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Major depression is one of the leading causes of premature death and disability. Although available drugs are effective, they also have substantial limitations. Recent advances in our understanding of the fundamental links between chronobiology and major mood disorders, as well as the development of new drugs that target the circadian system, have led to a renewed focus on this area. In this review, we summarise the associations between disrupted chronobiology and major depression and outline new antidepressant treatment strategies that target the circadian system. In particular, we highlight agomelatine, a melatonin-receptor agonist and selective serotonergic receptor subtype (ie, 5-HT 2C) antagonist that has chronobiotic, antidepressant, and anxiolytic effects. In the short-term, agomelatine has similar antidepressant efficacy to venlafaxine, fluoxetine, and sertraline and, in the longer term, fewer patients on agomelatine relapse (23·9%) than do those receiving placebo (50·0%). Patients with depression treated with agomelatine report improved sleep quality and reduced waking after sleep onset. As agomelatine does not raise serotonin levels, it has less potential for the common gastrointestinal, sexual, or metabolic side-effects that characterise many other antidepressant compounds.

Autonomic nervous system (ANS) dysfunction is a putative underlying mechanism for increased cardiovascular disease risk in individuals with psychiatric disorders. Previous studies suggest that this risk may be related to psychotropic medication use. In the present study we systematically reviewed and analyzed published studies of heart rate variability (HRV), measuring ANS output, to determine the effect of psychiatric illness and medication use. We searched for studies comparing HRV in physically healthy adults with a diagnosed psychiatric disorder to controls and comparing HRV pre- and post-treatment with a psychotropic medication. In total, 140 case–control (mood, anxiety, psychosis, dependent disorders, k = 151) and 30 treatment (antidepressants, antipsychotics; k = 43) studies were included. We found that HRV was reduced in all patient groups compared to controls (Hedges g = −0.583) with a large effect for psychotic disorders (Hedges g = −0.948). Effect sizes remained highly significant for medication-free patients compared to controls across all disorders. Smaller and significant reductions in HRV were observed for specific antidepressants and antipsychotics. Study quality significantly moderated effect sizes in case–control analyses, underscoring the importance of assessing methodological quality when interpreting HRV findings. Combined findings confirm substantial reductions in HRV across psychiatric disorders, and these effects remained significant even in medication-free individuals. Reductions in HRV may therefore represent a significant mechanism contributing to elevated cardiovascular risk in individuals with psychiatric disorders. The negative impact of specific medications on HRV suggest increased risk for cardiovascular disease in these groups, highlighting a need for treatment providers to consider modifiable cardiovascular risk factors to attenuate this risk.

As the popularity of e-therapies grows, so too has the body of literature supporting their effectiveness. However, these interventions are often plagued by high attrition rates and varying levels of user adherence. Understanding the role of adherence may be crucial to understanding how program usage influences the effectiveness of e-therapy interventions. The aim of this study was to systematically review the e-therapy literature to (1) describe the methods used to assess adherence and (2) evaluate the association of adherence with outcome of these interventions. A systematic review of e-therapy interventions was conducted across disease states and behavioral targets. Data were collected on adherence measures, outcomes, and analyses exploring the relationship between adherence measures and outcomes. Of 69 studies that reported an adherence measure, only 33 (48%) examined the relationship between adherence and outcomes. The number of logins was the most commonly reported measure of adherence, followed by the number of modules completed. The heterogeneity of adherence and outcome measures limited analysis. However, logins appeared to be the measure of adherence most consistently related to outcomes in physical health interventions, while module completion was found to be most related to outcomes in psychological health interventions. There is large variation in the reporting of adherence and the association of adherence with outcomes. A lack of agreement about how best to measure adherence is likely to contribute to the variation in findings. Physical and psychological outcomes seem influenced by different types of adherence. A composite measure encompassing time online, activity completion, and active engagements with the intervention may be the best measure of adherence. Further research is required to establish a consensus for measuring adherence and to understand the role of adherence in influencing outcomes.

Emerging evidence suggests that positive impacts can be generated when digital health interventions are designed to be responsive to the cultural and socioeconomic context of their intended audiences. This narrative review aims to synthesize the literature about the cultural adaptation of digital health interventions. It examines how concepts of culture and context feature in design and development processes, including the methods, models, and content of these interventions, with the aim of helping researchers to make informed decisions about how to approach cultural adaptation in digital health. Literature searches for this narrative review were conducted across 4 databases. Following full-text article screening by 2 authors, 16 studies of interventions predominantly focused on the self-management of health were selected based on their detailed focus on the process of cultural adaptation. Key considerations for cultural adaptation were identified and synthesized through a qualitative narrative approach, enabling an integrative and in-depth understanding of cultural adaptation. The literature demonstrates varying approaches and levels of cultural adaptation across stages of intervention development, involving considerations such as the research ethos orienting researchers, the methodologies and models used, and the resultant content adaptations. In relation to the latter, culturally appropriate and accessible user interface design and translation can be seen as particularly important in shaping the level of adaptation. Optimizing cultural adaptation involves linking culture with other contextual factors such as economic conditions and social systems to ensure accessibility and the sustained use of digital health interventions. Culturally humble approaches that use the involvement of a broad range of participants, experts, and other stakeholders are demonstrated to spark vital insights for content development, implementation, and evaluation.

