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BackgroundAlthough clozapine is the most efficacious medication for treatment-refractory schizophrenia, not all patients will have an adequate response. Optimising clozapine dose using therapeutic drug monitoring could therefore maximise response.AimsUsing individual patient data, we undertook a receiver operating characteristic (ROC) curve analysis to determine an optimal therapeutic range for clozapine levels to guide clinical practice.MethodWe conducted a systematic review of PubMed, PsycINFO and Embase for studies that provided individual participant level data on clozapine levels and response. These data were analysed using ROC curves to determine the prediction performance of plasma clozapine levels for treatment response.ResultsWe included data on 294 individual participants from nine studies. ROC analysis yielded an area under the curve of 0.612. The clozapine level at the point of optimal diagnostic benefit was 372 ng/mL; at this level, the response sensitivity was 57.3%, and specificity 65.7%. The interquartile range for treatment response was 223–558 ng/mL. There was no improvement in ROC performance with mixed models including patient gender, age or length of trial. Clozapine dose and clozapine concentration to dose ratio did not provide significantly meaningful prediction of response to clozapine.ConclusionsClozapine dose should be optimised based on clozapine therapeutic levels. We found that a range between 250 and 550 ng/mL could be recommended, while noting that a level of >350 ng/mL is the most optimal for response. Although some patients may not respond without clozapine levels >550 ng/mL, the benefits should be weighed against the increased risk of adverse drug reactions.

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

Objective: To examine psychological distress and professional burnout in a cohort of Australian mental healthcare workers during the COVID-19 pandemic Methods: This study examined a multi-disciplinary cohort of mental healthcare workers in a large metropolitan service in Australia. Demographic information as well as information on employment and individual’s personal experience of the COVID-19 pandemic was collected and correlated with cross-sectional assessments of anxiety, depression and professional burnout using validated clinical questionnaires Results: Mental healthcare workers reported high levels of anxiety, depression, and professional burnout. Participants reported some reduction in anxiety since the early phases of the pandemic, but the reduction was more modest in mental healthcare workers identifying as being “vulnerable” employees. Conclusion: Despite the low numbers of COVID-19 cases, mental healthcare workers in Australia report significant levels of psychological distress and professional burnout during the pandemic.

We included all 74,960 olanzapine LAI dispensings listed in the Pharmaceutical Benefits Schedule (PBS) database from the introduction of olanzapine LAI in January 2010 until the end of January 2020. Adverse event reports for all olanzapine formulations (and the subset of olanzapine LAI) were drawn from Australian Therapeutic Goods Association Database of Adverse Event Notifications (DAEN).

BackgroundIntratumoural heterogeneity is a poor prognostic feature in triple-negative breast cancer (TNBC) and other high-grade malignancies. It is caused by genomic instability and phenotypic plasticity, but how these features co-evolve during tumour development remains unclear. SOX10 is a transcription factor, neural crest stem cell (NCSC) specifier and candidate mediator of cancer-associated phenotypic plasticity.MethodsUsing immunophenotyping, we investigated the expression of SOX10 in normal human breast tissue and breast cancer (n=21 cosmetic breast reduction and 1,860 tumour samples with clinical annotation). We then defined the context and evolution of its expression in TNBC compared to 21 other malignancies using systems-level transcriptomics.ResultsSOX10 was detected in nuclei of normal mammary luminal progenitor cells, the histogenic origin of most TNBCs. In breast cancer, nuclear SOX10 predicted poor outcome amongst cross-sectional (log-rank p=0.0015, hazard ratio 2.02, n=224) and metaplastic (log-rank p=0.04, n=66) TNBCs. Systems-level transcriptional network analysis identified a core module in SOX10’s normal mammary epithelial transcription program that is rewired to NCSC genes in TNBC. Reprogramming was proportional to DNA damage and genome-wide promoter hypomethylation, particularly at CpG island shores. Using a novel network analysis pipeline, we found that NCSC-like transcriptional reprogramming is also strongly associated with promoter hypomethylation in other SOX10+ malignancies: glioma and melanoma.ConclusionsWe propose that cancer-associated genome hypomethylation simulates the open chromatin landscape of more primitive cell states, and that on this relatively unrestricted background, SOX10 recreates its ancestral gene regulatory circuits by default. These findings provide new insights about the basis of intratumoural heterogeneity and resurrection of developmental phenotypes in cancer; and highlight the potential for therapeutics that limit chromatin remodelling.

Objectives: Demand for places in postgraduate psychiatry training programmes has increased over recent years. All systems have capacity limits, and concerns have been raised regarding the sustainability of the current intake. This paper presents a modelling exercise to exploring the presence and strategies to resolve bottleneck in the Queensland training programme. Methods: Mathematical modelling based on the RANZCP training regulations and the characteristics of the accredited training programme. Results: A training bottleneck was identified which has been impacted by increased training intake, demand for Advanced Training certificates, and location factors. Conclusions: This investigation raises important questions regarding the future management of postgraduate training in psychiatry in Queensland that may be applicable more widely across Australia and New Zealand. In particular, it highlights the large impact that can result from even small incremental increases in trainees across varying levels of the postgraduate programme and the importance of limiting trainee intake in a manner proportional to the availability of mandatory terms.

