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Abstract Mental fitness is a construct that goes beyond a simple focus on subjective emotional wellbeing to encompass more broadly our ability to think, feel, and act to achieve what we want in our daily lives. The measurement and monitoring of multiple (often interacting) domains is crucial to gain a holistic and complete insight into an individual’s mental fitness. We aimed to demonstrate the capability of a new mobile app to characterise the mental fitness of a general population of Australians and to quantify the interrelationships among different domains of mental fitness. Cross-sectional data were collected from 4901 adults from the general population of Australians engaged in work or education who used a mobile app (Innowell) between September 2021 and November 2022. Individuals completed a baseline questionnaire comprised of 26 questions across seven domains of mental fitness (i.e., physical activity, sleep and circadian rhythms, nutrition, substance use, daily activities, social connection, psychological distress). Network analysis was applied at both a domain-level (e.g., 7 nodes representing each cluster of items) and an individual item-level (i.e., 26 nodes representing all questionnaire items). Only 612 people (12%) were functioning well across all domains. One quarter (n = 1204, 25%) had only one problem domain and most (n = 3085, 63%) had multiple problem domains. The two most problematic domains were physical activity (n = 2631, 54%) and social connection (n = 2151, 44%), followed closely by daily activity (n = 1914, 39%). At the domain-level, the strongest association emerged between psychological distress and daily activity (r = 0.301). Psychological distress was the most central node in the network (as measured by strength and expected influence), followed closely by daily activity, sleep and circadian rhythms and then social connection. The item-level network revealed that the nodes with the highest centrality in the network were: hopelessness, depression, functional impairment, effortfulness, subjective energy, worthlessness, and social connectedness. Social connection, sleep and circadian rhythms, and daily activities may be critical targets for intervention due to their widespread associations in the overall network. While psychological distress was not among the most common problems, its centrality may indicate its importance for indicated prevention and early intervention. We showcase the capability of a new mobile app to monitor mental fitness and identify the interrelationships among multiple domains, which may help people develop more personalised insights and approaches.

Abstract There has recently been an increase in ongoing patient-report routine outcome monitoring for individuals within clinical care, which has corresponded to increased longitudinal information about an individual. However, many models that are aimed at clinical practice have difficulty fully incorporating this information. This is in part due to the difficulty in dealing with the irregularly time-spaced observations that are common in clinical data. Consequently, we built individual-level continuous-time trajectory models of suicidal ideation for a clinical population (N = 585) with data collected via a digital platform. We demonstrate how such models predict an individual’s level and variability of future suicide ideation, with implications for the frequency that individuals may need to be observed. These individual-level predictions provide a more personalised understanding than other predictive methods and have implications for enhanced measurement-based care.

Introduction: Esketamine has been approved in Australia and New Zealand as a third-line antidepressant treatment for treatment resistant depression. This study describes changes in quality of life, depressive symptoms and productivity in participants treated with esketamine in real-world settings. Methods: Participants were recruited from an esketamine early access program and had not responded to two or more different antidepressants and not received neurostimulation for their current depressive episode. Participants received esketamine for 16 weeks or longer. Data collected included Assessment of Quality-of-Life scale (AQoL-8D), Hamilton Depression Rating Scale (HAM-D) and Work Productivity Activity Index (WPAI). Results: Participants (n = 105) had a mean age of 38.7 years (standard deviation (SD) = 14.6) and were predominantly female (59.0%). The mean duration of major depressive disorder was 7.2 years (SD = 4.2) and almost half of participants had been treated with 3–5 prior therapies. After 16-weeks on esketamine, participants showed improvement of greater than 10% across all dimensions of AQoL-8D, HAM-D scores decreased 8.0 points, and activity impairment decreased 20.4% as measured by WPAI. Limitations: This was a non-randomized and unblinded study and may have selection and reporting bias. The population was not necessarily representative of the broader Australian and New Zealand population. It is not possible to determine if the results will be sustained or changed if participants received treatment for longer. Conclusions: Esketamine early access program participants, who were a real-world cohort with extensive prior treatment, showed clinically significant improvements in quality of life, depression severity and productivity after 16-weeks on treatment.

Objective The Thrive by Five app promotes positive interactions between children and parents, extended family, and trusted community members that support optimal socio-emotional and cognitive development in the early years. This article aims to describe the protocol for a prospective mixed-methods multi-site study evaluating Thrive by Five using surveys, interviews, workshops, audio diaries from citizen ethnographers and app usage data. Methods The study activities and timelines differ by site, with an extensive longitudinal evaluation being conducted at two sites and a basic evaluation being conducted at five sites. The learnings from the more comprehensive evaluations inform the iterative research and development processes while also ensuring ongoing evaluation of usability, acceptability and effectiveness of the app and its content across varying contexts. The study evaluates: (1) the impact of the Thrive by Five content on caregiver knowledge, behaviours, attitudes and confidence; (2) how the content changes relationships at the familial, community and system level; (3) how cultural and contextual factors influence content engagement and effectiveness and (4) the processes that facilitate or disrupt the success of the implementation and dissemination. Results All in-country partners have been identified and data collection has been completed in Indonesia, Malaysia, Afghanistan, Kyrgyzstan, Uzbekistan, Namibia and Cameroon. Conclusions Very few digital health solutions have been trialled for usability and effectiveness in diverse cultural contexts. By combining quantitative, qualitative, process and ethnographic methodologies, this innovative study informs the iterative and ongoing optimisation of the cultural and contextual sensitivity of the Thrive by Five content and the processes supporting implementation and dissemination.

Background: In early 2020, we developed a dynamic model to support policy responses aimed at mitigating the adverse mental health effects of the COVID-19 pandemic in Australia. As the pandemic has progressed, it has become clear that our initial model forecasts overestimated the impacts of infection control measures (lockdowns, physical distancing, etc.) on suicide, intentional self-harm hospitalisation, and mental health-related emergency department (ED) presentation rates. Methods: Potential explanations for the divergence of our model predictions from observed outcomes were assessed by comparing simulation results for a set of progressively more refined models with data on the prevalence of moderate to very high psychological distress and numbers of suicides, intentional self-harm hospitalisations, and mental health-related ED presentations published after our modelling was released in July 2020. Results: Allowing per capita rates of spontaneous recovery and intentional self-harm to differ between people experiencing moderate to very high psychological distress prior to the pandemic and those developing comparable levels of psychological distress only as a consequence of infection control measures substantially improves the fit of our model to empirical estimates of the prevalence of psychological distress and leads to significantly lower predicted effects of COVID-19 on suicide, intentional self-harm hospitalisation, and mental health-related ED presentation rates. Conclusion: Accommodating the influence of prior mental health on the psychological effects of population-wide social and economic disruption is likely to be critical for accurately forecasting the mental health impacts of future public health crises as they inevitably arise.

Abstract Reward-seeking behavior drives adolescents toward risky decision-making. As compared to their older and younger peers, adolescents experience higher rates of anxiety and depressive disorders, leading to impaired decision-making with negative consequences. At two time points, separated by 6–8 weeks, we measured risky and ambiguous choices concurrently with levels of dysregulated emotion for youth aged 16–25 (N = 30, mean age 19.22 years, 19 males) attending a youth mental health clinic. The Kessler Psychological Distress Scale (10 items) (K10), the Quick Inventory of Depressive Symptomatology Adolescent (17 items) (QIDS-A17) specifically designed for youth, and the Somatic and Psychological Health Report (12 items) (SPHERE-12) questionnaires were used to evaluate participant’s self-reported anxiety and depression scores. Risk and ambiguity tolerance was calculated at the individual and group level. At baseline, 25 (83%) participants were rated as experiencing a mental health condition, and 15 (50%) rated high on all three psychological questionnaires combined, scoring “severely” depressed and “severely” anxious. At follow-up, 25 returning participants, 80% (N = 20) remained distressed, with 11 continuing to rate high on all psychological scores. In Session 1, participants had a mean of approximately 14 risky choices (SD = 4.6), and 11 ambiguous choices (SD = 7.6), whilst in Session 2, participants’ mean equated to approximately 13 ambiguous choices (SD = 8.5), but their risk increased to 15 choices (SD = 6.5). Applying a multiple regression analysis at the group level, the data suggests that participants were risk averse (α = 0.55, SE = 0.05), and preferred making ambiguous choices (β = 0.25, SE = 0.04). These results suggest that high trait-like anxiety in youth is associated with risk intolerance. These findings may have implications for screening young people with emerging mood disorders.

