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.

Staging 2·0: refining transdiagnostic clinical staging frameworks to enhance reliability and utility for youth mental health.

Globally, 75% of depressive, bipolar, and psychotic disorders emerge by age 25 years. However, these disorders are often preceded by non-specific symptoms or attenuated clinical syndromes. Difficulties in determining optimal treatment interventions for these emerging mental disorders, and uncertainties about accounting for co-occurring psychopathology and illness trajectories, have led many youth mental health services to adopt transdiagnostic clinical staging frameworks. In this Health Policy paper, an international working group highlights ongoing challenges in applying transdiagnostic staging frameworks in clinical research and practice, and proposes refinements to the transdiagnostic model to enhance its reliability, consistent recording, and clinical utility. We introduce the concept of within-stage heterogeneity and describe the advantages of defining stage in terms of clinical psychopathology and stage modifiers. Using examples from medicine, we discuss the utility of categorising stage modifiers into factors associated with progression (ie, potential predictors of stage transition) and extension (ie, factors associated with the current presentation that add complexity to treatment selection). Lastly, we suggest how it is possible to revise the currently used transdiagnostic staging approach to incorporate these key concepts, and how the revised framework could be applied in clinical and research practice.

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.

Evening Chronotypes With Depression Report Poorer Outcomes of Selective Serotonin Reuptake Inhibitors: A Survey-Based Study of Self-Ratings.

BACKGROUND: Preliminary evidence suggests that evening chronotype is related to poorer efficacy of selective serotonin reuptake inhibitors. It is unknown whether this is specific to particular medications, self-rated chronotype, or efficacy. METHODS: In the Australian Genetics of Depression Study (n = 15,108; 75% women; 18-90 years; 68% with ≥1 other lifetime diagnosis), a survey recorded experiences with 10 antidepressants, and the reduced Morningness-Eveningness Questionnaire was used to estimate chronotype. A chronotype polygenic score was calculated. Age- and sex-adjusted regression models (Bonferroni-corrected) estimated associations among antidepressant variables (how well the antidepressant worked [efficacy], duration of symptom improvement, side effects, discontinuation due to side effects) and self-rated and genetic chronotypes. RESULTS: The chronotype polygenic score explained 4% of the variance in self-rated chronotype (r = 0.21). Higher self-rated eveningness was associated with poorer efficacy of escitalopram (odds ratio [OR] = 1.04; 95% CI, 1.02 to 1.06; p = .000035), citalopram (OR = 1.03; 95% CI, 1.01 to 1.05; p = .004), fluoxetine (OR = 1.03; 95% CI, 1.01 to 1.05; p = .001), sertraline (OR = 1.02; 95% CI, 1.01 to 1.04; p = .0008), and desvenlafaxine (OR = 1.03; 95% CI, 1.01 to 1.05; p = .004), and a profile of increased side effects (80% of those recorded; ORs = 0.93-0.98), with difficulty getting to sleep the most common. Self-rated chronotype was unrelated to duration of improvement or discontinuation. The chronotype polygenic score was only associated with suicidal thoughts and attempted suicide (self-reported). While our measures are imperfect, and not of circadian phase under controlled conditions, the model coefficients suggest that dysregulation of the phenotypic chronotype relative to its genetic proxy drove relationships with antidepressant outcomes. CONCLUSIONS: The idea that variation in circadian factors influences response to antidepressants was supported and encourages exploration of circadian mechanisms of depressive disorders and antidepressant treatments.

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.

Polygenic risk scores and the prediction of onset of mood and psychotic disorders in adolescents and young adults.

AIM: To examine whether polygenic risk scores (PRS) for neuroticism, depression, bipolar disorder and schizophrenia are higher in individuals manifesting trans-diagnostic risk factors for the development of major mental disorders and whether PRS enhance prediction of early onset full-threshold disorders. METHODS: Using data from the Brisbane Longitudinal Twin Study, we examined individual PRS for neuroticism, depression, bipolar disorder and schizophrenia, recorded evidence of subthreshold syndromes and family history of mood and/or psychotic disorders and noted progression to trans-diagnostic clinical caseness (onset of major mental disorders) at follow-up. We undertook multivariate, receiver operating curve and logistic regression analyses that were adjusted for known variables of influence (age, twin status, and so on). RESULTS: Of 1473 eligible participants (female = 866, 59%; mean age 26.3 years), 28% (n = 409) met caseness criteria for a mood and/or psychotic disorder. All PRS were higher in cases versus non-cases but associations with different levels of risk were inconsistent. The prediction of caseness (reported as area under the curve with 95% confidence intervals [CI]) improved from 0.68 (95% CI: 0.65, 0.71) when estimated using clinical risk factors alone up to 0.71 (95% CI: 0.69, 0.73) when PRS were added to the model. Logistic regression identified five variables that optimally classified individuals according to caseness: age, sex, individual risk characteristics, PRS for depression and mental health case status of cotwins or siblings. CONCLUSIONS: The findings need replication. However, this exploratory study suggests that combining PRS with other risk factors has the potential to improve outcome prediction in youth.

