Patterns of stressful life events and polygenic scores for five mental disorders and neuroticism among adults with depression.

The dominant ('general') version of the diathesis-stress theory of depression views stressors and genetic vulnerability as independent risks. In the Australian Genetics of Depression Study (N = 14,146; 75% female), we tested whether polygenic scores (PGS) for major depression, bipolar disorder, schizophrenia, anxiety, ADHD, and neuroticism were associated with reported exposure to 32 childhood, past-year, lifetime, and accumulated stressful life events (SLEs). In false discovery rate-corrected models, the clearest PGS-SLE relationships were for the ADHD- and depression-PGSs, and to a lesser extent, the anxiety- and schizophrenia-PGSs. We describe the associations for childhood and accumulated SLEs, and the 2-3 strongest past-year/lifetime SLE associations. Higher ADHD-PGS was associated with all childhood SLEs (emotional abuse, emotional neglect, physical neglect; ORs = 1.09-1.14; p's < 1.3 × 10-5), more accumulated SLEs, and reported exposure to sudden violent death (OR = 1.23; p = 3.6 × 10-5), legal troubles (OR = 1.15; p = 0.003), and sudden accidental death (OR = 1.14; p = 0.006). Higher depression-PGS was associated with all childhood SLEs (ORs = 1.07-1.12; p's < 0.013), more accumulated SLEs, and severe human suffering (OR = 1.17; p = 0.003), assault with a weapon (OR = 1.12; p = 0.003), and living in unpleasant surroundings (OR = 1.11; p = 0.001). Higher anxiety-PGS was associated with childhood emotional abuse (OR = 1.08; p = 1.6 × 10-4), more accumulated SLEs, and serious accident (OR = 1.23; p = 0.004), physical assault (OR = 1.08; p = 2.2 × 10-4), and transportation accident (OR = 1.07; p = 0.001). Higher schizophrenia-PGS was associated with all childhood SLEs (ORs = 1.12-1.19; p's < 9.3-8), more accumulated SLEs, and severe human suffering (OR = 1.16; p = 0.003). Higher neuroticism-PGS was associated with living in unpleasant surroundings (OR = 1.09; p = 0.007) and major financial troubles (OR = 1.06; p = 0.014). A reversed pattern was seen for the bipolar-PGS, with lower odds of reported physical assault (OR = 0.95; p = 0.014), major financial troubles (OR = 0.93; p = 0.004), and living in unpleasant surroundings (OR = 0.92; p = 0.007). Genetic risk for several mental disorders influences reported exposure to SLEs among adults with moderately severe, recurrent depression. Our findings emphasise that stressors and diatheses are inter-dependent and challenge diagnosis and subtyping (e.g., reactive/endogenous) based on life events.

Markers of positive affect and brain state synchrony discriminate melancholic from non-melancholic depression using naturalistic stimuli.

Melancholia has been proposed as a qualitatively distinct depressive subtype associated with a characteristic symptom profile (psychomotor retardation, profound anhedonia) and a better response to biological therapies. Existing work has suggested that individuals with melancholia are blunted in their display of positive emotions and differ in their neural response to emotionally evocative stimuli. Here, we unify these brain and behavioural findings amongst a carefully phenotyped group of seventy depressed participants, drawn from an established Australian database (the Australian Genetics of Depression Study) and further enriched for melancholia (high ratings of psychomotor retardation and anhedonia). Melancholic (n = 30) or non-melancholic status (n = 40) was defined using a semi-structured interview (the Sydney Melancholia Prototype Index). Complex facial expressions were captured whilst participants watched a movie clip of a comedian and classified using a machine learning algorithm. Subsequently, the dynamics of sequential changes in brain activity were modelled during the viewing of an emotionally evocative movie in the MRI scanner. We found a quantitative reduction in positive facial expressivity amongst participants with melancholia, combined with differences in the synchronous expression of brain states during positive epochs of the movie. In non-melancholic depression, the display of positive affect was inversely related to the activity of cerebellar regions implicated in the processing of affect. However, this relationship was reduced in those with a melancholic phenotype. Our multimodal findings show differences in evaluative and motoric domains between melancholic and non-melancholic depression through engagement in ecologically valid tasks that evoke positive emotion. These findings provide new markers to stratify depression and an opportunity to support the development of targeted interventions.

