III (Madrid, Spain) (ISCIII PI16/01852), the Madrid Regional Government (Madrid, Spain) (B2017/BMD-3740 AGES-CM 2CM; Y2018/TCS-4705 PRACTICO-CM), and the Spanish Ministerio de Ciencia, Innovación y Universidades (TEC2017-92552-EXP). ASD acknowledges funding support from University College London, which covers his salary. The funders had no role in hypothesis generation, study design, decision to publish, or the manuscript writing. No funder has a conflict of interest in relation to the study's results and findings. The funding bodies supported the peer review for this manuscript.

PURPOSE: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a form of autoimmune encephalitis associated with EEG abnormalities. In view of the potentially severe outcomes, there is a need to develop prognostic tools to inform clinical management. The authors explored whether quantitative EEG was able to predict outcomes in patients with suspected anti-NMDAR encephalitis. METHODS: A retrospective, observational study was conducted of patients admitted to a tertiary clinical neuroscience center with suspected anti-NMDAR encephalitis. Peak power and peak frequency within delta (

BackgroundNeuroanatomical 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.MethodsStructural 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.ResultsFEP 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.ConclusionsThis 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.

BackgroundImpairments of contextual processing and theory of mind (ToM) have both been offered as accounts of the deviant language characterising formal thought disorder (FTD) in schizophrenia. This study investigated these processes in patients' dialogue. We predicted that FTD patients would show a decrement in linguistic alignment, associated with impaired ToM in dialogue.MethodsSpeech samples were elicited via participation in an interactive computer-based task and a semi-structured interview to assess contextual processing abilities and ToM skills in dialogue, respectively, and from an interactive card-sorting task to measure syntactic alignment. Degree of alignment in dialogue and the syntactic task, and evidence of ToM in (i) dialogue and (ii) a traditional ToM task were compared across schizophrenia patients with FTD (n = 21), non-FTD patients (n = 22) and healthy controls (n = 21).ResultsFTD patients showed less alignment than the other two groups in dialogue, and than healthy controls on the syntactic task. FTD patients showed poorer performance on the ToM task than the other two groups, but only compared to the healthy controls in dialogue. The FTD group's degree of alignment in dialogue was correlated with ToM performance in dialogue but not with the traditional ToM task or with syntactic alignment.ConclusionsIn dialogue, FTD patients demonstrate an impairment in employing available contextual information to facilitate their own subsequent production, which is associated with a ToM deficit. These findings indicate that a contextual processing deficit impacts on exploiting representations via the production system impoverishing the ability to make predictions about upcoming utterances in dialogue.

Summary Catatonia is a psychomotor disorder featuring stupor, posturing, and echophenomena. This Series paper examines the evidence for immune dysregulation in catatonia. Activation of the innate immune system is associated with mutism, withdrawal, and psychomotor retardation, which constitute the neurovegetative features of catatonia. Evidence is sparse and conflicting for acute-phase activation in catatonia, and whether this feature is secondary to immobility is unclear. Various viral, bacterial, and parasitic infections have been associated with catatonia, but it is primarily linked to CNS infections. The most common cause of autoimmune catatonia is N-methyl-D-aspartate receptor (NMDAR) encephalitis, which can account for the full spectrum of catatonic features. Autoimmunity appears to cause catatonia less by systemic inflammation than by the downstream effects of specific actions on extracellular antigens. The specific association with NMDAR encephalitis supports a hypothesis of glutamatergic hypofunction in catatonia.

BACKGROUND: There is a paucity of longitudinal research investigating vitamin D in people with early psychosis.METHOD: Vitamin D levels were measured in 168 patients (64% (n = 108) male, mean age 29.3 (9.8) years) with first episode psychosis (FEP), along with measures of clinical state at baseline and at 12 months follow up. We assessed the a) cross sectional, and; b) longitudinal relationships between continuous and categorical 25-hydroxyvitamin D (25(OH)D) levels and clinical symptoms at first contact for psychosis and at 12 months.RESULTS: In FEP, 80% (n = 134) at baseline, and 76% at 12 months follow up, had suboptimal vitamin D levels (CONCLUSION: We identified a prospective association between higher baseline serum Vitamin D levels and lower total psychotic symptoms and negative symptoms of psychosis at 12 months after first contact for psychosis. The results of this study require replication in larger prospective studies, and highlight the need for large randomised trials to assess the effect of vitamin D supplementation on symptoms of psychosis in FEP.