Abstract Background Factors influencing antidepressant treatment discontinuation are poorly understood. In the present study, we aimed to estimate the prevalence of antidepressant treatment discontinuation and identify demographic characteristics, psychiatric comorbidities, and specific side effects associated with treatment discontinuation. Methods We leveraged data from the Australian Genetics of Depression Study (AGDS; N = 20,941) to perform a retrospective cohort study on antidepressant treatment discontinuation. Participants were eligible if they were over 18 years of age, had taken antidepressants in the past 4 years, and provided informed consent. Results Among the ten antidepressants studied, the highest discontinuation rates were observed for Mirtazapine (57.3%) and Amitriptyline (51.6%). Discontinuation rates were comparable across sexes except for Mirtazapine, for which women were more likely to discontinue. The two most common side effects, reduced sexual function and weight gain, were not associated with increased odds of treatment discontinuation. Anxiety, agitation, suicidal thoughts, vomiting, and rashes were associated with higher odds for treatment discontinuation, as were lifetime diagnoses of PTSD, ADHD, and a higher neuroticism score. Educational attainment showed a negative (protective) association with discontinuation across medications. Conclusions Our study suggests that not all side effects contribute equally to discontinuation. Common side effects such as reduced sexual function and weight gain may not necessarily increase the risk of treatment discontinuation. Side effects linked to discontinuation can be divided into two groups, psychopathology related and allergy/intolerance.

Abstract 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.

Objectives: There is an ongoing necessity to match clinical interventions with the multidimensional needs of young people. A key step toward better service planning and the design of optimal models of care is to use multidimensional assessment to understand the clinical needs of those presenting to primary mental health care. Methods: 1284 people aged 12–25 years presenting to primary youth mental health services completed an online assessment at service entry. Latent class analysis was conducted for seven scales assessing anxiety, depression, psychosis, mania, functioning (indexed by Work and Social Adjustment Scale), and suicidality. Results: A three-class solution was identified as the optimal solution. Class 1 (n = 305, 23.75%), an early illness stage group, had low and mixed symptomatology with limited functional impairment, class 2 (n = 353, 27.49%) was made up of older persons with established depression and functional impairment, and class 3 (n = 626, 48.75%) had very high and complex needs, with functional impairment, suicidality, and at-risk mental states (psychosis or mania). Additional differentiating characteristics included psychological distress, circadian disturbances, social support, mental health history, eating disorder behaviours, and symptoms of post-traumatic stress disorder. Conclusions: A large proportion of help-seeking young people present with symptoms and functional impairment that may exceed the levels of care available from basic primary care or brief intervention services. These subgroups highlight the importance of multidimensional assessments to determine appropriate service pathways and care options.

Abstract Background Delayed initiation and early discontinuation of treatment due to limited availability and accessibility of services may often result in people with mild or moderate mental disorders developing more severe disorders, leading to an increase in demand for specialised care that would be expected to further restrict service availability and accessibility (due to increased waiting times, higher out-of-pocket costs, etc.). Methods We developed a simple system dynamics model of the interaction of specialised services capacity and disease progression to examine the impact of service availability and accessibility on the effectiveness and efficiency of mental health care systems. Results Model analysis indicates that, under certain conditions, increasing services capacity can precipitate an abrupt, step-like transition from a state of persistently high unmet need for specialised services to an alternative, stable state in which people presenting for care receive immediate and effective treatment. This qualitative shift in services system functioning results from a ‘virtuous cycle’ in which increasing treatment-dependent recovery among patients with mild to moderate disorders reduces the number of severely ill patients requiring intensive and/or prolonged treatment, effectively ‘releasing’ services capacity that can be used to further reduce the disease progression rate. We present an empirical case study of tertiary-level child and adolescent mental health services in the Australian state of South Australia demonstrating that the conditions under which such critical transitions can occur apply in real-world services systems. Conclusions Policy and planning decisions aimed at increasing specialised services capacity have the potential to dramatically increase the effectiveness and efficiency of mental health care systems, promoting long-term sustainability and resilience in the face of future threats to population mental health (e.g., economic crises, natural disasters, global pandemics).

Background Primary youth mental health services in Australia have increased access to care for young people, yet the longer-term outcomes and utilisation of other health services among these populations is unclear. Aims To describe the emergency department presentation patterns of a help-seeking youth mental health cohort. Method Data linkage was performed to extract Emergency Department Data Collection registry data (i.e. emergency department presentations, pattern of re-presentations) for a transdiagnostic cohort of 7024 youths (aged 12–30 years) who presented to mental health services. Outcome measures were pattern of presentations and reason for presentations (i.e. mental illness; suicidal behaviours and self-harm; alcohol and substance use; accident and injury; physical illness; and other). Results During the follow-up period, 5372 (76.5%) had at least one emergency department presentation. The presentation rate was lower for males (IRR = 0.87, 95% CI 0.86–0.89) and highest among those aged 18 to 24 (IRR = 1.117, 95% CI 1.086–1.148). Almost one-third (31.12%) had an emergency department presentation that was directly associated with mental illness or substance use, and the most common reasons for presentation were for physical illness and accident or injury. Index visits for mental illness or substance use were associated with a higher rate of re-presentation. Conclusions Most young people presenting to primary mental health services also utilised emergency services. The preventable and repeated nature of many presentations suggests that reducing the ongoing secondary risks of mental disorders (i.e. substance misuse, suicidality, physical illness) could substantially improve the mental and physical health outcomes of young people.

Abstract Background A reconceptualised global strategy is key as nations begin to shift from crisis management to medium- and long-term planning to rebuild and strengthen their economic, social and public health systems. Efforts towards measuring, modelling, and forecasting Mental Wealth could serve as the catalyst for this reconceptualization. The Mental Wealth approach builds systemic resilience through investments which promote collective cognitive and emotional wellbeing. This paper presents the theoretical foundations for Mental Wealth. It presents, for the first time, literature across the disciplines of health and social sciences, economics, business, and humanities to underpin the development of an operational metric of Mental Wealth. Discussion An approach which embeds social and psychological dimensions of prosperity, alongside the economic, is needed to inform the effective allocation of investments in the post-pandemic world. The authors advocate for a transdisciplinary framework of Mental Wealth to be applied in innovating population-level policy interventions to address the growing challenges brought on by COVID-19. Mental Wealth highlights the value generated by the deployment of collective mental assets and supporting social infrastructure. In order to inform this position, a review of the literature on the concepts underpinning Mental Wealth is presented, limitations of current measurement tools of mental and social resources are evaluated, and a framework for development of a Mental Wealth metric is proposed. Conclusion There are challenges in developing an operational Mental Wealth metric. The breadth of conceptual foundations to be considered is extensive, and there may be a lack of agreement on the appropriate tools for its measurement. While variability across current measurement approaches in social resources, wellbeing and mental assets contributes to the difficulty creating a holistic and generic metric, these variations are now clearer. The operationalisation of the Mental Wealth metric will require comprehensive mapping of the elements to be included against the data available.