Mapping gray and white matter volume abnormalities in early-onset psychosis: an ENIGMA multicenter voxel-based morphometry study.

INTRODUCTION: Regional gray matter (GM) alterations have been reported in early-onset psychosis (EOP, onset before age 18), but previous studies have yielded conflicting results, likely due to small sample sizes and the different brain regions examined. In this study, we conducted a whole brain voxel-based morphometry (VBM) analysis in a large sample of individuals with EOP, using the newly developed ENIGMA-VBM tool. METHODS: 15 independent cohorts from the ENIGMA-EOP working group participated in the study. The overall sample comprised T1-weighted MRI data from 482 individuals with EOP and 469 healthy controls. Each site performed the VBM analysis locally using the standardized ENIGMA-VBM tool. Statistical parametric T-maps were generated from each cohort and meta-analyzed to reveal voxel-wise differences between EOP and healthy controls as well as the individual-based association between GM volume and age of onset, chlorpromazine (CPZ) equivalent dose, and other clinical variables. RESULTS: Compared with healthy controls, individuals with EOP showed widespread lower GM volume encompassing most of the cortex, with the most marked effect in the left median cingulate (Hedges' g = 0.55, p = 0.001 corrected), as well as small clusters of lower white matter (WM), whereas no regional GM or WM volumes were higher in EOP. Lower GM volume in the cerebellum, thalamus and left inferior parietal gyrus was associated with older age of onset. Deficits in GM in the left inferior frontal gyrus, right insula, right precentral gyrus and right superior frontal gyrus were also associated with higher CPZ equivalent doses. CONCLUSION: EOP is associated with widespread reductions in cortical GM volume, while WM is affected to a smaller extent. GM volume alterations are associated with age of onset and CPZ equivalent dose but these effects are small compared to case-control differences. Mapping anatomical abnormalities in EOP may lead to a better understanding of the role of psychosis in brain development during childhood and adolescence.

Chronotype and subjective sleep quality predict white matter integrity in young people with emerging mental disorders.

Protecting brain health is a goal of early intervention. We explored whether sleep quality or chronotype could predict white matter (WM) integrity in emerging mental disorders. Young people (N = 364) accessing early-intervention clinics underwent assessments for chronotype, subjective sleep quality, and diffusion tensor imaging. Using machine learning, we examined whether chronotype or sleep quality (alongside diagnostic and demographic factors) could predict four measures of WM integrity: fractional anisotropy (FA), and radial, axial, and mean diffusivities (RD, AD and MD). We prioritised tracts that showed a univariate association with sleep quality or chronotype and considered predictors identified by ≥80% of machine learning (ML) models as 'important'. The most important predictors of WM integrity were demographics (age, sex and education) and diagnosis (depressive and bipolar disorders). Subjective sleep quality only predicted FA in the perihippocampal cingulum tract, whereas chronotype had limited predictive importance for WM integrity. To further examine links with mood disorders, we conducted a subgroup analysis. In youth with depressive and bipolar disorders, chronotype emerged as an important (often top-ranking) feature, predicting FA in the cingulum (cingulate gyrus), AD in the anterior corona radiata and genu of the corpus callosum, and RD in the corona radiata, anterior corona radiata, and genu of corpus callosum. Subjective quality was not important in this subgroup analysis. In summary, chronotype predicted altered WM integrity in the corona radiata and corpus callosum, whereas subjective sleep quality had a less significant role, suggesting that circadian factors may play a more prominent role in WM integrity in emerging mood disorders.

Brain-age prediction: Systematic evaluation of site effects, and sample age range and size.

Structural neuroimaging data have been used to compute an estimate of the biological age of the brain (brain-age) which has been associated with other biologically and behaviorally meaningful measures of brain development and aging. The ongoing research interest in brain-age has highlighted the need for robust and publicly available brain-age models pre-trained on data from large samples of healthy individuals. To address this need we have previously released a developmental brain-age model. Here we expand this work to develop, empirically validate, and disseminate a pre-trained brain-age model to cover most of the human lifespan. To achieve this, we selected the best-performing model after systematically examining the impact of seven site harmonization strategies, age range, and sample size on brain-age prediction in a discovery sample of brain morphometric measures from 35,683 healthy individuals (age range: 5-90 years; 53.59% female). The pre-trained models were tested for cross-dataset generalizability in an independent sample comprising 2101 healthy individuals (age range: 8-80 years; 55.35% female) and for longitudinal consistency in a further sample comprising 377 healthy individuals (age range: 9-25 years; 49.87% female). This empirical examination yielded the following findings: (1) the accuracy of age prediction from morphometry data was higher when no site harmonization was applied; (2) dividing the discovery sample into two age-bins (5-40 and 40-90 years) provided a better balance between model accuracy and explained age variance than other alternatives; (3) model accuracy for brain-age prediction plateaued at a sample size exceeding 1600 participants. These findings have been incorporated into CentileBrain (https://centilebrain.org/#/brainAGE2), an open-science, web-based platform for individualized neuroimaging metrics.