BACKGROUND: Metabolic abnormalities and peripheral inflammation have been increasingly reported in patients at the onset of psychosis and associated with important physical health disorders and increased mortality. However, the impact of an abnormal metabolic-inflammatory status on the psychiatric outcome of these patients has not yet been investigated.OBJECTIVES: The aims of this study were 1) to explore whether, in a sample of patients at their first episode of psychosis (FEP), an overall metabolic-inflammatory status may be measured, by combining metabolic and inflammatory variables in metabolic-inflammatory factors; 2) to explore the association between these factors and clinical outcome at 1-year follow-up (FU), in terms of symptoms severity and treatment response.METHODS: In this longitudinal study we recruited 42 FEP patients and 46 healthy controls (HC) matched with patients for age, gender and ethnicity. At baseline (T1) we measured high sensitivity C-reactive protein (hsCRP) as biomarker of inflammation, and body mass index (BMI), lipid profile and gluco-metabolic parameters (glycated hemoglobin (HbA1c) and fasting glucose) as metabolic variables. A principal component analysis (PCA) was then used to reduce the dimensionality of the dataset accounting for both inflammation and metabolic status. In FEP patients, we assessed symptoms severity at T1 and at 1-year FU (T2) as well as treatment response to antipsychotics at T2.RESULTS: at T1, FEP showed higher HbA1c (p = 0.034), triglycerides (TG) (p = 0.045) and BMI (p = 0.026) than HC. PCA identified 3 factors: factor 1 accounting for hsCRP, TG and BMI, factor 2 accounting for LDL and cholesterol, and factor 3 accounting for fasting glucose and HbA1c. Factor 1 was associated with T1 negative symptoms severity (p = 0.021) and predicted T2 positive (p = 0.004) and overall symptoms severity (0.001), as well as general psychopathology (p CONCLUSION: In this sample of FEP patients, inflammation and metabolism, closely correlated at the onset of psychosis, proved to play a key role as predictors of the clinical course of psychosis when combined in a single factor. These findings offer an important potential target for early screening and interventions.

AimsSuicide accounts for 2.2% of all years of life lost worldwide. We aimed to establish whether infectious epidemics are associated with any changes in the incidence of suicide or the period prevalence of self-harm, or thoughts of suicide or self-harm, with a secondary objective of establishing the frequency of these outcomes.MethodsIn this systematic review and meta-analysis, MEDLINE, Embase, PsycINFO and AMED were searched from inception to 9 September 2020. Studies of infectious epidemics reporting outcomes of (a) death by suicide, (b) self-harm or (c) thoughts of suicide or self-harm were identified. A random-effects model meta-analysis for the period prevalence of thoughts of suicide or self-harm was conducted.ResultsIn total, 1354 studies were screened with 57 meeting eligibility criteria, of which 7 described death by suicide, 9 by self-harm, and 45 thoughts of suicide or self-harm. The observation period ranged from 1910 to 2020 and included epidemics of Spanish Flu, severe acute respiratory syndrome, human monkeypox, Ebola virus disease and coronavirus disease 2019 (COVID-19). Regarding death by suicide, data with a clear longitudinal comparison group were available for only two epidemics: SARS in Hong Kong, finding an increase in suicides among the elderly, and COVID-19 in Japan, finding no change in suicides among children and adolescents. In terms of self-harm, five studies examined emergency department attendances in epidemic and non-epidemic periods, of which four found no difference and one showed a reduction during the epidemic. In studies of thoughts of suicide or self-harm, one large survey showed a substantial increase in period prevalence compared to non-epidemic periods, but smaller studies showed no difference. As a secondary objective, a meta-analysis of thoughts of suicide and self-harm found that the pooled prevalence was 8.0% overall (95% confidence interval (CI) 5.2–12.0%; 14 820 of 99 238 cases in 24 studies) over a time period of between seven days and six months. The quality assessment found 42 studies were of low quality, nine of moderate quality and six of high quality.ConclusionsThere is little robust evidence on the association of infectious epidemics with suicide, self-harm and thoughts of suicide or self-harm. There was an increase in suicides among the elderly in Hong Kong during SARS and no change in suicides among young people in Japan during COVID-19, but it is unclear how far these findings may be generalised. The development of up-to-date self-harm and suicide statistics to monitor the effect of the current pandemic is an urgent priority.