Abstract Background Clinical staging proposes that youth-onset mental disorders develop progressively, and that active treatment of earlier stages should prevent progression to more severe disorders. This retrospective cohort study examined the longitudinal relationships between clinical stages and multiple clinical and functional outcomes within the first 12 months of care. Methods Demographic and clinical information of 2901 young people who accessed mental health care at age 12–25 years was collected at predetermined timepoints (baseline, 3 months, 6 months, 12 months). Initial clinical stage was used to define three fixed groups for analyses (stage 1a: ‘non-specific anxious or depressive symptoms’, 1b: ‘attenuated mood or psychotic syndromes’, 2+: ‘full-threshold mood or psychotic syndromes’). Logistic regression models, which controlled for age and follow-up time, were used to compare clinical and functional outcomes (role and social function, suicidal ideation, alcohol and substance misuse, physical health comorbidity, circadian disturbances) between staging groups within the initial 12 months of care. Results Of the entire cohort, 2093 young people aged 12–25 years were followed up at least once over the first 12 months of care, with 60.4% female and a baseline mean age of 18.16 years. Longitudinally, young people at stage 2+ were more likely to develop circadian disturbances (odds ratio [OR]=2.58; CI 1.60–4.17), compared with individuals at stage 1b. Additionally, stage 1b individuals were more likely to become disengaged from education/employment (OR=2.11, CI 1.36–3.28), develop suicidal ideations (OR=1.92; CI 1.30–2.84) and circadian disturbances (OR=1.94, CI 1.31–2.86), compared to stage 1a. By contrast, we found no relationship between clinical stage and the emergence of alcohol or substance misuse and physical comorbidity. Conclusions The differential rates of emergence of poor clinical and functional outcomes between early versus late clinical stages support the clinical staging model's assumptions about illness trajectories for mood and psychotic syndromes. The greater risk of progression to poor outcomes in those who present with more severe syndromes may be used to guide specific intervention packages.

Abstract 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.

Abstract Preliminary evidence indicates beneficial effects of omega-3 polyunsaturated fatty acids (PUFAs) in early psychosis. The present study investigates the molecular mechanism of omega-3 PUFA-associated therapeutic effects in clinical high-risk (CHR) participants. Plasma samples of 126 CHR psychosis participants at baseline and 6-months follow-up were included. Plasma protein levels were quantified using mass spectrometry and erythrocyte omega-3 PUFA levels were quantified using gas chromatography. We examined the relationship between change in polyunsaturated PUFAs (between baseline and 6-month follow-up) and follow-up plasma proteins. Using mediation analysis, we investigated whether plasma proteins mediated the relationship between change in omega-3 PUFAs and clinical outcomes. A 6-months change in omega-3 PUFAs was associated with 24 plasma proteins at follow-up. Pathway analysis revealed the complement and coagulation pathway as the main biological pathway to be associated with change in omega-3 PUFAs. Moreover, complement and coagulation pathway proteins significantly mediated the relationship between change in omega-3 PUFAs and clinical outcome at follow-up. The inflammatory protein complement C5 and protein S100A9 negatively mediated the relationship between change in omega-3 PUFAs and positive symptom severity, while C5 positively mediated the relationship between change in omega-3 and functional outcome. The relationship between change in omega-3 PUFAs and cognition was positively mediated through coagulation factor V and complement protein C1QB. Our findings provide evidence for a longitudinal association of omega-3 PUFAs with complement and coagulation protein changes in the blood. Further, the results suggest that an increase in omega-3 PUFAs decreases symptom severity and improves cognition in the CHR state through modulating effects of complement and coagulation proteins.

Background Understanding premature mortality risk from suicide and other causes in youth mental health cohorts is essential for delivering effective clinical interventions and secondary prevention strategies. Aims To establish premature mortality risk in young people accessing early intervention mental health services and identify predictors of mortality. Method State-wide data registers of emergency departments, hospital admissions and mortality were linked to the Brain and Mind Research Register, a longitudinal cohort of 7081 young people accessing early intervention care, between 2008 and 2020. Outcomes were mortality rates and age-standardised mortality ratios (SMR). Cox regression was used to identify predictors of all-cause mortality and deaths due to suicide or accident. Results There were 60 deaths (male 63.3%) during the study period, 25 (42%) due to suicide, 19 (32%) from accident or injury and eight (13.3%) where cause was under investigation. All-cause SMR was 2.0 (95% CI 1.6–2.6) but higher for males (5.3, 95% CI 3.8–7.0). The mortality rate from suicide and accidental deaths was 101.56 per 100 000 person-years. Poisoning, whether intentional or accidental, was the single greatest primary cause of death (26.7%). Prior emergency department presentation for poisoning (hazard ratio (HR) 4.40, 95% CI 2.13–9.09) and psychiatric admission (HR 4.01, 95% CI 1.81–8.88) were the strongest predictors of mortality. Conclusion Premature mortality in young people accessing early intervention mental health services is greatly increased relative to population. Prior health service use and method of self-harm are useful predictors of future mortality. Enhanced care pathways following emergency department presentations should not be limited to those reporting suicidal ideation or intent.

Abstract Background The right to the highest attainable standard of mental health remains a distant goal worldwide. The Report of the UN Special Rapporteur on the right of all people to enjoyment of the highest attainable standard of physical and mental health pleaded the urgent need for governments to act through appropriate laws and policies. We argue that Australia is in breach of international obligations, with inadequate access to mental health services, inconsistent mental health legislation across jurisdictions and ongoing structural (systematic) and individual discrimination. Discussion Inadequate access to mental health services is a worldwide phenomenon. Australia has committed to international law obligations under the Convention on the Rights of Persons with Disabilities (CRPD) to ‘promote, protect and ensure the full and equal enjoyment of all human rights and fundamental freedoms by all persons with disability, with respect to their inherent dignity’. This includes people with mental health impairment and this convention includes the right to ‘the highest attainable standard of mental health’. Under the Australian Constitution, ratification of this convention enables the national government to pass laws to implement the convention obligations, and such national laws would prevail over any inconsistent state (or territory) laws governing mental health service provision. Summary The authors argue that enabling positive rights through legislation and legally binding mental health service standards may facilitate enhanced accountability and enforcement of such rights. These steps may support critical key stakeholders to improve the standards of mental health service provision supported by the implementation of international obligations, thereby accelerating mental health system reform. Improved legislation would encourage better governance and the evolution of better services, making mental health care more accessible, without structural or individual discrimination, enabling all people to enjoy the highest attainable standard of health.

Abstract Background There is a significant push to change the trajectory of youth mental ill-health and suicide globally. Ensuring that young people have access to services that meet their individual needs and are easily accessible is a priority. Genuine stakeholder engagement in mental health system design is critical to ensure that system strengthening is likely to be successful within these complex environments. There is limited literature describing engagement processes undertaken by research teams in mental health program implementation and planning. This protocol describes the methods that will be used to engage local communities using systems science methods to mobilize knowledge and action to strengthen youth mental health services. Methods Using participatory action research principles, the research team will actively engage with local communities to ensure genuine user-led participatory systems modelling processes and enhance knowledge mobilisation within research sites. Ensuring that culturally diverse and Aboriginal and Torres Strait Islander community voices are included will support this process. A rigorous site selection process will be undertaken to ensure that the community is committed and has capacity to actively engage in the research activities. Stakeholder engagement commences from the site selection process with the aim to build trust between researchers and key stakeholders. The research team will establish a variety of engagement resources and make opportunities available to each site depending on their local context, needs and audiences they wish to target during the process. Discussion This protocol describes the inclusive community engagement and knowledge mobilization process for the Right care, first time, where you live research Program. This Program will use an iterative and adaptive approach that considers the social, economic, and political context of each community and attempts to maximise research engagement. A theoretical framework for applying systems approaches to knowledge mobilization that is flexible will enable the implementation of a participatory action research approach. This protocol commits to a rigorous and genuine stakeholder engagement process that can be applied in mental health research implementation.

