BACKGROUND:Depression in both bipolar and major depressive disorder remains a major unmet need due to treatment resistance to the existing treatments. Emerging evidence implicates the renin-angiotensin system in regulating the cellular stress response relevant to depression, suggesting it as a novel therapeutic target for depression. Candesartan, a common hypertension medication, decreases neuroinflammation, oxidative and nitrosative pathway activation, and neurotrophic signalling of angiotensin II by predominantly blocking the angiotensin II type 1 receptors (AT1R). Given AT1R-induced activities are implicated in the pathophysiology of bipolar and major depressive disorder and with supportive pharmacoepidemiology data, candesartan may represent a novel antidepressant strategy. METHODS:The CADET Trials are 2 parallel 16-week double-blind randomized placebo-controlled trials of adjunctive candesartan (or placebo) for the treatment of bipolar depression (CADET-BD) and major depressive disorder (CADET-UD). Each trial aims to recruit 240 adult participants. The primary outcome is the between-group (ie, intervention vs. placebo) differential change from baseline to week 16 in depression symptoms as measured by the Montgomery Åsberg Depression Rating Scale. Secondary outcomes measure depression, mania, anxiety, quality of life, cost-effectiveness, functioning, substance use, cognition, and biological markers. FINDINGS:Findings are not yet available as the trial is ongoing. IMPLICATIONS:The CADET Trials examine the efficacy of candesartan in reducing depressive symptoms in both unipolar and bipolar depression, and whether its effects are mediated through the renin-angiotensin system. Candesartan is affordable, accessible, and well-tolerated. If effective, it could quickly be adopted into clinical practice as a new adjunctive medication for the treatment of these disorders.

Background Psychotropic medication use has been shown to be associated with decreased bone mineral density (BMD) and quality, and increased fracture risk. Less is known about psychotropic use and associated bone loss over time. Aims To determine the association between psychotropic medication use and bone loss in men. Method Data from 940 men (aged ≥20 years) participating in the Geelong Osteoporosis Study were used in this longitudinal study. BMD (g/cm2) at the spine and hip were measured with dual-energy X-ray absorptiometry at baseline, and 5 and 15 years post-baseline. Body mass index (BMI) was calculated, lifestyle factors and medication use was self-reported, and socioeconomic status was determined. Mood and anxiety disorders were identified through a clinical interview. Multivariable linear regression was used to determine the associations. Results Over the study period (median 13.2 years), psychotropic use was associated with change in BMD at the spine (unadjusted mean difference −0.063 g/cm2, 95% CI −0.096 to −0.031, p < 0.001) and hip (−0.038 g/cm2, 95% CI −0.059 to −0.017, p < 0.001). BMI was identified as an effect modifier. Psychotropic use was associated with spine and hip bone loss at the 25th (adjusted mean difference −0.077g/cm2 (95% CI −0.122 to −0.033); and −0.058 g/cm2 (95% CI −0.084 to −0.032), respectively) and 50th percentile (adjusted mean difference −0.053 g/cm2 (95% CI −0.089 to −0.018) and −0.038 g/cm2 (95% CI −0.059 to −0.017), respectively), but not the 75th percentile of BMI (p = 0.121 and p = 0.106, respectively). Conclusions Psychotropic use was associated with bone loss in non-obese men, highlighting the need for regular monitoring and preventive strategies to protect bone health.

Background:Depression in both bipolar and major depressive disorder remains a major unmet need due to treatment resistance to the existing treatments. Emerging evidence implicates the renin-angiotensin system in regulating the cellular stress response relevant to depression, suggesting it as a novel therapeutic target for depression. Candesartan, a common hypertension medication, decreases neuroinflammation, oxidative and nitrosative pathway activation, and neurotrophic signalling of angiotensin II by predominantly blocking the angiotensin II type 1 receptors (AT1R). Given AT1R-induced activities are implicated in the pathophysiology of bipolar and major depressive disorder and with supportive pharmacoepidemiology data, candesartan may represent a novel antidepressant strategy.MethodsThe CADET Trials are 2 parallel 16-week double-blind randomized placebo-controlled trials of adjunctive candesartan (or placebo) for the treatment of bipolar depression (CADET-BD) and major depressive disorder (CADET-UD). Each trial aims to recruit 240 adult participants. The primary outcome is the between-group (ie, intervention vs. placebo) differential change from baseline to week 16 in depression symptoms as measured by the Montgomery & Aring;sberg Depression Rating Scale. Secondary outcomes measure depression, mania, anxiety, quality of life, cost-effectiveness, functioning, substance use, cognition, and biological markers.Findings:Findings are not yet available as the trial is ongoing.Implications:The CADET Trials examine the efficacy of candesartan in reducing depressive symptoms in both unipolar and bipolar depression, and whether its effects are mediated through the renin-angiotensin system. Candesartan is affordable, accessible, and well-tolerated. If effective, it could quickly be adopted into clinical practice as a new adjunctive medication for the treatment of these disorders.

