British contributions to the therapeutic use of John Cade's lithium.

Coinciding with the 75th anniversary of John Cade's seminal publication that first reported lithium's antimanic efficacy, we briefly recount the salient findings of the historic paper and draw attention to the important psychiatric research in Britain that reinforced its findings and the critical British opinions that likely impeded its clinical use.

Psychiatrists and general practitioners perspectives on sexual wellbeing: Why it matters?

OBJECTIVE: Sexual wellbeing is a fundamental component of overall wellbeing and is often impacted by common psychiatric disorders such as depression. Despite this, research suggests it is underexplored in clinical practice. This preliminary study aimed to examine whether this is the case in both psychiatrists and general practitioners (GPs). METHOD: GPs and psychiatrists completed a survey examining the exploration of various sexual wellbeing domains with patients. It included open-ended questions regarding factors that influence this exploration, whether clinicians felt this was their responsibility, and their level of training in this area. RESULTS: Clinicians who felt it was their responsibility to enquire about sexual wellbeing reported exploring it in more patients than those who did not endorse this perspective. Overall, clinicians from both specialties demonstrated a reluctance to explore most sexual wellbeing topics, and this appeared to be due to many factors including views held by clinicians themselves. Most clinicians felt they had not received adequate training in this area. CONCLUSIONS: Domains of sexual wellbeing are largely underexplored by clinicians from both specialties. Educational materials and training for clinicians are needed to facilitate the exploration of this important area with patients, specifically in the context of mental health.

ICD-11 and bipolar II disorder: so much ado and yet nothing new.

The long-awaited 11th revision of the International Classification of Diseases (ICD-11) makes important advances but simultaneously compromises on some aspects, which may have a negative impact on clinical practice. This editorial illustrates the double-edged nature of some of the changes in ICD-11, focusing on mood disorders and specifically the subtyping of bipolar disorder.

The management of depression: the evidence speaks for itself.

Comparing the recommendations of two recently published national clinical practice guidelines for depression, this editorial highlights the concordance of advice concerning the selection and sequencing of therapies. Lifestyle and psychological interventions feature prominently and there is broad agreement regarding medication choice and optimisation strategies. The guidelines are therefore a useful resource.

The diagnosis of bipolar disorder in children and adolescents: Past, present and future.

AIMS: This article examines the ongoing debate concerning the diagnosis of bipolar disorder in children and adolescents. This contentious issue has generated robust discussion over the past two decades without consensus, and as such the true prevalence of so-called paediatric bipolar disorder (PBD) remains unknown. In this article we offer a solution to break this deadlock. METHODS: Recent meta-analyses and additional literature concerning the definition and prevalence of PBD was critically reviewed with a view to understanding the perspectives of those developing the taxonomy of PBD, and those engaged in research and clinical practice. RESULTS: A key finding is the lack of iteration and meaningful communication between the various groups interested in PBD that stems from deep-seated problems within our classificatory systems. This undermines our research efforts and complicates clinical practice. These problems make the already difficult diagnosis of bipolar disorder in adults even more challenging to transpose to younger populations, and additional complexities arise when parsing clinical phenomenology from normative developmental changes in youth. Therefore, in those manifesting bipolar symptoms post-puberty, we argue for the use of adolescent bipolar disorder to describe bipolar symptoms whereas in pre-pubertal children, we propose a reconceptualisation that allows symptomatic treatment to be advanced whilst requiring critical review of these symptoms over time. CONCLUSION: Significant changes in our current taxonomy are necessary and to be clinically meaningful, these revisions to our diagnoses need to be developmentally-informed.

Significant age by childhood trauma interactions on grey matter volumes: A whole brain VBM analysis.

BACKGROUND: Childhood trauma is deleterious to long term brain development. The changes are variable, and depend on gender, age and the nature of the trauma. In this exploratory analysis, we investigated the effects of exposure to emotional trauma on grey matter (GM) volumes in adolescent females. METHODS: We explored GM volumes in non-clinical females aged 12-17 years who had been exposed to either higher (HET; N = 75) or minimal (MET; N = 127) emotional trauma. High-resolution T1-weighted structural images were analysed with an optimised FSL-VBM protocol. The General Linear Model was run on HET versus MET with continuous age as an interaction. Mean GM volumes were extracted from significant corrected age interaction statistical maps and scrutinised with SPSS®. RESULTS: We observed greater HET*age than MET*age interactions (corrected p-value = 0.0002), in 4 separate bilateral cortical regions associated with mood disorders. Scrutiny of these regions showed significant GM volume enlargements in the early adolescent HET group (p = 0.017) and reductions in the late adolescent HET group (p < 0.0001). Notably, there were no differences in middle adolescence (p > 0.05). LIMITATIONS: Causality cannot be inferred from this cross-sectional study and the onset of trauma cannot be determined using retrospective measures. CONCLUSIONS: Whilst GM volumes diminish from early adolescence onwards, our results show that HET impacts this brain development, perhaps first via unstable adaptative mechanisms, followed by maladaptive processes in late adolescence. This suggests that compromises of emotional and cognitive self-regulation in mood disorders may underpin the structural abnormalities observed across multiple brain regions in these teenage girls.