Background: Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction. Methods: Genome-wide analysis of remission (nremit = 1852, nnonremit = 3299) and percentage improvement (n = 5218) was performed. Single nucleotide polymorphism–based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA. Results: Neither genome-wide association study identified genome-wide significant associations. Single nucleotide polymorphism–based heritability was significantly different from zero for remission (h2 = 0.132, SE = 0.056) but not for percentage improvement (h2 = −0.018, SE = 0.032). Better antidepressant response was negatively associated with genetic risk for schizophrenia and positively associated with genetic propensity for educational attainment. Leave-one-out validation of antidepressant response polygenic scores demonstrated significant evidence of out-of-sample prediction, though results varied in external cohorts. Gene-based analyses identified ETV4 and DHX8 as significantly associated with antidepressant response. Conclusions: This study demonstrates that antidepressant response is influenced by common genetic variation, has a genetic overlap schizophrenia and educational attainment, and provides a useful resource for future research. Larger sample sizes are required to attain the potential of genetics for understanding and predicting antidepressant response.

Abstract Aims The needs of young people attending mental healthcare can be complex and often span multiple domains (e.g., social, emotional and physical health factors). These factors often complicate treatment approaches and contribute to poorer outcomes in youth mental health. We aimed to identify how these factors interact over time by modelling the temporal dependencies between these transdiagnostic social, emotional and physical health factors among young people presenting for youth mental healthcare. Methods Dynamic Bayesian networks were used to examine the relationship between mental health factors across multiple domains (social and occupational function, self-harm and suicidality, alcohol and substance use, physical health and psychiatric syndromes) in a longitudinal cohort of 2663 young people accessing youth mental health services. Two networks were developed: (1) ‘initial network’, that shows the conditional dependencies between factors at first presentation, and a (2) ‘transition network’, how factors are dependent longitudinally. Results The ‘initial network’ identified that childhood disorders tend to precede adolescent depression which itself was associated with three distinct pathways or illness trajectories; (1) anxiety disorder; (2) bipolar disorder, manic-like experiences, circadian disturbances and psychosis-like experiences; (3) self-harm and suicidality to alcohol and substance use or functioning. The ‘transition network’ identified that over time social and occupational function had the largest effect on self-harm and suicidality, with direct effects on ideation (relative risk [RR], 1.79; CI, 1.59–1.99) and self-harm (RR, 1.32; CI, 1.22–1.41), and an indirect effect on attempts (RR, 2.10; CI, 1.69–2.50). Suicide ideation had a direct effect on future suicide attempts (RR, 4.37; CI, 3.28–5.43) and self-harm (RR, 2.78; CI, 2.55–3.01). Alcohol and substance use, physical health and psychiatric syndromes (e.g., depression and anxiety, at-risk mental states) were independent domains whereby all direct effects remained within each domain over time. Conclusions This study identified probable temporal dependencies between domains, which has causal interpretations, and therefore can provide insight into their differential role over the course of illness. This work identified social, emotional and physical health factors that may be important early intervention and prevention targets. Improving social and occupational function may be a critical target due to its impacts longitudinally on self-harm and suicidality. The conditional independence of alcohol and substance use supports the need for specific interventions to target these comorbidities.

Abstract Evaluating decision-making during youth is a complex area of research. Multiple factors influence the young person’s subjective decision-making at this stage of development. Sub-optimal decision-making can have lifelong consequences. Longer adolescence, life stressors, drugs and alcohol and adverse events impact the young person, making them vulnerable to emerging mood disorders, such as anxiety and depression. Behavioural economics with its cognitive and multidisciplinary approach examines decision-making in youth with emerging mood disorders, but few empirical studies exist outside of a laboratory setting. Of the few that apply a multidisciplinary approach, most focus on other mental disorders. This review qualitatively evaluates the decision science literature to firstly, investigate complex factors influencing decision-making between adolescence and young adulthood. Secondly, it investigates studies that have applied either a cognitive or multidisciplinary approach to evaluate how young people choose. With respect to the studies identified, this review found that as opposed to depression, clinical anxiety (trait) and its relationship to youth decision-making has not been well researched using the multidisciplinary approach. Studies that did apply this approach found that mood disordered young individuals overall performed worse than healthy controls. This review argues that applying the multidisciplinary approach to study subjective decision-making can provide an alternative measure to empirically evaluate early stages of psychopathology in a youth population. Investigating the critical time points where the decision process itself impacts affective states in individuals could further elucidate some of the challenges currently faced in decision-making studies.

Campos et al. study the genetic aetiology of antidepressant side effects. Using data from the Australian Genetics of Depression study, the authors show that polygenic risk scores for traits such as BMI, insomnia and headaches have a shared genetic basis with side effects to commonly used antidepressant drugs.

Background Cognitive impairments are well-established features of psychotic disorders and are present when individuals are at ultra-high risk for psychosis. However, few interventions target cognitive functioning in this population. Aims To investigate whether omega-3 polyunsaturated fatty acid (n−3 PUFA) supplementation improves cognitive functioning among individuals at ultra-high risk for psychosis. Method Data (N = 225) from an international, multi-site, randomised controlled trial (NEURAPRO) were analysed. Participants were given omega-3 supplementation (eicosapentaenoic acid and docosahexaenoic acid) or placebo over 6 months. Cognitive functioning was assessed with the Brief Assessment of Cognition in Schizophrenia (BACS). Mixed two-way analyses of variance were computed to compare the change in cognitive performance between omega-3 supplementation and placebo over 6 months. An additional biomarker analysis explored whether change in erythrocyte n−3 PUFA levels predicted change in cognitive performance. Results The placebo group showed a modest greater improvement over time than the omega-3 supplementation group for motor speed (ηp2 = 0.09) and BACS composite score (ηp2 = 0.21). After repeating the analyses without individuals who transitioned, motor speed was no longer significant (ηp2 = 0.02), but the composite score remained significant (ηp2 = 0.02). Change in erythrocyte n-3 PUFA levels did not predict change in cognitive performance over 6 months. Conclusions We found no evidence to support the use of omega-3 supplementation to improve cognitive functioning in ultra-high risk individuals. The biomarker analysis suggests that this finding is unlikely to be attributed to poor adherence or consumption of non-trial n−3 PUFAs.

Prospective cohort studies following individuals from acute infections have documented a prevalent post-infective fatigue state meeting diagnostic criteria for chronic fatigue syndrome (CFS) – that is, a post-infective fatigue syndrome (PIFS). The Dubbo Infection Outcomes Study (DIOS) was a prospective cohort following individuals from acute infection with Epstein-Barr virus (EBV), Ross River virus (RRV), or Q fever through to assessment of caseness for CFS designated by physician and psychiatrist assessments at 6 months. Previous studies in DIOS have revealed that functional genetic polymorphisms in both immunological (pro- and anti-inflammatory cytokines) and neurological (the purinergic receptor, P2X7) genes are associated with both the severity of the acute infection and subsequent prolonged illness. Principal components analysis was applied to self-report data from DIOS to describe the severity and course of both the overall illness and concurrent mood disturbance. Associations between demographics and acute infection characteristics, with prolonged illness course as well as the PIFS outcome were examined using multivariable statistics. Genetic haplotype-driven functional variations in the neuropeptide Y (NPY) gene previously shown to be associated with brain responses to stress, and to trait anxiety were also examined as predictors. The sample included 484 subjects (51% female, median age 32, IQR 19–44), of whom 90 (19%) met diagnostic criteria for CFS at 6 months. Participants with greater overall illness severity and concurrent mood disturbance in the acute illness had a more prolonged illness severity (HR = 0.39, 95% CI: 0.34–0.46, p < 0.001) and mood disturbance (HR = 0.36, 95% CI: 0.30–0.42, p < 0.001), respectively. Baseline illness severity and RRV infection were associated with delayed recovery. Female gender and mood disturbance in the acute illness were associated with prolonged mood disturbance. Logistic regression showed that the odds of an individual being diagnosed with PIFS increased with greater baseline illness severity (OR = 2.24, 95% CI: 1.71–2.94, p < 0.001). There was no association between the NPY haplotypes with overall illness severity or mood disturbance either during the acute illness phase or with prolonged illness (p > 0.05). Severe acute infective illnesses predicted prolonged illness, prolonged mood disturbance and PIFS. These factors may facilitate early intervention to manage both PIFS and mood disturbances.