The expression of suicidal ideation is considered to be an important warning sign for suicide. However, the predictive properties of suicidal ideation as a test of later suicide are unclear.AimsTo assess the strength of the association between suicidal ideation and later suicide measured by odds ratio (OR), sensitivity, specificity and positive predictive value (PPV). We located English-language studies indexed in PubMed that reported the expression or non-expression of suicidal ideation among people who later died by suicide or did not. A random effects meta-analysis was used to assess the pooled OR, sensitivity, specificity and PPV of suicidal ideation for later suicide among groups of people from psychiatric and non-psychiatric settings. There was a moderately strong but highly heterogeneous association between suicidal ideation and later suicide (n = 71, OR = 3.41, 95% CI 2.59-4.49, 95% prediction interval 0.42-28.1, I2 = 89.4, Q-value = 661, d.f.(Q) = 70, P ≤0.001). Studies conducted in primary care and other non-psychiatric settings had similar pooled odds to studies of current and former psychiatric patients (OR = 3.86 v. OR = 3.23, P = 0.7). The pooled sensitivity of suicidal ideation for later suicide was 41% (95% CI 35-48) and the pooled specificity was 86% (95% CI 76-92), with high between-study heterogeneity. Studies of suicidal ideation expressed by current and former psychiatric patients had a significantly higher pooled sensitivity (46% v. 22%) and lower pooled specificity (81% v. 96%) than studies conducted in non-psychiatric settings. The PPV among non-psychiatric cohorts (0.3%, 95% CI 0.1%-0.5%) was significantly lower (Q-value = 35.6, P < 0.001) than among psychiatric samples (3.9%, 95% CI 2.2-6.6). Estimates of the extent of the association between suicidal ideation and later suicide are limited by unexplained between-study heterogeneity. The utility of suicidal ideation as a test for later suicide is limited by a modest sensitivity and low PPV.Declaration interestM.M.L. and C.J.R. have provided expert evidence in civil, criminal and coronial matters. I.B.H. has been a Commissioner in Australia's National Mental Health Commission since 2012. He is the Co-Director, Health and Policy at the Brain and Mind Centre (BMC) University of Sydney. The BMC operates an early-intervention youth services at Camperdown under contract to Headspace. I.B.H. has previously led community-based and pharmaceutical industry-supported (Wyeth, Eli Lily, Servier, Pfizer, AstraZeneca) projects focused on the identification and better management of anxiety and depression. He is a Board Member of Psychosis Australia Trust and a member of Veterans Mental Health Clinical Reference group. He was a member of the Medical Advisory Panel for Medibank Private until October 2017. He is the Chief Scientific Advisor to, and an equity shareholder in, InnoWell. InnoWell has been formed by the University of Sydney and PricewaterhouseCoopers to administer the $30 M Australian Government Funded Project Synergy. Project Synergy is a 3-year programme for the transformation of mental health services through the use of innovative technologies.

Preventive interventions that are effective in reducing the incidence of mental disorders in adolescence and early adulthood may impact substantially on lifetime economic, educational, and health outcomes; however, relatively few studies have examined the capacity of alternative approaches to preventing youth mental disorders (specifically, universal, selective, and indicated prevention) to reduce disorder incidence at a population level. Using a dynamic model of the onset of non-specific, relatively mild symptoms and progression to more severe disease, we show that: (1) indicated preventive interventions, targeting adolescents and young adults experiencing subthreshold symptoms, may often be more effective in reducing mental disorder prevalence than universal interventions delivered to the general population (contrary to the widely accepted view that a ‘high risk’ prevention strategy, focussing on those individuals with the greatest risk of developing a disorder, will generally be less effective than a whole-population strategy); and (2) the ability of selective preventive interventions (targeting vulnerable, asymptomatic youth) to alter the prevalence of mental disorders is severely restricted by an inverse relationship between the prevalence of significant risk factors for mental illness and the relative risk of developing symptoms.

Oxytocin (OT) plays a key regulatory role in human social behaviour. While prior studies have examined the effects of OT on observable social behaviours, studies have seldom examined the effects of OT on psychophysiological markers such as heart rate variability (HRV), which provides an index of individual's motivation for social behaviour. Furthermore, no studies have examined the impact of OT on HRV under resting conditions, which provides an index of maximal capacity for social engagement. To examine the effects of OT on HRV measures in healthy male participants while at rest. OT was hypothesised to increase HRV, compared to placebo, and that the effects would be greatest for a non-linear measure of HRV (the detrended fluctuation scaling exponent). Twenty-one male participants were recruited for this study. Participants were non-smokers, not on any medications and reported no history of psychiatric illness, neurological disorder, or any other serious medical condition (e.g. diabetes, cardiovascular disease). The study employed a randomised, placebo-controlled, within-subject, crossover, experimental design. HRV was calculated from electrocardiography under a standardized, 10-minute, resting state condition. As hypothesised, OT increased HRV and these effects were largest using the detrended fluctuation scaling exponent, a non-linear measure. These changes were observed in the absence of any change in state mood, as measured by the profile of mood states. Importantly, participants were unable to correctly guess which treatment they had been assigned at either of the two assessments. Together with the broader literature on OT and HRV, findings suggest that acute administration of OT may facilitate a fundamental psychophysiological feature of social behaviour, increasing capacity for social engagement. Findings also suggest that HRV changes may provide a novel biomarker of response to OT nasal spray that can be incorporated into research on response to treatment.