Difficult decision-making in major depressive disorder: Practical guidance based on clinical research and experience.

OBJECTIVES: To extend current published guidance regarding the management of major depression in clinical practice, by examining complex cases that reflect real-world patients, and to integrate evidence and experience into recommendations. METHODS: The authors who contributed to recently published clinical practice guidelines were invited to identify important gaps in extant guidance. Drawing on clinical experience and shared knowledge, they then generated four fictional case studies to illustrate the real-world complexities of managing mood disorders. The cases focussed specifically on issues that are not usually addressed in clinical practice guidelines. RESULTS: The four cases are discussed in detail and each case is summarised using a life chart and accompanying information. The four cases reflect important real-world challenges that clinicians face when managing mood disorders in day-to-day clinical practice. To partly standardise the presentation of each case and for ease of reference we provide a Time Line, History Box and Management Chart, along with a synopsis where relevant. Discussion and formulation of the cases illustrate how to manage the complexities of each case and provide one possible pathway to achieving functional recovery. CONCLUSION: These cases draw on the combined clinical experience of the authors and illustrate how to approach diagnostic decision-making when treating major depressive disorder and having to contend with complex presentations. The cases are designed to stimulate discussion and provide a real-world context for the formulation of mood disorders.

A novel exploration of irritability in adolescent males: A preliminary study.

OBJECTIVE: Irritability is a key symptom of mood disorders and is common in adolescence; nevertheless, it is poorly understood and assessed. Research examining irritability and its relationship to mood and anxiety disorders risk factors in adolescent males is lacking. Therefore, the current study aimed to address this gap. METHOD: An online survey designed to interrogate the relationship between irritability and other risk factor variables was administered to 627 adolescent males (ages 12-17). Findings were analysed statistically using MANOVAs. RESULTS: When divided into high and low irritability groups, higher irritability scores were significantly correlated with higher scores on all risk factor variables. Further, higher irritability scores were associated with higher scores on all variables that indicate an increased risk for development of psychological disorders, such as depression and anxiety. CONCLUSION: This study is the first to focus on subjective irritability. In adolescent males, it identifies a potentially novel model of irritability's involvement in maladaptive processes relating to emotional dysregulation, behavioural difficulties and anxiety.

Positioning of psychodynamic psychotherapy in the treatment of depression: A comparison of the RANZCP 2020 and NICE 2022 guidelines.

OBJECTIVE: To compare the 2022 NICE guidelines (NG222) and 2020 RANZCP clinical practice guidelines (MDcpg2020) recommendations for the treatment of depression using psychodynamic psychotherapy. CONCLUSIONS: Both guidelines recommend psychological interventions first-line. However, only short-term psychodynamic psychotherapy (STPP) is recommended, and in the NG222 it is ranked last for less severe depression and 7th for more severe depression. In contrast, cognitive behavioural therapy and behavioural activation are deemed the more clinically effective and cost-effective psychological therapies. And antidepressants play a significant role - largely in more severe depression.

Improving Communication Between ICU Nurses and Anesthesia Providers Using a Standardized Handoff Protocol.

PURPOSE: This quality improvement (QI) project aimed to improve handoff communication between intensive care unit (ICU) nurses and anesthesia providers using a standardized preoperative handoff protocol for nonemergent and noncardiac procedures. DESIGN: A quality improvement project. METHODS: Following project approval, the project team provided staff education regarding a pre-populated handoff tool from the electronic medical record (EMR) adapted for perioperative use. In addition, the project team assessed the providers' perception and satisfaction with handoff communication before and after the intervention. FINDINGS: Of the 128 transfers, 76% completed the handoff tool during the 1-month implementation phase. CRNAs (n = 60), Registered Nurses (RNs; n = 88), and anesthesia residents (n = 30) completed the pre-and post-implementation surveys. Pre-implementation, 40% of providers were dissatisfied with communication, and only 14% reported dissatisfaction post-implementation. Also, 40% of providers believed this handoff protocol increased the amount of accurate information shared during reports without delaying the transition of care. CONCLUSIONS: The standardized handoff tool appears to improve information sharing during the transfer of care and improve provider satisfaction with the handoff process. Long term, it may reduce adverse patient events and improve outcomes. Use of a pre-populated handoff tool from the EMR provides a cost-effective solution to decrease erroneous reporting by removing human error associated with the recall.

