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Negative body image may be associated with heightened feelings of paranoia. The current study aimed to conduct multidimensional assessments of body image and psychosis facets in the general population. Respondents were 407 individuals, who provided basic sociodemographic information, and completed online questionnaires evaluating dysmorphic concerns, body consciousness, paranoia, persecutory and magical ideation and perceptual aberration. Correlation analysis and a series of regressions onto various body image facets (i.e. dysmorphic concerns, private body consciousness, public body consciousness and body competence) were conducted. Distinct patterns of significant associations were uncovered across the range of body image and psychosis facets examined. Paranoia significantly contributed to the severity of dysmorphic concerns, and magical ideation significantly contributed to private and public body consciousness, though effect sizes were modest. Our findings corroborate the relationship between paranoia and dysmorphic concerns, and tentatively suggest that challenging paranoid beliefs could be a useful strategy for managing negative body image.

Refereed/Peer-reviewed Cognitive flexibility is a widely studied construct and is considered an important treatment target for several psychological disorders. The convergence of several independent fields of research has led to assumptions about the assessment of cognitive flexibility – assumptions that are not empirically supported and often conflate different notions of flexibility. This critical review discusses how the conflation of self-report and neurocognitive assessments has seemingly arisen from literature on eating disorders. We describe how seminal early observations of “inflexible” personality characteristics, communication competence research, and investigations of frontal lobe function after injury led to two methods of assessing “cognitive flexibility”. We discuss the impact that conflation of self-report and neurocognitive assessments has had on the field, and we provide recommendations for assessing cognitive flexibility in both research and clinical settings.

The coronavirus (COVID-19) pandemic has caused major disruptions to social and other forms of functioning, which may influence schizotypy expression. The current study aimed to explore possible distal and proximal predictors contributing to schizotypy in a sample of the Australian general population during the COVID-19 pandemic. The COvid-19 and you: mentaL heaLth in AusTralia now survEy (COLLATE) project is an online mental health study aimed at tracking key mental health indicators over the progression of the pandemic. Adults residing in Australia were invited to take part using non-discriminative snowball sampling. Demographic-clinical information was collected for 850 participants in either October 2020 or January 2021. To assess schizotypy facets, the Launay-Slade Hallucinations Scale-Extended (LSHS-E) and Peters Delusions Inventory (PDI-21) were used to measure hallucination and delusion proneness respectively. Generalised linear models (with gamma and negative binomial distributions) were employed. Age, negative emotions and loneliness significantly contributed to both hallucination and delusion proneness; gender, education and religiosity also significantly contributed to delusion proneness, in the final regression models. Our study corroborated the specific contribution of loneliness, amongst other factors, in the prediction of schizotypy facets. Tackling loneliness represents a public health challenge that needs to be urgently addressed, especially in the face of the ongoing COVID-19 pandemic.

Objective Anorexia nervosa (AN) is associated with clinical characteristics including eating disorder symptomatology, negative mood states, perfectionism and cognitive inflexibility. Whether these characteristics differ across illness stages, and are also present in first-degree relatives, demonstrating heritability, is unclear. The aim of this research was to compare current AN (c-AN), weight-restored AN (wr-AN), sisters of individuals with AN (AN-sis) and healthy controls (HC) on these measures. Method Eighty participants ( n = 20/group) completed the study. Results Eating disorder symptomatology was similar among c-AN and wr-AN groups, whereas the AN-sis did not differ from either wr-AN or HC. Anxiety was significantly higher in c-AN, wr-AN and AN-sis groups, relative to HC. Increased perfectionism was identified in the c-AN and wr-AN groups compared to AN-sis and HC on the ‘concern over mistakes’, ‘personal standards’ and ‘doubt and actions’ subscales of the Multidimensional Perfectionism Scale. Group differences were not apparent on cognitive flexibility. Conclusions These findings suggest that anxiety may be a risk factor or linked to genetic susceptibility for AN, as well as specific aspects of perfectionism that relate to self-imposed standards.

This study seeks to determine the impact of food categorisation on desire to eat in high vs low restrictive eaters.

Abnormalities in autonomic function have been observed in people with anorexia nervosa. However, the majority of investigations have utilised heart rate variability as the sole assessment of autonomic activity. The current study utilised a variety of methodologies to assess autonomic nervous system function in women with a current diagnosis of anorexia, a past diagnosis of anorexia who were weight-restored, and healthy controls. The sample included 37 participants: 10 participants with anorexia, 17 weight-restored participants (minimum body mass index > 18.5 for minimum of 12 months) and 10 controls. Assessments of autonomic function included muscle sympathetic nerve activity (MSNA) using microneurography, heart rate variability, baroreflex sensitivity, blood pressure variability, head-up tilt table test, sudomotor function and assessment of plasma catecholamines. MSNA (bursts/min) was significantly decreased in both anorexia (10.22 ± 6.24) and weight-restored (17.58 ± 1.68) groups, as compared to controls (23.62 ± 1.01, p