BACKGROUNDInsight is often used in clinical and legal contexts e.g. as evidence of decision-making capacity. However, it is unclear whether this disadvantages certain groups protected under equality legislation. To our knowledge, this question has yet to be addressed systematically. Therefore, the present study reviews empirical studies that look at the relationship between insight and sociodemographic variables. METHODSA systematic search of six bibliographic databases (CENTRAL, CINAHL, Cochrane Library of Systematic Reviews, EMBASE, MEDLINE and PsycINFO) was conducted, which yielded 6192 results. Study characteristics and outcomes (associations between insight and socio-demographic variables) were then extracted from 207 eligible studies. This included protected characteristics under the Equality Act (2010): age, sex, ethnicity, marital status and religion. Weighted confidence estimates were calculated and relevant moderators included in a random effects meta-analysis. A study protocol was registered prospectively on PROSPERO, ID: CRD42019120117. RESULTSInsight was not strongly associated with age, gender or ethnicity. Better insight was weakly but significantly associated with white ethnicity, being employed, younger age and more years of education. The age associations were mostly explained relevant moderating variables. Cultural context (studies done in individualistic versus collectivist countries) did not moderate associations. For people with schizophrenia, the associations between sociodemographic variables and insight were comparable to associations with decision making capacity. CONCLUSIONSOur results moderate some concerns over whether insight is discriminatory if used as evidence in mental capacity assessment. We have identified specific subgroups where further research is needed to clarify potential associations.

The hyper-function of the striatal dopamine system has been suggested to underlie key pathophysiological mechanisms in schizophrenia. Moreover, patients have been observed to present a significant elevation of dopamine receptor availability compared to healthy controls. Although it is difficult to measure dopamine levels directly in humans, neurochemical imaging techniques such as single-photon emission computed tomography (SPECT) provide indirect indices ofWe focused on the role of dopamine postsynaptic regulation using [The mean specific striatal binding showed no significant difference between patients and controls (estimated difference = 0.001; 95% CI -0.11 to 0.11;Medication-naïve patients with recent-onset schizophrenia have similar D

Background: Several cross-sectional studies report brain structure differences between healthy volunteers and subjects at genetic or clinical high risk of developing schizophrenia. However, longitudinal studies are important to determine whether altered trajectories of brain development precede psychosis onset.Methods: We conducted a systematic review to determine if brain trajectories differ between (i) those with psychotic experiences (PE), genetic (GHR) or clinical high risk (CHR), compared to healthy volunteers, and (ii) those who transition to psychosis compared to those who do not.Results: Thirty-eight studies measured gray matter and 18 studies measured white matter in 2,473 high risk subjects and 990 healthy volunteers. GHR, CHR, and PE subjects show an accelerated decline in gray matter primarily in temporal, and also frontal, cingulate and parietal cortex. In those who remain symptomatic or transition to psychosis, gray matter loss is more pronounced in these brain regions. White matter volume and fractional anisotropy, which typically increase until early adulthood, did not change or reduced in high risk subjects in the cingulum, thalamic radiation, cerebellum, retrolenticular part of internal capsule, and hippocampal–thalamic tracts. In those who transitioned, white matter volume and fractional anisotropy reduced over time in the inferior and superior fronto-occipital fasciculus, corpus callosum, anterior limb of the internal capsule, superior corona radiate, and calcarine cortex.Conclusion: High risk subjects show deficits in white matter maturation and an accelerated decline in gray matter. Gray matter loss is more pronounced in those who transition to psychosis, but may normalize by early adulthood in remitters.

Highlights • 1st Neuroimaging Workgroup Meeting in Functional Neurological Disorder (FND). • Underscores the importance of FND cohort characterization in brain imaging research. • Details methodological approaches taken in FND neuroimaging research to date. • Research agenda proposed to definitely elucidate the neural circuitry of FND. • Discussions underway regarding having FND researchers join the ENIGMA consortium., Functional neurological disorder (FND) was of great interest to early clinical neuroscience leaders. During the 20th century, neurology and psychiatry grew apart – leaving FND a borderland condition. Fortunately, a renaissance has occurred in the last two decades, fostered by increased recognition that FND is prevalent and diagnosed using “rule-in” examination signs. The parallel use of scientific tools to bridge brain structure - function relationships has helped refine an integrated biopsychosocial framework through which to conceptualize FND. In particular, a growing number of quality neuroimaging studies using a variety of methodologies have shed light on the emerging pathophysiology of FND. This renewed scientific interest has occurred in parallel with enhanced interdisciplinary collaborations, as illustrated by new care models combining psychological and physical therapies and the creation of a new multidisciplinary FND society supporting knowledge dissemination in the field. Within this context, this article summarizes the output of the first International FND Neuroimaging Workgroup meeting, held virtually, on June 17th, 2020 to appraise the state of neuroimaging research in the field and to catalyze large-scale collaborations. We first briefly summarize neural circuit models of FND, and then detail the research approaches used to date in FND within core content areas: cohort characterization; control group considerations; task-based functional neuroimaging; resting-state networks; structural neuroimaging; biomarkers of symptom severity and risk of illness; and predictors of treatment response and prognosis. Lastly, we outline a neuroimaging-focused research agenda to elucidate the pathophysiology of FND and aid the development of novel biologically and psychologically-informed treatments.

