One hundred years ago: Nijinsky and the origins of schizophrenia.

A footpath in the Square de la Tour Saint-Jacques in Paris is named for the dancer Vaslav Nijinsky (1889–1950). It was in the nearby Théâtre du Châtelet that the ‘God of Dance’ astounded audiences and scandalized critics with his pioneering choreography. However, it would not last—in March 1919, Nijinsky was diagnosed with schizophrenia, and the world lost the art of its greatest dancer. His case captured the interest of clinicians and the general public during the first half of the 20th century. An acquaintance with royalty, politicians and leading artists, he became a case for some of the most renowned psychiatrists of the day, including Bleuler, Binswanger, Wagner-Jauregg, Jung, Adler and Sakel. However, this is not merely a case of historical interest. Schizophrenia is a neurodevelopmental disorder in which premorbid motor and intellectual abnormalities are present before the onset of psychosis, which generally occurs in late adolescence; but Nijinsky was aged 30 at the time of his diagnosis and had arguably the most finely tuned motor skills in history. Here, his case is revisited, and discussed through the prism of novel pathophysiological mechanisms

Well-being in clozapine-treated schizophrenia patients: The significance of positive symptoms.

OBJECTIVES: Well-being perception is seldom explored in schizophrenia patients. Recurrent limitations, such as the questionable applicability of gold standard definitions of health and well-being, and fewer tools available to assess well-being, are pronounced in this subpopulation. This cross-sectional study sought to explore potential clinical factors that may predict subjective well-being scores in chronic schizophrenia patients (N=142) receiving clozapine treatment. METHODS: The Short Warwick-Edinburgh Mental Well-being Scale (SWEMWBS) was used to measure well-being. We correlated SWEMWBS scores and 27 clinically recognized factors, spanning socio-demographics, symptom severity scores, physical health diagnosis, clozapine side effects, habits and prescribed medication. Factors with a p<0.2 correlation were included as a predictors in a linear regression model. RESULTS: Ten factors were included in the linear regression model, however only positive symptom severity was a significant predictor of SWEMWBS score (p<0.0001). CONCLUSIONS: We suggest that greater levels of clinical attention given to positive symptoms compared with other symptoms and aspects of well-being, during biomedical treatment for chronic schizophrenia, may partially explain the finding that only positive symptoms significantly predicted patient perceptions of low well-being.While not directly funding this study, the authors of this work are supported by the Australian Postgraduate Award (J.B., APA 1183a/2010) and Government of Catalonia with the Secretaria d‟Universitats i Recerca del Departament d‟Economia i Coneixement (G.M., 2014SGR441), the grant FIDGR-2013 Contract of the Agència de Gestió d‟Ajuts Universitaris i de Recerca (G.M., AGAUR, 2015 FI_B2 00100) and a 2009 Young Investigator Award (NARSAD) (E.F-E., RG53588). This study used data extracted from the Clinical and Research Database for Persistent Schizophrenia, partially funded by the UK-National Institute for Health Research - Biomedical Research Center Cambridge. We also thank service users and Clozapine Clinic staff for their participation and support.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.comppsych.2016.04.00

Mechanisms Underlying Motivational Dysfunction in Schizophrenia.

Negative symptoms are a debilitating feature of schizophrenia which are often resistant to pharmacological intervention. The mechanisms underlying them remain poorly understood, and diagnostic methods rely on phenotyping through validated questionnaires. Deeper endo-phenotyping is likely to be necessary in order to improve current understanding. In the last decade, valuable behavioural insights have been gained through the use of effort-based decision making (EBDM) tasks. These have highlighted impairments in reward-related processing in schizophrenia, particularly associated with negative symptom severity. Neuroimaging investigations have related these changes to dysfunction within specific brain networks including the ventral striatum (VS) and frontal brain regions. Here, we review the behavioural and neural evidence associated with negative symptoms, shedding light on potential underlying mechanisms and future therapeutic possibilities. Findings in the literature suggest that schizophrenia is characterised by impaired reward based learning and action selection, despite preserved hedonic responses. Associations between amotivation and reward-processing deficits have not always been clear, and may be mediated by factors including cognitive dysfunction or dysfunctional or self-defeatist beliefs. Successful endo-phenotyping of negative symptoms as a function of objective behavioural and neural measurements is crucial in advancing our understanding of this complex syndrome. Additionally, transdiagnostic research-leveraging findings from other brain disorders, including neurological ones-can shed valuable light on the possible common origins of motivation disorders across diseases and has important implications for future treatment development

The influence of negative and affective symptoms on anhedonia self-report in schizophrenia.