The influence of economic policies on social environments and mental health.

Despite increased advocacy and investments in mental health systems globally, there has been limited progress in reducing mental disorder prevalence. In this paper, we argue that meaningful advancements in population mental health necessitate addressing the fundamental sources of shared distress. Using a systems perspective, economic structures and policies are identified as the potential cause of causes of mental ill-health. Neoliberal ideologies, prioritizing economic optimization and continuous growth, contribute to the promotion of individualism, job insecurity, increasing demands on workers, parental stress, social disconnection and a broad range of manifestations well-recognized to erode mental health. We emphasize the need for mental health researchers and advocates to increasingly engage with the economic policy discourse to draw attention to mental health and well-being implications. We call for a shift towards a well-being economy to better align commercial interests with collective well-being and social prosperity. The involvement of individuals with lived mental ill-health experiences, practitioners and researchers is needed to mobilize communities for change and influence economic policies to safeguard well-being. Additionally, we call for the establishment of national mental wealth observatories to inform coordinated health, social and economic policies and realize the transition to a more sustainable well-being economy that offers promise for progress on population mental health outcomes.

Malgré une meilleure sensibilisation et des investissements accrus dans les systèmes de santé mentale à travers le monde, les progrès en matière de réduction du degré de prévalence des troubles mentaux demeurent très limités. Dans le présent document, nous estimons que, pour réaliser des avancées au niveau de la santé mentale des populations, il est impératif de s'attaquer aux sources de cette détresse collective. En adoptant une perspective systémique, force est de constater que les politiques et structures économiques constituent les causes potentielles d'une mauvaise santé mentale. Les idéologies néolibérales, qui privilégient l'optimisation économique et la croissance ininterrompue, contribuent à promouvoir l'individualisme, l'insécurité professionnelle, la pression pesant sur les travailleurs, le stress parental, l'isolement social et un large éventail de facteurs associés à une dégradation de la santé mentale. Nous insistons sur la nécessité de faire appel à des chercheurs et défenseurs actifs dans ce domaine, afin de jouer un rôle dans la politique économique en attirant l'attention sur les implications pour le bien-être et la santé mentale. Nous plaidons pour une transition vers une économie du bien-être visant à rapprocher les intérêts commerciaux de la prospérité sociale et collective. L'intervention de personnes ayant été confrontées à des troubles mentaux, de praticiens et de chercheurs est nécessaire pour mobiliser les communautés en faveur d'un changement et influencer les politiques économiques pour préserver le bien-être. Par ailleurs, nous militons pour la création d'observatoires nationaux de la santé mentale qui serviront à orienter des politiques économiques, sociales et sanitaires coordonnées, mais aussi à favoriser l'évolution vers une économie du bien-être plus durable, laissant entrevoir une amélioration de la santé mentale au sein de la population.

A pesar del aumento de la promoción y las inversiones en sistemas de salud mental en todo el mundo, los avances en la reducción de la prevalencia de los trastornos mentales han sido limitados. En este documento, sostenemos que para lograr avances significativos en la salud mental de la población es necesario abordar las fuentes fundamentales de la angustia compartida. Mediante una perspectiva sistémica, las estructuras y políticas económicas se identifican como la posible causa de los problemas de salud mental. Las ideologías neoliberales, que priorizan la optimización económica y el crecimiento continuo, contribuyen al fomento del individualismo, la inseguridad laboral, el aumento de las exigencias a los trabajadores, el estrés parental, la desconexión social y una gran variedad de manifestaciones bien reconocidas que perjudican la salud mental. Insistimos en la necesidad de que los investigadores y los defensores de la salud mental se impliquen cada vez más en el discurso de la política económica para atraer la atención sobre las implicaciones para la salud mental y el bienestar. Pedimos un cambio hacia una economía del bienestar para alinear mejor los intereses comerciales con el bienestar colectivo y la prosperidad social. Para movilizar a las comunidades en favor del cambio e influir en las políticas económicas con el fin de salvaguardar el bienestar, es necesaria la participación de personas que han padecido enfermedades mentales, profesionales e investigadores. Además, pedimos la creación de observatorios nacionales de bienestar mental que sirvan de base a las políticas sanitarias, sociales y económicas coordinadas y permitan la transición a una economía del bienestar más sostenible, que ofrezca perspectivas de progreso en los resultados de salud mental de la población.

