BACKGROUND:Growth Differentiation Factor-15 (GDF-15) has been proposed as a biomarker of inflammation and cellular stress, both of which are implicated in the pathophysiology of depression. We conducted a systematic review and meta-analysis to evaluate the association between circulating GDF-15 levels and depression. METHODS:Observational studies assessing GDF-15 levels in adults with depression were included. Eligible studies reported GDF-15 levels measured in blood and used standardized diagnostic criteria for depression. Study quality was assessed using the Newcastle-Ottawa Scale. A meta-analysis was performed on a subset of studies with available data. RESULTS:Thirteen studies with a total of 55,985 participants were included, of whom 4997 had depression. Study populations included late-life, post-stroke, male-only, and general adult cohorts. Most studies (n = 12) found elevated GDF-15 levels in individuals with depression. Six studies were included in the meta-analysis (n = 5657), which revealed significantly higher GDF-15 levels in depressed individuals compared to controls (standardized mean difference [SMD] = 0.39, 95% CI: 0.19 to 0.58; p = 0.0039). Heterogeneity was moderate to high (I2 = 68.7%) but reduced substantially upon exclusion of one study. Correlations between GDF-15 and depression severity were inconsistent across studies. CONCLUSIONS:Circulating GDF-15 levels are moderately but significantly elevated in individuals with depression, supporting its role as a potential inflammatory biomarker of depression. However, variability in measurement methods, study populations, and depression assessments limits generalizability. Further longitudinal and mechanistic studies are needed to clarify the clinical utility of GDF-15 in depression diagnosis and prognosis.

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.

Despite significant advancements in psychopharmacology, there are inadequate treatment options for many psychiatric disorders, including major depressive disorder, bipolar disorder, schizophrenia, and anxiety disorders. This review explores emerging neurobiological targets beyond conventional monoaminergic approaches, focusing on sodium channels, Neuropeptide Y (NPY), Neurokinin 1 (NK1) receptors, P2 × 7 purinergic receptors, Sigma-1 receptors, and Orexin. Recent evidence suggests that sodium channel modulators, such as evenamide, may offer therapeutic benefits for treatment-resistant schizophrenia by stabilizing glutamatergic neurotransmission. NPY-based therapies have potential in stress-related disorders, foreshadowing rapid anxiolytic and antidepressant effects through modulation of the stress response. NK1 receptor antagonists, although inconsistent in mood disorders, show promise in addiction treatment by reducing substance cravings. The P2 × 7 receptor, a key regulator of neuroinflammation, has been implicated in mood disorders, and its pharmacological inhibition may provide neuroprotective benefits. Additionally, Sigma-1 receptor agonists, including Blarcamesine and Pridopidine, have shown neuroprotective and cognitive-enhancing properties, making them attractive candidates for psychiatric and neurodegenerative disorders. Orexin receptor antagonists, such as suvorexant and seltorexant, have potential in mood disorders and substance dependence, highlighting the broader therapeutic applications of targeting the orexinergic system. While these emerging therapeutic targets hold promise, challenges remain in translating preclinical findings into effective clinical applications. Large-scale, placebo-controlled trials are necessary to establish their efficacy and safety. The identification of biomarkers for patient stratification will be critical in the hitherto elusive goal of developing precision medicine approaches. Targeted pharmacological interventions offer a path toward more effective, well-tolerated, and potentially individualized treatment options for patients with severe mental illness.

Conventional antidepressant, antipsychotics and mood stabilizing drugs share several characteristics. Firstly, they have a slow onset of action with benefits accruing late that is broadly mediated by long term homeostatic processes. Response generally predicts long term maintenance effects. They have little or no effect on the mental state of healthy individuals and can be conceptualized as targeting elements of pathophysiology. We can term them pathomodal. In contrast, psychotropic agents that are repurposed recreational drugs also share several effects. They have a rapid effect on mood states or perception and risk withdrawal symptoms that are generally the phenomenological mirror image of their acute effects and hence risks accrue late. Notwithstanding some heterogeneity, long term benefits are less clear than acute effects. Lastly, their effects are evident in all people who take them, and they can therefore be conceptualized as targeting elements of physiology. We can term them physiomodal. This categorization has several implications for both research design and clinical care.