Objective: Recent research has suggested that a type of atypical eye movement, called square wave jerks, together with anxiety, may distinguish individuals with anorexia nervosa from those without anorexia nervosa and may represent a biomarker and endophenotype for the illness. The aim of this study was to identify the presence of this proposed marker in individuals currently with anorexia nervosa relative to healthy controls, and to identify the state independence and heritability of this putative marker by exploring whether it also exists in individuals who are weight-restored from anorexia nervosa and first-degree relatives (i.e. sisters of people with anorexia nervosa). Methods: Data from 80 female participants (20/group: current anorexia nervosa, weight-restored from anorexia nervosa, sisters of people with anorexia nervosa and healthy controls) were analysed. Square wave jerk rate was acquired during a fixation task, and anxiety was measured with the State Trait Anxiety Inventory. Results: Current anorexia nervosa, weight-restored from anorexia nervosa and sisters of people with anorexia nervosa groups made significantly more square wave jerks than healthy controls, but did not differ from one another. Square wave jerk rate and anxiety were found to discriminate groups with exceptionally high accuracy (current anorexia nervosa vs healthy control = 92.5%; weight-restored from anorexia nervosa vs healthy control = 77.5%; sisters of people with anorexia nervosa vs healthy control = 77.5%; p Conclusion: The combination of square wave jerk rate and anxiety was found to be a promising two-element marker for anorexia nervosa, and has the potential to be used as a biomarker or endophenotype to identify people at risk of anorexia nervosa and inform future treatments.

We present a one-step Ugi reaction protocol for the expedient synthesis of photoaffinity probes for live-cell MS-based proteomics. The reaction couples an amine affinity function with commonly used photoreactive groups, and a variety of handle functionalities. Using this technology, a series of pan-BET (BET: bromodomain and extra-terminal domain) selective bromodomain photoaffinity probes were obtained by parallel synthesis. Studies on the effects of photoreactive group, linker length and irradiation wavelength on photocrosslinking efficiency provide valuable insights into photoaffinity probe design. Optimal probes were progressed to MS-based proteomics to capture the BET family of proteins from live cells and reveal their potential on- and off-target profiles.

Second-generation bromodomain and extra terminal (BET) inhibitors, which selectively target one of the two bromodomains in the BET proteins, have begun to emerge in the literature. These inhibitors aim to help determine the roles and functions of each domain and assess whether they can demonstrate an improved safety profile in clinical settings compared to pan-BET inhibitors. Herein, we describe the discovery of a novel BET BD2-selective chemotype using a structure-based drug design from a hit identified by DNA-encoded library technologies, showing a structural differentiation from key previously reported greater than 100-fold BD2-selective chemotypes GSK620, GSK046, and ABBV-744. Following a structure-based hypothesis for the selectivity and optimization of the physicochemical properties of the series, we identified 60 (GSK040), an in vitro ready and in vivo capable BET BD2-inhibitor of unprecedented selectivity (5000-fold) against BET BD1, excellent selectivity against other bromodomains, and good physicochemical properties. This novel chemical probe can be added to the toolbox used in the advancement of epigenetics research.

Owning a pet has often been associated with improved mental health among owners, including enhanced quality of life, and decreased levels of depression and loneliness. The aim of this study was to identify whether owning a cat and/or dog was associated with better psychological wellbeing during a strict lockdown period in Victoria, Australia, during the COVID-19 pandemic. Data were analysed from a large-scale mental health study: the COvid-19 and you: mentaL heaLth in AusTralia now survEy (COLLATE). The impact of pet ownership on levels of resilience, loneliness and quality of life were examined in a sample of 138 pet owners and 125 non-pet owners. Hierarchical linear regression analyses indicated that pet ownership was significantly associated with poorer quality of life, but not significantly associated with resilience or loneliness, after accounting for situational factors (e.g. job loss) and mood states. Contrary to expectations, the findings suggest that during a specific situation such as a pandemic, pets may contribute to increased burden among owners and contribute to poorer quality of life.

Background and Hypothesis Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, yet a significant proportion of individuals on clozapine continue to experience disabling symptoms, despite being treated with an adequate dose. There is a need for adjunct treatments to augment clozapine, notably for negative and cognitive symptoms. One such potential agent is the glutathione precursor N-acetylcysteine (NAC). Study Design A randomized double-blind, multi-center, placebo-controlled trial for clozapine patients with enduring psychotic symptoms (n = 84) was undertaken to investigate the efficacy of adjunctive NAC (2 g daily) for negative symptoms, cognition and quality of life (QoL). Efficacy was assessed at 8, 24, and 52 weeks. Study Results NAC did not significantly improve negative symptoms (P = .62), overall cognition (P = .71) or quality of life (Manchester quality of life: P = .11; Assessment of quality of life: P = .57) at any time point over a 1-year period of treatment. There were no differences in reported side effects between the groups (P = .26). Conclusions NAC did not significantly improve schizophrenia symptoms, cognition, or quality of life in treatment-resistant patients taking clozapine. This trial was registered with “Australian and New Zealand Clinical Trials” on the 30 May, 2016 (Registration Number: ACTRN12615001273572).