Genome-wide meta-analysis of ascertainment and symptom structures of major depression in case-enriched and community cohorts.

BACKGROUND: Diagnostic criteria for major depressive disorder allow for heterogeneous symptom profiles but genetic analysis of major depressive symptoms has the potential to identify clinical and etiological subtypes. There are several challenges to integrating symptom data from genetically informative cohorts, such as sample size differences between clinical and community cohorts and various patterns of missing data. METHODS: We conducted genome-wide association studies of major depressive symptoms in three cohorts that were enriched for participants with a diagnosis of depression (Psychiatric Genomics Consortium, Australian Genetics of Depression Study, Generation Scotland) and three community cohorts who were not recruited on the basis of diagnosis (Avon Longitudinal Study of Parents and Children, Estonian Biobank, and UK Biobank). We fit a series of confirmatory factor models with factors that accounted for how symptom data was sampled and then compared alternative models with different symptom factors. RESULTS: The best fitting model had a distinct factor for Appetite/Weight symptoms and an additional measurement factor that accounted for the skip-structure in community cohorts (use of Depression and Anhedonia as gating symptoms). CONCLUSION: The results show the importance of assessing the directionality of symptoms (such as hypersomnia versus insomnia) and of accounting for study and measurement design when meta-analyzing genetic association data.

The effect of oxytocin nasal spray on social interaction in young children with autism: a randomized clinical trial.

Early supports to enhance social development in children with autism are widely promoted. While oxytocin has a crucial role in mammalian social development, its potential role as a medication to enhance social development in humans remains unclear. We investigated the efficacy, tolerability, and safety of intranasal oxytocin in young children with autism using a double-blind, randomized, placebo-controlled, clinical trial, following a placebo lead-in phase. A total of 87 children (aged between 3 and 12 years) with autism received 16 International Units (IU) of oxytocin (n = 45) or placebo (n = 42) nasal spray, morning and night (32 IU per day) for twelve weeks, following a 3-week placebo lead-in phase. Overall, there was no effect of oxytocin treatment over time on the caregiver-rated Social Responsiveness Scale (SRS-2) (p = 0.686). However, a significant interaction with age (p = 0.028) showed that for younger children, aged 3-5 years, there was some indication of a treatment effect. Younger children who received oxytocin showed improvement on caregiver-rated social responsiveness ( SRS-2). There was no other evidence of benefit in the sample as a whole, or in the younger age group, on the clinician-rated Clinical Global Improvement Scale (CGI-S), or any secondary measure. Importantly, placebo effects in the lead-in phase were evident and there was support for washout of the placebo response in the randomised phase. Oxytocin was well tolerated, with more adverse side effects reported in the placebo group. This study suggests the need for further clinical trials to test the benefits of oxytocin treatment in younger populations with autism.Trial registration www.anzctr.org.au (ACTRN12617000441314).

Towards a youth mental health paradigm: a perspective and roadmap.

Most mental disorders have a typical onset between 12 and 25 years of age, highlighting the importance of this period for the pathogenesis, diagnosis, and treatment of mental ill-health. This perspective addresses interactions between risk and protective factors and brain development as key pillars accounting for the emergence of psychopathology in youth. Moreover, we propose that novel approaches towards early diagnosis and interventions are required that reflect the evolution of emerging psychopathology, the importance of novel service models, and knowledge exchange between science and practitioners. Taken together, we propose a transformative early intervention paradigm for research and clinical care that could significantly enhance mental health in young people and initiate a shift towards the prevention of severe mental disorders.

Social and joint attention during shared book reading in young autistic children: a potential marker for social development.