EMPOWERED trial: protocol for a randomised control trial of digitally supported, highly personalised and measurement-based care to improve functional outcomes in young people with mood disorders.

OBJECTIVES: Many adolescents and young adults with emerging mood disorders do not achieve substantial improvements in education, employment, or social function after receiving standard youth mental health care. We have developed a new model of care referred to as 'highly personalised and measurement-based care' (HP&MBC). HP&MBC involves repeated assessment of multidimensional domains of morbidity to enable continuous and personalised clinical decision-making. Although measurement-based care is common in medical disease management, it is not a standard practice in mental health. This clinical effectiveness trial tests whether HP&MBC, supported by continuous digital feedback, delivers better functional improvements than standard care and digital support. METHOD AND ANALYSIS: This controlled implementation trial is a PROBE study (Prospective, Randomised, Open, Blinded End-point) that comprises a multisite 24-month, assessor-blinded, follow-up study of 1500 individuals aged 15-25 years who present for mental health treatment. Eligible participants will be individually randomised (1:1) to 12 months of HP&MBC or standardised clinical care. The primary outcome measure is social and occupational functioning 12 months after trial entry, assessed by the Social and Occupational Functioning Assessment Scale. Clinical and social outcomes for all participants will be monitored for a further 12 months after cessation of active care. ETHICS AND DISSEMINATION: This clinical trial has been reviewed and approved by the Human Research Ethics Committee of the Sydney Local Health District (HREC Approval Number: X22-0042 & 2022/ETH00725, Protocol ID: BMC-YMH-003-2018, protocol version: V.3, 03/08/2022). Research findings will be disseminated through peer-reviewed journals, presentations at scientific conferences, and to user and advocacy groups. Participant data will be deidentified. TRIAL REGISTRATION NUMBER: ACTRN12622000882729.

The temporal dependencies between social, emotional and physical health factors in young people receiving mental healthcare: a dynamic Bayesian network analysis.

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.

Developing Culturally Appropriate Content for a Child-Rearing App to Support Young Children's Socioemotional and Cognitive Development in Afghanistan: Co-Design Study.

BACKGROUND: Optimal child-rearing practices can help mitigate the consequences of detrimental social determinants of health in early childhood. Given the ubiquity of personal digital technologies worldwide, the direct delivery of evidence-based information about early childhood development holds great promise. However, to make the content of these novel systems effective, it is crucial to incorporate place-based cultural beliefs, traditions, circumstances, and value systems of end users. OBJECTIVE: This paper describes the iterative approach used to develop the Thrive by Five child-rearing app in collaboration with Afghan parents, caregivers (eg, grandparents, aunts, and nannies), and subject matter experts (SMEs). We outline how co-design methodologies informed the development and cultural contextualization of content to meet the specific needs of Afghan parents and the content was tested and refined in collaboration with key Afghan stakeholders. METHODS: The preliminary content was developed based on a comprehensive literature review of the historical and sociocultural contexts in Afghanistan, including factors that influence child-rearing practices and early childhood development. After an initial review and refinement based on feedback from SMEs, this content was populated into a beta app for testing. Overall, 8 co-design workshops were conducted in July and August 2021 and February 2022 with 39 Afghan parents and caregivers and 6 SMEs to collect their feedback on the app and its content. The workshops were audio recorded and transcribed; detailed field notes were taken by 2 scribes. A theoretical thematic analysis using semantic codes was conducted to inform the refinement of existing content and development of new content to fulfill the needs identified by participants. RESULTS: The following 4 primary themes were identified: child-rearing in the Afghan sociocultural context, safety concerns, emotion and behavior management, and physical health and nutrition. Overall, participants agreed that the app had the potential to deliver valuable information to Afghan parents; however, owing to the volatility in the country, participants recommended including more activities that could be safely done indoors, as mothers and children are required to spend most of their time at home. Additionally, restrictions on public engagement in music required the removal of activities referencing singing that might be performed outside the home. Further, activities to help parents reduce their children's screen time, promote empathy, manage emotions, regulate behavior, and improve physical health and nutrition were requested. CONCLUSIONS: Direct engagement with Afghan parents, caregivers, and SMEs through co-design workshops enabled the development and refinement of evidence-based, localized, and contextually relevant child-rearing activities promoting healthy social, emotional, and cognitive development during the first 5 years of children's lives. Importantly, the content was adapted for the ongoing conflict in Afghanistan with the aim of empowering Afghan parents and caregivers to support their children's developmental potential despite the security concerns and situational stressors.