While physical inactivity is associated with adverse psychological outcomes, less is known about the psychological outcomes associated with sedentary behaviour, and specifically, its mentally active and passive forms. The COVID-19 pandemic represents a unique opportunity to study associations between these variables in light of widespread stay-at-home mandates and restrictions on outdoor exercise/social activities. Using a cross-sectional dataset acquired during the COVID-19 pandemic in Australia, we examined whether physical activity and sedentary behaviour were associated with subjective quality of life (sQoL) and subjective cognitive dysfunction, and whether these associations were mediated by depressive symptoms.658 participants (males = 169, females = 489) self-reported data on physical activity and sedentary behaviour in an online survey during May 2020-May 2021. Data on physical activity and sedentary behaviour (both mentally active and passive types) was compared according to whether it was collected during or out of a lockdown period. Regression models were used to test associations of physical activity and sedentary behaviour with sQoL and subjective cognitive dysfunction, and whether these associations were mediated by depression severity.Physical activity was beneficially associated with sQoL, whereas sedentary behaviour (both total hours and the reduction of mentally active/increase in mentally passive behaviour) was detrimentally associated with sQoL. These associations were mediated by depression severity. Physical activity and sedentary behaviour were also indirectly associated with subjective cognitive dysfunction by virtue of their associations with depression severity.There are important differences in the psychological correlates of mentally passive and active sedentary behaviours. Our findings suggest that health promotion strategies should focus on not only increasing physical activity but also reducing

A number of reports have recently been published describing the discovery and optimization of bromo and extraterminal inhibitors which are selective for the second bromodomain (BD2); these include our own work toward GSK046 (3) and GSK620 (5). This paper describes our approach to mitigating the genotoxicity risk of GSK046 by replacement of the acetamide functionality with a heterocyclic ring. This was followed by a template-hopping and hybridization approach, guided by structure-based drug design, to incorporate learnings from other BD2-selective series, optimize the vector for the amide region, and explore the ZA cleft, leading to the identification of potent, selective, and bioavailable compounds 28 (GSK452), 39 (GSK737), and 36 (GSK217).

Pan-bromodomain and extra terminal (BET) inhibitors interact equipotently with all eight bromodomains of the BET family of proteins. They have shown profound efficacy in vitro and in vivo in oncology and immunomodulatory models, and a number of them are currently in clinical trials where significant safety signals have been reported. It is therefore important to understand the functional contribution of each bromodomain to assess the opportunity to tease apart efficacy and toxicity. This article discloses the in vitro and cellular activity profiles of GSK789, a potent, cell-permeable, and highly selective inhibitor of the first bromodomains of the BET family.

Previous research has indicated that lifetime body image concerns are associated with increased odds of paranoid ideation. In this study, we sought to replicate and extend this finding by exploring how paranoia relates to different aspects of body image concern using a comprehensive, cross-sectional design. Women without a mental health diagnosis (n = 119) completed online questionnaires assessing paranoia, shape and weight concerns, and figure ratings for how they "think" their body looks and how they "feel" in their body. Participant's "actual" figure ratings were estimated from height and weight; discrepancy scores were then calculated for "actual-think" and "actual-feel" figure ratings. Correlational analyses, and mediation models testing paranoia as a mediator between "actual-feel" and shape and weight concerns, were conducted. Paranoia was significantly correlated with increased shape and weight concerns, and with "feeling" larger. Paranoia significantly mediated paths from feeling larger to increased shape or weight concerns. There were no significant associations of paranoia with "actual-think" ratings. Limitations include that height and weight data could not be objectively confirmed, and only women were included in the study. Further research is needed to understand mechanisms by which paranoia may influence shape and weight concerns and vice versa, and how "feeling" larger may feed paranoia. Future research should investigate these relationships among clinical eating disorder groups.

Objective: Anorexia nervosa (AN) is a serious eating disorder associated with several cognitive difficulties including poor cognitive flexibility (i.e. difficulties in effectively adapting to changes in the environment and/or changing task demands). AN research has primarily assessed cognitive flexibility using neurocognitive tests, and little is known about the differences or similarities between self-report and neurocognitive assessments of cognitive flexibility. This study investigated the relationship between self-report and neurocognitive assessments of cognitive flexibility in people with no history of an eating disorder (n = 207) and people with a self-reported lifetime diagnosis of AN (n = 19). Methods: Participants completed self-report and neurocognitive assessments of cognitive flexibility through an online study. Results: No significant correlations were found between self-report and neurocognitive assessments of cognitive flexibility for either group of the sample, suggesting that these assessments may evaluate different aspects of cognitive flexibility. Further, negative mood and self-reported eating disorder symptoms were found to significantly relate to self-reported cognitive flexibility, but were not associated with performance on neurocognitive tests of cognitive flexibility. Conclusions: To provide a comprehensive understanding of perceived and objective cognitive flexibility in AN, future research and clinical assessments should include both self-report and neurocognitive assessments.

Supplemental material, sj-docx-1-anp-10.1177_00048674211047189 for A biomarker and endophenotype for anorexia nervosa? by Andrea Phillipou, Susan L Rossell, Caroline Gurvich, David J Castle, Denny Meyer and Larry A Abel in Australian & New Zealand Journal of Psychiatry

Supplemental material, sj-docx-1-hpq-10.1177_13591053221133890 for Intersections of paranoia and the body in the general population by Wei Lin Toh, Andrea Phillipou, Erica Neill and Susan L Rossell in Journal of Health Psychology

Supplemental material, sj-docx-2-hpq-10.1177_13591053221133890 for Intersections of paranoia and the body in the general population by Wei Lin Toh, Andrea Phillipou, Erica Neill and Susan L Rossell in Journal of Health Psychology

Objective Eating disorders (EDs) have their onset most frequently in adolescence and young adulthood. Treatment for EDs lack efficacy, and we have made little progress in improving outcomes for patients over the course of the last several decades. As with other mental health conditions, early intervention may greatly improve outcomes, yet, little research exists in this area. Conclusions More effective evidence-based treatments are sorely needed for EDs, particularly for early stages of the illness to minimise the potential harms of treatment and long-standing illness. Treatment service models would also benefit from taking an approach that ensures continuation of care from adolescence to young adulthood.

