The role of psychosis and clozapine load in excessive checking in treatment-resistant schizophrenia: longitudinal observational study.

BACKGROUND: A significant proportion of people with clozapine-treated schizophrenia develop 'checking' compulsions, a phenomenon yet to be understood. AIMS: To use habit formation models developed in cognitive neuroscience to investigate the dynamic interplay between psychosis, clozapine dose and obsessive-compulsive symptoms (OCS). METHOD: Using the anonymised electronic records of a cohort of clozapine-treated patients, including longitudinal assessments of OCS and psychosis, we performed longitudinal multi-level mediation and multi-level moderation analyses to explore associations of psychosis with obsessiveness and excessive checking. Classic bivariate correlation tests were used to assess clozapine load and checking compulsions. The influence of specific genetic variants was tested in a subsample. RESULTS: A total of 196 clozapine-treated individuals and 459 face-to-face assessments were included. We found significant OCS to be common (37.9%), with checking being the most prevalent symptom. In mediation models, psychosis severity mediated checking behaviour indirectly by inducing obsessions (r = 0.07, 95% CI 0.04-0.09; P < 0.001). No direct effect of psychosis on checking was identified (r = -0.28, 95% CI -0.09 to 0.03; P = 0.340). After psychosis remission (n = 65), checking compulsions correlated with both clozapine plasma levels (r = 0.35; P = 0.004) and dose (r = 0.38; P = 0.002). None of the glutamatergic and serotonergic genetic variants were found to moderate the effect of psychosis on obsession and compulsion (SLC6A4, SLC1A1 and HTR2C) survived the multiple comparisons correction. CONCLUSIONS: We elucidated different phases of the complex interplay of psychosis and compulsions, which may inform clinicians' therapeutic decisions.

Should vaccination status be a consideration during secondary triage?

The rapid development of widely available and effective vaccines has been integral to the international response to the COVID-19 pandemic. However, a significant minority of those offered vaccination have refused, often due to their adherence to 'anti-vax' beliefs. These beliefs include that vaccines are dangerous, render the recipient magnetic or contain government microchips.During the pandemic, numerous calls were made for those voluntarily refusing vaccination to be deprioritised when allocating scarce healthcare resources. While these calls were rejected, the likelihood of the same calls being made during future pandemics necessitates a thorough examination of the ethical implications entailed by such a policy.Here, I consider an intuitive argument for the use of vaccination status when allocating healthcare resources. This argument claims that, by avoiding vaccination, vaccine refusers are failing to fulfil a social obligation to protect those around them from harm by facilitating herd immunity. They are, therefore, less deserving of healthcare than their vaccinated peers.I explore three objections to this argument. While a first objection, asserting that no individual can be held responsible for a failure to develop herd immunity, fails, I find two further responses, respectively asserting the primacy of patient autonomy and highlighting the harms deprioritising vaccine refusers would cause to disadvantaged minorities, compelling. I, therefore, conclude that vaccination status should not be considered during healthcare resource allocation, as such discrimination would disproportionately harm marginalised communities.

Clozapine-related obsessive-compulsive symptoms and their impact on wellbeing: a naturalistic longitudinal study.

BACKGROUND: Obsessive-compulsive symptoms (OCS) are commonly associated with clozapine treatment but are frequently overlooked by clinicians despite their potential impact on patients' quality of life. In this study, we explored whether OCS severity impacted subjective wellbeing and general functioning, independently of depressive and psychotic symptoms. METHODS: We used anonymised electronic healthcare records from a large cohort of patients who were treated with clozapine and assessed annually for OCS, wellbeing, general functioning, and psychopathology using standardised scales as part of routine clinical practice. We used statistical mixed linear model techniques to evaluate the longitudinal influence of OCS severity on wellbeing and general functioning. RESULTS: A total of 184 patients were included, with 527 face-to-face assessments and 64.7% evaluated three or more times. Different linear mixed models demonstrated that OCS in patients treated with clozapine were associated with significantly worse wellbeing scores, independently of depression and psychotic symptoms, but OCS did not impair general functioning. Obsessional thinking and hoarding behaviour, but not compulsions, were significantly associated with the impact on wellbeing, which may be attributable to the ego-syntonic nature of the compulsions. CONCLUSIONS: Given the frequent occurrence of OCS and their negative impact on wellbeing, we encourage clinicians to routinely assess and treat OCS in patients who are taking clozapine.

Postoperative risks of stoma formation in patients with dementia.

Stoma formation for patients with dementia presents an increasing problem in a global ageing population. While potentially lifesaving, stomas impose significant, long-term postoperative burdens on patients, and may particularly challenge those with cognitive impairment.In this case, a patient was considered for colostomy to manage a colovesical fistula. The patient's cognitive status significantly influenced clinicians' beliefs concerning suitability for stoma formation.The relevance of dementia to stoma formation is underdiscussed within the literature. In this report, we outline the postoperative risks to which those with dementia undergoing stoma formation are particularly vulnerable. These include increased risk of psychological harm, of relocation to a nursing home, and of stoma-related complications.We hope an increased appreciation of these postoperative challenges will inform decisions concerning suitability for stoma formation in this patient group.

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.

Longitudinal effects of clozapine concentration and clozapine to N-desmethylclozapine ratio on cognition: A mediation model.

Previous cross-sectional studies have found clozapine to N-desmethylclozapine (CLZ:NDMC) ratio to be negatively correlated with cognition in clozapine-treated patients with schizophrenia. However, no work has examined the association between CLZ:NDMC ratio and cognition using a within-subjects design. Here, we investigate the longitudinal effects of changes in the clozapine load and the CLZ:NDMC ratio on cognition whilst controlling for a range of independent factors. We analyzed data from a cohort of seventeen clozapine-treated patients who have been repeatedly assessed with the Brief Assessment of Cognition for Schizophrenia (BACS). The Positive symptoms sub-score of the Clinical Global Impression for Schizophrenia (CGI-P) was used to assess severity of psychosis. Blood samples were collected to measure the plasmatic levels of clozapine (CLZ) and of N-desmethylclozapine, allowing calculation of the CLZ:NDMC ratio. Our analyses included bivariate and partial correlations, along with a mediation model analysis. We found that both plasmatic levels of CLZ and the CLZ:NDMC ratio were negatively correlated with cognitive performance, and that these associations were independent of changes in both daily clozapine dose and severity of psychotic symptoms. Mediation analyses further revealed the association between CLZ concentration and cognition to be partially mediated by changes in the CLZ:NDMC ratio. This is the first longitudinal analysis of the influence of CLZ concentration and CLZ:NDMC ratio on cognition. Our findings suggest that reduction of CLZ concentration and the CLZ:NDMC ratio might favorably affect cognition. Thus, the CLZ:NDMC ratio may represent a promising target for novel therapeutic strategies aiming to ameliorate cognitive impairment in clozapine-treated patients.

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.