Evaluating the epidemiology of clozapine-associated neutropenia among people on clozapine across Australia and Aotearoa New Zealand: a retrospective cohort study.

BACKGROUND: Clozapine is associated with the risk of serious neutropenia. However, this risk might decrease over time, meaning that indefinite absolute neutrophil count (ANC) monitoring could be unnecessary. We aimed to determine the epidemiology and timing of clozapine-associated neutropenia outcomes, to investigate variables that might contribute to the odds of neutropenia, and to determine risk of competing neutropenic events during clozapine treatment. METHODS: We performed a retrospective analysis of the Australian and New Zealand Viatris Pharmacovigilance system (one of two monitoring databases for these two countries) between June 6, 1990, and Oct 25, 2022. Patients were excluded from analysis if they commenced clozapine before 1990, did not have a haematology test within 2 weeks of commencement date, or had no follow-up. We measured minor neutropenia (ANC 1·0-1·5 × 109 per L) and serious neutropenia (ANC <1·0 × 109 per L) leading to cessation of clozapine within 6 weeks of the neutropenic event. We determined the rates of minor and serious neutropenia and calculated odds ratios (ORs) for the likelihood of neutropenia leading to cessation. For serious neutropenia leading to cessation, we used time-to-event to calculate rolling weekly averages and to perform competing risk analysis of outcomes using Cox proportional hazards models and a Fine-Gray subdistribution hazards regression model. For the subset of data where information on previous clozapine use was available, we did an analysis for participants who did and did not have previous clozapine exposure. FINDINGS: We included 26 630 people, with 2·6 million ANC values. Within the total cohort, 17 585 people (66%) were male, 9025 (33·9%) female, and 20 (0·1%) other gender, and the mean age was 36·1 years (SD 13·7). We did not have data on race or ethnicity. Of the 26 630 people taking clozapine, 1146 (4·3%) had minor neutropenia, 313 (1·2%) had serious neutropenia leading to cessation, and 223 (0·8%) had serious neutropenia unrelated to clozapine without cessation. In people with no previous exposure to clozapine (n=15 973), the cumulative incidence of serious neutropenia leading to cessation was 0·9% at 18 weeks and 1·4% at 2 years; the weekly incidence rate for serious neutropenia leading to cessation peaked at 9 weeks (0·128%) and fell to a rolling average weekly incidence of 0·001% by 2 years. For minor neutropenia, the cumulative incidence was 1·7% at 18 weeks and 3·5% at 2 years; the weekly incidence rate peaked at 9 weeks (0·218%) and fell to a stable rolling average of 0·01%. The median time to a serious neutropenic event leading to cessation was 17 weeks (IQR 9·96-102). Previous clozapine exposure reduced the risk of serious neutropenia leading to cessation (OR 0·19, 95% CI 0·12-0·31; p <0·0001). INTERPRETATION: Most serious neutropenia leading to clozapine cessation occurs within 18 weeks of treatment and becomes negligible after 2 years. Weekly haematological monitoring after the first 18 weeks could be safely reduced to once every 4 weeks and ceased after 2 years unless clinically indicated. Clozapine retrial after interruption with 2 cumulative years of unremarkable testing might not require further haematological monitoring. A serious neutropenia ANC threshold of ≤1·0 × 109 per L could be used in more jurisdictions. FUNDING: None.

The role of metformin as a treatment for neuropsychiatric illness.

Advances in psychopharmacology have been significantly slower to evolve than in other disciplines of medicine and therefore investigation into novel therapeutic approaches is required. Additionally, concurrent metabolic conditions are prevalent among people with mental disorders. Metformin is a widely used hypoglycaemic agent that is now being studied for use beyond diabetes management. Evidence is emerging that metformin has multiple effects on diverse neurobiological pathways and consequently may be repurposed for treating mental illness. Metformin may have beneficial neuroimmunological, neuroplastic, neuro-oxidative and neuro-nitrosative effects across a range of psychiatric and neurodegenerative illnesses. Mechanisms include glucose lowering effects and effects on AMP-activated protein kinase (AMPK) signalling, however the best evidence for clinical benefit is through the glucose lowering effects, with other mechanisms less supported by the current evidence base. This narrative review aims to draw together the existing evidence for use of metformin as a psychopharmaceutical and present the role of metformin in the context of physical and psychiatric ill health, including metabolic, endocrinological and cancer domains. It not only has therapeutic potential in medical comorbidity but may have potential in core illness domains.

Leveraging orthology within maize and Arabidopsis QTL to identify genes affecting natural variation in gravitropism.

