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.

Anthropometry in antipsychotic-naïve first-episode psychosis patients: An exploratory approach to the role of environmental early life events in two independent samples.

BACKGROUND: Patients with schizophrenia exhibit a reduced life expectancy mainly due to medical-related pathologies which might have been initiated due to stressful events during fetal development. Indeed, intra-uterus growth patterns predict anthropometric measures in adulthood, describing risk factors for schizophrenia and metabolic disorders. We aim to evaluate anthropometric values in two cohorts of antipsychotic-naïve first-episode episode psychosis (FEP) and correlated them with surrogate markers of the fetal environment such as birth weight (BW) and season of birth. METHODS: BW, season of birth, and anthropometric values from 2 cohorts of FEP patients (Barcelona and Santander) were evaluated. In cohort B, 91 patients, and 110 controls while in cohort S, 644 and 235 were included respectively. RESULTS: Patients were shorter, slimmer, and with lower BMI compared with controls. In both cohorts, patients, and female patients born in winter displayed the shortest height. Regarding BW, height was significantly associated with the interaction of diagnosis and BW in the whole sample and the male subsample. CONCLUSIONS: Our results confirm reduced anthropometric features in FEP at onset while suggesting the influence of winter birth and BW, highlighting the role of early life events in the later outcome of FEP with sex differences.

Impact of Pharmacogenetic Testing on Clozapine Treatment Efficacy in Patients with Treatment-Resistant Schizophrenia.

Managing schizophrenia with clozapine poses a significant challenge due to prevalent therapeutic failures. The increasing interest in personalized medicine underscores the importance of integrating pharmacogenetic information for effective pharmacotherapeutic monitoring in patients. The objective of this study was to explore the correlation between DRD2, HTR2A, SLC6A4, CYP1A2, and ABCB1 polymorphisms and clozapine response in 100 patients with Treatment-Resistant Schizophrenia. Different scales such as the Positive and Negative Syndrome Scale (PANSS), the Warwick-Edinburgh Mental Wellbeing Scale (SWEMWBS), the Global Assessment of Functioning Scale (GAF), the Brief Negative Symptom Scale (BNSS), and pharmacokinetic parameters were used to analyse the efficacy of the treatment. Patients who exclusively responded to clozapine compared to the patients with augmentation strategies exhibited distinctive features, such as lower doses, plasma levels, and presented less-pronounced symptomatology. Genetic associations were explored, highlighting SLC6A4, HTR2A, and the *1F/*1F polymorphism for the CYP1A2 gene.

The longitudinal structure of negative symptoms in treatment resistant schizophrenia.

BACKGROUND AND HYPOTHESIS: The negative symptoms of schizophrenia are strong prognostic factors but remain poorly understood and treated. Five negative symptom domains are frequently clustered into the motivation and pleasure (MAP) and emotional expression (EE) 'dimensions', but whether this structure remains stable and behaves as a single entity or not remains unclear. STUDY DESIGN: We examined a cohort of 153 patients taking clozapine for treatment-resistant schizophrenia in a regional mental health clinic. Patients were assessed longitudinally over a mean period of 45 months using validated scales for positive, negative and mood symptoms. Network analyses were performed to identify symptom 'communities' and their stability over time. The influence of common causes of secondary negative symptoms as well as centrality measures were also examined. STUDY RESULTS: Across patients at baseline, two distinct communities matching the clinical domains of MAP and EE were found. These communities remained highly stable and independent over time. The communities remained stabled when considering psychosis, depression, and sedation severity, and these causes of secondary negative symptoms were clustered into the MAP community. Centrality measures also remained stable over time, with similar centrality measures across symptoms. CONCLUSIONS: Our results suggest that MAP and EE are independent dimensions that remain highly stable over time in chronic schizophrenia patients treated with clozapine. Common causes of secondary negative symptoms mapped onto the MAP dimension. Our results emphasise the need for clinical trials to address either MAP or EE, and that treating causes of secondary negative symptoms may improve MAP.

Revealing the reporting disparity: VigiBase highlights underreporting of clozapine in other Western European countries compared to the UK.