Previous in vitro and postmortem research suggests that inflammation may lead to structural brain changes via activation of microglia and/or astrocytic dysfunction in a range of neuropsychiatric disorders.To investigate the relationship between inflammation and changes in brain structures in vivo and to explore a transcriptome-driven functional basis with relevance to mental illness.This study used multistage linked analyses, including mendelian randomization (MR), gene expression correlation, and connectivity analyses. A total of 20 688 participants in the UK Biobank, which includes clinical, genomic, and neuroimaging data, and 6 postmortem brains from neurotypical individuals in the Allen Human Brain Atlas (AHBA), including RNA microarray data. Data were extracted in February 2021 and analyzed between March and October 2021.Genetic variants regulating levels and activity of circulating interleukin 1 (IL-1), IL-2, IL-6, C-reactive protein (CRP), and brain-derived neurotrophic factor (BDNF) were used as exposures in MR analyses.Brain imaging measures, including gray matter volume (GMV) and cortical thickness (CT), were used as outcomes. Associations were considered significant at a multiple testing-corrected threshold of P 1.1 × 10-4. Differential gene expression in AHBA data was modeled in brain regions mapped to areas significant in MR analyses; genes were tested for biological and disease overrepresentation in annotation databases and for connectivity in protein-protein interaction networks.Of 20 688 participants in the UK Biobank sample, 10 828 (52.3%) were female, and the mean (SD) age was 55.5 (7.5) years. In the UK Biobank sample, genetically predicted levels of IL-6 were associated with GMV in the middle temporal cortex (z score, 5.76; P = 8.39 × 10-9), inferior temporal (z score, 3.38; P = 7.20 × 10-5), fusiform (z score, 4.70; P = 2.60 × 10-7), and frontal (z score, -3.59; P = 3.30 × 10-5) cortex together with CT in the superior frontal region (z score, -5.11; P = 3.22 × 10-7). No significant associations were found for IL-1, IL-2, CRP, or BDNF after correction for multiple comparison. In the AHBA sample, 5 of 6 participants (83%) were male, and the mean (SD) age was 42.5 (13.4) years. Brain-wide coexpression analysis showed a highly interconnected network of genes preferentially expressed in the middle temporal gyrus (MTG), which further formed a highly connected protein-protein interaction network with IL-6 (enrichment test of expected vs observed network given the prevalence and degree of interactions in the STRING database: 43 nodes/30 edges observed vs 8 edges expected; mean node degree, 1.4; genome-wide significance, P = 4.54 × 10-9). MTG differentially expressed genes that were functionally enriched for biological processes in schizophrenia, autism spectrum disorder, and epilepsy.In this study, genetically determined IL-6 was associated with brain structure and potentially affects areas implicated in developmental neuropsychiatric disorders, including schizophrenia and autism.

BACKGROUND Ecological momentary assessment (EMA) tools appear to be useful interventions for collecting real-time data on patients’ behavior and functioning. However, concerns have been voiced regarding the acceptability of EMA among patients with schizophrenia and the factors influencing EMA acceptability. OBJECTIVE The aim of this study was to investigate the acceptability of a passive smartphone-based EMA app, evidence-based behavior (eB2), among patients with schizophrenia spectrum disorders and the putative variables underlying their acceptance. METHODS The participants in this study were from an ongoing randomized controlled trial (RCT) of metacognitive training, consisting of outpatients with schizophrenia spectrum disorders (F20-29 of 10th revision of the International Statistical Classification of Diseases and Related Health Problems), aged 18-64 years, none of whom received any financial compensation. Those who consented to installation of the eB2 app (users) were compared with those who did not (nonusers) in sociodemographic, clinical, premorbid adjustment, neurocognitive, psychopathological, insight, and metacognitive variables. A multivariable binary logistic regression tested the influence of the above (independent) variables on “being user versus nonuser” (acceptability), which was the main outcome measure. RESULTS Out of the 77 RCT participants, 24 (31%) consented to installing eB2, which remained installed till the end of the study (median follow-up 14.50 weeks) in 14 participants (70%). Users were younger and had a higher education level, better premorbid adjustment, better executive function (according to the Trail Making Test), and higher cognitive insight levels (measured with the Beck Cognitive Insight Scale) than nonusers (univariate analyses) although only age (OR 0.93, 95% CI 0.86-0.99; P=.048) and early adolescence premorbid adjustment (OR 0.75, 95% CI 0.61-0.93; P=.01) survived the multivariable regression model, thus predicting eB2 acceptability. CONCLUSIONS Acceptability of a passive smartphone-based EMA app among participants with schizophrenia spectrum disorders in this RCT where no participant received financial compensation was, as expected, relatively low, and linked with being young and good premorbid adjustment. Further research should examine how to increase EMA acceptability in patients with schizophrenia spectrum disorders, in particular, older participants and those with poor premorbid adjustment. CLINICALTRIAL ClinicalTrials.gov NCT04104347; https://clinicaltrials.gov/ct2/show/NCT04104347