Population ageing increases multimorbidity, which in turn contributes to polypharmacy, elevating fall risk through drug interactions and adverse effects on cognition or balance. Although polypharmacy is recognised as a risk factor, specific fall-risk-increasing drugs (FRIDs) may pose greater hazards. This study aimed to examine the associations of polypharmacy, diuretic and antipsychotic use with injurious falls among older adults. Data from 952 participants (590 men and 362 women) aged ≥ 65 years in the Geelong Osteoporosis Study were linked with the Victorian Emergency Minimum Dataset. The outcome variable was time to first fall-related emergency presentation or injurious falls, with polypharmacy, diuretics and antipsychotics as exposure variables. The associations were examined using competing risk regression, with results presented as adjusted subdistribution hazard ratios (aSHR) and 95

Joint replacement (JR) is influenced by multiple determinants. Identifying an appropriate variable selection method is essential for accurate and interpretable models in musculoskeletal epidemiology. Although penalized methods such as LASSO are increasingly recommended, stepwise regression remains common in applied research. We compared these approaches for predicting JR in a large musculoskeletal cohort. Data from 2931 participants aged 20-96y from the Geelong Osteoporosis Study were analysed. Potential determinants included sociodemographic, lifestyle, body composition, and comorbidity variables. Stepwise Cox regression was implemented using the stepAIC() function in the ‘MASS’ package, and Cox-LASSO regression was performed using cv.glmnet() in the ‘glmnet’ package, using R version 4.3.1. Model performance and generalizability were assessed through independent test validation and 5-fold cross-validation. Bootstrap resampling was used to evaluate performance differences between models. Over a median follow-up of 16.7y (IQR:9.7–23.2), both models consistently identified age, spine bone mineral density, and prior fracture as key determinants of JR. Stepwise Cox regression using forward selection achieved slightly higher C-index scores across independent train–test splits and 5-fold cross-validation. All models demonstrated good discriminatory ability (C-index > 0.7). Bootstrap resampling confirmed that the performance difference was unlikely due to random variation (95

This reference, now in its second edition, is a comprehensive guide that focuses on the practical aspects of excavating and recovering human remains, as well as any associated evidence, from crime scenes. It highlights the protocols and techniques that are used to successfully survey, map, recover, document, collect, and transport evidence. New add

OBJECTIVES:To investigate pharmacological treatment patterns in individuals with bipolar disorder (BD) with and without comorbid substance use disorder (SUD) and anxiety disorder (AX), we leveraged the Global Bipolar Cohort to analyze cross-regional practices across North America, Europe, and the Pacific. METHODS:Fourteen cohorts contributed aggregate data on pharmacotherapy, demographics, diagnostic subtypes, and comorbidities. Proportional meta-analyses using generalized linear mixed models were conducted to examine prescription trends and identify clinical differences. RESULTS:The sample (N = 11,521) was 60% female and 84% Caucasian. Participants were categorized into four mutually exclusive groups based on comorbidity status: those with comorbid AX only, comorbid SUD only, both AX and SUD, or neither. The AX+SUD subgroup showed higher rates of attention-deficit/hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), rapid cycling, obesity, and unemployment, reflecting a more severe clinical profile. Regional variations were notable: North American cohorts reported higher prevalence of AX and SUD than European and Pacific cohorts. Antidepressants use for AX were more common in Europe and the Pacific, while North American prescribing patterns were more variable. Benzodiazepine use was high among individuals with SUD across all regions. Lithium and first-generation antipsychotic prescriptions varied, with higher rates observed in Europe. CONCLUSIONS:Findings underscore the heterogeneity of BD and the influence of comorbid AX and SUD on illness burden and treatment. Regional prescribing variations underscore the need for context-specific guidelines. Gaps in data on medication-assisted treatment for SUD point to areas for future research. These insights can support more individualized and effective care for complex BD presentations.