Objective:There is accumulating evidence that adjunctive treatment with N-acetylcysteine may be effective for schizophrenia. This study aimed to conduct a comprehensive meta-analysis examining the efficacy of randomised control trials investigating N-acetylcysteine as an adjunct treatment for schizophrenia and the first to investigate cognition as an outcome.Methods:We systematically reviewed Medline, EmCare, PsycINFO, Embase, CINAHL Complete, China Knowledge Resource Integrated Database and the Cochrane Clinical Trials online registry for randomised control trials of N-acetylcysteine for schizophrenia. We undertook pairwise meta-analyses of N-acetylcysteine vs placebo for psychosis symptoms and cognition.Results:Seven studies, including n = 220 receiving N-acetylcysteine and n = 220 receiving placebo, met inclusion criteria for the pairwise meta-analyses. Positive and Negative Syndrome Scale negative and total scores were significantly improved in the N-acetylcysteine group after 24 weeks of treatment. The cognitive domain of working memory improved with N-acetylcysteine supplementation.Conclusion:Evidence supports the notion that N-acetylcysteine may be a useful adjunct to standard treatment for the improvement of schizophrenia symptoms, as well as the cognitive domain of working memory. Treatment effects were observed at the later time point (⩾24 weeks), suggesting that longer interventions are required for the success of N-acetylcysteine treatment.

Anorexia nervosa (AN) is a complex psychiatric disorder [...]

Abnormalities in autonomic function have been observed in people with anorexia nervosa. However, the majority of investigations have utilised heart rate variability as the sole assessment of autonomic activity. The current study utilised a variety of methodologies to assess autonomic nervous system function in women with a current diagnosis of anorexia, a past diagnosis of anorexia who were weight-restored, and healthy controls.The sample included 37 participants: 10 participants with anorexia, 17 weight-restored participants (minimum body mass index 18.5 for minimum of 12 months) and 10 controls. Assessments of autonomic function included muscle sympathetic nerve activity (MSNA) using microneurography, heart rate variability, baroreflex sensitivity, blood pressure variability, head-up tilt table test, sudomotor function and assessment of plasma catecholamines.MSNA (bursts/min) was significantly decreased in both anorexia (10.22 ± 6.24) and weight-restored (17.58 ± 1.68) groups, as compared to controls (23.62 ± 1.01, p 0.001 and p = 0.033, respectively). Participants with anorexia had a significantly lower standard deviation in heart rate, lower blood pressure variability and decreased sudomotor function as compared to controls. Weight-restored participants demonstrated decreased baroreflex sensitivity in response to head-up tilt as compared to controls.Women with a current or previous diagnosis of anorexia have significantly decreased sympathetic activity, which may reflect a physiological response to decreased energy intake. During the state of starvation, women with anorexia also displayed decreased sudomotor function. The consequences of a sustained decrease in MSNA are unknown, and future studies should investigate autonomic function in long-term weight-restored participants to determine whether activity returns to normal.

Interoceptive awareness - the sense and awareness of the internal state of our bodies - has been of increasing interest in anorexia nervosa (AN) given the observation that people with AN do not respond appropriately to hunger cues. Despite the interest in the area, very little research has been undertaken to specifically assess interoceptive awareness in AN. The aim of this study was to explore levels of interoceptive awareness in individuals at different stages of AN, as well as first-degree relatives. Eighty participants were compared on self-reported interoceptive awareness using the Multidimensional Assessment of Interoceptive Awareness (MAIA), including participants with a current diagnosis of AN (c-AN), individuals who were weight-restored from AN (wr-AN), biological sisters of individuals with AN (AN-sis), and healthy controls (HC). Significant group differences were found for the noticing, not-distracting, self-regulation and trusting subscales of the MAIA; but not for the not-worrying, attention regulation, emotional awareness or body listening subscales. Specifically, wr-AN and AN-sis scored higher on the noticing subscale than HC; c-AN and wr-AN scored lower on the not-distracting subscale than HC; and the c-AN group showed lower scores on the self-regulation and trusting subscales than other groups. The results suggest that specific aspects of interoceptive awareness such as increased awareness of body sensations and reduced trusting of one's body, may relate to AN symptomatology such as ignoring hunger cues, and may represent trait factors that increase the risk of developing AN.