BACKGROUND: Pharmacovigilance studies indicate clozapine history is marked by adverse drug reactions (ADRs). OBJECTIVE: In a 2021 article, the United Kingdom (UK) had >90 % of European clozapine-related fatal outcomes in VigiBase, the World Health Organization's pharmacovigilance database. Two possibly opposing hypotheses could explain this disparity: 1) fewer reported fatal outcomes in other Western European countries mainly reflect underreporting to VigiBase, and 2) the higher number of UK reports reflects higher real relative mortality. METHODS: VigiBase reports from clozapine's introduction to December 31, 2022, were studied for ADRs and the top 10 causes of fatal outcomes. The UK was compared with 11 other top reporting Western countries (Germany, Denmark, France, Finland, Ireland, Italy, Netherlands, Norway, Spain, Sweden and Switzerland). Nine countries (except Ireland and Switzerland) were compared after controlling for population and clozapine prescriptions. RESULTS: The UK accounted for 29 % of worldwide clozapine-related fatal outcomes, Germany 2 % and <1 % in each of the other countries. The nonspecific label "death" was the top cause in the world (46 %) and in the UK (33 %). "Pneumonia" was second in the world (8 %), the UK (12 %), Ireland (8 %) and Finland (14 %). Assuming that our corrections for population and clozapine use are correct, other countries underreported only 1-10 % of the UK clozapine fatal outcome number. CONCLUSIONS: Different Western European countries consistently underreport to VigiBase compared to the UK, but have different reporting/publishing styles for clozapine-related ADRs/fatal outcomes. Three Scandinavian registries suggest lives are saved as clozapine use increases, but this cannot be studied in pharmacovigilance databases.

[The structural stability of negative symptoms over time].

Negative symptoms remain poorly understood and treated despite their huge impact on patients' lives and clinical outcomes. This is partly because of ongoing debates about the clinical constructs underlying negative symptoms. A longitudinal analysis of the structure of negative symptoms presented in BJPsych Open reports striking temporal stability of symptom structure, which behaves as a few independent domains. This further underscores the need to address specific symptom domains when considering interventions or pathophysiology studies.

Influence of time to clozapine prescription on the clinical outcome.

BACKGROUND: This study investigates whether early clozapine use is associated with improved responses in different clinical domains, including positive and negative symptoms, functioning, and well-being. METHODS: Data from 254 clozapine-treated patients at Cambridgeshire and Peterborough NHS Foundation Trust (CPFT) were analysed. Among them, 231 (90.9 %) had a diagnosis of schizophrenia, 21 (8.3 %) schizoaffective disorder, and 2 (0.8 %) had other diagnoses. The International Classification of Diseases-Mortality and Morbidity Statistics criteria (ICD-10) were employed (World Health Organization, 1992). The cohort was assessed using the positive and negative syndrome scale (PANSS), the Brief Negative Symptom Scale (BNSS), Global Assessment of Functioning Scale (GAF), and the short version of Warwick-Edinburgh Mental Well-being Scale (SWEMWBS). Logistic regression models (for positive and negative symptom remission) and linear regression (for functioning and well-being) were utilized to assess the influence of time to clozapine initiation (TCI), age at the first episode of psychosis (AFE), duration of clozapine treatment (DCT), and gender. RESULTS: Early clozapine treatment (within the first three years after the first episode of psychosis) was associated with increased negative symptom remission (exp (B) = 0.38; p = 0.02) and higher functioning scores (ß = -0.12, p = 0.046). However, no effect of time to clozapine initiation was found on positive symptom remission rates or well-being scores. CONCLUSIONS: Initiating clozapine treatment within the first 3 years of the first episode of psychosis may lead to reduced severity of negative symptoms and improved functioning in clozapine-treated patients. The time to clozapine initiation did not influence its effect on positive symptom remission rates.

Relationship between severe mental illness and physical multimorbidity: a meta-analysis and call for action.