BACKGROUND: Atypical patterns of social engagement and joint attention behaviors are diagnostic criteria for people with autism spectrum disorder. Experimental tasks using eye-tracking methodologies have, however, shown inconsistent results. The development of tasks with greater ecological validity and relevance for developmentally appropriate social milestones has been identified as important for the field. METHODS: We developed a novel, dynamic eye-tracking task emulating a shared book reading (SBR) scenario. Four SBR videos of an adult reader engaging with the viewer while reading a children's picture book and including sequenced bids for joint attention were developed. Participants included 90 children (N = 56 autistic children, N = 34 neurotypical children; aged 3-12). Social attention was also measured in a live free play task between participants and an experimenter. RESULTS: Compared to neurotypical children, autistic children displayed reduced attention to socially salient stimuli including the reader's face and picture book across SBR videos and during joint attention bids specifically. In contrast, they showed increased attention to nonsalient background stimuli compared to their neurotypical peers. These attention patterns in autistic children were associated with reduced verbal and nonverbal cognitive skills and increased symptoms associated with autism. Interestingly, positive correlations in the frequency of eye gaze between SBR and free play suggested a potential predictive value for social attention in live social interactions. CONCLUSIONS: Findings highlight the utility of SBR eye-tracking tasks in understanding underlying divergences in social engagement and joint attention between autistic and neurotypical children. This commonly practiced early childhood activity may provide insights into the relationship between social engagement and learning to reveal how such attentional patterns might influence broader developmental and educational outcomes.

Reducing mental health emergency visits: population-level strategies from participatory modelling.

BACKGROUND: Emergency departments (EDs) are often the front door for urgent mental health care, especially when demand exceeds capacity. Long waits in EDs exert strain on hospital resources and worsen distress for individuals experiencing a mental health crisis. We used as a test case the Australian Capital Territory (ACT), with a population surge of over 27% across 2011-2021 and a lagging increase in mental health care capacity, to evaluate population-based approaches to reduce mental health-related ED presentations. METHODS: We developed a system dynamics model for the ACT region using a participatory approach involving local stakeholders, including health planners, health providers and young people with lived experience of mental health disorders. Outcomes were projected over 2023-2032 for youth (aged 15-24) and for the general population. RESULTS: Improving the overall mental health care system through strategies such as doubling the annual capacity growth rate of mental health services or leveraging digital technologies for triage and care coordination is projected to decrease youth mental health-related ED visits by 4.3% and 4.8% respectively. Implementation of mobile crisis response teams (consisting of a mental health nurse accompanying police or ambulance officers) is projected to reduce youth mental health-related ED visits by 10.2% by de-escalating some emergency situations and directly transferring selected individuals to community mental health centres. Other effective interventions include limiting re-presentations to ED by screening for suicide risk and following up with calls post-discharge (6.4% reduction), and limiting presentations of frequent users of ED by providing psychosocial education to families of people with schizophrenia (5.1% reduction). Finally, combining these five approaches is projected to reduce youth mental health-related ED presentations by 26.6% by the end of 2032. CONCLUSIONS: Policies to decrease youth mental health-related ED presentations should not be limited to increasing mental health care capacity, but also include structural reforms.

Youth Perspectives on 'Highly Personalised and Measurement-Based Care': Qualitative Co-Design of Education Materials.

OBJECTIVES: Despite high levels of mental ill-health amongst young people (aged 15-30), this group demonstrates low help-seeking and high drop-out from mental health services (MHS). Whilst shared decision-making can assist people in receiving appropriate and effective health care, young people frequently report that they do not feel involved in treatment decisions. The current study focused on co-design of a clinical education and participant information programme for the Brain and Mind Centre Youth Model of Care. This model, which articulates a youth-focused form of highly personalised and measurement-based care, is designed to promote shared decision-making between young people and clinical service providers. METHODS: We conducted workshops with 24 young people (16-31; MAge = 21.5) who had accessed mental health services. Participants were asked what advice they would give to young people entering services, before giving advice on existing materials. Workshops were conducted and transcripts were coded using thematic analysis by two lived experience researchers and a clinical researcher. RESULTS: Young people found it empowering to be educated on transdiagnostic models of mental illness, namely clinical staging, which gives them a better understanding of why certain treatments may be inappropriate and ineffective, and thus reduce self-blame. Similarly, young people had limited knowledge of links between mental health and other life domains and found it helpful to be educated on multidisciplinary treatment options. Measurement-based care was seen as an important method of improving shared decision-making between young people and health professionals; however, to facilitate shared decision-making, young people also wanted better information on their rights in care and more support to share their expertise in their own needs, values and treatment preferences. CONCLUSIONS: These findings will inform the delivery of the further development and implementation of a youth-specific clinical education and participant information programme for the BMC Youth Model. PATIENT OR PUBLIC CONTRIBUTION: Workshops were facilitated by researchers with lived expertise in mental ill-health (A.H. and/or C.G.) and a clinical researcher (who has expertise as an academic and a clinical psychologist). A.H. and C.G. were also involved in conceptualisation, analysis, interpretation, review and editing of this paper.