Intrinsic capacity (IC) is defined as the composite of physical and mental abilities an individual possesses, encompassing 5 domains: cognition, psychological health, sensory function, vitality, and locomotion. This construct is central to the World Health Organization's framework for assessing functional ability in older adults. Growing evidence highlights the critical role of the musculoskeletal system in maintaining these domains, while conditions such as sarcopenia, osteoporosis, and their coexistence as osteosarcopenia (OS) are increasingly associated with IC decline. This narrative review compiles current evidence on the modulatory role of muscles and bones in IC and the impacts of sarcopenia, osteoporosis, and OS. Most findings suggest that musculoskeletal tissues influence IC not only through biomechanical functions but also as secretory organs, releasing myokines and osteokines with endocrine, paracrine, and autocrine effects. Among the most studied are brain-derived neurotrophic factor, irisin, osteocalcin, and interleukin-6. Dysregulation of these pathways, along with biomechanical dysfunction and systemic inflammation, links sarcopenia, osteoporosis, and OS to IC impairment. Further research is needed to clarify the specific mechanisms involved, particularly in the sensory and vitality domains, to inform targeted interventions that promote healthy aging.

Abstract Background Hip and knee replacement (arthroplasty) is used to treat advanced joint disease by reducing pain and restoring joint function. This study aimed to identify determinants associated with a lower risk of joint replacement (JR). Methods Longitudinal data from the Geelong Osteoporosis Study (GOS) were used. JR was identified via linkage with the Barwon Joint Registry, medical records, and self-report. Anthropometry, body composition, and blood biomarkers were obtained. Demographics, lifestyle, and comorbidities were self-reported. Fractures were identified from radiological reports. Participants with JR before baseline were excluded, leaving 2,882 eligible participants (1,436 men, 1,446 women; ages 20–96 years). A time-dependent Cox regression model with age as the primary time scale and sex as a stratification variable was fitted. Forward stepwise and the least absolute shrinkage and selection operator (LASSO) regression identified relevant predictors. Results Over a median follow-up of 16.7 years (IQR: 9.7–23.2), 223 participants (7.7%) underwent JR. Factors with the reduced risk of JR included lower body mass index (HR 0.96, 95% CI, 0.94–0.99), lower spine bone mineral density (BMD) (0.84, 0.77–0.92), lower procollagen type 1 N-terminal propeptide (0.69, 0.50–0.96), non-fallers (0.74, 0.55–0.99) and no history of cancer (0.66, 0.48–0.90). Lower dietary calcium intake (0.74, 0.52–1.04) was associated with the reduced risk of JR in the main models, but this association was attenuated after accounting for supplement use. Compared with low socioeconomic status (SES), participants with medium and high SES had higher JR risk (1.91, 1.04–3.50; 1.88, 1.13–3.15), although the association was weaker in women (interaction: 0.48, 0.25–0.91). Conclusion Age-related spine degeneration may explain the link between higher spine BMD and JR. The association between lower dietary calcium intake and reduced JR risk is likely driven by confounding by indication or reverse causality. Lower BMI and lower P1NP levels emerged as potentially modifiable pathways. The absence of falls and no history of cancer were associated with reduced JR risk; however, the cancer association was attenuated in the Fine-Gray analysis when competing mortality was accounted for, and the fall association should be interpreted as observational rather than as evidence of a modifiable pathway. Socioeconomic disparities also highlight potential avenues for reducing JR risk. Overall, these findings suggest that biological, lifestyle, and social determinants may play important roles in shaping long-term JR outcomes.

Objective: This study investigated the association between gait speed, handgrip strength, and their combination, and the risk for developing clinically relevant depressive symptoms in community-dwelling older adults. Methods: A secondary analysis was conducted using data from the ASPirin in Reducing Events in the Elderly study. Participants were community-dwelling older adults in Australia and the United States of America followed for a median (interquartile range) of 3.97 (2.26) years. Baseline handgrip strength and gait speed were used as exposure variables, and their combination categories were also explored. Depression was measured using the modified Center for Epidemiological Studies Depression 10-item scale (CES-D 10). Cox regression was used to estimate Adjusted Hazard Ratios (AHR) with 95 % Confidence Intervals (CI) after adjusting for a range of potential confounders. Result: A total of 17,231 participants (55.3 % women) were included in the analysis. Slow gait and weak grip at baseline were associated with the risk of depression (AHR: 1.20; CI: 1.11-1.29 and 1.14; 1.06-1.23, respectively). The combination of the two physical performance measures was associated with a 31 % increase in the risk of depression (1.31; 1.16-1.47) and a significant dose-response association was observed for quintiles of gait and grip with depression. Limitations: Although the CES-D 10 is a validated scale, it is a self-reported tool rather than a clinical diagnosis of depression. Conclusion: Low physical function may be a risk factor for depression in older adults. This highlights the inextricable link between the physical and mental health of older adults, which can inform potential clinical and public health prevention strategies for depression in later life.