Wolframin is a novel regulator of tau pathology and neurodegeneration.

Selective neuronal vulnerability to protein aggregation is found in many neurodegenerative diseases including Alzheimer's disease (AD). Understanding the molecular origins of this selective vulnerability is, therefore, of fundamental importance. Tau protein aggregates have been found in Wolframin (WFS1)-expressing excitatory neurons in the entorhinal cortex, one of the earliest affected regions in AD. The role of WFS1 in Tauopathies and its levels in tau pathology-associated neurodegeneration, however, is largely unknown. Here we report that WFS1 deficiency is associated with increased tau pathology and neurodegeneration, whereas overexpression of WFS1 reduces those changes. We also find that WFS1 interacts with tau protein and controls the susceptibility to tau pathology. Furthermore, chronic ER stress and autophagy-lysosome pathway (ALP)-associated genes are enriched in WFS1-high excitatory neurons in human AD at early Braak stages. The protein levels of ER stress and autophagy-lysosome pathway (ALP)-associated proteins are changed in tau transgenic mice with WFS1 deficiency, while overexpression of WFS1 reverses those changes. This work demonstrates a possible role for WFS1 in the regulation of tau pathology and neurodegeneration via chronic ER stress and the downstream ALP. Our findings provide insights into mechanisms that underpin selective neuronal vulnerability, and for developing new therapeutics to protect vulnerable neurons in AD.

Lithium replacement dose recommendations using Monte Carlo simulations.

OBJECTIVES: Missed medication doses are a common clinical problem, and cause consternation when prescribing lithium because its plasma levels must be kept within a narrow therapeutic window. Therefore, this study set out to determine the potential impact of missed lithium doses on its pharmacokinetics, and to explore the optimal compensatory dosing scheme. This is difficult to determine clinically and in research because of ethical constraints and therefore we modelled the effects using simulations. METHODS: Monte Carlo simulations were used to simulate lithium concentrations under different missed dose scenarios. For patients with normal renal function, the optimal replacement dosing scheme was selected based on the lowest percentage of deviation from the full adherence scenario. However, for patients with renal impairment the appropriate dosing schedule was selected based on the lowest number of simulated concentrations above the upper range of 1.2 mEq/L. RESULTS: The impact of a missed lithium dose depended on its daily dose. The higher the daily dose, the higher the deviation from full adherence. In patients with normal renal function, replacement with a regular dose was most appropriate. But in patients with renal impairment, replacement with a partial dose appeared to be most suitable. CONCLUSIONS: This study has enabled insights into the optimal suitable lithium replacement dosing schemes for patients with normal renal function and renal impairment. These proposed schemes can be used cautiously in clinical practice in conjunction with clinician judgment and can also be used as a basis for future clinical research.

MicroRNA-575 acts as a novel oncogene via targeting multiple signaling pathways in glioblastoma.

PURPOSE: Glioblastoma (GBM) patients currently face poor survival outcomes with an average survival period of <15 months, while only 3-5% of patients survive longer than 36 months. Although the mechanisms of tumorigenesis are still being elucidated, miRNAs are promising candidates to explore as novel and prognostic biomarkers in GBM. In this study, we identified the association between miR-575 expression and overall survival (OS) of primary GBM patients and undertook functional studies to discern the contribution of miR-575 to GBM tumorigenesis. METHODS: Total RNAs were isolated from 254 FFPE GBM tumor samples and miR expression was assayed (simultaneously) using NanoString Technologies. To determine the association between miR-575 and patients' prognosis, Kaplan-Meier, univariable and multivariable Cox regression analyses were performed. Cell proliferation, colony formation, migration assays were conducted to investigate the function of miR-575 in vitro and in vivo. In silico target gene network analysis was performed to identify the putative targets of miR-575 in GBM, which were further verified by luciferase reporter assay, as well as qPCR and immunoblotting. RESULTS: Our clinical data (n = 254) show that miR-575 is associated with worse GBM OS by univariable analysis (UVA, HR = 1.27, p-value<0.001) and multivariable (MVA, HR = 1.23, p = 0.007) analysis incorporating critical clinical variables. Functional studies indicated that overexpression of miR-575 significantly increased cell proliferation and migration of GBM cells in vitro, as well as tumor growth in vivo. Subsequent in silico target gene network and mechanistic studies identified CDKN1B/p27 and PTEN, as potential targets of miR-575 in GBM. MicroRNA-575 can also regulate the activity of AKT and ERK pathways in GBM. CONCLUSION: miR-575 has prognostic value in GBM, with higher expression associating with worse OS of patients, and contributes to GBM tumorigenesis by regulating multiple signaling pathways in GBM.