Teachers as first responders: classroom experiences and mental health training needs of Australian schoolteachers.

BACKGROUND: Schoolteachers are often the first to respond when a student presents with a mental health issue in the classroom. This places a burden on schools that impacts school staff, healthcare workers and teachers. More broadly, it places a responsibility on the education system to address students' mental health. This study examines Australian teachers' classroom experiences and the training areas identified by teachers as necessary to manage these issues. METHOD: Interviews were undertaken with 18 in-service teachers between 2020 and 2021 from Catholic, Independent and Public schools. Data were gathered via multiple interviews and analysed using thematic content analysis. RESULTS: The major mental health issues identified by teachers related to mental disorders, depression, anxiety, and a complex range of negative emotional states. Teachers requested training in child and adolescent mental health, counselling skills, early detection and intervention, and training skills to manage the complex relationship with parents and external health and community personnel. Teachers also reported the need to access mental health resources, support and training, which were differentially accessed along socioeconomic status and postcodes. CONCLUSION: The data show that teachers are often placed as first responders when a student has a mental health issue but feel inadequately trained to manage these issues in the classroom. We identified mental health issues presenting in Australian classrooms and documented critical features of mental-health training asked for by teachers in order to address those issues. Given the increasing demands on teachers to address the mental health of children and adolescents, we argue that an urgent review of mental health training for teachers is needed.

Cultural and Contextual Adaptation of Digital Health Interventions: Narrative Review.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Rest-activity rhythms and tract specific white matter lesions in older adults at risk for cognitive decline.

White matter lesions (WMLs) are common in older adults and represent an important predictor of negative long-term outcomes. Rest-activity rhythm disturbance is also common, however, few studies have investigated associations between these factors. We employed a novel AI-based automatic WML segmentation tool and diffusion-weighted tractography to investigate associations between tract specific WML volumes and non-parametric actigraphy measures in older adults at risk for cognitive decline. The primary non-parametric measures of interest were inter-daily stability (IS), intra-daily variability and relative amplitude, with the anterior thalamic radiation (ATR), superior longitudinal fasciculus (SLF) and inferior longitudinal fasciculus (ILF) selected as tracts of interest. One hundred and eight participants at risk for cognitive decline (classified as experiencing subjective or objective cognitive decline) were included (mean age = 68.85 years, SD = 8.91). Of the primary non-parametric measures of interest, results showed that lower IS was associated with a greater likelihood of higher WML burden in the ATR (OR = 1.82, 95% CI [1.12,3.15]). Analysis of secondary non-parametric measures revealed later onset of the least active period to be associated with greater likelihood of high WML burden in the SLF (OR = 1.55, 95% CI [1.00,2.53]) and increased activity during the least active 5-h period to be associated with a greater likelihood of high whole-brain WML burden (OR = 1.83, 95% CI [1.06,3.47]). This study shows integrity of the ATR and SLF, and overall WML burden is linked to altered rest-activity rhythms in older adults at risk for cognitive decline, with those demonstrating altered rest-activity rhythms showing 50%-80% higher odds of having high WML burden.

Structural brain alterations associated with suicidal thoughts and behaviors in young people: results from 21 international studies from the ENIGMA Suicidal Thoughts and Behaviours consortium.

