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Objective To investigate whether patients with clozapine treatment are at an increased risk of a more severe COVID-19 infection as compared with patients on other antipsychotic drugs. Methods In this register-based cohort study, all residents (age 18 or older) in the Stockholm Region with a psychotic disorder diagnosis and antipsychotic treatment were included (N = 8 233) and followed from March 1, 2020 to January 14, 2021. The exposure was defined as clozapine treatment and the outcome measures (indicating a more severe COVID-19 infection) were: inpatient care, care within intensive care unit or death due to COVID-19 infection. Differences in outcome rates between exposed (n = 966) and unexposed (other antipsychotics; n = 7 267) were examined using Cox proportional hazards models and expressed as hazard ratios (HR) with 95% confidence intervals (CI). Results No statistically significant differences in outcome rates were found between the two groups of patients after adjusting for age, sex, and residence in retirement homes. The adjusted HR for the exposed compared to the unexposed was 0.96 (95% CI: 0.54, 1.70) for inpatient care; 1.69 (0.48, 5.93) for care in intensive care unit (ICU); and 0.86 (0.26, 2.80) for death. Regarding inpatient care, additional adjusting for country of birth, living in socioeconomically vulnerable areas, number of care visits during the previous year, and comorbid medical illnesses did not alter the results. Conclusions Our results may add support to the present guidelines, recommending sustained clozapine treatment during the current COVID-19 pandemic with careful monitoring and readiness to alter drug doses as needed.

Objective Early treatment of schizophrenia improves outcomes. Clozapine appears to have unique benefit when other antipsychotic medication has failed. This systematic review and meta-analysis aims to assess clozapine's superiority over alternative antipsychotic medication and examine whether earlier use is associated with additional benefit. Method Systematic retrieval of blinded, randomized controlled trials comparing clozapine with alternative antipsychotics in adults with schizophrenia. The effect of mean age on relative clozapine response was examined using random effects meta-regression, and multiple linear regression on available patient data. Results A total of 276 studies were retrieved. Thirty-four studies were included in the meta-analysis. Clozapine was significantly more effective than alternative antipsychotics in reducing psychotic symptoms and increasing response. However, meta-regression failed to show a more significant effect in younger patients (age on effect size (total psychotic symptoms) 0.00, P = 0.79 CI -0.03 to 0.03). Individual patient data were available for two studies, the larger of which showed a significant interaction between younger age and superiority of clozapine. Conclusion The results support clozapine's superiority over other antipsychotics. A convincing effect of age on this effect was not demonstrated, although this was suggested in one study. In view of the age of many of the included studies, and changes in reporting practice over time, new clozapine RCTs, which include age of illness onset as well as age at trial time, would be welcome in order to provide meta-analysable data for future use.

Objective Large‐scale epidemiological studies have demonstrated a protective effect of clozapine on mortality in people with schizophrenia. Clozapine is reserved for use in patients with treatment‐resistant schizophrenia (TRS), but evidence of clozapine's effect on mortality exclusively within TRS samples is inconclusive. Hence, we aimed to investigate the effect of clozapine use on all‐cause mortality in TRS patients. Methods A historical patient cohort sample of 2837 patients, who met criteria for TRS between 1 Jan 2008 and 1 Jan 2016, were selected from the South London and Maudsley NHS Foundation Trust (SLAM) electronic health records (EHR). The national Zaponex Treatment Access System (ZTAS) mandatory monitoring system linked to the SLAM EHR was used to distinguish which patients were initiated on clozapine (n = 1025). Cox proportional hazard models were used, adjusting for sociodemographics, clinical monitoring, mental and physical illness severity and functional status. Results After controlling for potential confounders, the protective effect of clozapine on all‐cause mortality was significant (adjusted hazard ratio 0.61; 95% confidence interval 0.38–0.97; P = 0.04). Conclusions Clozapine reduces the risk of mortality in patients who meet criteria for TRS. We provide further evidence that improving access to clozapine in TRS is likely to reduce the mortality gap in schizophrenia.

ObjectivesTo investigate the association between long‐term antipsychotic polypharmacy use and mortality; and determine whether this risk varies by cause of death and antipsychotic dose.MethodsUsing data from a large anonymised mental healthcare database, we identified all adult patients with serious mental illness (SMI) who had been prescribed a single antipsychotic or polypharmacy, for six or more months between 2007 and 2014. Multivariable Cox regression models were constructed, adjusting for sociodemographic, socioeconomic, clinical factors and smoking, to examine the association between APP use and the risk of death.ResultsWe identified 10 945 adults with SMI who had been prescribed long‐term antipsychotic monotherapy (76.9%) or APP (23.1%). Patients on long‐term APP had a small elevated risk of mortality, which was significant in some but not all models. The adjusted hazard ratios for death from natural and unnatural causes associated with APP were 1.2 (0.9–1.4, P = 0.111) and 1.1 (0.7–1.9, P = 0.619) respectively. The strengths of the associations between APP and mortality outcomes were similar after further adjusting for % BNF antipsychotic dose (P = 0.031) or olanzapine equivalence (P = 0.088).ConclusionThe findings suggest that the effect of long‐term APP on mortality is not clear‐cut, with limited evidence to indicate an association, even after controlling for the effect of dose.