Importance For people with bipolar disorder, recovery from manic or mixed episodes is frequently complicated by depression. Depression after manic/mixed episodes may occur within a broader episode sequence pattern of mania-depression-euthymic interval, proposed as a subtype for which lithium is likely effective. However, the window of risk for mania/mixed-to-depression transition remains unclear, as are its clinical associations. Objective To determine the rate of transition from manic/mixed episodes to depression, and identify risk factors and outcomes. Design: Retrospective cohort study. Setting: NeuroBlu health record database (United States; 1959 to 2025). Participants: 10,806 people with bipolar disorder (44,691 mood episodes; 112,742 person-years), defined as having ≥1 record of each of manic/mixed episodes and depression. Median follow-up: 7.0 years [IQR: 4.0-12.4]. Exposures: Clinical features (previous short transition, hospitalisation, clinical severity) and medications prescribed during the manic/mixed episode. Main Outcomes, Measures: Transition time from manic/mixed episodes to depression. Results 10,806 people with bipolar disorder (44,691 mood episodes) were included (mean age at mood episode 43.3 years (SD=15.3), 62% female). 28% of manic and 23% of mixed episodes transitioned to depression within 1 month: an incidence >10-times higher than the overall per-month depression rate. The depression transition rate plateaued by 6 months. Short depression transition time (≤1 month) was associated with previous short transition (post-mania RR=2.50, 95%CI: 2.15-2.90; post-mixed RR=2.84, 95%CI: 2.34-3.44), higher manic/mixed severity (post-mania RR=1.26 per 1 point CGI-S increase, 95%CI: 1.16-1.37; post-mixed RR=1.42, 95%CI: 1.29-1.55) and hospitalisation for the mania/mixed episode (post-mania RR=1.30, 95%CI: 1.14-1.47; post-mixed RR=1.71, 95%CI: 1.49-1.95). Among medications prescribed during hospital-associated manic/mixed episodes, lithium (post-mania RR=0.75, 95%CI: 0.62-0.91; post-mixed RR=0.64, 95%CI: 0.47-0.88), antiepileptic mood stabilisers (post-mania: RR=0.79, 95%CI: 0.69-0.89; post-mixed: RR=0.66, 95%CI: 0.57-0.78), antipsychotics for mania (RR=0.80, 95%CI: 0.71-0.91) and antidepressants for mixed episodes (RR=0.82, 95%CI: 0.72-0.94) were associated with longer transition time. Shorter transition time was associated with more depression-related hospital days (post-mania: 17% fewer days per month delay to depression, 95%CI: 9-24%; post-mixed: 12% fewer, 95%CI: 5-19%). Conclusions, Relevance It is important to monitor for depression soon after manic/mixed episodes. This depression may be predictable, and might be modifiable by some medications prescribed during the manic/mixed episode.

A proposed interdisciplinary fetal neonatal neurology collaborative offers life-course brain health training across three time-sensitive teaching opportunities. The educational organization includes a broad representation of inter-related fields. Formal training will re-enforce career-long learning that fosters creative thinking. Acquiring a life-course perspective of brain health can contribute solutions to the global public health crisis involving neurological and mental health disorders across the lifespan. Teaching transdisciplinary interventions begins with parental childhood and reproductive health which will influence the maternal-placental-fetal triad throughout pregnancy into labor and delivery. The second teaching opportunity focuses on the symptomatic minority who receive neonatal neurocritical care and convalescent care. The third educational cluster focuses on improving clinical skills as the unrecognized majority of children present over the preschool years with continued development through the school years. Teaching preventive neurology and mental health introduce proactive interventions that more effectively support rescue and reparative choices into adulthood. The science of uncertainty will be taught to all stakeholders that integrates information to improve critical thinking skills. This tripartite interdisciplinary educational program will help trainees distinguish adverse effects from neurodegeneration on primary fetal neuroplasticity mechanisms from secondary pathways based on systems-science. Supervised clinical experiences during each rotation will supplement didactic teaching with input from each trainee’s mentoring committee. Future providers will learn to anticipate adaptive from maladaptive disease pathways to prepare for career-long experiences. Curriculum topics will focus on brain health strategies that differentiate resilience from vulnerability based on time-dependent gene–environment interactions. Attention to structural, social and environmental drivers of health will incorporate intersectionality perspectives into equitable neuroprotective plans. Training will engage, educate and empower women to improve brain health for themselves and their children. This interdisciplinary collaborative program will apply real-world situations to encourage research development that will narrow the knowledge-practice gap. Continuity of brain care bundles will enable providers, women, and their families to achieve brain health across each and successive generations. A lower global burden of neurologic and mental health disorders will contribute to an improved quality of life with greater economic prosperity.