The COVID-19 pandemic has exposed the deep links and fragility of economic, health and social systems. Discussions of reconstruction include renewed interest in moving beyond GDP and recognizing “human capital”, “brain capital”, “mental capital”, and “wellbeing” as assets fundamental to economic reimagining, productivity, and prosperity. This paper describes how the conceptualization of Mental Wealth provides an important framing for measuring and shaping social and economic renewal to underpin healthy, productive, resilient, and thriving communities. We propose a transdisciplinary application of systems modeling to forecast a nation's Mental Wealth and understand the extent to which policy-mediated changes in economic, social, and health sectors could enhance collective mental health and wellbeing, social cohesion, and national prosperity. Specifically, simulation will allow comparison of the projected impacts of a range of cross-sector strategies (education sector, mental health system, labor market, and macroeconomic reforms) on GDP and national Mental Wealth, and provide decision support capability for future investments and actions to foster Mental Wealth. Finally, this paper introduces the Mental Wealth Initiative that is harnessing complex systems science to examine the interrelationships between social, commercial, and structural determinants of mental health and wellbeing, and working to empirically challenge the notion that fostering universal social prosperity is at odds with economic and commercial interests.

Abstract Background The World Economic Forum has recently highlighted substantial problems in mental health service provision and called for the rapid deployment of smarter, digitally-enhanced health services as a means to facilitate effective care coordination and address issues of demand. In mental health, the biggest enabler of digital solutions is the implementation of an effective model of care that is facilitated by integrated health information technologies (HITs); the latter ensuring the solution is easily accessible, scalable and sustainable. The University of Sydney’s Brain and Mind Centre (BMC) has developed an innovative digital health solution – delivered through the Youth Mental Health and Technology Program – which incorporates two components: 1) a highly personalised and measurement-based (data-driven) model of youth mental health care; and 2) an industrial grade HIT registered on the Australian Register of Therapeutic Goods. This paper describes a research protocol to evaluate the impact of implementing the BMC’s digital health solution into youth mental health services (i.e. headspace - a highly accessible, youth-friendly integrated service that responds to the mental health, physical health, alcohol or other substance use, and vocational concerns of young people aged 12 to 25 years) within urban and regional areas of Australia. Methods The digital health solution will be implemented into participating headspace centres using a naturalistic research design. Quantitative and qualitative data will be collected from headspace health professionals, service managers and administrators, as well as from lead agency and local Primary Health Network (PHN) staff, via service audits, Implementation Officer logs, online surveys, and semi-structured interviews, at baseline and then three-monthly intervals over the course of 12 months. Discussion At the time of publication, six headspace centres had been recruited to this study and had commenced implementation and impact evaluation. The first results are expected to be submitted for publication in 2021. This study will focus on the impact of implementing a digital health solution at both a service and staff level, and will evaluate digital readiness of service and staff adoption; quality, usability and acceptability of the solution by staff; staff self-reported clinical competency; overall impact on headspace centres as well as their lead agencies and local PHNs; and social return on investment.

Abstract Improving our understanding of the causes of functional impairment in young people is a major global challenge. Here, we investigated the relationships between self-reported days out of role and the total quantity and different patterns of self-reported somatic, anxious-depressive, psychotic-like, and hypomanic symptoms in a community-based cohort of young adults. We examined self-ratings of 23 symptoms ranging across the four dimensions and days out of role in >1900 young adult twins and non-twin siblings participating in the “19Up” wave of the Brisbane Longitudinal Twin Study. Adjusted prevalence ratios (APR) and 95% confidence intervals (95% CI) quantified associations between impairment and different symptom patterns. Three individual symptoms showed significant associations with days out of role, with the largest association for impaired concentration. When impairment was assessed according to each symptom dimension, there was a clear stepwise relationship between the total number of somatic symptoms and the likelihood of impairment, while individuals reporting ≥4 anxious-depressive symptoms or five hypomanic symptoms had greater likelihood of reporting days out of role. Furthermore, there was a stepwise relationship between the total number of undifferentiated symptoms and the likelihood of reporting days out of role. There was some suggestion of differences in the magnitude and significance of associations when the cohort was stratified according to sex, but not for age or twin status. Our findings reinforce the development of early intervention mental health frameworks and, if confirmed, support the need to consider interventions for subthreshold and/or undifferentiated syndromes for reducing disability among young people.

Abstract For more than a decade, suicide rates in Australia have shown no improvement despite significant investment in reforms to support regionally driven initiatives. Further recommended reforms by the Productivity Commission call for Federal and State and Territory Government funding for mental health to be pooled and new Regional Commissioning Authorities established to take responsibility for efficient and effective allocation of ‘taxpayer money.’ This study explores the sufficiency of this recommendation in preventing ongoing policy resistance. A system dynamics model of pathways between psychological distress, the mental health care system, suicidal behaviour and their drivers was developed, tested, and validated for a large, geographically diverse region of New South Wales; the Hunter New England and Central Coast Primary Health Network (PHN). Multi-objective optimisation was used to explore potential discordance in the best-performing programs and initiatives (simulated from 2021 to 2031) across mental health outcomes between the two state-governed Local Health Districts (LHDs) and the federally governed PHN. Impacts on suicide deaths, mental health-related emergency department presentations, and service disengagement were explored. A combination of family psychoeducation, post-attempt aftercare, and safety planning, and social connectedness programs minimises the number of suicides across the PHN and in the Hunter New England LHD (13.5% reduction; 95% interval, 12.3–14.9%), and performs well in the Central Coast LHD (14.8% reduction, 13.5–16.3%), suggesting that aligned strategic decision making between the PHN and LHDs would deliver substantial impacts on suicide. Results also highlighted a marked trade-off between minimising suicide deaths versus minimising service disengagement. This is explained in part by the additional demand placed on services of intensive suicide prevention programs leading to increases in service disengagement as wait times for specialist community based mental health services and dissatisfaction with quality of care increases. Competing priorities between the PHN and LHDs (each seeking to optimise the different outcomes they are responsible for) can undermine the optimal impact of investments for suicide prevention. Systems modelling provides essential regional decision analysis infrastructure to facilitate coordinated federal and state investments for optimal impacts.

BackgroundMental illness costs the world economy over US2.5 Bn each year, including premature mortality, morbidity, and productivity losses. Multisector approaches are required to address the systemic drivers of mental health and ensure adequate service provision. There is an important role for economics to support priority setting, identify best value investments and inform optimal implementation. Mental health can be defined as a complex dynamic system where decision makers are challenged to prospectively manage the system over time. This protocol describes the approach to equip eight system dynamics (SD) models across Australia to support priority setting and guide portfolio investment decisions, tailored to local implementation context.MethodsAs part of a multidisciplinary team, three interlinked protocols are developed; (i) the participatory process to codesign the models with local stakeholders and identify interventions for implementation, (ii) the technical protocol to develop the SD models to simulate the dynamics of the local population, drivers of mental health, the service system and clinical outcomes, and (iii) the economic protocol to detail how the SD models will be equipped to undertake a suite of economic analysis, incorporating health and societal perspectives. Models will estimate the cost of mental illness, inclusive of service costs (health and other sectors, where necessary), quality-adjusted life years (QALYs) lost, productivity costs and carer costs. To assess the value of investing (disinvesting) in interventions, economic analysis will include return-on-investment, cost-utility, cost benefit, and budget impact to inform affordability. Economic metrics are expected to be dynamic, conditional upon changing population demographics, service system capacities and the mix of interventions when synergetic or antagonistic interactions. To support priority setting, a portfolio approach will identify best value combinations of interventions, relative to a defined budget(s). User friendly dashboards will guide decision makers to use the SD models to inform resource allocation and generate business cases for funding.DiscussionEquipping SD models to undertake economic analysis is intended to support local priority setting and help optimise implementation regarding the best value mix of investments, timing and scale. The objectives are to improve allocative efficiency, increase mental health and economic productivity.