An Evidence-Based Perspective on The 2020 Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines.

OBJECTIVE: To rebut the claims made in an opinion piece by Anaf and colleagues regarding the recommendations for psychotherapy within the 2020 RANZCP Mood Disorders Clinical Practice Guidelines (CPG). CONCLUSIONS: The CPG attaches importance to psychological interventions and recommends their administration as first-line in the treatment of depression. The concerns raised by Anaf and colleagues have no basis and are readily dismissed by referring to the guidelines. Therefore, we strongly encourage clinicians to formulate their own views by reading the guidelines for themselves.

Questions in Psychiatry (QuiP): Is staging bipolar disorder possible? If so, where to begin?

The prospect of staging psychiatric disorders has been a source of ongoing controversy since the idea was first proposed in the early 1990s, based on the staging models used for cancer. More recently, several staging models have been proposed for bipolar disorder; however, as yet there is no consensus as to which model (or composite) is best, and there is no substantive evidence in support of any one of the models. The fundamental problem is that, unlike cancer, the pathophysiology of psychiatric disorders such as bipolar disorder is essentially unknown. The illness has many neurobiological underpinnings, but whether these are truly causal and if so how they lead to the illness, remains a mystery. As a consequence, there is no way of predicting when the illness will emerge and what trajectory it will take. Its response to treatment and prognosis is equally unpredictable, and therefore, models attempting to stage the disorder on the basis of clinical markers have limited utility. This is especially so, because the clinical presentation of bipolar disorder is particularly complex as it often occurs in the context of comorbidities, which further obscure the clinical picture. Therefore, in this QuiP, we provide insights as to why current methods of staging bipolar disorder are hamstrung and propose a way forward that may yield meaningful insights.

Pediatric Gliosarcoma With and Without Neurofibromatosis Type 1: A Whole-exome Comparison of 2 Patients.

Gliosarcoma is rare among pediatric patients and among individuals with Neurofibromatosis Type 1 (NF1). Here we compare 2 pediatric gliosarcoma patients, one of whom has NF1. We performed whole-exome sequencing, methylation, and copy number analysis on tumor and blood for both patients. Whole-exome sequencing showed higher mutational burden in the tumor of the patient without NF1. Copy number analysis showed differences in chromosomal losses/gains between the tumors. Neither tumor showed O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. The NF1 patient survived without progression while the other expired. This is the first reported case of gliosarcoma in a child with NF1.

Is the response to rTMS largely the result of non-specific effects?

The efficacy of repetitive transcranial magnetic stimulation (rTMS) in the treatment of depression is disputed. This is partly because, to date, insufficient good-quality studies have been conducted, and a definitive clinical profile for which rTMS is best suited is yet to be determined. However, another equally important reason for questioning the efficacy of rTMS is that the clinical response to its application is thought to be the result of predominantly non-specific and placebo effects. Therefore, in this viewpoint we examine this possibility in detail and propose a meaningful way forward for rTMS research.

Profiling rTMS: A critical response.