OBJECTIVES:This World Federation of Societies of Biological Psychiatry (WFSBP) consensus paper aims to summarise and evaluate the published study results on objectively measurable biological markers associated with anorexia nervosa (AN). METHODS:The relevant literature was reviewed by the WFSBP Task Forces on Eating Disorders and on Biological Markers, and a consensus regarding the significance of the published evidence was reached. RESULTS:Candidate biological markers that have been associated with AN include clinical (e.g. body weight), molecular (e.g. genetic, epigenetic, hormonal, immunological, metabolomic), cellular (e.g. leukocytes), neuroimaging (e.g. structure, function, connectivity), digital, cardiac and neurophysiological parameters. Some clinical and laboratory parameters are risk markers in clinical practice. Biological markers have pathophysiological relevance in understanding the biological and metabolic pathophysiology of AN and its physical health consequences. Few studies have examined pharmacogenetics or therapeutic drug monitoring as tools to monitor and guide the treatment of AN. CONCLUSIONS:Biological markers will hopefully soon enable clinicians to intervene earlier in a more targeted manner to mitigate treatment resistance. However, the current scientific basis for most biological markers are group comparisons only. Studies on sensitivity, specificity and the prognostic value of these markers are lacking.

Importance:Methamphetamine use disorder is a global health challenge for which there are no approved pharmacotherapies. The safety and effectiveness of mirtazapine, a promising candidate for methamphetamine use disorder, has not been established in routine clinical practice. Objective:To determine the safety and effectiveness of mirtazapine as a pharmacotherapy for methamphetamine use disorder in routine clinical practice. Design, Setting, and Participants:This phase 3, parallel-group, double-blind, placebo-controlled randomized clinical trial was conducted between November 16, 2022, and May 1, 2025, at 6 outpatient alcohol and other drug clinics in Australia among adults with moderate to severe methamphetamine use disorder. Data analysis was conducted from May to September 2025. Intervention:Mirtazapine (30 mg daily for 12 weeks) or equivalent placebo. Main Outcomes and Measures:The primary end point was the change in days of methamphetamine use in the past 28 days from baseline to week 12. Secondary end points were depression, insomnia, HIV risk behavior, quality of life, and methamphetamine-negative oral fluid samples. Results:Of 344 participants randomized, 339 participants received the intervention (167 in the placebo group and 172 in the mirtazapine group). Mean (SD) age was 42.0 (8.6) years, 126 participants (37.2%) were female, and participants had used methamphetamine for a median (IQR) of 24 days (17-28) of the past 28 days at baseline. The mean reduction in days of methamphetamine use from baseline to week 12 was greater in the mirtazapine group (7.0 days of 28 days) than in the placebo group (4.8 days of 28 days; mean difference, 2.2 days; 95% CI, -4.2 to -0.2 days; P = .02). More participants in the mirtazapine group reported drowsiness (47% vs 33%) and weight gain (10% vs 3%). Forty participants (23%) discontinued mirtazapine due to adverse events compared to 25 participants (15%) in the placebo group. No significant effects of mirtazapine on secondary end points were found. Conclusions and Relevance:In this parallel-group randomized clinical trial, mirtazapine delivered in routine clinical practice reduced methamphetamine use in adults with methamphetamine use disorder. No unexpected safety concerns delivering mirtazapine in this setting were found; this finding has important clinical implications in the absence of any approved pharmacotherapies for methamphetamine use disorder. Trial Registration:anzctr.org.au Identifier: ACTRN12622000235707.