Parenting app to support socio-emotional and cognitive development in early childhood: iterative codesign learnings from nine low-income and middle-income countries.

OBJECTIVE: Many children in low-income and middle-income countries are disadvantaged in achieving early developmental potential in childhood as they lack the necessary support from their surroundings, including from parents and caregivers. Digital technologies, such as smartphone apps, coupled with iterative codesign to engage end-users in the technology-delivered content development stages, can help overcome gaps in early child development (ECD). We describe the iterative codesign and quality improvement process that informs the development of content for the Thrive by Five International Program, localised for nine countries in Asia and Africa. DESIGN: Between 2021 and 2022, an average of six codesign workshops in each country were conducted in Afghanistan, Indonesia, Kyrgyzstan, Uzbekistan, Cameroon, the Democratic Republic of the Congo, Ethiopia, Kenya and Namibia.ParticipantsA total of 174 parents and caregivers and 58 in-country subject matter experts participated and provided feedback to refine and inform the cultural appropriateness of the Thrive by Five app and its content. Detailed notes from the workshops and written feedback were coded and analysed using established thematic techniques. RESULTS: Four themes emerged from the codesign workshops: local realities, barriers to positive parenting, child development and lessons learnt about the cultural context. These themes, as well as various subthemes, informed content development and refinement. For example, childrearing activities were requested and developed to promote inclusion of families from diverse backgrounds, encourage best parenting practices, increase engagement of fathers in ECD, address parents' mental well-being, educate children about cultural values and help bereaved children with grief and loss. Also, content that did not align with the laws or culture of any country were removed. CONCLUSIONS: The iterative codesign process informed the development of a culturally relevant app for parents and caregivers of children in the early years. Further evaluation is required to assess user experience and impact in real world settings.

Dynamic modelling of chronotype and hypo/manic and depressive symptoms in young people with emerging mental disorders.

There is significant interest in the possible influence of chronotype on clinical states in young people with emerging mental disorders. We apply a dynamic approach (bivariate latent change score modelling) to examine the possible prospective influence of chronotype on depressive and hypo/manic symptoms in a youth cohort with predominantly depressive, bipolar, and psychotic disorders (N = 118; 14-30-years), who completed a baseline and follow-up assessment of these constructs (mean interval = 1.8-years). Our primary hypotheses were that greater baseline eveningness would predict increases in depressive but not hypo/manic symptoms. We found moderate to strong autoregressive effects for chronotype (ß = -0.447 to -0.448, p < 0.001), depressive (ß = -0.650, p < 0.001) and hypo/manic symptoms (ß = -0.819, p < 0.001). Against our predictions, baseline chronotypes did not predict change in depressive (ß = -0.016, p = 0.810) or hypo/manic symptoms (ß = 0.077, p = 0.104). Similarly, the change in chronotype did not correlate with the change in depressive symptoms (ß = -0.096, p = 0.295) nor did the change in chronotype and the change in hypo/manic symptoms (ß = -0.166, p = 0.070). These data suggest that chronotypes may have low utility for predicting future hypo/manic and depressive symptoms in the short term, or that more frequent assessments over longer periods are needed to observe these associations. Future studies should test whether other circadian phenotypes (e.g. sleep-wake variability) are better indicators of illness course.

Designing an App for Parents and Caregivers to Promote Cognitive and Socioemotional Development and Well-being Among Children Aged 0 to 5 Years in Diverse Cultural Settings: Scientific Framework.

Recent years have seen remarkable progress in our scientific understanding of early childhood social, emotional, and cognitive development, as well as our capacity to widely disseminate health information by using digital technologies. Together, these scientific and technological advances offer exciting opportunities to deliver high-quality information about early childhood development (ECD) to parents and families globally, which may ultimately lead to greater knowledge and confidence among parents and better outcomes among children (particularly in lower- and middle-income countries). With these potential benefits in mind, we set out to design, develop, implement, and evaluate a new parenting app-Thrive by Five-that will be available in 30 countries. The app will provide caregivers and families with evidence-based and culturally appropriate information about ECD, accompanied by sets of collective actions that go beyond mere tips for parenting practices. Herein, we describe this ongoing global project and discuss the components of our scientific framework for developing and prototyping the app's content. Specifically, we describe (1) 5 domains that are used to organize the content and goals of the app's information and associated practices; (2) 5 neurobiological systems that are relevant to ECD and can be behaviorally targeted to potentially influence social, emotional, and cognitive development; (3) our anthropological and cultural framework for learning about local contexts and appreciating decolonization perspectives; and (4) our approach to tailoring the app's content to local contexts, which involves collaboration with in-country partner organizations and local and international subject matter experts in ECD, education, medicine, psychology, and anthropology, among others. Finally, we provide examples of the content that was incorporated in Thrive by Five when it launched globally.