Cardiovascular complications have been demonstrated in patients with anorexia nervosa (AN) in both the state of starvation and during weight restoration, however, the underlying mechanisms remain unclear. The current study aimed to assess arterial stiffness via carotid-femoral pulse wave velocity (cfPWV) in the acute and weight-restored states of AN. The study also aimed to determine the association between psychological distress and cfPWV. The sample included 37 participants; 10 participants with AN, 17 who were weight-restored (AN-WR; minimum body mass index >18.5 for at least 12 months) and 10 healthy controls (HCs). cfPWV via applanation tonometry was conducted to assess arterial stiffness. Psychological distress was assessed using the depression anxiety stress scale (DASS-21) and the state-trait anxiety inventory (STAI). Between-group comparisons were performed to determine differences between groups, a two-stage hierarchical regression model was performed to determine the contribution of physiological and psychological variables on cfPWV and correlation analyses were also performed. Vascular stiffness was significantly increased in the AN and AN-WR groups, relative to HCs. The total DASS score was the only significant predictor of cfPWV across the sample. There were positive associations between cfPWV and depression, anxiety and stress, as assessed by the DASS. Furthermore, cfPWV was positively associated with STAI trait anxiety. Arterial stiffness was increased in individuals in the acute and weight-restored states of AN, demonstrating early signs of the development of arteriosclerotic cardiovascular disease. Increased arterial stiffness was associated with increased psychological distress, which may be a contributing mechanism to the increased cardiovascular risk in AN.

The profound efficacy of pan-BET inhibitors is well documented, but these epigenetic agents have shown pharmacology-driven toxicity in oncology clinical trials. The opportunity to identify inhibitors with an improved safety profile by selective targeting of a subset of the eight bromodomains of the BET family has triggered extensive medicinal chemistry efforts. In this article, we disclose the identification of potent and selective drug-like pan-BD2 inhibitors such as pyrazole 23 (GSK809) and furan 24 (GSK743) that were derived from the pyrrole fragment 6. We transpose the key learnings from a previous pyridone series (GSK620 2 as a representative example) to this novel class of inhibitors, which are characterized by significantly improved solubility relative to our previous research.

Impaired cognitive flexibility has been suggested as a risk factor for the development of anorexia nervosa (AN). The current study aimed to 1) investigate cognitive flexibility in people at various levels of risk of AN; and 2) compare people with a history of AN to people at different levels of risk of AN in cognitive flexibility. The sample comprised of 262 community participants (79% female) and 36 participants with a lifetime diagnosis of AN (97.2% female) aged between 18 and 64 years old. Participants completed self-report (the Depression Anxiety Stress Scale short-form version, the Eating Disorders Examination-Questionnaire, the Neuroticism Scale, and the Cognitive Flexibility Inventory) and neurocognitive (the Trail Making Test and the Wisconsin Card Sorting Test) assessments online to evaluate eating disorder symptoms, depression, neuroticism, and cognitive flexibility. Using a cluster analysis, participants were allocated into low-, medium-, and high-risk of AN groups (n = 88, 128, 46, and 36 respectively). Although high-risk participants self-reported significantly poorer cognitive flexibility than the other risk groups, performance on the neurocognitive tasks was similar across groups. Further, participants with lifetime AN reported significantly poorer cognitive flexibility than the low-risk group. People at high-risk of AN may perceive themselves to have poorer cognitive flexibility compared to those at a lower risk of AN. These results have implications for early identification of people at high-risk of AN.

OBJECTIVE: Anorexia nervosa (AN) is a serious psychiatric condition often associated with poor outcomes. Biologically informed treatments for AN, such as brain stimulation, are lacking, in part due to the unclear nature of the neurobiological contributions to the illness. However, recent research has suggested a specific neurobiological target for the treatment of AN, namely stimulation of the inferior parietal lobe (IPL). The aim of this study was to stimulate-noninvasively-the left IPL in individuals with AN using high-definition transcranial direct current stimulation (HD-tDCS). METHOD: Twenty participants will be randomized to receive 10 daily sessions of HD-tDCS or sham HD-tDCS (placebo). Assessments will be carried out at baseline and end point, as well as 4- and 12-week follow-ups. DISCUSSION: This pilot investigation will primarily determine the feasibility and acceptability of this intervention.

Objectives: Anorexia nervosa and body dysmorphic disorder share a hallmark clinical feature of severe body image disturbance. This study aimed to document major demographic and clinical characteristics in anorexia nervosa versus body dysmorphic disorder, and it was the first to compare specific body parts related to body image dissatisfaction across these disorders directly. Methods: Anorexia nervosa ( n=26) and body dysmorphic disorder ( n=24) patients were administered a range of clinical measures, including key questions about the specificities of their body image concerns. Results: Results revealed increased psychiatric and personality co-morbidities in anorexia nervosa relative to body dysmorphic disorder. The anorexia nervosa group was mostly preoccupied with three body zones typically linked to weight concerns, whereas the body dysmorphic disorder group fixated on facial features, hair and skin. Conclusions: These findings may help inform differential diagnosis in complex cases and aid in the formulation of targeted interventions.

[Image: see text] Bromodomain containing proteins and the acetyl-lysine binding bromodomains contained therein are increasingly attractive targets for the development of novel epigenetic therapeutics. To help validate this target class and unravel the complex associated biology, there has been a concerted effort to develop selective small molecule bromodomain inhibitors. Herein we describe the structure-based efforts and multiple challenges encountered in optimizing a naphthyridone template into selective TAF1(2) bromodomain inhibitors which, while unsuitable as chemical probes themselves, show promise for the future development of small molecules to interrogate TAF1(2) biology. Key to this work was the introduction and modulation of the basicity of a pendant amine which had a substantial impact on not only bromodomain selectivity but also cellular target engagement.