Abstract Background People with neurodegenerative disorders show diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease. Results We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson’s disease (and none with Alzheimer’s disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights. Conclusions We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences.

Abstract Background There is a strong research imperative to investigate effective treatment options for adolescents and adults with autism spectrum disorder (ASD). Elevated social anxiety, difficulties with social functioning and poor mental health have all been identified as core treatment targets for this group. While theoretical models posit a strong bidirectionality between social anxiety and ASD social functioning deficits, few interventions have targeted both domains concurrently. Of the two group interventions previously conducted with adolescents and adults with ASD, significant results have only been observed in either social anxiety or social functioning, and have not generalised to changes in overall mood. The aim of this study was to evaluate the potential benefit, tolerability and acceptability of a group cognitive-behaviour therapy (CBT) intervention in young adults with ASD. Primary treatment outcomes were social anxiety symptoms and social functioning difficulties; secondary outcomes were self-reported mood and overall distress. Method Ten groups of participants completed an eight-week, modified group CBT intervention targeting both social anxiety and social functioning, that included social skills training, exposure tasks and behavioural experiment components. Seventy-eight adolescents and young adults with ASD, without intellectual impairment, aged between 16 and 38 (M = 22.77; SD = 5.31), were recruited from the community, Headspace centres and the Autism Clinic for Translational Research at the Brain and Mind Centre, University of Sydney. Outcomes (social anxiety, social functioning and mood) were measured pre- and post-intervention via self-report questionnaires (administered either online or through the return of hard-copy booklets), and participants were invited to provide anonymous feedback on the intervention (at the mid-point and end of the intervention). Results Participants demonstrated statistically significant improvements on all outcome measures in response to the intervention. Specifically, social anxiety symptoms decreased (p

Abstract Background Despite the widely acknowledged potential for health information technologies to improve the accessibility, quality and clinical safety of mental health care, implementation of such technologies in services is frequently unsuccessful due to varying consumer, health professional, and service-level factors. The objective of this co-design study was to use process mapping (i.e. service mapping) to illustrate the current consumer journey through primary mental health services, identify barriers to and facilitators of quality mental health care, and highlight potential points at which to integrate the technology-enabled solution to optimise the provision of care based on key service performance indicators. Methods Interactive, discussion-based workshops of up to six hours were conducted with representative stakeholders from each participating service, including health professionals, service managers and administrators from Open Arms – Veterans & Families Counselling Service (Sydney), a counselling service for veterans and their families, and five headspace centres in the North Coast Primary Health Network, primary youth mental health services. Service maps were drafted and refined in real time during the workshops. Through both group discussion and the use of post-it notes, participants worked together to evaluate performance indicators (e.g. safety) at each point in the consumer journey (e.g. intake) to indicate points of impact for the technology-enabled solution, reviewing and evaluating differing opinions in order to reach consensus. Results Participants (n=84 across participating services) created service maps illustrating the current consumer journey through the respective services and highlighting barriers to and facilitators of quality mental health care. By consensus, the technology-enabled solution as facilitated by the InnoWell Platform was noted to enable the early identification of risk, reduce or eliminate lengthy intake processes, enable routine outcome monitoring to revise treatment plans in relation to consumer response, and serve as a personal data record for consumers, driving person-centred, coordinated care. Conclusions Service mapping was shown to be an effective methodology to understand the consumer’s journey through a service and served to highlight how the co-designed technology-enabled solution can optimise service pathways to improve the accessibility, quality and clinical safety of care relative to key service performance indicators, facilitating the delivery of the right care.

Abstract It has been difficult to find robust brain structural correlates of the overall severity of major depressive disorder (MDD). We hypothesized that specific symptoms may better reveal correlates and investigated this for the severity of insomnia, both a key symptom and a modifiable major risk factor of MDD. Cortical thickness, surface area and subcortical volumes were assessed from T1-weighted brain magnetic resonance imaging (MRI) scans of 1053 MDD patients (age range 13-79 years) from 15 cohorts within the ENIGMA MDD Working Group. Insomnia severity was measured by summing the insomnia items of the Hamilton Depression Rating Scale (HDRS). Symptom specificity was evaluated with correlates of overall depression severity. Disease specificity was evaluated in two independent samples comprising 2108 healthy controls, and in 260 clinical controls with bipolar disorder. Results showed that MDD patients with more severe insomnia had a smaller cortical surface area, mostly driven by the right insula, left inferior frontal gyrus pars triangularis, left frontal pole, right superior parietal cortex, right medial orbitofrontal cortex, and right supramarginal gyrus. Associations were specific for insomnia severity, and were not found for overall depression severity. Associations were also specific to MDD; healthy controls and clinical controls showed differential insomnia severity association profiles. The findings indicate that MDD patients with more severe insomnia show smaller surfaces in several frontoparietal cortical areas. While explained variance remains small, symptom-specific associations could bring us closer to clues on underlying biological phenomena of MDD.

Abstract Background Subthreshold/attenuated syndromes are established precursors of full-threshold mood and psychotic disorders. Less is known about the individual symptoms that may precede the development of subthreshold syndromes and associated social/functional outcomes among emerging adults. Methods We modeled two dynamic Bayesian networks (DBN) to investigate associations among self-rated phenomenology and personal/lifestyle factors (role impairment, low social support, and alcohol and substance use) across the 19Up and 25Up waves of the Brisbane Longitudinal Twin Study. We examined whether symptoms and personal/lifestyle factors at 19Up were associated with (a) themselves or different items at 25Up, and (b) onset of a depression-like, hypo-manic-like, or psychotic-like subthreshold syndrome (STS) at 25Up. Results The first DBN identified 11 items that when endorsed at 19Up were more likely to be reendorsed at 25Up (e.g., hypersomnia, impaired concentration, impaired sleep quality) and seven items that when endorsed at 19Up were associated with different items being endorsed at 25Up (e.g., earlier fatigue and later role impairment; earlier anergia and later somatic pain). In the second DBN, no arcs met our a priori threshold for inclusion. In an exploratory model with no threshold, >20 items at 19Up were associated with progression to an STS at 25Up (with lower statistical confidence); the top five arcs were: feeling threatened by others and a later psychotic-like STS; increased activity and a later hypo-manic-like STS; and anergia, impaired sleep quality, and/or hypersomnia and a later depression-like STS. Conclusions These probabilistic models identify symptoms and personal/lifestyle factors that might prove useful targets for indicated preventative strategies.

Abstract Background While reducing the burden of mental and substance use disorders is a global challenge, it is played out locally. Mental disorders have early ages of onset, syndromal complexity and high individual variability in course and response to treatment. As most locally-delivered health systems do not account for this complexity in their design, implementation, scale or evaluation they often result in disappointing impacts. Discussion In this viewpoint, we contend that the absence of an appropriate predictive planning framework is one critical reason that countries fail to make substantial progress in mental health outcomes. Addressing this missing infrastructure is vital to guide and coordinate national and regional (local) investments, to ensure limited mental health resources are put to best use, and to strengthen health systems to achieve the mental health targets of the 2015 Sustainable Development Goals. Most broad national policies over-emphasize provision of single elements of care (e.g. medicines, individual psychological therapies) and assess their population-level impact through static, linear and program logic-based evaluation. More sophisticated decision analytic approaches that can account for complexity have long been successfully used in non-health sectors and are now emerging in mental health research and practice. We argue that utilization of advanced decision support tools such as systems modelling and simulation, is now required to bring a necessary discipline to new national and local investments in transforming mental health systems. Conclusion Systems modelling and simulation delivers an interactive decision analytic tool to test mental health reform and service planning scenarios in a safe environment before implementing them in the real world. The approach drives better decision-making and can inform the scale up of effective and contextually relevant strategies to reduce the burden of mental disorder and enhance the mental wealth of nations.