Plants typically orient their organs with respect to the Earth's gravity field by a dynamic process called gravitropism. To discover conserved genetic elements affecting seedling root gravitropism, we measured the process in a set of Zea mays (maize) recombinant inbred lines with machine vision and compared the results with those obtained in a similar study of Arabidopsis thaliana. Each of the several quantitative trait loci that we mapped in both species spanned many hundreds of genes, too many to test individually for causality. We reasoned that orthologous genes may be responsible for natural variation in monocot and dicot root gravitropism. If so, pairs of orthologous genes affecting gravitropism may be present within the maize and Arabidopsis QTL intervals. A reciprocal comparison of sequences within the QTL intervals identified seven pairs of such one-to-one orthologs. Analysis of knockout mutants demonstrated a role in gravitropism for four of the seven: CCT2 functions in phosphatidylcholine biosynthesis, ATG5 functions in membrane remodeling during autophagy, UGP2 produces the substrate for cellulose and callose polymer extension, and FAMA is a transcription factor. Automated phenotyping enabled this discovery of four naturally varying components of a conserved process (gravitropism) by making it feasible to conduct the same large-scale experiment in two species.

Demonstration of automated non-adherence and service disengagement risk monitoring with active follow-up for severe mental illness.

AIMS: Medication cessation and service disengagement often precedes relapse in people with severe mental illnesses but currently specialist mental health services only become involved after a relapse. Early detection of non-adherence is needed to enable intervention to avert relapse. This paper aims to demonstrate how digitally automated non-adherence risk monitoring from Medicare data with active follow-up can work and perform in practice in a real-world mental health service setting. METHODS: AI2 software is an automated risk monitoring tool to detect non-adherence using Medicare data. It was implemented prospectively in a cohort of 354 registered patients of a community mental health clinic between July 2019 and February 2020. Patients flagged as at risk by the software were reviewed by two clinicians. We describe the risks automatically flagged for non-adherence and the clinical responses. We examine differences in clinical and demographic factors in patients flagged at increased risk of non-adherence. RESULTS: In total, 46.7% (142/304) were flagged by the software as at risk of non-adherence, and 22% (31/142) received an intervention following clinician review of their case notes. Patients flagged by the software were older in age and had more prior mental health treatment episodes. More alerts were associated with patients who had been transferred from the mental health service to the care of their general practitioners, and those with more alerts were more likely to receive a follow-up intervention. CONCLUSION: Digitally automated monitoring for non-adherence risk is feasible and can be integrated into clinical workflows in community psychiatric and primary care settings. The technology may assist clinicians and services to detect non-adherence behaviour early, thereby triggering interventions that have the potential to reduce rates of mental health deterioration and acute illness relapse.

Instructions for Australian and New Zealand trainees in developing skills in formulation: a systematic review of local evidence.

OBJECTIVE: To examine the peer-reviewed literature on psychiatric formulation. METHODS: The term (formula*) was used to systematically search Australasian Psychiatry, Australian and New Zealand Journal of Psychiatry, British Journal of Psychiatry, BJPsych Bulletin, American Journal of Psychiatry and Academic Psychiatry. The resulting papers were reviewed. RESULTS: Of the 42 papers located, 22 (52%) were published between 2002 and 2019; 90% papers were published in Australasian Psychiatry (15), Academic Psychiatry (12) or BJPsych Bulletin (10), journals that focus on training and clinical practice. The papers varied in their aims and recommendations and not all justified the need for formulation. Formulation was recommended as a necessity for training, a communication tool and a guide to treatment. No article provided evidence for the superiority of any type of formulation, and the role of consumers in formulation was conspicuously lacking. CONCLUSION: There are many ways to structure formulation. However, the existing literature does not support any particular approach. More consideration needs to be given to the needs of consumers in conceptualising and practicing formulation.

Screening for obstructive sleep apnoea in an early psychosis cohort: a pilot study.

OBJECTIVE: Rates of obstructive sleep apnoea (OSA) appear to be lower in the youth population (< 4%) compared to the general population (6%-17%); rates in people with psychotic illness are estimated at 13.5%-57.1%. We hypothesised that this comorbidity extends to early psychosis (EP) populations, and used previously validated OSA questionnaires to screen for OSA in an EP cohort. METHOD: Fifty-three patients were screened using the OSA50 and STOP-Bang questionnaires with collection of anthropometric measures. Patients who screened positively were referred for polysomnography. RESULTS: Fifteen per cent (8/53) screened positively; most frequently endorsed measures included BMI > 25, snoring, hypertension, neck circumference (> 40 cm) and male gender. Only 2/8 patients accepted polysomnography. CONCLUSIONS: Screening indicates OSA may be more prevalent in EP populations than age-equivalent cohorts, but ongoing research is required.