Background\ud When psychosis develops in NMDA receptor (NMDAR) antibody encephalitis, it usually has an acute or subacute onset, and antipsychotic treatment may be ineffective and associated with adverse effects. Serum NMDAR antibodies have been reported in a minority of patients with first-episode psychosis (FEP), but their role in psychosis onset and response to antipsychotic treatment is unclear.\ud \ud Methods\ud Sera from 387 patients with FEP (duration of psychosis

ObjectivesTranscranial magnetic stimulation (TMS) has been used therapeutically for functional (conversion) motor symptoms but there is limited evidence for its efficacy and the optimal protocol. We examined the feasibility of a novel randomised controlled trial (RCT) protocol of TMS to treat functional limb weakness.DesignA double-blind (patient, outcome assessor) two parallel-arm, controlled RCT.SettingSpecialist neurology and neuropsychiatry services at a large National Health Service Foundation Trust in London, UK.ParticipantsPatients with a diagnosis of functional limb weakness (Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition). Exclusion criteria included comorbid neurological or major psychiatric disorder, contraindications to TMS or previous TMS treatment.InterventionsPatients were randomised to receive either active (single-pulse TMS to primary motor cortex (M1) above resting motor threshold) or inactive treatment (single-pulse TMS to M1 below resting motor threshold). Both groups received two TMS sessions, 4 weeks apart.Outcome measuresWe assessed recruitment, randomisation and retention rates. The primary outcome was patient-rated symptom change (Clinical Global Impression–Improvement scale, CGI-I). Secondary outcomes included clinician-rated symptom change, psychosocial functioning and disability. Outcomes were assessed at baseline, both TMS visits and at 3-month follow-up.ResultsTwenty-two patients were recruited and 21 (96%) were successfully randomised (active=10; inactive=11). Nineteen (91%) patients were included at follow-up (active=9; inactive=10). Completion rates for most outcomes were good (80%–100%). Most patients were satisfied/very satisfied with the trial in both groups, although ratings were higher in the inactive arm (active=60%, inactive=92%). Adverse events were not more common for the active treatment. Treatment effect sizes for patient-rated CGI-I scores were small-moderate (Cliff’s delta=−0.1–0.3, CIs−0.79 to 0.28), reflecting a more positive outcome for the active treatment (67% and 44% of active arm-rated symptoms as ‘much improved’ at session 2 and follow-up, respectively, vs 20% inactive group). Effect sizes for secondary outcomes were variable.ConclusionsOur protocol is feasible. The findings suggest that supramotor threshold TMS of M1 is safe, acceptable and potentially beneficial as a treatment for functional limb weakness. A larger RCT is warranted.Trial registration numberNCT51225587.

Background Patients continue to suffer from medically unexplained symptoms otherwise referred to as persistent physical symptoms (PPS). General practitioners (GPs) play a key role in the management of PPS and require further training. Patients are often frustrated with the care they receive. This study aims to assess the acceptability of an ‘integrated GP care’ approach which consists of offering self-help materials to patients with PPS and offering their GPs training on how to utilise cognitive behavioural skills within their consultations, as well as assessing the feasibility of conducting a future trial in primary care to evaluate its benefit. Methods A feasibility cluster randomised controlled trial was conducted in primary care, South London, UK. GP practices (clusters) were randomly allocated to ‘integrated GP care plus treatment as usual’ or ‘treatment as usual’. Patients with PPS were recruited from participating GP practices before randomisation. Feasibility parameters, process variables and potential outcome measures were collected at pre-randomisation and at 12- and 24-weeks post-randomisation at cluster and individual participant level. Results Two thousand nine hundred seventy-eight patients were identified from 18 GP practices. Out of the 424 patients who responded with interest in the study, 164 fully met the eligibility criteria. One hundred sixty-one patients provided baseline data before cluster randomisation and therefore were able to participate in the study. Most feasibility parameters indicated that the intervention was acceptable and a future trial feasible. 50 GPs from 8 GP practices (randomised to intervention) attended the offer of training and provided positive feedback. Scores in GP knowledge and confidence increased post-training. Follow-up rate of patients at 24 weeks was 87%. However estimated effect sizes on potential clinical outcomes were small. Conclusions It was feasible to identify and recruit patients with PPS. Retention rates of participants up to 24 weeks were high. A wide range of health services were used. The intervention was relatively low cost and low risk. This complex intervention should be further developed to improve patients’/GPs’ utilisation of audio/visual and training resources before proceeding to a full trial evaluation. Trial registration NCT02444520 (ClinicalTrials.gov).