Background Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem disorder characterised by profound fatigue, post-exertional malaise, muscle pain and weakness. Although skeletal muscle abnormalities and mitochondrial alterations have been reported in people with ME/CFS, the underlying biological processes remain poorly understood, and no validated disease models, biomarkers or effective treatments are currently available. This study used patient-derived induced pluripotent stem cell (iPSC) myogenic progenitor (MP) cells to investigate intrinsic transcriptomic abnormalities in ME/CFS and identify potential drug repurposing candidates. Methods MP cells were generated from iPSCs derived from people with ME/CFS and healthy controls, and successfully characterised. Global mRNA sequencing was performed to compare transcriptomic profiles between ME/CFS and control MP cells (n = 6 ME/CFS; n = 7 controls). Differentially expressed genes and pathways were identified, followed by drug repurposing analysis using the Library of Integrated Network-based Cellular Signatures drug database (LINCS2) and supporting literature review. Results RNA sequencing identified seven differentially expressed genes at adjusted p < 0.05, including MIR205HG , FEZF1 , HLA-DMB , SLC1A2 , SYT13 , GALNT4 , and SLC2A14 . Pathway analysis identified 73 differentially expressed pathways, of which 96% were downregulated in ME/CFS MP cells. Downregulated pathways included those involved in cell cycle regulation, DNA replication, mismatch repair, immune response and muscle cytoskeleton regulation-related pathways. In contrast, upregulated pathways were associated with metabolic reprogramming, including increased reliance on branched-chain amino acids for energy production. These findings suggest intrinsic abnormalities in ME/CFS-derived MP cells, particularly involving metabolic regulation, mitochondrial function and muscle-related cellular processes. Based on the differentially expressed genes, LINCS2-based drug repurposing analysis and literature review identified 22 candidate drugs with potential relevance to ME/CFS. These included safe and widely available agents such as leflunomide, melatonin and midodrine, which target pathways related to antiviral defence, immunomodulation, neurotransmitter modulation, autonomic regulation and vascular function. Conclusions Patient-derived iPSC-MP cells provide a useful model for investigating intrinsic skeletal muscle-related abnormalities in ME/CFS. Transcriptomic profiling revealed altered pathways related to cell cycle regulation, immune function, cytoskeletal organisation and energy metabolism, supporting the involvement of mitochondrial and metabolic dysfunction in ME/CFS pathobiology. Drug repurposing analysis identified several clinically relevant candidates that may warrant further functional validation as potential therapeutic options for ME/CFS.

Posttraumatic stress disorder (PTSD) is a common and potentially debilitating psychiatric disorder. Current and emerging evidence-based treatments for PTSD have significant limitations. Silexan is an orally administered lavender oil preparation whose main constituents are the monoterpenoids linalool and linalyl acetate. It has a novel pharmacodynamic profile that includes inhibition of voltage-gated calcium channels and promotion of neuroplasticity. Silexan is effective in the treatment of Generalized Anxiety Disorder, subthreshold anxiety disorders and mild-to-moderate Major Depressive Disorder. It has an excellent safety and tolerability profile. Promising pilot data suggest that Silexan may be effective for PTSD. The Silexan in the Treatment Of Posttraumatic stress disorder (STOP) trial aims to investigate the effectiveness of adjunctive Silexan in PTSD. The STOP trial is a 12-week, parallel-arm, randomised, placebo-controlled, double-blind trial. Adults living in Australia who meet diagnostic criteria for PTSD according to the Mini-International Neuropsychiatric Interview-7 and have a score of ≥ 33 on the PTSD Checklist for DSM-5 will be eligible to participate. Participants will have the option of taking part in the trial remotely via videoconferencing software. They will receive either Silexan 160 mg or an inactive placebo daily for 12 weeks in addition to their usual prescribed medications. The primary outcome measure will be the change in total symptom severity score on the Clinician-Administered PTSD Scale for DSM-5 from baseline to week 12. Secondary outcome measures will include self-report measures of anxiety symptoms, depressive symptoms, somatic symptoms, sleep quality, subjective wellbeing, quality-of-life and problematic alcohol use. Additional secondary outcome measures will include objective measures of sleep, physical activity and physiology derived from data collected by actigraphy watches. The target sample size will be 278 participants. If Silexan is found to be effective for PTSD, it is likely to be an attractive treatment option for many patients given its favourable safety and tolerability profile. Silexan is already licensed for use in 14 countries, enabling a rapid translation into clinical care. The STOP trial is registered on the National Institutes of Health clinicaltrials.gov website (ID: NCT06412757, URL: https://clinicaltrials.gov/study/NCT06412757, date of registration: 9 May 2024).