Predictive modelling of deliberate self-harm and suicide attempts in young people accessing primary care: a machine learning analysis of a longitudinal study.

PURPOSE: Machine learning (ML) has shown promise in modelling future self-harm but is yet to be applied to key questions facing clinical services. In a cohort of young people accessing primary mental health care, this study aimed to establish (1) the performance of models predicting deliberate self-harm (DSH) compared to suicide attempt (SA), (2) the performance of models predicting new-onset or repeat behaviour, and (3) the relative importance of factors predicting these outcomes. METHODS: 802 young people aged 12-25 years attending primary mental health services had detailed social and clinical assessments at baseline and 509 completed 12-month follow-up. Four ML algorithms, as well as logistic regression, were applied to build four distinct models. RESULTS: The mean performance of models predicting SA (AUC: 0.82) performed better than the models predicting DSH (AUC: 0.72), with mean positive predictive values (PPV) approximately twice that of the prevalence (SA prevalence 14%, PPV: 0.32, DSH prevalence 22%, PPV: 0.40). All ML models outperformed standard logistic regression. The most frequently selected variable in both models was a history of DSH via cutting. CONCLUSION: History of DSH and clinical symptoms of common mental disorders, rather than social and demographic factors, were the most important variables in modelling future behaviour. The performance of models predicting outcomes in key sub-cohorts, those with new-onset or repetition of DSH or SA during follow-up, was poor. These findings may indicate that the performance of models of future DSH or SA may depend on knowledge of the individual's recent history of either behaviour.

Double-blind, randomised placebo-controlled clinical trial of metformin as an adjunct to a sleep-wake, activity and metabolically focused behavioural intervention to improve cardiometabolic outcomes and mood symptoms in youth with major mood syndromes: study protocol.

INTRODUCTION: Metformin is a medication likely to improve measures of cardiometabolic disturbance in young people with mental illness. Evidence also suggests metformin may improve depressive symptoms. This 52-week double-blind randomised control trial (RCT) aims to investigate the efficacy of metformin pharmacotherapy as an adjunct to a healthy lifestyle behavioural intervention in improving cardiometabolic outcomes, and depressive, anxiety and psychotic symptoms in youth with clinically diagnosed major mood syndromes. METHODS AND ANALYSIS: At least 266 young people aged 16-25 presenting for mental healthcare for major mood syndromes who are also at risk for poor cardiometabolic outcomes will be invited to participate in this study. All participants will engage in a 12-week sleep-wake, activity and metabolically focused behavioural intervention programme. As an adjunctive intervention, participants will receive either metformin (500-1000 mg) or placebo pharmacotherapy for 52 weeks.Participants will undergo a series of assessments including: (1) self-report and clinician-administered assessments; (2) blood tests; (3) anthropometric assessments (height, weight, waist circumference and blood pressure); and (4) actigraphy. Univariate and multivariate tests (generalised mixed-effects models) will be used to examine changes in primary and secondary outcomes (and associations with predetermined predictor variables). ETHICS AND DISSEMINATION: This study has been approved by the Sydney Local Health District Research Ethics and Governance Office (X22-0017). The results of this double-blind RCT will be disseminated into the scientific and broader community through peer-reviewed journals, conference presentations, social media and university websites. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ANZCTR) Number: ACTRN12619001559101p, 12 November 2019.

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.

Cross-sectional and longitudinal associations between cardiometabolic measures and clinical stage in young people accessing early intervention mental health services.