Abstract Background Depression is common in older people and is associated with underlying brain change increasing the risk of dementia. Sleep disturbance is frequently reported by those with lifetime depression, however whether circadian misalignment also exists is unclear. We aimed to examine circadian rhythms and sleep associations in older patients with and without lifetime depression. Methods Thirty-four older people meeting DSM-IV criteria for lifetime major depression (mean age = 63.9 years), and 30 healthy controls (mean age = 65.7 years) were recruited. Participants underwent 2-weeks of actigraphy followed by a 3-night protocol including dim light melatonin onset (DLMO) assessment and overnight polysomnography (PSG) for sleep architecture. DLMO and phase angle of entrainment were computed. Results Compared to controls, participants with depression had a significantly longer phase angle of entrainment (6.82 h ± 1.45 vs. 5.87 h ± 1.60, p = 0.02, Cohens-d = 0.62). A small to moderate yet non-significant difference in DLMO times, with earlier DLMO (34 ± 27 min) observed in depression (20:36 ± 1:48 vs. 21:10 ± 1:48, p = 0.22, Cohens-d = 0.32). Individuals with depression had longer sleep latency and latency to rapid eye movement sleep than controls (all p

Background: The prevalence of insomnia and hypersomnia in depressed individuals is substantially higher than that found in the general population. Unfortunately, these concurrent sleep problems can have profound effects on the disease course. Although the full biology of sleep remains to be elucidated, a recent genome-wide association (GWAS) of insomnia, and other sleep traits in over 1 million individuals was recently published and provides many promising hits for genetics of insomnia in a population-based sample.Methods: Using data from the largest available GWAS of insomnia and other sleep traits, we sought to test if sleep variable PRS scores derived from population-based studies predicted sleep variables in samples of depressed cases [Psychiatric Genomics Consortium - Major Depressive Disorder subjects (PGC MDD)]. A leave-one-out analysis was performed to determine the effects that each individual study had on our results.Results: The only significant finding was for insomnia, where p-value threshold, p = 0.05 was associated with insomnia in our PGC MDD sample (R2 = 1.75−3, p = 0.006).Conclusion: Our results reveal that

Background: Current global challenges are generating extensive social disruption and uncertainty that have the potential to undermine the mental health, wellbeing, and futures of young people. The scale and complexity of challenges call for engagement with systems science-based decision analytic tools that can capture the dynamics and interrelationships between physical, social, economic, and health systems, and support effective national and regional responses. At the outset of the pandemic mental health-related systems models were developed for the Australian context, however, the extent to which findings are generalisable across diverse regions remains unknown. This study aims to explore the context dependency of systems modelling insights.Methods: This study will employ a comparative case study design, applying participatory system dynamics modelling across eight diverse regions of Australia to answer three primary research questions: (i) Will current regional differences in key youth mental health outcomes be exacerbated in forward projections due to the social and economic impacts of COVID-19?; (ii) What combination of social policies and health system strengthening initiatives will deliver the greatest impacts within each region?; (iii) To what extent are optimal strategic responses consistent across the diverse regions? We provide a detailed technical blueprint as a potential springboard for more timely construction and deployment of systems models in international contexts to facilitate a broader examination of the question of generalisability and inform investments in the mental health and wellbeing of young people in the post COVID-19 recovery.Discussion: Computer simulation is known as the third pillar of science (after theory and experiment). Simulation allows researchers and decision makers to move beyond what can be manipulated within the scale, time, and ethical limits of the experimental approach. Such learning when achieved collectively, has the potential to enhance regional self-determination, help move beyond incremental adjustments to the status quo, and catalyze transformational change. This research seeks to advance efforts to establish regional decision support infrastructure and empower communities to effectively respond. In addition, this research seeks to move towards an understanding of the extent to which systems modelling insights may be relevant to the global mental health response by encouraging researchers to use, challenge, and advance the existing work for scientific and societal progress.

Background Regional planning may help to ensure that the specific measures implemented as part of a national suicide prevention strategy are aligned with the varying needs of local services and communities; however, there are concerns that the reliability of local programme development may be limited in practice. Aims The potential impacts of independent regional planning on the effectiveness of suicide prevention programmes in the Australian state of New South Wales were quantified using a system dynamics model of mental health services provision and suicidal behaviour in each of the state's ten Primary Health Network (PHN) catchments. Method Reductions in projected suicide mortality over the period 2021–2031 were calculated for scenarios in which combinations of four and five suicide prevention and mental health services interventions (selected from 13 possible interventions) are implemented separately in each PHN catchment. State-level impacts were estimated by summing reductions in projected suicide mortality for each intervention combination across PHN catchments. Results The most effective state-level combinations of four and five interventions prevent, respectively, 20.3% and 22.9% of 10 312 suicides projected under a business-as-usual scenario (i.e. no new policies or programmes, constant services capacity growth). Projected numbers of suicides under the optimal intervention scenarios for each PHN are up to 6% lower than corresponding numbers of suicides projected for the optimal state-level intervention combinations. Conclusions Regional suicide prevention planning may contribute to significant reductions in suicide mortality where local health authorities are provided with the necessary resources and tools to support reliable, evidence-based decision-making.

Most mental disorders emerge before the age of 25 years and, if left untreated, have the potential to lead to considerable lifetime burden of disease. Many services struggle to manage high demand and have difficulty matching individuals to timely interventions due to the heterogeneity of disorders. The technological implementation of clinical staging for youth mental health may assist the early detection and treatment of mental disorders. We describe the development of a theory-based automated protocol to facilitate the initial clinical staging process, its intended use, and strategies for protocol validation and refinement. The automated clinical staging protocol leverages the clinical validation and evidence base of the staging model to improve its standardization, scalability, and utility by deploying it using Health Information Technologies (HIT). Its use has the potential to enhance clinical decision-making and transform existing care pathways, but further validation and evaluation of the tool in real-world settings is needed.

Epigenetic mechanisms have been associated with genes involved in Posttraumatic stress disorder (PTSD). PTSD often co-occurs with other health conditions such as depression, cardiovascular disorder and respiratory illnesses. PTSD and migraine have previously been reported to be symptomatically positively correlated with each other, but little is known about the genes involved. The aim of this study was to understand the comorbidity between PTSD and migraine using a monozygotic twin disease discordant study design in six pairs of monozygotic twins discordant for PTSD and 15 pairs of monozygotic twins discordant for migraine. DNA from peripheral blood was run on Illumina EPIC arrays and analyzed. Multiple testing correction was performed using the Bonferroni method and 10% false discovery rate (FDR). We validated 11 candidate genes previously associated with PTSD including DOCK2, DICER1, and ADCYAP1. In the epigenome-wide scan, seven novel CpGs were significantly associated with PTSD within/near IL37, WNT3, ADNP2, HTT, SLFN11, and NQO2, with all CpGs except the IL37 CpG hypermethylated in PTSD. These results were significantly enriched for genes whose DNA methylation was previously associated with migraine (p-value = 0.036). At 10% FDR, 132 CpGs in 99 genes associated with PTSD were also associated with migraine in the migraine twin samples. Genes associated with PTSD were overrepresented in vascular smooth muscle, axon guidance and oxytocin signaling pathways, while genes associated with both PTSD and migraine were enriched for AMPK signaling and longevity regulating pathways. In conclusion, these results suggest that common genes and pathways are likely involved in PTSD and migraine, explaining at least in part the co-morbidity between the two disorders.