BACKGROUND:Obesity, which is common in bipolar disorder (BD), is associated with smaller hippocampal volumes. We do not know the role of weight/weight gain in relation to longitudinal hippocampal changes among individuals with BD. METHODS:In collaboration with the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis)-BD Working Group, we obtained T1-weighted magnetic resonance imaging and clinical data from 233 participants with BD and 701 healthy control participants (HCs) scanned twice, 2.84 ± 1.63 years apart on average. We estimated subcortical volumes using FreeSurfer longitudinal image processing stream and used linear mixed models to assess the bidirectional relationship between baseline body mass index (BMI) or BMI change and hippocampal volume or volume change. While the hippocampus was our a priori region of interest, we repeated these analyses in other subcortical regions. RESULTS:Baseline BMI predicted future hippocampal atrophy, but baseline brain structure did not predict future weight changes. BMI increased significantly over time (F1,1085 = 15.98, p < .001). Individuals with lower baseline BMI experienced greater weight gain (F1,922 = 105.12, p < .001). Greater weight gain was associated with greater hippocampal atrophy over time (F1,899 = 16.33, p = .001), more so in participants with BD than HCs (F1,898 = 6.91, p = .009). Consequently, lower baseline BMI predicted greater future hippocampal volume loss (F1,904 = 14.77, p < .001). These associations were not observed in other subcortical regions. CONCLUSIONS:Our findings suggest that weight gain is a modifiable risk factor for hippocampal atrophy, especially in individuals with lower BMI and those with BD. Prevention of weight gain in general, but especially in people with BD, could provide neuroprotective benefits.

Loneliness among older adults represents a significant public health concern with far-reaching social and economic implications, currently emphasised by a large cohort of Baby Boomers making the transition into retirement and the proposed extensions to retirement age in many countries. This paper investigates the impact of retirement on loneliness using two decades of detailed longitudinal data from Australia that ask respondents uniquely about their feelings of loneliness in every wave (year). Employing a fixed-effects instrumental variables (FE-IV) strategy, we exploit the eligibility threshold for the Australian Age Pension as an exogenous determinant of retirement decisions. Our analysis reveals no statistically significant effects of retirement on loneliness, a result consistent across various demographic groups and individual circumstances. These findings suggest individuals mostly adapt to retirement successfully, and that retirement itself may not substantially alter older adults’ social connectedness. Policy efforts aimed at reducing loneliness might therefore consider factors beyond retirement transition, focusing instead on promoting sustained social engagement throughout later life.