ImportanceDepression and anxiety are common mood disorders that show higher prevalence in adults with joint hypermobility, a consequence of a constitutional variant of connective tissue structure. In adolescents, an association between mood disorder and hypermobility may enhance the potential understanding of risk factors for emotional disorder and provide opportunities for early intervention approaches.ObjectiveTo test the hypothesis that joint hypermobility, a consequence of constitutional variant of connective tissue, is associated with common mental illness in adolescents.DesignThis was a longitudinal prospective study.SettingThe Avon Longitudinal Study of Parents and Children (ALSPAC) is a prospective ongoing general population birth cohort study based in Avon County, England.ParticipantsThe original data set comprised 6105 individuals from the cohort with data available on joint hypermobility at age 14 years; a sub-sample (n=3803) had later psychiatric assessments.Measurement of ExposureJoint hypermobility was measured by physical examination at age 14 and 18 years, using the Beighton ScaleMain Outcome and MeasuresParticipants were assessed at age 18 years. ICD-10 diagnoses of Depression and Anxiety were obtained using the Clinical Interview Schedule-Revised (CIS-R) and levels of anxiety quantified using the Anxiety Sensitivity Index (ASI)ResultsPresence of generalized joint hypermobility (GJH) at age 14 years predicted depression at 18 years in males (Odds Ratio (OR) 2.10; 95%CI, 1.17-3.76) but not females After accounting for missing data it was determined that this relationship was mediated by heart rate, a potential measure of physiological arousal. Symptomatic hypermobility ((GJH plus chronic widespread pain (CWP)) at age 18 years was further associated with the presence of anxiety disorder (OR 3.13; 95% CI 1.52-6.46) and level of anxiety (Beta = 0.056, t(3315)=3.27), depressive disorder (adjusted OR 3.52; 95%CI, 1.67 – 7.40) and degree of psychiatric symptomatology (Beta 0.096, t(2064)=4.38)Conclusions and relevanceGeneralized joint hypermobility and symptomatic hypermobility are associated with common mental disorders in adolescence. Consideration of hypermobility may provide important opportunities for intervention to mitigate psychiatric disorder.KEY POINTSQuestionIs joint hypermobility related to depression and anxiety in adolescence?FindingsIn this longitudinal study presence of generalized joint hypermobility at 14 predicted subsequent adolescent depression in males only and this relationship was mediated by heart rate. At age 18 symptomatic hypermobility was associated with both presence of anxiety and depression and psychiatric symptom severity.MeaningGeneralized joint hypermobility and symptomatic hypermobility are associated with common mental disorders in adolescence.

Repetitive transcranial magnetic stimulation is a potential treatment option for depression, with the newer intermittent theta-burst stimulation (iTBS) protocols providing brief intervention. However, their mechanism of action remains unclear. We investigated the hypothesis that iTBS influences brain circuits involved in emotion processing that are also affected by antidepressants. We predicted that iTBS would lead to changes in performance on emotion-processing tasks. We investigated the effects of intermittent TBS (iTBS) over the left dorsolateral prefrontal cortex (DLPFC) on the processing of emotional information (word recall and categorization, facial emotion recognition, and decision-making) in 28 healthy volunteers by contrasting these effects with those of sham stimulation. Each volunteer received iTBS and sham stimulation in a blinded crossover design and completed the emotion-processing tasks before and after stimulation. Compared to sham stimulation, iTBS increased positive affective processing for word recall, yet had an unexpected effect on facial emotion recognition for happy and sad faces. There was no evidence of an effect on decision-making or word categorization. We found support for our hypothesis that iTBS influences emotion processing, though some changes were not in the expected direction. These findings suggest a possible common mechanism of action between iTBS and antidepressants, and a complex neural circuitry involved in emotion processing that could potentially be tapped into via brain stimulation. Future research should investigate the neural correlates of emotion processing more closely to inform future iTBS protocols.