BACKGROUND:With Australia's aging population, the incidence of falls is expected to rise. The proportion of adults aged ≥65 years is projected to increase from 15 % in 2017 to 22 % by 2057, highlighting the growing need for effective fall prevention measures. Therefore, this study aimed to assess fall trends and determinants using repeated follow-up data from a population-based study. METHODS:This study utilized data from the Geelong Osteoporosis Study (GOS) to analyse fall trends in men and women. Men's data were collected at baseline (2001-2006; n = 1533), 5 years (2006-2011; n = 968), and 15 years (2016-2021; n = 627), while women's data were from 6 years (2001-2003; n = 1014), 10 years (2004-2008; n = 1098), and 15 years (2011-2014; n = 844). Falls data, self-reported for the past 12 months, were age-standardised to the Australian population. Data included self-reported prior fractures, medications, comorbidities, alcohol use, and smoking, along with measured anthropometrics, muscle strength, biochemical tests, and imaging. A multivariable Generalised Estimating Equation model identified fall determinants, reporting adjusted odds ratios (AORs) and 95 % confidence intervals. RESULTS:In men, the age-adjusted prevalence of falls declined over time, while in women, it initially dropped by 4.2 % before a slight 0.6 % increase. After adjusting for confounders, each additional year of age raised the fall risk by 1 % (AOR = 1.01, 95 % CI: 1.00-1.02). Women had a 52 % higher likelihood of falling than men (AOR = 1.52, 95 % CI: 1.22-1.88). Diabetes increased the risk by 69 % (AOR = 1.69, 95 % CI: 1.23-2.31), while a 1 N/kg increase in hip flexion strength lowered the risk by 3 % (AOR = 0.97, 95 % CI: 0.95-0.99). CONCLUSION:Men experienced a steady decrease in fall prevalence over time, whereas women displayed a more intricate trend, with falls initially declining before subsequently rising, following a polynomial pattern. The key predictors of falls included age, sex, diabetes and hip flexion strength. Policies should prioritize tailored fall prevention, strength training, and diabetes care integration.

Introduction:Bipolar disorder is associated with several physical conditions and possibly increased pain, although research outside hospital settings is limited. We compared perceived pain among population-based women with and without bipolar disorder. Method:This study examined 113 women with bipolar disorder (59 euthymic, 54 symptomatic in past month) and 316 age-matched women without bipolar disorder drawn from studies located in the same region of south-eastern Australia. Mental disorders were confirmed by clinical interview (SCID-I/NP). Pain during the past week was determined by numeric rating scale (0-10, 10 = pain as severe as I can imagine) and deemed present if ≥5. Demographic, lifestyle, and health information was obtained via questionnaire. Odds ratios (OR) with 95% confidence intervals for the likelihood of pain were estimated using marginal binary logistic regression models, adjusting for potential confounders. Results:Women with bipolar disorder who were euthymic at the appointment were at increased odds of headache [adjOR 3.4, 95% CI (1.4, 7.9)], back pain [2.6 (1.3, 5.4)], overall pain(s) [5.7 (2.9, 11.4)], pain at ≥3 sites [2.3 (1.0, 5.2)] and were in pain ≥50% time spent awake [2.3 (1.1, 5.1)] compared to women without bipolar disorder. The pattern of association was similar but stronger for women symptomatic in the past month; headache [6.0 (2.6, 13.9)], back pain [4.2 (2.0, 8.5)], overall pain(s) [7.2 (3.4, 15.4)], pain at ≥3 sites [5.1 (2.3, 11.1)] and ≥50% time in pain [4.5 (2.2, 9.3)]. Daily activity interference from pain did not differ between groups (all p > 0.05). Conclusion:Women with bipolar disorder are more likely to report pain regardless of phase. Assessment and management of pain is necessary to reduce associated burden.

