Risk factors for clozapine-induced myocarditis and cardiomyopathy: A systematic review and meta-analysis.

OBJECTIVE: Clozapine is the most effective medication for treatment-refractory schizophrenia, but it is associated with severe cardiac adverse events including myocarditis and cardiomyopathy. To aid treatment decision-making for clinicians, patients and their carers, we conducted a systematic review and meta-analysis to identify potential risk factors for clozapine-induced myocarditis and cardiomyopathy. METHODS: A systematic search was conducted of PubMed, Embase, CINAHL, Web of Science, Cochrane and PsycInfo for studies reporting myocarditis and cardiomyopathy among people on clozapine and potential risk factors. We calculated pooled effect sizes on risk factors using a random-effects meta-analytic model. Risk of publication bias was assessed using the Newcastle-Ottawa scale. RESULTS: Seven studies met the inclusion criteria, of which six studies had quantitative data included in the meta-analysis. The odds of clozapine-induced myocarditis increased with concurrent sodium valproate use (k = 6, n = 903, pooled OR 3.58, 95% CI 1.81-7.06), but were not significantly greater with the use of quetiapine, lithium or selective serotonin reuptake inhibitors. Our qualitative review identified conflicting results reported for increasing age and higher clozapine dose as risk factors for myocarditis. No other factors, including genetic risk, sex, ethnicity, smoking, alcohol, substance abuse or cardiometabolic disease, were associated with greater odds of myocarditis. No risk factors for cardiomyopathy were identified in the literature. CONCLUSION: Concurrent use of sodium valproate increases the odds of clozapine-induced myocarditis. Thus, clinicians should consider the temporary cessation of sodium valproate during the initial titration phase of clozapine.

Electroconvulsive therapy, personal protective equipment and aerosol generating procedures: a review to guide practice during Coronavirus Disease 2019 (COVID-19) pandemic.

OBJECTIVE: To review the literature on the definition of aerosol-generating procedures (AGPs), identify high-risk AGPs, guidelines to use personal protective equipment (PPE) and review evidence to see if electroconvulsive therapy (ECT) is a high-risk AGP requiring the use of PPE. METHODS: Existing guidelines and research data were reviewed to answer the questions. RESULTS: There is consensus about the type of anaesthesia used during ECT, what constitutes AGPs and what PPE should be used. It was not clear if ECT was an AGP, but we argue that it is one based on evidence. CONCLUSION: We conclude that ECT is an AGP and that it requires the appropriate use of PPE after taking in to account local supply and demand.

Documentation of medication changes in inpatient clinical notes: an audit to support quality improvement.

OBJECTIVE: To describe completeness and accuracy of recording medication changes in progress notes during psychiatric inpatient admissions. METHOD: A retrospective audit of records of 54 randomly selected psychiatric admissions at a metropolitan tertiary hospital. Medication changes recorded on National Inpatient Medication Chart (NIMC) were compared to documentation in the clinical progress records and assessed for completeness against seven quality criteria. RESULTS: With between one and 32 medication changes per admission, a total of 519 changes were recorded in NIMCs. Just over half were documented in progress notes. Psychotropic and regular medications were more frequently charted than 'other' and 'if required' medications. Documentation was seldom comprehensive. Medication name was most frequently documented; desired therapeutic effect or potential adverse effects were rarely documented. Evidence of patient involvement in, and an explicit rationale for, a change were infrequently recorded. CONCLUSIONS: Revealing substantial gaps in communication about medication changes during psychiatric admission, this audit sheds light on a previously undescribed source of medication error, warranting attention. Further research is needed to examine barriers to best practice, to support design and implementation of quality improvement activities but in the interim, attention should be addressed to development and articulation of content and procedures for documentation.

Monitoring and management of metabolic abnormalities: mixed-method evaluation of a successful intervention.

OBJECTIVE: To describe the process and impact of a service-level intervention on metabolic monitoring and follow-up of patients of a mental health service who were prescribed clozapine, and describe the metabolic health of these patients. METHODS: The intervention - Let's Get Physical - involved designating two months annually as 'physical health months', during which revised service protocol required metabolic monitoring for all eligible patients. Mixed methods were used to assess rates of monitoring at baseline, during the two physical health months, and follow-up and factors influencing practice. Data was analysed using a descriptive statistics and framework approach. RESULTS: Monitoring was completed for around two thirds of eligible patients during each physical health month, representing a statistically significant increase (approximately fourfold) from baseline. Perceptions regarding scope of practice and perceived competency managing metabolic abnormalities were key determinants of clinicians' practice. Low rates and inconsistency of follow-up were observed. CONCLUSION: Let's Get Physical is cost effective in enhancing adherence to monitoring guidelines. The use of clinical algorithms supporting timely response to abnormalities should be considered. Ongoing education, role clarity and dedicated resources are required if psychiatrists are to contribute meaningfully to improving the physical health of people with mental illness.