BACKGROUND: Anhedonia, a symptom prevalent in schizophrenia patients, is thought to arise either within negative symptomatology or from secondary sources, such as depression. The common co-occurrence of these diseases complicates the assessment of anhedonia in schizophrenia. METHOD: In a sample of 40 outpatients with chronic schizophrenia, we explored both the validity of the Snaith-Hamilton Pleasure Scale (SHAPS) self-report for anhedonia assessment and those factors influenced its scoring. We assessed negative symptoms using the Brief Negative Symptom Scale (BNSS), depression symptoms using the Calgary Depression Scale for Schizophrenia (CDSS) and cognitive impairment using the Brief Assessment of Cognition in Schizophrenia (BACS), before exploring associations between these scales. RESULTS: The SHAPS was validated for use in schizophrenia. SHAPS scores were not associated with negative symptoms or cognitive impairment, but were linked to a single Depression symptom: Hopelessness (r = 0.52, p < 0.001). CONCLUSIONS: SHAPS scores, therefore, appear to only reflect anticipatory anhedonia arising from the affective domain. We advocate the development of multi-faceted self-report measures to more holistically assess anhedonia in schizophrenia.M.H is funded by a Wellcome Trust Principal Research Fellowship and by the NIHR BRC at Oxford. E.F.E and the research database were supported by intramural funding from CPFT and the UK National Institute of Health Research (NIHR) Cambridge Biomedical Research Centre (BRC)

Birth weight, family history of diabetes and diabetes onset in schizophrenia.

INTRODUCTION:The prevalence of diabetes in schizophrenia is twice that in the general population, but there are few reliable predictors of which individuals will develop glucose dysregulation. OBJECTIVE:To test if abnormal birth weight (either too low or too high) and parental diabetes, both variables that can be ascertained in the clinic, can predict diabetes onset in patients with schizophrenia. RESEARCH DESIGN AND METHODS:Electronic records of a cohort of 190 clozapine-treated patients (37% treated for more than 20 years) and Cox regression survival analysis (with any type of glucose dysregulation as the event) to account for differences in length of treatment before the event and age at clozapine treatment initiation. RESULTS:Age at clozapine initiation (Exp(B)=1.098; p<0.001), family history of diabetes (Exp(B)=2.299; p=0.049) and birth weight2 (Exp(B)=0.999; p=0.013) were significant predictors of glucose dysregulation onset, while gender was not (Exp(B)=0.1.350; p=0.517). Among individuals with 10 years of follow-up, 80% of those with both abnormal birth weight and a family history of diabetes developed diabetes compared with 56% with only abnormal birth weight, 40% with only a family history of diabetes and 20% in those with neither. CONCLUSIONS:Since 48% of cases had at least one risk factor and 6% had both risk factors, there is a substantial proportion of patients for whom preventive strategies could be implemented

Longer-term mortality following SARS-CoV-2 infection in people with severe mental illness: retrospective case-matched study.

Persisting symptoms and dysfunction after SARS-CoV-2 infection have frequently been observed. However, information on the aftermath of COVID-19 is inadequate. We followed up people with severe mental illness (SMI) infected with SARS-CoV-2, and evaluated their longer-term mortality, using data from Cambridgeshire and Peterborough NHS Foundation Trust, UK. We examined the time course and duration of mortality risk from the point of diagnosis. After SARS-CoV-2 infection, people with SMI had a substantially higher risk of death (hazard ratio (HR) = 5.16, 95% confidence interval (CI) 1.56-17.03; P = 0.007) during the first 28 days and during the following 28-60 days (HR = 2.96, 95% CI 1.21-7.26; P = 0.018) than those without infection, but after 60 days the additional risk of death was no longer significant (HR = 2.33, 95% CI 0.83-6.53; P = 0.107)

A cross sectional study of impact and clinical risk factors of antipsychotic-induced OCD.