A meta-analysis of controlled studies comparing the association between clozapine and other antipsychotic medications and the development of neutropenia.

BACKGROUND: In most countries, clozapine can only be prescribed with regular monitoring of white blood cell counts because of concerns that clozapine has a stronger association with neutropenia than other antipsychotics. However, this has not been previously demonstrated conclusively with meta-analysis of controlled studies. METHODS: The aim of this study was to assess the strength of the association between clozapine and neutropenia when compared to other antipsychotic medications by a meta-analysis of controlled studies. An electronic search of Medline (1948-2018), PsycINFO (1967-2018) and Embase (1947-2018) using search terms (clozapine OR clopine OR clozaril OR zaponex) AND (neutropenia OR agranulocytosis) was undertaken. Random-effects meta-analysis using Mantel-Haenszel risk ratio was used to assess the strength of the effect size. RESULTS: We located 20 studies that reported rates of neutropenia associated with clozapine and other antipsychotic medications. The risk ratio was not significantly increased in clozapine-exposed groups compared to exposure to other antipsychotic medications (Mantel-Haenszel risk ratio = 1.45, 95% confidence interval = [0.87, 2.42]). This also applied to severe neutropenia (absolute neutrophil count < 500 per µL) when compared to other antipsychotics (Mantel-Haenszel risk ratio = 1.65, 95% confidence interval = [0.58, 4.71]). The relative risk of neutropenia associated with clozapine exposure was not significantly associated with any individual antipsychotic medication. CONCLUSION: Data from controlled trials do not support the belief that clozapine has a stronger association with neutropenia than other antipsychotic medications. This implies that either all antipsychotic drugs should be subjected to haematological monitoring or monitoring isolated to clozapine is not justified.

'Having a mentor helped me with difficult times': a trainee-run mentoring project.

OBJECTIVE: A mentoring programme was established in South Australia in 2014 by psychiatry trainees, with the goal of reducing stress and burnout amongst first-year trainees. All first-year trainees are offered the opportunity to have a senior trainee as a mentor. This article describes the mentoring programme, presents feedback from participants and identifies areas for further development. METHOD: The majority (72/76) of first-year trainees entering psychiatry training in South Australia from 2014-2018 were allocated a mentor. Surveys were sent out in 2014, 2015 and 2017. Twenty of 42 (48%) mentors and 17 of 42 (40%) of mentees completed a 10-item questionnaire, with free text responses. RESULTS: Mentee feedback was mostly positive, reporting that mentors offered them reassurance and support. The most common challenges were advice about training, managing work-life balance and issues with supervision. The main barrier to the mentoring programme was lack of time to meet. Mentors identified that they would have liked more training in mentoring. CONCLUSION: The trainee mentoring programme has been a useful initiative. As consultant psychiatrists are likely to provide mentoring for more junior colleagues, the authors propose that training in mentoring should be part of the Royal Australian and New Zealand College of Psychiatrists education programme.

Cognition in schizophrenia improves with treatment of severe obstructive sleep apnoea: A pilot study.

Previous studies have shown that people with schizophrenia have high rates of Obstructive Sleep Apnoea (OSA). Despite this, intervention studies to treat OSA in this population have not been undertaken. The ASSET (Assessing Sleep in Schizophrenia and Evaluating Treatment) pilot study investigated Continuous Positive Airway Pressure (CPAP) treatment of severe OSA in participants recruited from a clozapine clinic in Adelaide. Participants with severe untreated OSA (Apnoea-Hypopnoea Index (AHI) > 30), were provided with CPAP treatment, and assessed at baseline and six months across the following domains: physical health, quality of sleep, sleepiness, cognition, psychiatric symptoms and CPAP adherence. Six of the eight ASSET participants with severe OSA accepted CPAP. At baseline, half of the cohort had hypertension, all were obese with a mean BMI of 45, and they scored on average 1.47 standard deviations below the normal population in cognitive testing. The mean AHI was 76.8 and sleep architecture was markedly impaired with mean rapid eye movement (REM) sleep 4.1% and mean slow wave sleep (SWS) 4.8%. After six months of treatment there were improvements in cognition (BACS Z score improved by an average of 0.59) and weight loss (mean weight loss 7.3 ±â€¯9 kg). Half of the participants no longer had hypertension and sleep architecture improved with mean REM sleep 31.4% of the night and mean SWS 24% of the night. Our data suggests CPAP may offer novel benefits to address cognitive impairment and sleep disturbance in people with schizophrenia.