Identifying brain alterations associated with suicidal thoughts and behaviors (STBs) in young people is critical to understanding their development and improving early intervention and prevention. The ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium analyzed neuroimaging data harmonized across sites to examine brain morphology associated with STBs in youth. We performed analyses in three separate stages, in samples ranging from most to least homogeneous in terms of suicide assessment instrument and mental disorder. First, in a sample of 577 young people with mood disorders, in which STBs were assessed with the Columbia Suicide Severity Rating Scale (C-SSRS). Second, in a sample of young people with mood disorders, in which STB were assessed using different instruments, MRI metrics were compared among healthy controls without STBs (HC; N = 519), clinical controls with a mood disorder but without STBs (CC; N = 246) and young people with current suicidal ideation (N = 223). In separate analyses, MRI metrics were compared among HCs (N = 253), CCs (N = 217), and suicide attempters (N = 64). Third, in a larger transdiagnostic sample with various assessment instruments (HC = 606; CC = 419; Ideation = 289; HC = 253; CC = 432; Attempt=91). In the homogeneous C-SSRS sample, surface area of the frontal pole was lower in young people with mood disorders and a history of actual suicide attempts (N = 163) than those without a lifetime suicide attempt (N = 323; FDR-p = 0.035, Cohen's d = 0.34). No associations with suicidal ideation were found. When examining more heterogeneous samples, we did not observe significant associations. Lower frontal pole surface area may represent a vulnerability for a (non-interrupted and non-aborted) suicide attempt; however, more research is needed to understand the nature of its relationship to suicide risk.

Does circadian dysrhythmia drive the switch into high- or low-activation states in bipolar I disorder?

OBJECTIVES: Emerging evidence suggests a role of circadian dysrhythmia in the switch between "activation" states (i.e., objective motor activity and subjective energy) in bipolar I disorder. METHODS: We examined the evidence with respect to four relevant questions: (1) Are natural or environmental exposures that can disrupt circadian rhythms also related to the switch into high-/low-activation states? (2) Are circadian dysrhythmias (e.g., altered rest/activity rhythms) associated with the switch into activation states in bipolar disorder? (3) Do interventions that affect the circadian system also affect activation states? (4) Are associations between circadian dysrhythmias and activation states influenced by other "third" factors? RESULTS: Factors that naturally or experimentally alter circadian rhythms (e.g., light exposure) have been shown to relate to activation states; however future studies need to measure circadian rhythms contemporaneously with these natural/experimental factors. Actigraphic measures of circadian dysrhythmias are associated prospectively with the switch into high- or low-activation states, and more studies are needed to establish the most relevant prognostic actigraphy metrics in bipolar disorder. Interventions that can affect the circadian system (e.g., light therapy, lithium) can also reduce the switch into high-/low-activation states. Whether circadian rhythms mediate these clinical effects is an unknown but valuable question. The influence of age, sex, and other confounders on these associations needs to be better characterised. CONCLUSION: Based on the reviewed evidence, our view is that circadian dysrhythmia is a plausible driver of transitions into high- and low-activation states and deserves prioritisation in research in bipolar disorders.

Prevalence and Correlates of Tobacco Use in Young People Presenting to Australian Primary Mental Health Services.

INTRODUCTION: In Australian youth primary mental health settings it is unclear as to the rates and correlates of tobacco use at service entry. AIMS AND METHODS: We aimed to delineate the prevalence and correlates of recent tobacco use (eg, cigarettes, chewing tobacco, cigars, etc) in the past 3 months in young people at their first presentation to primary mental health services as a function of age. Cross-sectional self-report measures were collected using a tablet device from young people presenting to one of five Australian primary mental health (headspace) services. Logistic regression assessed correlates of past 3-month tobacco use in adolescents (12-17 years) and young adults (18-25 years). RESULTS: Regular (at least monthly) tobacco use in the past 3 months was found in 23.4% (n = 247, N = 1055) of the sample. Increasing age (odds ratio [OR] =1.47 per year; 95% confidence interval [CI]: 1.15 to 1.89), male sex (OR = 1.98; 95% CI: 1.02 to 3.83), being in a relationship (OR = 1.96; 95% CI: 1.01 to 3.82), and poorer functioning (OR = 0.95 per unit Social and Occupational Functioning Assessment Scale increase; 95% CI: 0.91 to 0.99) predicted regular tobacco use in adolescents, but not in young adults. Living in a regional location (OR = 2.10; 95% CI: 1.40 to 3.13) and not studying (OR = 0.47; 95% CI: 0.31 to 0.73) predicted tobacco use in young adults. Having a diagnosed mental illness other than depression and/or anxiety predicted tobacco use in both groups (adolescents OR = 2.49; 95% CI: 1.26 to 4.94; young adults OR = 1.80; 95% CI: 1.13 to 2.89). CONCLUSIONS: Nearly a quarter of young people with mental illness are using tobacco, supporting the need for early intervention approaches. Adapting treatment targets by age could improve the impact of interventions in adolescents versus young adults. Poor functioning and lack of engagement in education were associated with tobacco use in both age groups, respectively; however, more research is needed to determine the direction of these relationships. IMPLICATIONS: Young people with mental illness have a high prevalence of recent tobacco use and this is evident when they first present to youth primary mental health services. Youth-oriented mental health settings may provide a unique window for tobacco use prevention and early intervention to reduce smoking in people with mental illness, a priority population. Age-specific targeted approaches might be needed in adolescents and young adults.