AIM: This retrospective cohort study aimed to identify the cardiometabolic characteristics, cross-sectionally and longitudinally, associated with clinical stage in youth accessing early intervention mental health services. METHODS: Cardiometabolic data we collected in 511 young people (aged 12-25 years at entry) receiving mental health care at the early intervention services in Sydney, Australia. RESULTS: The majority of young people (N = 448, 87.67%) were classified in stage 1a or 1b at entry. At entry to care, there was no cross-sectional relationship between clinical stage and age, gender, fasting insulin, fasting glucose, updated homeostatic model assessment for insulin resistance (HOMA2-IR) score, BMI or waist circumference. Of the 111 (21.7%) young people initially classified at stage 1a ('non-specific symptoms') and the 337 (65.9%) classified in stage 1b ('attenuated syndromes'), 40 individuals transitioned to stage 2+ (7.8%) ("full-threshold disorders") longitudinally. No cardiometabolic factors predicted clinical stage transitions. However, those with an increase in BMI over the course of care (n = 54) were 1.46 (OR; 95% CI: 1.02-2.17) times more likely to progress to stage 2+ at follow up. CONCLUSIONS: Whilst no relationships were found between demographic or cardiometabolic variables and clinical stage at entry to care, an increased BMI over time was associated with clinical stage transition longitudinally. Further longitudinal research is needed to understand the demographic, clinical, illness progression or treatment factors associated with changes in cardiometabolic status.

Clinical staging and the differential risks for clinical and functional outcomes in young people presenting for youth mental health care.

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.

Developing a Parenting App to Support Young Children's Socioemotional and Cognitive Development in Culturally Diverse Low- and Middle-Income Countries: Protocol for a Co-design Study.

BACKGROUND: Digital technologies are widely recognized for their equalizing effect, improving access to affordable health care regardless of gender, ethnicity, socioeconomic status, or geographic region. The Thrive by Five app is designed to promote positive interactions between children and their parents, extended family, and trusted members of the community to support socioemotional and cognitive development in the first 5 years of life and to strengthen connections to culture and community. OBJECTIVE: This paper aims to describe the iterative co-design process that underpins the development and refinement of Thrive by Five's features, functions, and content. Minderoo Foundation commissioned this work as a quality improvement activity to support an engaging user experience and inform the development of culturally appropriate and relevant content for parents and caregivers in each country where the app is implemented. METHODS: The app content, referred to as Collective Actions, comprises "The Why," that presents scientific principles that underpin socioemotional and cognitive development in early childhood. The scientific information is coupled with childrearing activities for parents, extended family, and members of the community to engage in with the children to support their healthy development and to promote positive connections between parents, families, and communities and these young children. Importantly, the initial content is designed and iteratively refined in collaboration with a subject matter expert group from each country (ie, alpha testing). This content is then configured into the app (either a beta version or localized version) for testing (ie, beta testing) by local parents and caregivers as well as experts who are invited to provide their feedback and suggestions for improvements in app content, features, and functions via a brief web-based survey and a series of co-design workshops. The quantitative survey data will be analyzed using descriptive statistics, whereas the analysis of qualitative data from the workshops will follow established thematic techniques. RESULTS: To date, the co-design protocol has been completed with subject matter experts, parents, and caregivers from 9 countries, with the first results expected to be published by early 2023. The protocol will be implemented serially in the remaining 21 countries. CONCLUSIONS: Mobile technologies are the primary means of internet connection in many countries worldwide, which underscores the potential for mobile health programs to improve access to valuable, evidence-based, and previously unavailable parenting information. However, for maximum impact, it is critically important to ensure that mobile health programs are designed in collaboration with the target audience to support the alignment of content with parents' cultural values and traditions and its relevance to their needs and circumstances. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/39225.

Sex differences in fronto-limbic white matter tracts in youth with mood disorders.

AIMS: Patients with depression and bipolar disorder have previously been shown to have impaired white matter (WM) integrity compared with healthy controls. This study aimed to investigate potential sex differences that may provide further insight into the pathophysiology of these highly debilitating mood disorders. METHODS: Participants aged 17 to 30 years (168 with depression [60% females], 107 with bipolar disorder [74% females], and 61 controls [64% females]) completed clinical assessment, self-report measures, and a neuropsychological assessment battery. Participants also underwent magnetic resonance imaging from which diffusion tensor imaging data were collected among five fronto-limbic WM tracts: cingulum bundle (cingulate gyrus and hippocampus subsections), fornix, stria terminalis, and the uncinate fasciculus. Mean fractional anisotropy (FA) scores were compared between groups using analyses of variance with sex and diagnosis as fixed factors. RESULTS: Among the nine WM tracts analyzed, one revealed a significant interaction between sex and diagnosis, controlling for age. Male patients with bipolar disorder had significantly lower FA scores in the fornix compared with the other groups. Furthermore, partial correlations revealed a significant positive association between FA scores for the fornix and psychomotor speed. CONCLUSIONS: Our findings suggest that males with bipolar disorder may be at increased risk of disruptions in WM integrity, especially in the fornix, which is thought to be responsible for a range of cognitive functions. More broadly, our findings suggest that sex differences may exist in WM integrity and thereby alter our understanding of the pathophysiology of mood disorders.