BACKGROUND: People with severe mental illness (SMI) have a higher prevalence of several chronic physical health conditions, and the prevalence of physical multimorbidity is expected to rise. The aim of this study was to assess the strength of the association between SMI and physical multimorbidity. STUDY SELECTION AND ANALYSIS: We systematically searched PubMed/Medline, Scopus, Embase, Web of Science, PsycINFO and the behavioural sciences collection databases, from inception to 31 January 2023, for studies that investigated the association between SMI and physical multimorbidity. Humans of any age either clinically diagnosed and/or currently receiving treatment for SMI, specified as schizophrenia (and related psychotic disorders), bipolar disorder and psychotic depression, were eligible. Data from studies selected for inclusion were converted into ORs, with a subsequent meta-analysis conducted. FINDINGS: We included 19 studies with a total of 194 123 patients with SMI with different diagnoses and drawn from the general population. The pooled OR for physical multimorbidity in people with versus without SMI was 1.84 (95% CI 1.33 to 2.54), with the analysis indicating a high level of heterogeneity (98.38%). The other 15 studies included in the systematic review for which it was not possible to conduct a meta-analysis showed strong associations between SMI and physical multimorbidity. CONCLUSIONS: The current evidence highlights the link between SMI and physical multimorbidity. A multidisciplinary approach is now urgent to develop the best models of services tailored to patients with SMI with physical multimorbidities to improve physical, mental and social outcomes. PROSPERO registration number CRD42023395165.

Eating disorders and physical multimorbidity in the English general population.

PURPOSE: People with eating disorders may be at increased risk for physical health problems, but there are no data on the relationship between eating disorders and physical multimorbidity (i.e., ≥ 2 physical conditions) and its potential mediators. Thus, we investigated this association in a representative sample of adults from the UK, and quantified the extent to which this can be explained by various psychological and physical conditions, and lifestyle factors. METHODS: Cross-sectional data of the 2007 Adult Psychiatric Morbidity Survey were analyzed. Questions from the five-item SCOFF screening instrument were used to identify possible eating disorder. Respondents were asked about 20 physical health conditions. Multivariable logistic regression and mediation analysis were conducted. RESULTS: Data on 7403 individuals aged ≥ 16 years were analyzed [mean (SD) age 46.3 (18.6) years; 48.6% males]. After adjustment, possible eating disorder was associated with 2.11 (95%CI = 1.67-2.67) times higher odds for physical multimorbidity. Anxiety disorder explained the largest proportion this association (mediated percentage 26.3%), followed by insomnia (21.8%), perceived stress (13.4%), depression (13.1%), obesity (13.0%), and alcohol dependence (4.3%). CONCLUSION: Future longitudinal studies are warranted to understand potential causality and the underlying mechanisms in the association between eating disorder and multimorbidity, and whether addressing the identified potential mediators in people with eating disorders can reduce multimorbidity.

Exploring low clozapine C/D ratios, inverted clozapine-norclozapine ratios and undetectable concentrations as measures of non-adherence in clozapine patients: A literature review and a case series of 17 patients from 3 studies.

BACKGROUND: Up to 1/2 of outpatients prescribed clozapine may be partially/fully non-adherent, based on therapeutic drug monitoring (TDM). Three indices for measuring partial/full non-adherence are proposed a: 1) clozapine concentration/dose (C/D) ratio which drops to half or more of what is expected in the patient; 2) clozapine/norclozapine ratio that becomes inverted; and 3) clozapine concentration that becomes non-detectable. METHODS: These 3 proposed indices are based on a literature review and 17 cases of possible non-adherence from 3 samples: 1) an inpatient study in a Chinese hospital, 2) an inpatient randomized clinical trial in a United States hospital, and 3) and a Uruguayan outpatient study. RESULTS: The first index of non-adherence is a clozapine C/D ratio which is less than half the ratio corresponding to the patient's specific ancestry group and sex-smoking subgroup. Knowing the minimum therapeutic dose of the patient based on repeated TDM makes it much easier to establish non-adherence. The second index is inverted clozapine/norclozapine ratios in the absence of alternative explanations. The third index is undetectable concentrations. By using half-lives, the chronology of the 3 indices of non-adherence was modeled in two patients: 1) the clozapine C/D ratio dropped to ≥1/2 of what is expected from the patient (around day 2); 2) the clozapine/norclozapine ratio became inverted (around day 3); and 3) the clozapine concentration became undetectable by the laboratory (around days 9-11). CONCLUSION: Prospective studies should further explore these proposed clozapine indices in average patients, poor metabolizers (3 presented) and ultrarapid metabolizers (2 presented).

A new era for the negative symptoms of schizophrenia.

Negative symptoms remain one of the major unmet needs for people with schizophrenia, and the past decade has witnessed a surge in interest in negative symptoms. In this themed issue, we present new concepts of negative symptoms and recent findings on their epidemiology and pathophysiology and on therapeutic options for their management.

CONSENSUS BY THE COLLECTIVE OF PSYCHIATRISTS FOR THE CLOZAPINE UPDATE.