The value of services for those with the ‘At Risk Mental State for Psychosis’ (ARMS) continues to be disputed. ARMS services have provided a valuable stimulus to academic research into the transition into psychosis. Furthermore, there is currently a welcome trend to transform such clinics into youth mental health services catering for the broader clientele of young people suffering from anxiety and depression, who already constitute the bulk of those seen at ARMS clinics. However, such services are never likely to make major inroads into preventing psychosis because they only reach a small proportion of those at risk. Evidence from medicine shows that avoiding exposure to factors which increase the risk of disease (e.g. poor nutrition, transmission of infection, tobacco smoking), produces greater public benefit than focussing efforts on individuals with, or about to develop, disease. We consider that the most productive approach for psychosis prevention is avoiding exposure to risk-increasing factors. The best-established risk factors for psychosis are obstetric events, childhood abuse, migration, city living, adverse life events and cannabis use. Some as city living, are likely proxies for an unknown causal factor(s) while preventing others such as childhood abuse is currently beyond our powers. The risk factor for psychosis which is most readily open to this approach is the use of cannabis. Therefore, as an initial step towards a strategy for universal primary prevention, we advocate public health campaigns to educate young people about the harms of regular use of high potency cannabis.

Treatment of psychosis in Parkinson’s disease (PD) is challenging; pharmacological options are limited, with clozapine considered most effective. The risk of agranulocytosis restricts the use of clozapine, but, where this occurs, cautious re-challenge with granulocyte stimulating factor can be successful. We present a unique case of a patient who developed early-onset PD on a background of antecedent treatment-resistant schizophrenia, who had been treated effectively with clozapine for over 15 years with no adverse events. However, during a hospital admission intended to optimise her Parkinsonian medications, she developed persistent neutropenia necessitating clozapine discontinuation. Numerous attempts to re-challenge with clozapine failed until augmentation with lithium and G-CSF was trialled. Two doses of G-CSF led to a sustained increase in the neutrophil count, allowing the continuation of clozapine therapy in the 1 year of follow up. This illustrates the potential for G-CSF to be used to facilitate clozapine use in a patient population not described previously. Neutrophil augmentation allowed the sustained continuation of this effective therapy, treating her psychotic symptoms without detriment to her movement disorder. We suggest that G-CSF might be considered as a treatment option in other cases where clozapine-associated neutropenia obstructs its use.

BACKGROUNDThe influence of age upon intensive care unit (ICU) decision-making is complex and it is unclear if it is based on expected subjective or objective patient outcomes. To address recent concerns over age-based ICU decision-making we explored patient-assessed quality of life (QoL) in ICU survivors.METHODSWe conducted a rapid database search of cohort studies published between January 2000 to April 2020, of elderly patients admitted to ICUs. We extracted data on self-reported QoL (EQ-5D composite score), study characteristics and demographic and clinical variables. Using a random-effects model, we then compared QoL scores at follow-up to scores either before admission, age-matched population controls or younger ICU survivors. Finally, we conducted follow-up quantitative analyses to explore potential moderators of these effects, and a qualitative synthesis of QoL subscores. A study protocol was registered prospectively on PROSPERO, ID: CRD42020181181.FINDINGSOur database search found 2536 studies and from these we reviewed 376 potentially relevant full texts. 21 of these studies met the inclusion criteria for qualitative synthesis and 18 were also included in the meta-analysis (N= 2090 elderly adults). The follow-up periods ranged between 3-100 months. There was no significant difference in the elderly’s QoL scores between one month before ICU and follow-up, or between follow-up and age-matched community controls. QoL in elderly ICU survivors was significantly worse than younger ICU survivors, with a small-to-medium effect size (d= .33 [.10 to .55]). Mortality rates and length of follow up were possible intermediary factors. The qualitative synthesis suggested that any reductions in QoL were primarily due to reductions in physical health, rather than mental health items.INTERPRETATIONOverall, elderly ICU patients did not experience significantly impaired QoL at follow up, compared to before ICU or their healthy peers. Elderly patients who survive ICU can be expected to have slightly worse QoL compared to younger patients, especially in the longterm. The results suggest that the proportionality of age as a determinant of (population level) ICU resource allocation should be kept under close review and that subjective QoL outcomes (not only objective survival data) should inform person-centred decision making in elderly ICU patients.DECLARATIONS OF INTERESTAlex Ruck Keene is an adviser on the Faculty of Intensive Care Medicine’s Legal and Ethical Policy Unit. We report no other competing interests.