A large proportion of schizophrenia patients treated with second generation antipsychotics will develop Obsessive Compulsive Disorder (OCD). However, there are few studies about the impact of this comorbidity and who is at higher risk. In this study of clozapine-treated patients, we aimed to determine the impact on outcome of clozapine-induced OCD, as well as the clinical and sociodemographic risk factors related to OCD-onset in clozapine patients. We had strict and novel inclusion criteria to minimise mis-identification of cases. The Obsessive-Compulsive Inventory-Revised (OCI-R) was used to divide 231 clozapine-treated patients into extreme cases of OCD (OCI  ≥ 24 or checking subscale ≥6) versus non-OCD (OCI <15 and checking subscale <4). The Global Assessment of Functioning (GAF), short version of Warwick-Edinburgh Wellbeing scale and Clinical Global Impression for schizophrenia (CGI) scales were used to determine outcome. Socio-demographic information was used to identify the risk factors for OCD development. We found that schizophrenia patients with OCD symptoms had a significantly lower patient rated wellbeing scores (p < 0.001) only (no difference in clinician rated wellbeing scores), higher CGI positive (p < 0.01) and higher CGI depressive scores (p < 0.05). The only risk factors that reached significance level were higher treatment dose (p < 0.01) and younger paternal age at birth (p < 0.05). There is scope for future studies based on e.g. imaging and genetic studies to further investigate causality, and in improving clinician screening for OCD.MB was supported by her studentship from the Mental Health Research UK. YW is supported by the Association Française du syndrome de Gilles de la Tourette, Foundation de recherche Medicale and Dystonia Foundation for Medical Research (USA). NF has held research or networking grants from the ECNP, UK NIHR, EU H2020, has accepted paid speaking engagements including travel and hospitality in industry supported symposia for Abbott, SunPharma, has accepted travel and hospitality expenses from the BAP, ECNP, RCPsych, CINP, receives payment from Taylor and Francis for editorial duties. TWR was supported by Wellcome Trust Senior Investigator Award 104631/X/14/Z. EF received intramural funding from CPFT/NIHR-CRN supported setting the database

Association of birth weight and the development of antipsychotic induced adiposity in individuals with treatment resistant schizophrenia.

Though weight gain is a common side effect of antipsychotic treatment, there are no useful predictors of which patients are likely to be affected and to what degree. It has been shown that exposure to adverse conditions during intra-uterine life confers a vulnerability to the development of later life metabolic complications and low birth weight for gestational age has been shown to be a robust marker of such prenatal adversity. We hypothesised that patients with schizophrenia with a lower birth weight will have increased vulnerability to the weight inducing effects of antipsychotic treatment. The relationship between birth weight and total and central adiposity, measured as body mass index (BMI) and waist-to-hip ratio (WHR) respectively, was examined in three groups: drug naïve first episode of psychosis (FEP) patients (n=41), treatment resistant schizophrenia (TRS) patients (n=42) and matched healthy volunteers (n=72). All analyses were controlled for age, gender and duration of treatment exposure. We found that a lower birth weight was associated with higher BMI and WHR only in TRS patients but not in FEP or controls, suggesting that prenatal adversity, as indicated by the surrogate marker of a lower birth weight, confers an increased vulnerability to clozapine induced weight gain.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.euroneuro.2016.03.00

Brain Metabolism during Hallucination-Like Auditory Stimulation in Schizophrenia

Auditory verbal hallucinations (AVH) in schizophrenia are typically characterized by rich emotional content. Despite the prominent role of emotion in regulating normal perception, the neural interface between emotion-processing regions such as the amygdala and auditory regions involved in perception remains relatively unexplored in AVH. Here, we studied brain metabolism using FDG-PET in 9 remitted patients with schizophrenia that previously reported severe AVH during an acute psychotic episode and 8 matched healthy controls. Participants were scanned twice: (1) at rest and (2) during the perception of aversive auditory stimuli mimicking the content of AVH. Compared to controls, remitted patients showed an exaggerated response to the AVH-like stimuli in limbic and paralimbic regions, including the left amygdala. Furthermore, patients displayed abnormally strong connections between the amygdala and auditory regions of the cortex and thalamus, along with abnormally weak connections between the amygdala and medial prefrontal cortex. These results suggest that abnormal modulation of the auditory cortex by limbic-thalamic structures might be involved in the pathophysiology of AVH and may potentially account for the emotional features that characterize hallucinatory percepts in schizophrenia