This article is a detailed response to the criticisms levelled by the authors of an accompanying viewpoint, which claims that the positioning of repetitive transcranial magnetic stimulation (rTMS) in the 2020 Royal Australian and New Zealand College of Psychiatrists (RANZCP) clinical practice guidelines for the management mood disorders (MDcpg2020) is incorrect. We, the authors of the MDcpg2020, strongly refute these assertions and argue that first we have determined the positioning of rTMS using the same criteria as those applied to other treatments for depression. Second, in accordance with National Health and Medical Research Council (NHMRC) guidelines, the processes by which we have developed the MDcpg2020 have been guided by best practice and have been overseen throughout by the RANZCP. Third, our objective and detailed examination of the relevant research has shown that the evidence needed to support the positioning of rTMS alongside standard therapies for depression is severely deficient. And therefore, as a consequence, we set out clearly both our logic and reasoning with respect to interpreting rTMS data and outline our evidence-informed position in which rTMS remains a potential alternative therapy that can be considered in certain clinical circumstances once both suitable psychological and pharmacological treatments have been trialled. We also discuss why, until further research is conducted, rTMS is perhaps best regarded as an experimental therapy and an investigational tool, and to assist in this regard, we propose a framework for consideration by those conducting rTMS studies in the future. Thus, based on current knowledge, we conclude that rTMS does not have a sufficient evidence base to warrant recognition as a standard therapy for depression alongside established treatments such as psychological interventions, pharmacotherapy, and electroconvulsive therapy. Furthermore, there is no clinical profile for depressed patients that might benefit from rTMS and therefore tolerability alone is not good enough reason to promote rTMS in the management of major depression.

The 2020 Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders.

OBJECTIVES: To provide advice and guidance regarding the management of mood disorders, derived from scientific evidence and supplemented by expert clinical consensus to formulate s that maximise clinical utility. METHODS: Articles and information sourced from search engines including PubMed, EMBASE, MEDLINE, PsycINFO and Google Scholar were supplemented by literature known to the mood disorders committee (e.g. books, book chapters and government reports) and from published depression and bipolar disorder guidelines. Relevant information was appraised and discussed in detail by members of the mood disorders committee, with a view to formulating and developing consensus-based recommendations and clinical guidance. The guidelines were subjected to rigorous consultation and external review involving: expert and clinical advisors, key stakeholders, professional bodies and specialist groups with interest in mood disorders. RESULTS: The Royal Australian and New Zealand College of Psychiatrists mood disorders clinical practice guidelines 2020 (MDcpg2020) provide up-to-date guidance regarding the management of mood disorders that is informed by evidence and clinical experience. The guideline is intended for clinical use by psychiatrists, psychologists, primary care physicians and others with an interest in mental health care. CONCLUSION: The MDcpg2020 builds on the previous 2015 guidelines and maintains its joint focus on both depressive and bipolar disorders. It provides up-to-date recommendations and guidance within an evidence-based framework, supplemented by expert clinical consensus. MOOD DISORDERS COMMITTEE: Gin S Malhi (Chair), Erica Bell, Darryl Bassett, Philip Boyce, Richard Bryant, Philip Hazell, Malcolm Hopwood, Bill Lyndon, Roger Mulder, Richard Porter, Ajeet B Singh and Greg Murray.

The 2020 Royal Australian and New Zealand College of psychiatrists clinical practice guidelines for mood disorders: Bipolar disorder summary.

OBJECTIVES: To provide a succinct, clinically useful summary of the management of bipolar disorder, based on the 2020 Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders (MDcpg2020 ). METHODS: To develop the MDcpg2020 , the mood disorders committee conducted an extensive review of the available literature to develop evidence-based recommendations (EBR) based on National Health and Medical Research Council (NHMRC) guidelines. In the MDcpg2020 , these recommendations sit alongside consensus-based recommendations (CBR) that were derived from extensive deliberations of the mood disorders committee, drawing on their expertise and clinical experience. This guideline summary is an abridged version that focuses on bipolar disorder. In collaboration with international experts in the field, it synthesises the key recommendations made in relation to the diagnosis and management of bipolar disorder. RESULTS: The bipolar disorder summary provides a systematic approach to diagnosis, and a logical clinical framework for management. It addresses the acute phases of bipolar disorder (mania, depression and mixed states) and its longer-term management (maintenance and prophylaxis). For each phase it begins with Actions, which include important strategies that should be implemented from the outset wherever possible. These include for example, lifestyle changes, psychoeducation and psychological interventions. In each phase, the summary advocates the use of Choice medications for pharmacotherapy, which are then used in combinations along with additional Alternatives to manage acute symptoms or maintain mood stability and provide prophylaxis. The summary also recommends the use of electroconvulsive therapy (ECT) for each of the acute phases but not for maintenance therapy. Finally, it briefly considers bipolar disorder in children and its overlap in adults with borderline personality disorder. CONCLUSIONS: The bipolar disorder summary provides up to date guidance regarding the management of bipolar disorder, as set out in the MDcpg2020 . The recommendations are informed by evidence and clinical expertise and experience. The summary is intended for use by psychiatrists, psychologists and primary care physicians but will be of interest to anyone involved in the management of patients with bipolar disorder.