Background and purpose: Cauda equina syndrome (CES) is a neurosurgical emergency which warrants lumbar magnetic resonance imaging (MRI). Many patients with suggestive symptoms of CES have no radiological correlate. A functional (non-organic) aetiology has been proposed in some, but currently little is known about this patient group and their clinical outcomes. Methods: At a tertiary referral centre, 155 adult patients underwent urgent lumbar MRI for suspected CES in 1 year from December 2014. Data regarding clinical symptoms and follow-up were obtained from records. Patients were divided into CES (n = 25), radiculopathy (n = 68) and scan-negative (SN) groups (n = 62) from scans. Up to 3 years post-discharge, postal questionnaires were sent to patients with Oswestry Disability Index, Pain Catastrophizing score, Patient Health Questionnaire (PHQ) 9, Generalized Anxiety Disorder (GAD) 7, PHQ 15 and Work and Social Adjustment Scale measures. Results: No clinical symptoms were found to differentiate CES from SN patients. Functional comorbidities were significantly more common in SN patients but mental health diagnosis frequency did not differ. Follow-up was variable with no consistent referral pathways, particularly for the SN group. 33% (n = 47) responded to the postal questionnaires; high levels of pain, symptom chronicity and disability were ubiquitous but self-reported mental health diagnoses and PHQ 15 were higher for SN patients. Conclusions: Conflicting data suggest further research is needed to investigate the prevalence of mental illness and somatic symptoms in SN cases. SN patients have higher rates of comorbid functional disorders and inconsistent referral pathways. Self-report measures indicate impaired quality of life across all groups. The low response rate limits the generalizability of findings but neuropsychiatric assessment and care pathway optimization should be considered.

Summary 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.

OBJECTIVE: The authors investigated the incidence, course, and outcome of psychotic experiences from childhood through early adulthood in the general population and examined prediction of psychotic disorder. METHODS: This was a population-based cohort study using the semistructured Psychosis-Like Symptoms Interview at ages 12, 18, and 24 (N=7,900 with any data). Incidence rates were estimated using flexible parametric modeling, and positive predictive values (PPVs), sensitivity, specificity, and area under the curve were estimated for prediction. RESULTS: The incidence rate of psychotic experiences increased between ages 13 and 24, peaking during late adolescence. Of 3,866 participants interviewed at age 24, 313 (8.1%, 95% CI=7.2, 9.0) had a definite psychotic experience since age 12. A total of 109 individuals (2.8%) met criteria for a psychotic disorder up to age 24, of whom 70% had sought professional help. Prediction of current psychotic disorder at age 24 (N=47, 1.2%), by both self-report and interviewer-rated measures of psychotic experiences at age 18 (PPVs, 2.9% and 10.0%, respectively), was improved by incorporating information on frequency and distress (PPVs, 13.3% and 20.0%, respectively), although sensitivities were low. The PPV of an at-risk mental state at age 18 predicting incident disorder at ages 18-24 was 21.1% (95% CI=6.1, 45.6) (sensitivity, 14.3%, 95% CI=4.0, 32.7). CONCLUSIONS: The study results show a peak in incidence of psychotic experiences during late adolescence as well as an unmet need for care in young people with psychotic disorders. Because of the low sensitivity, targeting individuals in non-help-seeking samples based only on more severe symptom cutoff thresholds will likely have little impact on population levels of first-episode psychosis.

Introduction A proportion of patients admitted to acute-stroke settings have not had a stroke, but have conditions mimicking a stroke. Approximately 25% of suspected stroke cases are “stroke mimics” and 2% are patients with functional symptoms — “functional stroke mimics”. This study aimed to explore experiences and illness perceptions of patients with functional symptoms admitted to hyperacute stroke wards. Methods This study used mixed methods. Patients with functional stroke symptoms participated in semistructured qualitative interviews immediately after admission to one of two acute-stroke units in London and again 2 months after hospital discharge. Qualitative data were assessed using thematic analysis. The Brief Illness Perception Questionnaire (Brief-IPQ) measured illness perceptions at admission and at 2-month follow-up. Results A total of 36 participants completed baseline interviews and 25 completed follow-up. Six themes emerged: physical symptom experience, emotional and coping responses, symptom causes, hospital experiences, views on the future, and uncertainty after hospital discharge. Mean Brief-IPQ score at admission was 49.3 (SD: 9.9), indicating a moderate–high level of perceived illness threat. Participants presented with a range of functional symptoms. At baseline, participants were highly concerned about their symptoms, but this had decreased at 2-month follow-up. Two months later, many were confused as to the cause of their admission. Conclusion This is the first study to examine functional stroke patients’ experiences of acute-stroke admission. At admission, patients expressed confusion regarding their diagnosis, experienced high levels of emotional distress, and were concerned they were perceived as time wasting by stroke clinicians. While most participants experienced symptom recovery, there was a significant subgroup for whom symptoms persisted or worsened. A lack of care guidelines on the management of functional stroke patients may perpetuate functional symptoms.