BACKGROUND:Lesbian, gay, bisexual, transgender, queer or questioning, asexual or aromantic and more (LGBTQA+) populations face disparities in health outcomes, which are particularly pronounced in relation to mental health. While psychotic disorders are associated with added barriers to treatment, they are rarely included in conversations around improving healthcare for LGBTQA+ individuals. The present study compared the healthcare experiences reported by LGBTQA+ individuals with psychotic disorders, common mental disorders (anxiety and depressive disorders) and physical health conditions. METHODS:A large online cross-sectional survey of LGBTQA+ adults in Australia was completed by 6835 individuals: 84 diagnosed with psychotic disorders, 521 diagnosed only with common mental disorders and 318 diagnosed only with common physical health conditions. Logistic regression analyses were used to investigate the association between diagnostic groups and health service access, service satisfaction and perceived respect for identity, and the importance of service LGBTQA+ inclusivity. RESULTS:Compared to those with psychotic disorders and common mental disorders, participants with physical health conditions were more likely to access mainstream clinics that are not explicitly LGBTQA+ inclusive and demonstrated a trend towards lower importance of service LGBTQA+ inclusivity. Participants with psychosis reported lower levels of respect for gender identity in LGBTQA+ inclusive services than those with common mental disorders. DISCUSSION:Differences in healthcare experiences between LGBTQA+ participants with physical health conditions, common mental disorders and psychotic disorders are present but not marked. Findings highlight a need for improved LGBTQA+ competencies in mainstream services and resource allocation to community-led services. Further research is needed to explore the factors contributing to worsened healthcare experiences for individuals with psychosis.

The extent to which genetic predisposition contributes to late-life depression risk, particularly after age 70, remains unclear, despite the high prevalence of depression in this age group and the variability in risk factors by age. This study investigated the association between a polygenic score (PGS) and depression outcomes, including severity, trajectories of depression, and antidepressant medication use, in a longitudinal cohort of 12,029 genotyped older adults of European descent aged ≥70 years, with no history of diagnosed cardiovascular disease events, dementia, or permanent physical disability at baseline. Participants were followed for a median of 4.7 years. The PGS was derived using the latest Psychiatric Genomics Consortium data for major depression. Depression was defined by the CES-D-10 score thresholds of ≥8 (primary outcome), ≥10, and ≥12 (secondary outcomes), alongside antidepressant medication use and four previously established longitudinal trajectories of depressive symptoms: low (non-depressed), moderate (subthreshold), high (persistent), and initially low but increasing (emerging). Multivariable models were used to examine associations between the PGS (per standard deviation, SD) and outcomes, adjusting for covariates. At baseline, mean participant age was 75.1 years, 54.9% were female, and 9.1% had depression (CES-D-10 ≥ 8). The PGS was significantly associated with baseline depression (OR = 1.23 [1.15–1.31]), incident depression (HR = 1.18 [1.14–1.23]) and antidepressant medication use (OR = 1.39 [1.31–1.47]). Compared with non-depressed participants, the PGS was associated with increasing severity of depression trajectory classes (subthreshold depression OR = 1.15 [1.11–1.20], emerging depression OR = 1.22 [1.13–1.31], persistent depression OR = 1.40 [1.31–1.49]). These findings suggest that the PGS may play an important role in risk stratification for late-life depression.

People impacted by bipolar disorder are confronted by many unmet needs that contribute to the overall burden associated with the disorder. We do not have a good understanding of the underlying pathology of bipolar disorder, so we do not have biomarkers to accurately identify those who are at risk of developing the disorder. Delayed diagnosis is the norm, and it can take a decade or more for an individual to receive a diagnosis and to start appropriate treatment. We have evidence-based treatments such as lithium and psychosocial therapies; however, their availability and use are limited. We need a consolidated approach to advance indicated prevention and early intervention for bipolar disorder. In this viewpoint article, we describe these barriers in detail as well as introduce international and national work that is being done to progress the field. At the national level, we introduce the National Health and Medical Research Council Centre for Research Excellence in Bipolar Disorder. The Centre for Research Excellence in Bipolar Disorder comprises a multidisciplinary team of experts from Australia and internationally who are working together to develop a better understanding of opportunities for indicated prevention and early intervention as well as to improve interventions for those impacted by the disorder. Here we describe our research framework, stakeholder engagement activities and strategies for workforce development and capacity building. Ultimately by working together we will attempt to address many of issues faced by individuals impacted by bipolar disorder.

Existing pharmacotherapies and psychotherapies are often inadequate, and discovery for new pharmacological treatments in psychiatry is slow. Existing pharmacotherapies are, however, often inadequate. Few truly novel pharmacotherapies have emerged in the past four decades, largely due to the absence of a known pathophysiology for each disorder. In this Personal View, we describe the platform we have adopted that enables targeted drug repurposing. With this approach, patient-derived stem cells are used to detect transcriptomic targets to identify existing drugs that address these targets. These drugs are then validated in non-human animal models and pharmacoepidemiological studies before being tested in clinical trials. Our targeted drug repurposing platform bypasses the absence of known pathophysiology. Validation steps bring greater scientific rigour and mechanistic insights to drug repurposing to allow only drug candidates with the strongest mechanistic evidence to be tested in clinical trials.