The bidirectional relationship between depression and chronic pain is well-recognized, but their clinical management remains challenging. Here we characterize the shared risk factors and outcomes for their comorbidity in the Australian Genetics of Depression cohort study (N = 13,839). Participants completed online questionnaires about chronic pain, psychiatric symptoms, comorbidities, treatment response and general health. Logistic regression models were used to examine the relationship between chronic pain and clinical and demographic factors. Cumulative linked logistic regressions assessed the effect of chronic pain on treatment response for 10 different antidepressants. Chronic pain was associated with an increased risk of depression (OR = 1.86 [1.37–2.54]), recent suicide attempt (OR = 1.88 [1.14–3.09]), higher use of tobacco (OR = 1.05 [1.02–1.09]) and misuse of painkillers (e.g., opioids; OR = 1.31 [1.06–1.62]). Participants with comorbid chronic pain and depression reported fewer functional benefits from antidepressant use and lower benefits from sertraline (OR = 0.75 [0.68–0.83]), escitalopram (OR = 0.75 [0.67–0.85]) and venlafaxine (OR = 0.78 [0.68–0.88]) when compared to participants without chronic pain. Furthermore, participants taking sertraline (OR = 0.45 [0.30–0.67]), escitalopram (OR = 0.45 [0.27–0.74]) and citalopram (OR = 0.32 [0.15–0.67]) specifically for chronic pain (among other indications) reported lower benefits compared to other participants taking these same medications but not for chronic pain. These findings reveal novel insights into the complex relationship between chronic pain and depression. Treatment response analyses indicate differential effectiveness between particular antidepressants and poorer functional outcomes for these comorbid conditions. Further examination is warranted in targeted interventional clinical trials, which also include neuroimaging genetics and pharmacogenomics protocols. This work will advance the delineation of disease risk indicators and novel aetiological pathways for therapeutic intervention in comorbid pain and depression as well as other psychiatric comorbidities.

Background: Light therapy yields inconsistent results in people with non-seasonal depression, which may in part be due to heterogeneous responses and the temporal dynamics of changes in sleep, daytime functioning and mood. This study assessed the timeline of the antidepressant effects of light therapy and sleep rescheduling relative to changes in sleep and daytime sleep-related factors, and sought to identify predictors of treatment response in young people with depression. Methods: Twenty-four individuals with depression (mean±SD: 21.2±1.0 years old;17% male) underwent adjunctive morning light therapy with a wake-up phase advance over four weeks. They completed the Beck Depression Inventory-II (BDI-II) and Leeds Sleep Evaluation Questionnaire. Results: On average, BDI-II scores decreased significantly after four weeks of intervention (F(2,32)=3.5, p=.044, ηp2=0.18). After two weeks, improvements in the ease of getting to sleep and sleep quality were significantly associated with BDI-II improvements (F(2,21)=6.3, p=.007). From two to four weeks, improvements in daytime sleep-related factors were significantly associated with BDI-II improvements (F(2,12)=6.0, p=.015). More sleep-related difficulties prior to the intervention tended to predict BDI-II improvements across the four weeks of light therapy (F(2,14)=3.7, p=.053). Limitations: Open-label design and small sample size. Conclusions: Sleep-enhancement emerging in the early phase of light therapy and sleep rescheduling may subsequently alleviate sleep-related daytime dysfunctions, which may in turn further improve mood. Controlled trials are required to confirm whether the antidepressant effects of light may be linked to the attenuation of sleep-related difficulties, and whether sleep difficulties may be useful predictors of the antidepressant response to light therapy.

Background: Whilst apps and e-tools have tremendous potential as low-cost, scalable mental health intervention and prevention tools, it is essential that consumers and health professionals have a means by which to evaluate their quality and safety. Objective: This study aimed to: 1) adapt the original Mobile App Rating Scale (MARS) in order to be appropriate for the evaluation of both mobile phone applications as well as e-tools; 2) test the reliability of the revised scale; and 3) develop a quality assurance protocol for identifying and rating new apps and e-tools to determine appropriateness for use in clinical practice. Methods: The MARS was adapted to include items specific to health-related apps and e-tools, such as the availability of resources, strategies for self-management, and quality information. The 41 apps and e-tools in the standard youth configuration of the InnoWell Platform, a digital tool designed to support or enhance mental health service delivery, were independently rated by two expert raters using the A-MARS. Cronbach's alpha was used to calculate the internal consistency and interclass correlation coefficients were used to calculate interrater reliability. Results: The A-MARS was shown to be a reliable scale with acceptable to excellent internal consistency and moderate to excellent interrater reliability across the subscales. Given the ever-increasing number of health information technologies on the market, a protocol to identify and rate new apps and e-tools for potential clinical use is presented. Conclusions: Whilst the A-MARS is a useful tool to guide health professionals as they explore available apps and e-tools for potential clinical use, the training, time, and skill required to use it effectively may be prohibitive. As such, health professionals and services are likely to benefit from including a digital navigator as part of the care team to assist in selecting and rating apps and e-tools, increasing the usability of the data, and technology troubleshooting. When selecting, evaluating and/or recommending apps and e-tools to consumers, it is important to consider: 1) the availability of explicit strategies to set, monitor and review SMART goals; 2) the accessibility of credible, user friendly information and resources from reputable sources; 3) evidence of effectiveness; and 4) interoperability with other health information technologies.

Background The schizophrenia polygenic risk score (SCZ-PRS) is an emerging tool in psychiatry. Aims We aimed to evaluate the utility of SCZ-PRS in a young, transdiagnostic, clinical cohort. Method SCZ-PRSs were calculated for young people who presented to early-intervention youth mental health clinics, including 158 patients of European ancestry, 113 of whom had longitudinal outcome data. We examined associations between SCZ-PRS and diagnosis, clinical stage and functioning at initial assessment, and new-onset psychotic disorder, clinical stage transition and functional course over time in contact with services. Results Compared with a control group, patients had elevated PRSs for schizophrenia, bipolar disorder and depression, but not for any non-psychiatric phenotype (for example cardiovascular disease). Higher SCZ-PRSs were elevated in participants with psychotic, bipolar, depressive, anxiety and other disorders. At initial assessment, overall SCZ-PRSs were associated with psychotic disorder (odds ratio (OR) per s.d. increase in SCZ-PRS was 1.68, 95% CI 1.08–2.59, P = 0.020), but not assignment as clinical stage 2+ (i.e. discrete, persistent or recurrent disorder) (OR = 0.90, 95% CI 0.64–1.26, P = 0.53) or functioning (R = 0.03, P = 0.76). Longitudinally, overall SCZ-PRSs were not significantly associated with new-onset psychotic disorder (OR = 0.84, 95% CI 0.34–2.03, P = 0.69), clinical stage transition (OR = 1.02, 95% CI 0.70–1.48, P = 0.92) or persistent functional impairment (OR = 0.84, 95% CI 0.52–1.38, P = 0.50). Conclusions In this preliminary study, SCZ-PRSs were associated with psychotic disorder at initial assessment in a young, transdiagnostic, clinical cohort accessing early-intervention services. Larger clinical studies are needed to further evaluate the clinical utility of SCZ-PRSs, especially among individuals with high SCZ-PRS burden.

BackgroundSubjective cognitive difficulties are common in mental illness and have a negative impact on role functioning. Little is understood about subjective cognition and the longitudinal relationship with depression and anxiety symptoms in young people.AimsTo examine the relationship between changes in levels of depression and anxiety and changes in subjective cognitive functioning over 3 months in help-seeking youth.MethodThis was a cohort study of 656 youth aged 12–25 years attending Australian headspace primary mental health services. Subjective changes in cognitive functioning (rated as better, same, worse) reported after 3 months of treatment was assessed using the Neuropsychological Symptom Self-Report. Multivariate multinomial logistic regression analysis was conducted to evaluate the impact of baseline levels of and changes in depression (nine-item Patient Health Questionnaire; PHQ9) and anxiety symptoms (seven-item Generalised Anxiety Disorder scale; GAD7) on changes in subjective cognitive function at follow-up while controlling for covariates.ResultsWith a one-point reduction in PHQ9 at follow-up, there was an estimated 11–18% increase in ratings of better subjective cognitive functioning at follow-up, relative to stable cognitive functioning. A one-point increase in PHQ9 from baseline to follow-up was associated with 7–14% increase in ratings of worse subjective cognitive functioning over 3 months, relative to stable cognitive functioning. A similar attenuated pattern of findings was observed for the GAD7.ConclusionsA clear association exists between subjective cognitive functioning outcomes and changes in self-reported severity of affective symptoms in young people over the first 3 months of treatment. Understanding the timing and mechanisms of these associations is needed to tailor treatment.