BACKGROUND:Treatment expectancy is a key mechanism underlying placebo. While well-documented in psychopharmacology and psychotherapy, its role in lifestyle-based interventions for mental disorders is uncertain. Given the emerging role of lifestyle-based mental health care, a comprehensive evaluation of the role of treatment expectancy has not yet been explored, especially when compared to other more established therapies. The potential for genuine treatment efficacy to be masked by placebo response may bring into question the magnitude of effects of this treatment. METHODS:We sought to: 1) investigate the role of treatment expectancy as a moderator of depression treatment outcomes in a completed randomised controlled trial of psychotherapy versus lifestyle therapy (the CALM trial); and 2) provide guidance on measuring and reporting expectancy effects in future trials. CALM was a two-arm, parallel-group, non-inferiority randomised controlled trial, comparing lifestyle therapy (delivered by accredited dietitians and exercise physiologists) and psychotherapy (facilitated by psychologists). A total of 182 participants (91 per arm) experiencing psychological distress (equivalent to 'indicative depression') during the COVID-19 pandemic were randomised. We assessed associations of expectancy (measured prior to randomisation using the Credibility-Expectancy Questionnaire) with reductions in depressive symptoms (as measured by the PHQ-9). RESULTS:Expectancy scores did not differ between treatment groups at baseline (β = 1.14; 95%CI = -1.93, 4.22). Both arms reduced PHQ-9 between baseline and 8-weeks (lifestyle mean difference = -30.25%, SD = 58.23%; psychotherapy mean difference = -22.46%, SD = 66.87%). However, higher expectancy was associated with a greater reduction in depression only in the psychotherapy arm: for every 1-unit increase in expectancy score depressive symptoms reduced by an additional 3.21% for psychotherapy compared to lifestyle therapy (95%CI = -5.77, -0.65). CONCLUSIONS:In this study we showed that participants' expectations about treatment at enrolment were only associated with treatment response in psychotherapy. These findings highlight the need to account for modality-specific drivers of expectancy when evaluating all treatments for depression, and support the inclusion of expectancy in reporting guidelines for future trials. REGISTRATION:The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12621000387820; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=380897).

BACKGROUND:Physical function decline and depression are major challenges of the rapidly growing older population. This longitudinal study aimed to investigate the bidirectional longitudinal association between physical function and depressive symptoms, which are poorly understood in older adults. METHODS:We utilised data from the ASPirin in Reducing Events in the Elderly (ASPREE) clinical trial and extended follow-up cohort between 2010 and 2022. The presence of depressive symptoms was defined as a score of ≥ 8 on the Center for Epidemiologic Studies Depression 10-item scale. Physical function was assessed using gait speed for physical performance and handgrip strength for muscle strength. Gait speed and handgrip strength were categorised using the European Working Group on Sarcopenia in Older People (EWGSOP2) cut-off points. The bidirectional association between physical function and depressive symptoms was estimated using generalised estimating equations models. The robustness of the longitudinal bidirectional relationship was assessed using random-intercept cross-lagged panel models. RESULTS:Among 19 114 ASPREE participants, 15 854 (56% females) older adults (mean age 75 years) were included in the analysis. During a median follow-up of 8.4 years, participants with combined poor physical performance and weak muscle strength had 81% higher odds of developing depressive symptoms compared to those with good performance and strength (OR = 1.81, 95% CI: 1.55-2.11). Conversely, participants with depressive symptoms had 70% higher odds of reduced physical function (combined poor physical performance and weak muscle strength) compared to those with no depressive symptoms (OR = 1.70, 95% CI: 1.61-1.80). The random-intercept cross-lagged panel models verified the bidirectional longitudinal associations between physical function and depressive symptoms across the follow-up waves. CONCLUSIONS:Reduced physical function and depressive symptoms are associated bidirectionally over time of a similar magnitude. Understanding this reciprocal association is crucial for developing effective prevention and treatment strategies for physical and mental health conditions.

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.