Objective: This study investigates (1) the proportion of people with psychosis who are on long-acting injectable antipsychotics; (2) the difference in the demographic, clinical, substance use and adverse drug reaction profiles of people taking long-acting injectables compared to oral antipsychotics; and (3) the differences in the same profiles of those on first-generation antipsychotic versus second-generation antipsychotic long-acting injectables. Methods: Data were collected as part of the Survey of High Impact Psychosis. For this study, participants with diagnoses of schizophrenia or schizoaffective disorder who were on any antipsychotic medication were included ( N = 1049). Results: Nearly a third (31.5%) of people with psychosis were on long-acting injectables, of whom 49.7% were on first-generation antipsychotic long-acting injectables and 47.9% were on second-generation antipsychotic long-acting injectables. This contrasts with oral antipsychotics where there was a higher utilisation of second-generation antipsychotics (86.3%). Of note, compared to those on the oral formulation, people on long-acting injectables were almost four times more likely to be under a community treatment order. Furthermore, people on long-acting injectables were more likely to have a longer duration of illness, reduced degree of insight, increased cognitive impairment as well as poor personal and social functioning. They also reported more adverse drug reactions. Compared to those on first-generation antipsychotic long-acting injectables, people on SGA long-acting injectables were younger and had had a shorter duration of illness. They were also more likely to experience dizziness and increased weight, but less likely to experience muscle stiffness or tenseness. Conclusion: Long-acting injectable use in Australia is associated with higher rates of community treatment order use, as well as poorer insight, personal and social performance, and greater cognitive impairment. While long-acting injectables may have the potential to improve the prognosis of people with psychosis, a better understanding of the choices behind the utilisation of long-acting injectable treatment in Australia is urgently needed.

The predominant assay detection methodologies used for enzyme inhibitor identification during early-stage drug discovery are fluorescence-based. Each fluorophore has a characteristic fluorescence decay, known as the fluorescence lifetime, that occurs throughout a nanosecond-to-millisecond timescale. The measurement of fluorescence lifetime as a reporter for biological activity is less common than fluorescence intensity, even though the latter has numerous issues that can lead to false-positive readouts. The confirmation of hit compounds as true inhibitors requires additional assays, cost, and time to progress from hit identification to lead drug-candidate optimization. To explore whether the use of fluorescence lifetime technology (FLT) can offer comparable benefits to label-free-based approaches such as RapidFire mass spectroscopy (RF-MS) and a superior readout compared to time-resolved fluorescence resonance energy transfer (TR-FRET), three equivalent assays were developed against the clinically validated tyrosine kinase 2 (TYK2) and screened against annotated compound sets. FLT provided a marked decrease in the number of false-positive hits when compared to TR-FRET. Further cellular screening confirmed that a number of potential inhibitors directly interacted with TYK2 and inhibited the downstream phosphorylation of the signal transducer and activator of transcription 4 protein (STAT4).

Although the inclusion of individuals with lived experience is encouraged within the research process, there remains inconsistent direct involvement in many mental health fields. Within the eating disorders field specifically, there is a very strong and increasing presence of lived experience advocacy. However, due to a number of potential challenges, research undertaken in consultation or in collaboration with individuals with lived experience of an eating disorder is scarce. This paper describes the significant benefits of the inclusion of individuals with lived experience in research. The specific challenges and barriers faced in eating disorders research are also outlined. It is concluded that in addition to existing guidelines on working with lived experience collaborators in mental health research, more specific procedures are required when working with those with eating disorders.

The mental health consequences of the COVID-19 pandemic have been significant in Australia. The aim of this study was to investigate coping strategies that individuals have adopted to assist them through this stressful period. Survey data collected in September and December 2020 as part of a larger study (the COLLATE project) was analysed. The number of adaptive coping strategies endorsed by respondents had a significant negative relationship with depression and a significant positive relationship with resilience. Females tended to use more of these strategies than men, as did people who said their mental health had improved rather than deteriorated because of the COVID-19 restrictions imposed by government. Specific adaptive coping strategies differed for those with and without a mental illness. People with a mental illness were more likely to seek professional and online help, while people without a mental illness were more likely to use self-help. Focusing on what one is grateful for and keeping oneself productively occupied (“using the time to do things around the house”) were the most beneficial coping strategies in terms of alleviating depression, anxiety and stress. Public health messaging promoting adaptive coping strategies may be useful in bolstering the mental health of individuals during lockdown periods. In particular, the promotion of coping flexibility should be recommended rather than the frequent use of the same coping strategies. Funding: AP and WLT are supported by National Health and Medical Research Council of Australia (NHMRC) Project Grants (CIA- GNT1159953, CIA- GNT1161609, respectively). SLR holds a Senior NHMRC Fellowship (GNT1154561), and EJT (GNT1142424) and TVR (GNT1088785) hold Early Career NHMRC Fellowships. Declaration of Interests: None to declare. Ethics Approval Statement: The COLLATE project received ethics approval from the Swinburne University Human Ethics Review Committee (approval number: 20202917-4107) and complied with the Declaration of Helsinki.