Improving access to mental health care: a system dynamics model of direct access to specialist care and accelerated specialist service capacity growth.

OBJECTIVE: To simulate the impact on population mental health indicators of allowing people to book some Medicare-subsidised sessions with psychologists and other mental health care professionals without a referral (direct access), and of increasing the annual growth rate in specialist mental health care capacity (consultations). DESIGN: System dynamics model, calibrated using historical time series data from the Australian Bureau of Statistics, HealthStats NSW, the Australian Institute of Health and Welfare, and the Australian Early Development Census. Parameter values that could not be derived from these sources were estimated by constrained optimisation. SETTING: New South Wales, 1 September 2021 - 1 September 2028. MAIN OUTCOME MEASURES: Projected mental health-related emergency department presentations, hospitalisations following self-harm, and deaths by suicide, both overall and for people aged 15-24 years. RESULTS: Direct access (for 10-50% of people requiring specialist mental health care) would lead to increases in the numbers of mental health-related emergency department presentations (0.33-1.68% of baseline), hospitalisations with self-harm (0.16-0.77%), and deaths by suicide (0.19-0.90%), as waiting times for consultations would increase, leading to disengagement and consequently to increases in adverse outcomes. Increasing the annual rate of growth of mental health service capacity (two- to fivefold) would reduce the frequency of all three outcomes; combining direct access to a proportion of services with increased growth in capacity achieved substantially greater gains than an increase in service capacity alone. A fivefold increase in the annual service growth rate would increase capacity by 71.6% by the end of 2028, compared with current projections; combined with direct access to 50% of mental health consultations, 26 616 emergency department presentations (3.6%), 1199 hospitalisations following self-harm (1.9%), and 158 deaths by suicide (2.1%) could be averted. CONCLUSION: The optimal combination of increased service capacity growth (fivefold) and direct access (50% of consultations) would have double the impact over seven years of accelerated capacity growth alone. Our model highlights the risks of implementing individual reforms without knowledge of their overall system effect.

Phenotypic and genetic factors associated with donation of DNA and consent to record linkage for prescription history in the Australian Genetics of Depression Study.

Samples can be prone to ascertainment and attrition biases. The Australian Genetics of Depression Study is a large publicly recruited cohort (n = 20,689) established to increase the understanding of depression and antidepressant treatment response. This study investigates differences between participants who donated a saliva sample or agreed to linkage of their records compared to those who did not. We observed that older, male participants with higher education were more likely to donate a saliva sample. Self-reported bipolar disorder, ADHD, panic disorder, PTSD, substance use disorder, and social anxiety disorder were associated with lower odds of donating a saliva sample, whereas anorexia was associated with higher odds of donation. Male and younger participants showed higher odds of agreeing to record linkage. Participants with higher neuroticism scores and those with a history of bipolar disorder were also more likely to agree to record linkage whereas participants with a diagnosis of anorexia were less likely to agree. Increased likelihood of consent was associated with increased genetic susceptibility to anorexia and reduced genetic risk for depression, and schizophrenia. Overall, our results show moderate differences among these subsamples. Most current epidemiological studies do not search for attrition biases at the genetic level. The possibility to do so is a strength of samples such as the AGDS. Our results suggest that analyses can be made more robust by identifying attrition biases both on the phenotypic and genetic level, and either contextualising them as a potential limitation or performing sensitivity analyses adjusting for them.