Epithelial to mesenchymal transition (EMT) in cancer is important in therapeutic resistance and invasiveness. Calcium signaling is key to the induction of EMT in breast cancer cells. Although inhibition of specific calcium-permeable ion channels regulates the induction of a sub-set of EMT markers in breast cancer cells, it is still unclear if activation of a specific calcium channel can be a driver for the induction of EMT events. In this study, we exploited the availability of a selective pharmacological activator of the calcium-permeable ion channel TRPV4 to assess the direct role of calcium influx in EMT marker induction. Gene association studies revealed a link between TRPV4 and gene-ontologies associated with EMT and poorer relapse-free survival in lymph node-positive basal breast cancers. TRPV4 was an important component of the calcium influx phase induced in MDA-MB-468 breast cancer cells by the EMT inducer epidermal growth factor (EGF). Pharmacological activation of TRPV4 then drove the induction of a variety of EMT markers in breast cancer cells. These studies demonstrate that calcium influx through specific pathways appears to be sufficient to trigger EMT events.

Objective: Safe and effective antipsychotic prescribing is a fundamental skill in psychiatric practice; however, antipsychotic medications are not without risk. These risks are increased when antipsychotics are prescribed in high doses, with or without polypharmacy. Decision-making regarding antipsychotic prescribing can be hampered by a lack of readily available or easily approachable tools for calculating and interpreting total daily doses, especially when antipsychotic polypharmacy is involved. Our objective was to create an accessible method for calculating antipsychotic total daily dosing. Methods: We have developed an online calculator for determining antipsychotic total daily dose using information on recommended maximum total daily dosing based on the British National Formulary. Results: This calculator is free, easy to implement and allows for users to input a large variety of possible antipsychotic dosing regimens. Conclusions: It is hoped that this tool will allow clinicians to readily review their prescribing practice, inform decision-making and improve patient safety outcomes. Further research may be appropriate to determine the impact of this tool on these intended goals.

Interactions between long non-coding RNAs (lncRNAs) and proteins contribute to the epigenetic regulation of gene expression, and defects in such interactions have been implicated in several diseases, including cancer. Basal-like breast cancer accounts for approximately 15% of all breast cancer and is a major clinical problem given its poor survival and lack of responsiveness to targeted breast cancer treatments. DNA methylation is non-random and is much more pronounced in basal-like breast cancer (BLBC) compared to other molecular subtypes of breast cancer, raising the possibility that hypermethylation could be important in the genesis of BLBCs. LncRNAs are aberrantly expressed in multiple subtypes of breast cancer, including BLBC, and are considered to have significant prognostic potential. In order to explore the potential roles of DNA methylation and lncRNAs in BLBC, we investigated lncRNA-protein interactions using bioinformatics and molecular techniques, focusing on proteins that actively perform DNA methylation - the DNA methyltransferase (DNMT) family. Our novel bioinformatic methods revealed that BLBC may be sub-classified according to methylation profile in a way that could predict disease survival. We then identified candidate lncRNAs that are over-expressed in BLBC and statistically predicted to interact with DNMT proteins. Using RNA immunoprecipitation of BLBC cell lines, we have identified potential lncRNA-protein interactions that may be involved in epigenetic remodelling in BLBC. The role of these lncRNAs in epigenetic gene regulation and BLBC is currently being explored. Citation Format: Northwood K, Saunus J, Milevskiy M, Lakhani S, Brown M. RNA immunoprecipitation reveals lncRNA-protein interactions in basal-like breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-04-05.

Background\ud \ud MicroRNAs are potent post-transcriptional regulators involved in all hallmarks of cancer. Mir-196a is transcribed from two loci and has been implicated in a wide range of developmental and pathogenic processes, with targets including Hox, Fox, Cdk inhibitors and annexins. Genetic variants and altered expression of MIR196A are associated with risk and progression of multiple cancers including breast cancer, however little is known about the regulation of the genes encoding this miRNA, nor the impact of variants therein.\ud \ud Methods\ud \ud Genomic data and chromatin interaction analysis were used to discover functional promoter and enhancer elements for MIR196A. Expression data were used to associate MIR196A with mechanisms of resistance, breast cancer subtypes and prognosis.\ud \ud Results\ud \ud Here we demonstrate that MIR196A displays complex and dynamic expression patterns, in part controlled by long-range transcriptional regulation between promoter and enhancer elements bound by ERα. Expression of this miRNA is significantly increased in drug-resistant models of hormone-receptor positive disease. The expression of MIR196A also proves to be a robust prognostic factor for patients with advanced and post-menopausal ER+ disease.\ud \ud Conclusion\ud \ud This work sheds light on the normal and abnormal regulation of MIR196A and provides a novel stratification method for therapeutically resistant breast cancer.