Treatment-resistant schizophrenia affects one in three patients with schizophrenia, constituting the most severe group of the disease spectrum.

Clozapine ultrarapid metabolism during weak induction probably exists but requires careful diagnosis. A literature review, five new cases and a proposed definition.

During weak induction (from smoking and/or valproate co-prescription), clozapine ultrarapid metabolizers (UMs) need very high daily doses to reach the minimum therapeutic concentration of 350 ng/ml in plasma; clozapine UMs need clozapine doses higher than: 1) 900 mg/day in patients of European/African ancestry, or 2) 600 mg/day in those of Asian ancestry. Published clozapine UMs include 10 males of European/African ancestry, mainly assessed with single concentrations. Five new clozapine UMs (two of European and three of Asian ancestry) with repeated assessments are described. A US double-blind randomized trial included a 32-year-old male smoking two packages/day with a minimum therapeutic dose of 1,591 mg/day from a single TDM during open treatment of 900 mg/day. In a Turkish inpatient study, a 30-year-old male smoker was a possible clozapine UM needing a minimum therapeutic dose of 1,029 mg/day estimated from two trough steady-state concentrations on 600 mg/day. In a Chinese study, three possible clozapine UMs (all male smokers) were identified. The clozapine minimum therapeutic dose estimated with trough steady-state concentrations >150 ng/ml was: 1) 625 mg/day, based on a mean of 20 concentrations in Case 3; 2) 673 mg/day, based on a mean of 4 concentrations in Case 4; and 3) 648 mg/day, based on a mean of 11 concentrations in Case 5. Based on these limited studies, clozapine UMs during weak induction may account for 1-2% of clozapine-treated patients of European ancestry and <1% of those of Asian ancestry. A clozapine-to-norclozapine ratio <0.5 should not be used to identify clozapine UMs.

Clozapine Optimization: A Delphi Consensus Guideline From the Treatment Response and Resistance in Psychosis Working Group.

BACKGROUND AND HYPOTHESIS: There is limited evidence to guide the approaches to clozapine treatment. Accordingly, an international initiative was undertaken with the aim of developing consensus recommendations for the optimization of clozapine monotherapy. STUDY DESIGN: We conducted an online Delphi survey among members of the Treatment Response and Resistance in Psychosis (TRRIP) working group comprising experts from twenty-nine countries. The threshold criterion for a consensus recommendation was ≥ 75% agreement ("agree" and "strongly agree" responses) on a question. Agreement of ≥ 50% but < 75% in a second or third Delphi round was deemed to provide guidance. STUDY RESULTS: Forty-nine (first round), 32 (second round), and 48 (third round) of the 91 current TRRIP members participated. Expert recommendations at ≥ 75% comprised second-line treatment with clozapine in cases of persistent positive symptoms with co-occurring extrapyramidal symptoms, tardive dyskinesia, or suicidality/aggression. There was considerable disagreement on myocarditis screening parameters. The management of somatic and neuropsychiatric adverse drug reactions warrants further research for more evidence-based recommendations. Rechallenge with clozapine was recommended for eosinophilia, sinus tachycardia and fever and guidance (agreement ≥ 50%) was reached for pneumonia and thrombocytopenia. CONCLUSIONS: Given the limited evidence available, this consensus-based series of recommendations and guidance statements supports clinical decision-making to optimize clozapine monotherapy and provides guidance for future research in treatment-resistant schizophrenia.

Longitudinal effect of clozapine-associated sedation on motivation in schizophrenia: naturalistic longitudinal study.

Negative symptoms of schizophrenia manifest as reduced motivation and pleasure (MAP) and impaired emotional expressivity (EXP). These can occur as primary phenomena, but have also been suggested to occur secondary to other clinical factors, including antipsychotic-induced sedation. However, this relationship has not been established formally. Here, we examined the effect of antipsychotic-induced sedation (assessed via the proxy of total daily sleep duration) on MAP and EXP in a cohort of 187 clozapine-treated patients with schizophrenia followed for over 2 years on average, using multilevel regression and mediation models. MAP, but not EXP, was adversely influenced by sedation, independently of the severity of psychosis or depression. Moreover, clozapine impaired MAP indirectly by worsening sedation, but after accounting for clozapine-induced sedation, clozapine improved MAP. Our results highlight the importance of addressing sedative side-effects of antipsychotics to improve clinical outcomes.

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.