Background Multiple studies indicate that the prevalence of mental disorders in high-income countries has remained stable or increased despite substantial increases in the provision of care, leading some authors to question the effectiveness of increasing access to current treatments as a means of improving population mental health. Methods We developed a system dynamics model of mental disorder incidence and treatment-dependent recovery to assess two potential explanations for the apparent failure of increasing treatment provision to reduce mental disorder prevalence: 1) an increase in the individual-level risk of disorder onset; and 2) declining effectiveness of care resulting from insufficient services capacity growth. Bayesian Markov Chain Monte Carlo (MCMC) methods were used to fit the model to data on the prevalence of high to very high psychological distress in Australia for the period 2008–2019. Results Estimates of yearly rates of increase in the per capita incidence of high to very high psychological distress and the proportion of patients recovering when treated indicate that the individual-level risk of developing high to very high levels of distress increased between 2008 and 2019 (posterior probability > 0.999) but provide no evidence for declining treatment effectiveness. Simulation analyses suggest that the prevalence of high to very high psychological distress would have decreased from 14.4% in 2008 to 13.6% in 2019 if per capita incidence had not increased over this period (prevalence difference 0.0079, 95% credible interval 0.0015–0.0176). Conclusions Our analyses indicate that a modest but significant effect of increasing access to mental health care in Australia between 2008 and 2019 was obscured by a concurrent increase in the incidence of high to very high psychological distress.

Polyvagal theory emphasizes that autonomic nervous system functioning plays a key role in social behavior and emotion. The theory predicts that psychiatric disorders of social dysfunction are associated with reduced heart rate variability, an index of autonomic control, as well as social inhibition and avoidance. The purpose of this study was to examine whether heart rate variability was reduced in treatment-seeking patients diagnosed with social anxiety disorder, a disorder characterized by social fear and avoidance. Social anxiety patients (n = 53) were recruited prior to receiving psychological therapy. Healthy volunteers were recruited through the University of Sydney and the general community and were matched by gender and age (n = 53). Heart rate variability was assessed during a five-minute recording at rest, with participants completing a range of self-report clinical symptom measures. Compared to controls, participants with social anxiety exhibited significant reductions across a number of heart rate variability measures. Reductions in heart rate variability were observed in females with social anxiety, compared to female controls, and in patients taking psychotropic medication compared to non-medicated patients. Finally, within the clinical group, we observed significant associations between reduced heart rate variability and increased social interaction anxiety, psychological distress, and harmful alcohol use. The results of this study confirm that social anxiety disorder is associated with reduced heart rate variability. Resting state heart rate variability may therefore be considered a marker for social approach-related motivation and capacity for social engagement. Additionally, heart rate variability may provide a useful biomarker to explain underlying difficulties with social approach, impaired stress regulation, and behavioral inhibition, especially in disorders associated with significant impairments in these domains.

A priority for health services is to reduce self-harm in young people. Predicting self-harm is challenging due to their rarity and complexity, however this does not preclude the utility of prediction models to improve decision-making regarding a service response in terms of more detailed assessments and/or intervention. The aim of this study was to predict self-harm within six-months after initial presentation. The study included 1962 young people (12-30 years) presenting to youth mental health services in Australia. Six machine learning algorithms were trained and tested with ten repeats of ten-fold cross-validation. The net benefit of these models were evaluated using decision curve analysis. Out of 1962 young people, 320 (16%) engaged in self-harm in the six months after first assessment and 1642 (84%) did not. The top 25% of young people as ranked by mean predicted probability accounted for 51.6% - 56.2% of all who engaged in self-harm. By the top 50%, this increased to 82.1%-84.4%. Models demonstrated fair overall prediction (AUROCs; 0.744-0.755) and calibration which indicates that predicted probabilities were close to the true probabilities (brier scores; 0.185-0.196). The net benefit of these models were positive and superior to the 'treat everyone' strategy. The strongest predictors were (in ranked order); a history of self-harm, age, social and occupational functioning, sex, bipolar disorder, psychosis-like experiences, treatment with antipsychotics, and a history of suicide ideation. Prediction models for self-harm may have utility to identify a large sub population who would benefit from further assessment and targeted (low intensity) interventions. Such models could enhance health service approaches to identify and reduce self-harm, a considerable source of distress, morbidity, ongoing health care utilisation and mortality.