Sexual and Reproductive Health in Adolescents and Young Adults With Psychotic Disorders: A Scoping Review.

BACKGROUND AND HYPOTHESIS: The sexual and reproductive health (SRH) of young people with psychosis has been largely overlooked. We hypothesised that there are key deficiencies in the existing literature on the SRH of adolescents and young adults with psychotic disorders. STUDY DESIGN: We conducted a systematic scoping review using Pubmed, Web of Science, Embase, PsycINFO, and CINAHL. We included empirical studies and case reports focused on SRH issues in young people (aged 14-24 years) with psychotic disorders. A qualitative synthesis was completed. Joanna Briggs Institute Critical Appraisal Tools were utilized to assess study quality. STUDY RESULTS: Seventeen empirical studies and 52 case reports met inclusion criteria. Most focused on sexual dysfunction which was identified as common among this cohort and associated with both psychotic disorders and antipsychotics. The study population was more likely to engage in sexual risk-taking behavior and was at higher risk of sexually transmissible infections than those without psychosis. SRH topics of clinical relevance in older patients with psychosis such as pregnancy, abortion, sexual violence, coercion, sexual identity, and gender were poorly addressed in this younger group. We found empirical studies generally lacked identification and controlling of confounders whilst case reports provided limited description of mental health and SRH outcomes following clinical intervention. CONCLUSION: Research and clinical practice addressing sexual and reproductive health is needed for young people living with psychosis. To address research gaps future studies should focus on women's health, sexual violence, gender, and sexuality in young people with psychosis.

A new clinical protocol for the pharmacological management of acute behavioural disturbance.

OBJECTIVE: Psychiatry is awash with pharmacological acute behavioural disturbance protocols which list oral or intramuscular benzodiazepines and antipsychotics with numerous options. This results in frequent over-sedation and occasional profound sedation and death. This paper describes the development of a simplified sedation protocol for the pharmacological management of acute behavioural disturbance. METHOD: Following the wider availability of intramuscular lorazepam in 2008, Metro North Mental Health developed a protocol utilizing only two products - oral or intramuscular lorazepam or olanzapine - which was subsequently developed into a statewide protocol. RESULTS: The advantage of utilizing only two sedating medications is that it greatly reduces the risk of profound sedation and theoretically reduces the risk of other complications including deaths. Clinical staff who have utilized the protocol report a reduction in over-sedation of inpatients. CONCLUSION: A simplified protocol makes the pharmacological management of acute behaviour disturbance safer for both patients and staff.

CoMET: a randomised controlled trial of co-commencement of metformin versus placebo as an adjunctive treatment to attenuate weight gain in patients with schizophrenia newly commenced on clozapine.

BACKGROUND: There is limited evidence on interventions to minimise weight gain at clozapine commencement. We compared the effect of adjunctive metformin versus placebo at clozapine initiation. METHODS: People with schizophrenia commencing on clozapine were randomised to either metformin or placebo for 24 weeks. The primary outcome was difference in the change of body weight. Secondary outcomes included comparative rates of weight gain of more than 5%, overall weight gain/loss, and differences in metabolic and psychosis outcomes. RESULTS: The study was closed prematurely in March 2020 due to COVID-19 restrictions. Ten participants were randomised to each of the metformin and placebo groups. Eight metformin group and five placebo group participants completed the trial and were included in the analysis. The study was insufficiently powered to detect difference between the metformin and placebo groups for the primary outcome of change in weight (0.09 kg vs 2.88 kg, p = 0.231). In terms of secondary outcomes, people in the metformin group were significantly less likely to gain >5% of their body weight (12.5% vs 80%, p = 0.015) and were more likely to lose weight (37.5% vs 0% p = 0.024) compared to placebo. There was no difference between the groups in terms of adverse drug reactions (ADRs). CONCLUSION: While limited by the forced premature closure of the trial due to COVID19, the findings from this randomised controlled trial are promising. Clozapine and metformin co-commencement may be a promising treatment to prevent clozapine-associated weight gain, especially given the low rates of ADRs associated with metformin. This supports the consideration of use of metformin to prevent weight gain in people initiated on clozapine; however, further studies are needed to confirm this finding. TRIAL REGISTRATION: ACTRN12617001547336.

Cadence discovery: study protocol for a dose-finding and mechanism of action clinical trial of sodium benzoate in people with treatment-refractory schizophrenia.