Supplemental material, sj-docx-1-anp-10.1177_00048674211009602 for Characteristics of people on long-acting injectable antipsychotics in Australia: Data from the 2010 National Survey of High Impact Psychosis by Shuichi Suetani, Dan Siskind, Andrea Phillipou, Anna Waterreus, Vera A Morgan and David Castle in Australian & New Zealand Journal of Psychiatry

Supplemental material, sj-pdf-1-jbx-10.1177_24725552211002472 for Reducing False Positives through the Application of Fluorescence Lifetime Technology: A Comparative Study Using TYK2 Kinase as a Model System by Luke A. Greenhough, Gabriella Clarke, Alexander N. Phillipou, Faith Mazani, Bhumika Karamshi, Sam Rowe, Paul Rowland, Cassie Messenger, Carl P. Haslam, Ryan P. Bingham and Peter D. Craggs in SLAS Discovery

Supplemental material, sj-pdf-1-jbx-10.1177_24725552211002472 for Reducing False Positives through the Application of Fluorescence Lifetime Technology: A Comparative Study Using TYK2 Kinase as a Model System by Luke A. Greenhough, Gabriella Clarke, Alexander N. Phillipou, Faith Mazani, Bhumika Karamshi, Sam Rowe, Paul Rowland, Cassie Messenger, Carl P. Haslam, Ryan P. Bingham and Peter D. Craggs in SLAS Discovery

Objective:There is ongoing debate regarding the relationship between clinical symptoms and cognition in schizophrenia spectrum disorders (SSD). The present study aimed to explore the potential relationships between symptoms, with an emphasis on negative symptoms, and social and non-social cognition.Method:Hierarchical cluster analysis with k-means optimisation was conducted to characterise clinical subgroups using the Scale for the Assessment of Negative Symptoms and Scale for the Assessment of Positive Symptoms in n = 130 SSD participants. Emergent clusters were compared on the MATRICS Consensus Cognitive Battery, which measures non-social cognition and emotion management as well as demographic and clinical variables. Spearman’s correlations were then used to investigate potential relationships between specific negative symptoms and emotion management and non-social cognition.Results:Four distinct clinical subgroups were identified: 1. high hallucinations, 2. mixed symptoms, 3. high negative symptoms, and 4. relatively asymptomatic. The high negative symptom subgroup was found to have significantly poorer emotion management than the high hallucination and relatively asymptomatic subgroups. No further differences between subgroups were observed. Correlation analyses revealed avolition-apathy and anhedonia-asociality were negatively correlated with emotion management, but not non-social cognition. Affective flattening and alogia were not associated with either emotion management or non-social cognition.Conclusions:The present study identified associations between negative symptoms and emotion management within social cognition, but no domains of non-social cognition. This relationship may be specific to motivation, anhedonia and apathy, but not expressive deficits. This suggests that targeted interventions for social cognition may also result in parallel improvement in some specific negative symptoms.

Anorexia nervosa (AN) is associated with poor sleep and altered circadian rhythms. Evidence is unclear as to whether these features relate to ongoing psychiatric symptoms of AN, or are merely concomitant with low weight. In this study, we sought to evaluate subjective sleep quality and sleep–wake preferences in a sample of individuals with lifetime AN. Furthermore, we aimed to examine whether sleep quality would significantly predict AN symptom severity, after accounting for demographic features and negative emotions (depression, anxiety and stress). Adults with a lifetime diagnosis of AN (n = 96) or no lifetime psychiatric diagnoses (NC; n = 246) completed an online survey assessing demographics, sleep quality, circadian sleep–wake preferences, eating disorder symptoms, and negative emotions. AN participants reported significantly poorer sleep quality overall, including increased sleep disturbances, use of sleep medications, and daytime dysfunction, as compared to NC participants. Groups did not differ significantly in circadian sleep–wake preferences. Regression analysis showed that among AN participants, sleep quality and negative emotions significantly predicted AN symptom severity, while sex and body mass index (BMI) did not. The findings demonstrate that poor sleep quality was associated with more severe symptoms of AN, even when accounting for negative emotions and BMI. Future research should investigate causal interactions between sleep quality and AN symptom severity longitudinally and across different recovery stages. Level III—Cohort and case–control analytic studies.

There are currently no validated biomarkers for anorexia nervosa (AN), though recent literature suggests an increased research interest in this area. Biomarkers are objective, measurable indicators of illness that can be used to assist with diagnosis, risk assessment, and tracking of illness state. Related to biomarkers are endophenotypes, which are quantifiable phenomena that are distinct from symptoms and which link genes to manifest illness. In this scoping review, we sought to provide a summary of recent research conducted in the pursuit of biomarkers and endophenotypes for AN. The findings indicate that a number of possible biomarkers which can assess the presence or severity of AN independently of weight status, including psychophysical (e.g., eye-tracking) and biological (e.g., immune, endocrine, metabolomic, neurobiological) markers, are currently under investigation. However, this research is still in early phases and lacking in replication studies. Endophenotype research has largely been confined to the study of several neurocognitive features, with mixed evidence to support their classification as possible endophenotypes for the disorder. The study of biomarkers and endophenotypes in AN involves significant challenges due to confounding factors of illness-related sequalae, such as starvation. Future research in these areas must prioritise direct evaluation of the sensitivity, specificity and test-retest reliability of proposed biomarkers and enhanced control of confounding physical consequences of AN in the study of biomarkers and endophenotypes.