Obstructive sleep apnoea is more prevalent in men with schizophrenia compared to general population controls: results of a matched cohort study.

OBJECTIVES:: Obstructive sleep apnoea (OSA) may be more common in people with schizophrenia compared to the general population, but the relative prevalence is unknown. Here, we determine the relative prevalence of severe OSA in a cohort of men with schizophrenia compared to representative general population controls, and investigate the contribution of age and body mass index (BMI) to differences in prevalence. METHODS:: Rates of severe OSA (apnoea-hypopnoea index > 30) were compared between male patients with schizophrenia and controls from a representative general population study of OSA. RESULTS:: The prevalence of severe OSA was 25% in the schizophrenia group and 12.3% in the general population group. In subgroups matched by age, the relative risk of severe OSA was 2.9 ( p = 0.05) in the schizophrenia subjects, but when adjusted for age and BMI, the relative risk dropped to 1.7 and became non-significant ( p = 0.17). CONCLUSIONS:: OSA is prevalent in men with schizophrenia. Obesity may be an important contributing factor to the increased rate of OSA.

Use of granulocyte-colony stimulating factor to prevent recurrent clozapine-induced neutropenia on drug rechallenge: A systematic review of the literature and clinical recommendations.

BACKGROUND: Clozapine is the most effective medication for treatment-refractory schizophrenia; however, its use is contraindicated in people who have had previous clozapine-induced neutropenia. Co-prescription of granulocyte-colony stimulating factor may prevent recurrent neutropenia and allow continuation or rechallenge of clozapine. OBJECTIVE AND METHODS: Systematic review of literature reporting the use of granulocyte-colony stimulating factor to allow rechallenge or continuation of clozapine in people with previous episodes of clozapine-induced neutropenia. The efficacy of granulocyte-colony stimulating factor and predictors of successful rechallenge will be determined to elucidate whether evidence-based recommendations can be made regarding the use of granulocyte-colony stimulating factor in this context. RESULTS: A total of 17 articles were identified that reported on clozapine rechallenge with granulocyte-colony stimulating factor support. In all, 76% of cases were able to continue clozapine at median follow-up of 12 months. There were no clear clinical or laboratory predictors of successful rechallenge; however, initial neutropenia was more severe in successful cases compared to unsuccessful cases. Cases co-prescribed lithium had lower success rates of rechallenge (60%) compared to those who were not prescribed lithium (81%). The most commonly reported rechallenge strategy was use of filgrastim 150-480 µg between daily to three times a week. There were no medication-specific side effects of granulocyte-colony stimulating factor reported apart from euphoria in one case. Three cases who failed granulocyte-colony stimulating factor had bacterial infection at time of recurrent neutropenia. No deaths were reported. CONCLUSION: Preliminary data suggest granulocyte-colony stimulating factor is safe and effective in facilitating rechallenge with clozapine. Clinical recommendations for use are discussed.

Developing a metformin prescribing tool for use in adults with mental illness to reduce medication-related weight gain and cardiovascular risk.

OBJECTIVES: There is considerable evidence that metformin reduces weight gain associated with antipsychotic medication. The aim of this study was to develop an easy-to-use metformin prescribing tool in order to enable clinicians to prescribe metformin safely and confidently. METHODS: The authors undertook a survey of clinicians and reviewed the published literature and existing guidelines concerning the use of metformin to reduce weight gain in adults with mental illness. RESULTS: A metformin prescribing tool was devised based on the literature, national cardiovascular and diabetes guidelines and Australian metformin prescribing recommendations. The metformin prescribing tool guides clinicians through the considerations required for appropriate selection of the target patient population and safe prescription of metformin. CONCLUSIONS: A novel, easy-to-use, one-page reference has been developed for busy clinicians that can be laminated and displayed in consulting rooms and psychiatric inpatient units to address weight gain and obesity associated with antipsychotic medications in people with mental illness.

Known unknowns and unknown unknowns in suicide risk assessment: evidence from meta-analyses of aleatory and epistemic uncertainty.

Suicide risk assessment aims to reduce uncertainty in order to focus treatment and supervision on those who are judged to be more likely to die by suicide. In this article we consider recent meta-analytic research that highlights the difference between uncertainty about suicide due to chance factors (aleatory uncertainty) and uncertainty that results from lack of knowledge (epistemic uncertainty). We conclude that much of the uncertainty about suicide is aleatory rather than epistemic, and discuss the implications for clinicians.