BACKGROUND: Schizophrenia is a persistent psychotic disorder often accompanied by severe disability and premature mortality. New pharmacological treatments are urgently needed. Sodium benzoate, a common food preservative holds potential to be an effective, accessible treatment for schizophrenia, though the optimal dosing and mechanism of action of the compound requires further investigation. METHODS: Individuals with persistent treatment-refractory schizophrenia (n=52) will be recruited. Patients will be randomised in a 1:1:1:1 ratio to receive treatment of one of three active doses (1000, 2000 or 4000 mg daily) of sodium benzoate or placebo for 6 weeks duration. The primary outcome measurement is change in the Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcome measurements are PANSS subscales, Global Assessment of Function (GAF), Clinical Global Impression (CGI) and Patient Global Impression (PGI-I). Change in concentrations of peripheral amino acids (D-alanine, L-alanine, D-serine, L-serine, glycine and glutamate), plasma sodium benzoate, plasma catalase, 3-nitrotyrosine, malondialdehyde and high-sensitivity C-reactive protein (hs-CRP) will be determined as tertiary measures. DISCUSSION: This trial seeks to build upon previous research indicating potential efficacy of sodium benzoate for reduction of symptoms in individuals with treatment-refractory schizophrenia. The trial aims to improve the understanding of the mechanism of action of the compound. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12621000327886 . Registered on 23 March 2021.

CoMET: a protocol for a randomised controlled trial of co-commencement of METformin as an adjunctive treatment to attenuate weight gain and metabolic syndrome in patients with schizophrenia newly commenced on clozapine.

INTRODUCTION: Clozapine, while effective in treatment refractory schizophrenia, is associated with significant weight gain, heart disease and increased risk of type 2 diabetes mellitus (T2DM). Although there is evidence for weight loss with metformin for people with obesity who are already taking clozapine, there have been no published trials that have investigated the effect of metformin in attenuating weight gain at the time of clozapine initiation. METHODS AND ANALYSIS: A 24-week double-blind placebo-controlled trial of concomitant prescription of metformin at clozapine commencement. Eighty-six people being commenced on clozapine will be randomised to placebo or metformin (variable dose, up to 2 g/day). The primary outcome is comparative end point body weight, between the placebo and metformin groups. Secondary outcomes are comparative rates of conversion to T2DM, alteration of metabolic syndrome parameters, proportion gaining >5% body weight and changes in diet and appetite. We will additionally examine biomarkers associated with change in weight among trial participants. ETHICS AND DISSEMINATION: Ethics approval was granted by the Metro South Human Research Ethics Committee HREC/17/QPAH/538-SSA/17/QPAH/565. We plan to submit a manuscript of the results to a peer-reviewed journal, and present results at conferences, consumer forums and hospital grand rounds. TRIAL REGISTRATION NUMBER: ACTRN12617001547336; Pre-results.

Clozapine and concomitant medications: Assessing the completeness and accuracy of medication records for people prescribed clozapine under shared care arrangements.

RATIONALE, AIM, AND OBJECTIVE: The objective of the study is to assess the completeness and accuracy of medication records held by stakeholders (secondary care, general practice, and community pharmacy) for clozapine consumers managed in a shared care programme. METHODS: This was an exploratory, descriptive study examining secondary and primary care medication records in a large, urban, public mental health service setting in Queensland, Australia. Consumers (18-65 years old) prescribed clozapine under shared care management with capacity to consent were eligible (n = 55) to participate. Information from medication and dispensing records was used by a pharmacist to compile a best possible medication history for each consumer. Discrepancies were identified through reconciliation of stakeholder records with the history. Discrepancies were defined as an omission, addition, or administration discrepancy (difference in dose, frequency, or clozapine brand). RESULTS: Thirty-five (63.6%) consumers consented for records to be reviewed. Overall, 32 (91.4%) consumers had at least 1 discrepancy in their records with a mean of 4.9 discrepancies per consumer. Of 172 discrepancies, 127 (73.8%) were omissions. Primarily, concomitant medicines were omitted in 19/35 (54%) of secondary care records while clozapine was omitted in 13/32 (40.6%) of community pharmacies records. CONCLUSIONS: Discrepancies were highly prevalent in the shared care medication records of clozapine consumers of this service. Where there is incomplete and inaccurate medication information, there is a risk of suboptimal clinical decision making, increasing the likelihood of adverse drug events. This study demonstrates a need for improved documentation and timely access to accurate and complete medication records for shared care stakeholders. Expanding the pharmacist's role in this setting could improve medication accuracy in documentation and related communication.

Psychiatrists' follow-up of identified metabolic risk: a mixed-method analysis of outcomes and influences on practice.

Aims and method To describe and explain psychiatrists' responses to metabolic abnormalities identified during screening. We carried out an audit of clinical records to assess rates of monitoring and follow-up practice. Semi-structured interviews with 36 psychiatrists followed by descriptive and thematic analyses were conducted. Results Metabolic abnormalities were identified in 76% of eligible patients screened. Follow-up, recorded for 59%, was variable but more likely with four or more abnormalities. Psychiatrists endorse guidelines but ambivalence about responsibility, professional norms, resource constraints and skills deficits as well as patient factors influences practice. Therapeutic optimism and desire to be a 'good doctor' supported comprehensive follow-up. Clinical implications Psychiatrists are willing to attend to physical healthcare, and obstacles to recommended practice are surmountable. Psychiatrists seek consensus among stakeholders about responsibilities and a systemic approach addressing the social determinants of health inequities. Understanding patients' expectations is critical to promoting best practice.