Life satisfaction is a core aspect of an individual's wellbeing and describes the subjective assessment of their quality of life. Reduced life satisfaction is frequently reported in anorexia nervosa (AN), but the factors contributing to this are still unclear. This study sought to extend previous work by examining 12 potential correlates of AN life satisfaction. One hundred and five female AN patients were administered questionnaires assessing life satisfaction, depression, anxiety, stress, employment status, marital status, body mass index, eating disorder symptomatology, perceived disability and readiness for change. A stepwise linear regression revealed that only depression, perceived disability and employment status were significantly associated with AN life satisfaction. The findings thus highlight prevailing mood and personal functioning as critical foci for clinical management strategies in people with AN. Addressing depressive symptoms and perceived disability while bettering employment prospects could facilitate improved AN life satisfaction.

Contemporary drug discovery typically quantifies the effect of a molecule on a biological target using the equilibrium-derived measurements of IC50, EC50, or KD. Kinetic descriptors of drug binding are frequently linked with the effectiveness of a molecule in modulating a disease phenotype; however, these parameters are yet to be fully adopted in early drug discovery. Nanoluciferase bioluminescence resonance energy transfer (NanoBRET) can be used to measure interactions between fluorophore-conjugated probes and luciferase fused target proteins. Here, we describe an intracellular NanoBRET competition assay that can be used to quantify cellular kinetic rates of compound binding to nanoluciferase-fused bromodomain and extra-terminal (BET) proteins. Comparative rates are generated using a cell-free NanoBRET assay and by utilizing orthogonal recombinant protein-based methodologies. A screen of known pan-BET inhibitors is used to demonstrate the value of this approach in the investigation of kinetic selectivity between closely related proteins.

Objective Differences in saccadic eye movements are widely reported in mental illnesses, and can indirectly inform our understanding of neurobiological and cognitive underpinnings of psychiatric conditions, including anorexia nervosa (AN). Preliminary research has suggested that individuals with AN may show specific eye movement abnormalities; whether these deficits are representative of state or trait effects is, however, unclear. The aim of this study was to identify whether there are demonstrable differences in performance on saccadic eye movement tasks in individuals with current AN (c-AN), those who are weight-restored from AN (wr-AN), biological sisters of individuals with AN (AN-sis), and healthy controls (HC). Methods Eighty participants took part in the study (n = 20/group). A set of saccadic eye movement tasks was administered, including prosaccade, antisaccade, memory-guided saccade, and visual scanpath tasks. Results The c-AN group showed an increased rate of inhibitory errors to 10° targets on the memory-guided saccade task. Discussion The results are discussed in terms of the potential role of the superior colliculus in AN, and that the findings may reflect a state measure of AN.

ER aminopeptidase 1 (ERAP1) is an intracellular enzyme that generates antigenic peptides and is an emerging target for cancer immunotherapy and the control of autoimmunity. ERAP1 inhibitors described previously target the active site and are limited in selectivity, minimizing their clinical potential. To address this, we targeted the regulatory site of ERAP1 using a high-throughput screen and discovered a small molecule hit that is highly selective for ERAP1. (4aR,5S,6R,8S,8aR)-5-(2-(Furan-3-yl)ethyl)-8-hydroxy-5,6,8a-trimethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalene-1-carboxylic acid is a natural product found in Dodonaea viscosa that constitutes a submicromolar, highly selective, and cell-active modulator of ERAP1. Although the compound activates hydrolysis of small model substrates, it is a competitive inhibitor for physiologically relevant longer peptides. Crystallographic analysis confirmed that the compound targets the regulatory site of the enzyme that normally binds the C-terminus of the peptide substrate. Our findings constitute a novel starting point for the development of selective ERAP1 modulators that have potential for further clinical development.

Background After receiving intensive medical treatment; individuals with eating disorders often require ongoing care to maintain their recovery, build social networks, and reduce risk of relapse. Methods To address this important transition period, a six-month peer mentoring program was developed and piloted in Melbourne, Australia. Twelve adults with a past history of an eating disorder (mentors) were paired with 14 individuals with a current eating disorder (mentees). Pairs met for thirteen mentoring sessions in community settings. Throughout the program mentees and mentors completed reflective questions online. Upon completion of the program, qualitative interviews were conducted. Both online reflections and interviews explored themes relating to perceived benefits and challenges of participation in the peer mentoring program, and the differences between mentoring and traditional treatment. Results Thematic analysis identified several benefits for mentees; including hope, reconnection with others, and re-engaging with the world. The majority of mentees described their mentor as uniquely supportive due to their past experience of an eating disorder. Mentors reported experiencing benefits such as increased connection with self and others, and indicated that the experience helped them positively reframe their past experience of an eating disorder. Ending the relationship at the completion of the program was a significant challenge for both groups, and managing boundaries was deemed a main challenge by mentors. Conclusions Overall, results indicated that this mode of informal support may be worthy of further investigation as an adjunct to clinical treatment programs for this population. Trial registration Australian and New Zealand Clinical Trials registration number - ACTRN12617001412325 - Date of registration – 05/10/2017 (Retrospectively registered)

Additional file 1: Appendix A. Online Reflection Questions.