The critical role of calcium signalling in processes related to cancer cell proliferation and invasion has seen a focus on pharmacological inhibition of overexpressed ion channels in specific cancer subtypes as a potential therapeutic approach. However, despite the critical role of calcium in cell death pathways, pharmacological activation of overexpressed ion channels has not been extensively evaluated in breast cancer. Here we define the overexpression of transient receptor potential vanilloid 4 (TRPV4) in a subgroup of breast cancers of the basal molecular subtype. We also report that pharmacological activation of TRPV4 with GSK1016790A reduced viability of two basal breast cancer cell lines with pronounced endogenous overexpression of TRPV4, MDA-MB-468 and HCC1569. Pharmacological activation of TRPV4 produced pronounced cell death through two mechanisms: apoptosis and oncosis in MDA-MB-468 cells. Apoptosis was associated with PARP-1 cleavage and oncosis was associated with a rapid decline in intracellular ATP levels, which was a consequence of, rather than the cause of, the intracellular ion increase. TRPV4 activation also resulted in reduced tumour growth in vivo. These studies define a novel therapeutic strategy for breast cancers that overexpress specific calcium permeable plasmalemmal ion channels with available selective pharmacological activators. Refereed/Peer-reviewed

Predicting response to endocrine therapy and survival in oestrogen receptor positive breast cancer is a significant clinical challenge and novel prognostic biomarkers are needed. Long-range regulators of gene expression are emerging as promising biomarkers and therapeutic targets for human diseases, so we have explored the potential of distal enhancer elements of non-coding RNAs in the prognostication of breast cancer survival. HOTAIR is a long non-coding RNA that is overexpressed, promotes metastasis and is predictive of decreased survival. Here, we describe a long-range transcriptional enhancer of the HOTAIR gene that binds several hormone receptors and associated transcription factors, interacts with the HOTAIR promoter and augments transcription. This enhancer is dependent on Forkhead-Box transcription factors and functionally interacts with a novel alternate HOTAIR promoter. HOTAIR expression is negatively regulated by oestrogen, positively regulated by FOXA1 and FOXM1, and is inversely correlated with oestrogen receptor and directly correlated with FOXM1 in breast tumours. The combination of HOTAIR and FOXM1 enables greater discrimination of endocrine therapy responders and non-responders in patients with oestrogen receptor positive breast cancer. Consistent with this, HOTAIR expression is increased in cell-line models of endocrine resistance. Analysis of breast cancer gene expression data indicates that HOTAIR is co-expressed with FOXA1 and FOXM1 in HER2-enriched tumours, and these factors enhance the prognostic power of HOTAIR in aggressive HER2+ breast tumours. Our study elucidates the transcriptional regulation of HOTAIR, identifies HOTAIR and its regulators as novel biomarkers of patient response to endocrine therapy and corroborates the importance of transcriptional enhancers in cancer.

Long-range regulators of gene expression are emerging as promising new biomarkers and therapeutic targets for human diseases including cancer. As current breast cancer biomarkers have limited power for predicting disease progression and response to therapy, we have explored the potential of long-range regulators of non-coding RNAs to be useful in the prognostication of breast cancer. HOTAIR is a long non-coding RNA that is overexpressed, promotes metastasis, and is predictive of poor prognosis in breast cancer. Here we describe a long-range transcriptional enhancer of the HOTAIR gene that binds several hormone receptors and associated transcription factors, interacts with the HOTAIR promoter and augments HOTAIR transcription. This enhancer is dependent on FOXA1 and FOXM1 transcription factors and functionally interacts with a novel alternate HOTAIR promoter. Analysis of breast cancer gene expression data indicates that HOTAIR is co-expressed with FOXA1 and FOXM1 in HER2-enriched tumours, and these factors enhance the prognostic power of HOTAIR in this subtype of breast cancer. The combination of HOTAIR and FOXM1 also enables better predictions of response to endocrine therapy for ER+ breast cancer. FOXM1 is a member of the recently described chromosome instability module and consistent with this, the expression of HOTAIR and FOXM1 is associated with increased frequency of copy number alterations and somatic non-synonymous mutations. Our study corroborates the importance of enhancers in breast cancer, elucidates the transcriptional regulation of HOTAIR, suggests HOTAIR as a novel biomarker of patient response to endocrine therapy, and implicates HOTAIR in chromosome instability. Citation Format: Michael J. Milevskiy, Fares Al-Ejeh, Jodi M. Saunus, Korinne S. Northwood, Amy E. McCart-Reed, Eloise Dray, Kenneth Nephew, Peter J. Bailey, Joshua A. Betts, Andrew Stone, Julia M W Gee, Annette M. Shewan, Juliet D. French, Stacey L. Edwards, Susan J. Clark, Sunil R. Lakhani, Melissa A. Brown. Long-range regulation of HOTAIR identifies novel biomarkers of breast cancer outcome and suggests a role in genome instability. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1980.