Daily smoking has been associated with a greater risk of psychosis. However, we are still lacking studies to adjust for baseline psychotic experiences and other substance use. We examined associations between daily smoking and psychosis risk in a 15-year follow-up while accounting for these covariates in a prospective sample (N = 6081) from the Northern Finland Birth Cohort 1986.Self-report questionnaires on psychotic experiences (PROD-screen), tobacco smoking and other substance use were completed when the cohort members were 15-16 years old. Tobacco smoking was categorized into three groups (non-smokers, 1-9 cigarettes and ≥10 cigarettes/day). Psychosis diagnoses were obtained from national registers until the age of 30 years.Subjects in heaviest smoking category were at increased risk of subsequent psychosis (unadjusted HR = 3.15; 95% CI 1.94-5.13). When adjusted for baseline psychotic experiences the association persisted (HR = 2.87; 1.76-4.68) and remained significant even after adjustments for multiple known risk factors such as cannabis use, frequent alcohol use, other illicit substance use, parental substance abuse, and psychosis. Furthermore, number of smoked cigarettes increased psychosis risk in a dose-response manner (adjusted OR = 1.05; 1.01-1.08).Heavy tobacco smoking in adolescence was associated with a greater risk for psychosis even after adjustment for confounders.

Objective To describe a practical approach to the community management of treatment-resistant schizophrenia (TRS). Method A descriptive review of an approach to the assessment and management of patients with TRS, including the community titration of clozapine treatment, and a report of the management recommendations for the first one hundred patients assessed by the Treatment REview and Assessment Team (TREAT). Results The standardized model for the community assessment, management and titration of clozapine is described. To date, 137 patients have been referred to this service and 100 patients (72%) attended for assessment. Of these, 33 have been initiated on clozapine while fifteen have had clozapine recommended but have not wished to undertake clozapine treatment. Other management options recommended have included augmentation strategies and long-acting injectable antipsychotics. Conclusion The service had increased the number of patients receiving community assessment and initiation of clozapine by five-fold relative to the rate prior to the establishment of the service. The large number of referrals and high attendance rate indicates that there is clinical demand for the model. Systematic evaluation is required to determine the clinical and cost-effectiveness of this model and its potential application to other clinical settings.

Bundy H, Stahl D, MacCabe JH. A systematic review and meta-analysis of the fertility of patients with schizophrenia and their unaffected relatives. Objective: We aimed to systematically evaluate the empirical evidence for the commonly held view that the reduced reproductive output in patients with schizophrenia is compensated for by an increased fitness in unaffected relatives. Secondary aims were to quantify the magnitude of the fertility disadvantage and the apparent gender difference in fertility of patients with schizophrenia. Method: We carried out a systematic review and meta-analysis of studies investigating the fertility of patients with schizophrenia, their siblings, their parents and the general population. Results: Patients with schizophrenia had reduced fertility compared with the general population, [Fertility Ratio (FR) = 0.39 (95% Confidence Interval (CI) = 0.35–0.44)]. Siblings of patients with schizophrenia had somewhat fewer offspring than the general population (FR = 0.96, 95% CI = 0.93–1.00). Parents of patients with schizophrenia had fertility similar to the general population (FR = 1.17, 95% CI = 0.94–1.46). Men had a greater impairment in fertility than women, both in patients (FR = 0.54, 95% CI = 0.50–0.57) and in their unaffected siblings (FR = 0.81, 95% CI = 0.71–0.92). Conclusion: Compensatory fitness advantage in siblings and parents cannot explain the maintenance of schizophrenia in the population. Alternative explanations include mutation-selection balance and the role of quantitative traits.

We aimed to systematically evaluate the empirical evidence for the commonly held view that the reduced reproductive output in patients with schizophrenia is compensated for by an increased fitness in unaffected relatives. Secondary aims were to quantify the magnitude of the fertility disadvantage and the apparent gender difference in fertility of patients with schizophrenia.We carried out a systematic review and meta-analysis of studies investigating the fertility of patients with schizophrenia, their siblings, their parents and the general population.Patients with schizophrenia had reduced fertility compared with the general population, [Fertility Ratio (FR)=0.39 (95% Confidence Interval (CI)=0.35-0.44)]. Siblings of patients with schizophrenia had somewhat fewer offspring than the general population (FR=0.96, 95% CI=0.93-1.00). Parents of patients with schizophrenia had fertility similar to the general population (FR=1.17, 95% CI=0.94-1.46). Men had a greater impairment in fertility than women, both in patients (FR=0.54, 95% CI=0.50-0.57) and in their unaffected siblings (FR=0.81, 95% CI=0.71-0.92).Compensatory fitness advantage in siblings and parents cannot explain the maintenance of schizophrenia in the population. Alternative explanations include mutation-selection balance and the role of quantitative traits.