Background:Programs to support mental health in workplaces, particularly those using digital methods, show promise for increasing appropriate use of services. However, it is unclear which factors influence the successful implementation of such programs. Methods:Implementation outcomes from a cluster randomised trial (cRCT) of a digital single-session intervention (Helipad program) for improving mental health help seeking in employees were explored using both qualitative interviews (n = 16) and quantitative data collected at post-test during the cRCT (N = 344). Linear regression analyses tested predictors of participation (uptake) by workplace, and predictors of participant views about the acceptability, appropriateness, and feasibility of both the Helipad program and the control (static psychoeducation only). Qualitative data were thematically analysed to summarise feedback and recommendations around implementing the program, based on the Consolidated Framework for Implementation Research. Results:The Helipad program performed better than the control program for participant implementation outcomes, with significantly superior acceptability, appropriateness, and feasibility. More intensive methods to encourage participation such as additional emails, meetings, and delivery via a learning management system were associated with significantly greater uptake. There were few differences in acceptability ratings between workplace types indicating that the program may be useful and acceptable in a broad range of settings. Qualitative data indicated that the Helipad program was easy-to-use and contained a broad range of information on workplace mental health. A challenge identified by participants was how to best engage people with less interest or low perceived need for mental health support. Recommendations for implementation included ensuring workplace leader investment, allowing time during work to complete the program and modelling positive attitudes and behaviours towards mental health and help seeking. Conclusions:Implementation of workplace mental health interventions can be enhanced by clear communication with workplace leaders about its benefits, and by facilitating engagement of employees with the program during work time. Partnerships with stakeholders such as insurance companies or industry bodies may improve reach.Trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12623000270617.

BACKGROUND:Most antidepressants do not independently treat impaired cognition associated with major depressive disorder (MDD). Elevated brain cortisol levels are associated with both MDD and cognitive impairment. Emestedastat is a brain-penetrant, intracellular cortisol synthesis inhibitor. AIMS:The XanaCIDD trial aimed to determine whether emestedastat 10 mg could improve both cognitive impairment and depression in a population with persistent MDD and cognitive impairment. METHOD:Participants had a diagnosis of MDD, with persistent depression (Hamilton Rating Scale for Depression-17 ≥17) and cognitive impairment (coding test ≤0.5 s.d. of normal). Randomised treatment (1:1) was continued for 6 weeks (week 6), with 4 weeks' blinded follow-up (week 10). The primary end-point was cognition (composite of attention/working memory) at week 6. Depression end-points included Montgomery-Åsberg Depression Rating Scale (MADRS) and Patient Global Impression of Severity (PGI-S). Analyses used a mixed model for repeated measures (cognitive impairment and MADRS one-sided tests, others two-sided) and Cohen's d effect size. No adjustments were made for multiple comparisons. RESULTS:A total of 165 participants were enrolled and treated: 134 (81%) were on background antidepressants, 62% were female, mean prior number of MDD episodes was 10 and mean coding z-score was -1.47. There was no benefit on the primary cognitive end-point at week 6 (p = 0.17 favouring placebo), with the cognitive composite improving markedly in both groups without correlation to depressive symptoms or baseline characteristics (R2 ≤ 0.02). The trend towards benefit on the prespecified secondary depression end-point, MADRS, began at week 6 and was maximal at week 10 (2.7 points, Cohen's d 0.43, p = 0.05). A trend towards potential emestedastat benefit in PGI-S scores was also maximal at week 10 (p = 0.12). Mild-moderate transaminase elevations were seen in 10% of emestedastat participants (≤2 times normal in 7 of 8 cases, 1 discontinuation) versus 1% of the placebo group. CONCLUSIONS:There was no benefit of emestedastat on the primary end-point of cognitive impairment and a large placebo effect, without correlation of cognitive impairment to depression changes or baseline characteristics. Trends towards potential antidepressant activity suggest that emestedastat may be a novel antidepressant worthy of further investigation.

Metabolic dysfunction–associated steatotic liver disease (MASLD) is a common, often overlooked liver condition. Its impact on quality-of-life in older adults is not well understood. We examined the association between MASLD and physical and mental quality of life in a well-characterized cohort of Australians aged 70 and older. MASLD was identified using Fatty Liver Index ≥ 60 and consensus lifestyle and cardiometabolic criteria and assessed at baseline and at 3 years. PCS and MCS scores were measured annually using the 12-Item Short Form Health Survey. Generalized estimating equations adjusted for key confounders were used to evaluate the association of baseline and time-updated MASLD with longitudinal HRQoL outcomes. Analysis of 8880 participants (median follow-up 5.5 years) showed that baseline MASLD was associated with lower, then declining PCS over follow-up compared with no MASLD (mean difference −1.3; 95