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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).

Background Major depressive disorder (MDD) is a common and highly heterogeneous psychiatric disorder but little is known about the genetic characterisation of this heterogeneity. Understanding the genetic etiology of MDD can be challenging as large sample sizes are needed for gene discovery – often achieved with a trade-off in the depth phenotyping. Methods The Australian Genetics of Depression Study is the largest stand-alone depression cohort with both genetic data and in-depth phenotyping and comprises a total of 15,792 participants of European ancestry, 92% of whom, met diagnostic criteria for MDD. We leveraged the unique nature of this cohort to conduct a meta-analysis with the largest depression GWAS to date and subsequently used polygenic scores (PGS) to investigate genetic heterogeneity across various clinical subtypes of MDD. Results We increased the number of known genome-wide significant variants associated with depression from 103 to 126 and found evidence of association of novel genes implicated in neuronal development. We show that a PGS for depression explains 5.7% of variance in MDD liability in our sample. Lastly, we find strong support for genetic heterogeneity in depression with differential associations of multiple psychiatric and comorbid traits with age of onset, longitudinal course and various subtypes of MDD. Conclusions Until now, this degree of detailed phenotyping in such a large sample of MDD cases has not been possible. Along with discovery of novel loci, we provide support for differential pathways to illness models that recognize both the overlap with other common psychiatric disorders, as well as pathophysiological differences.

Objective Youth with early-onset mood or psychotic disorders are occasionally prescribed metformin to manage cardiometabolic risk. This retrospective study explores the demographic, clinical and metabolic factors associated with metformin prescription youth with mood or psychotic disorders. Method Participants included 72 youth with mood or psychotic disorders from a young adult mental health inpatient unit, of which 18 (33%) were newly prescribed metformin, and 54 (66%) were not prescribed metformin. Demographic and clinical information were extracted from the patients’ medical files along with body mass index (BMI), fasting serum bloods and calculated updated homeostatic model of insulin resistance assessment (HOMA2-IR) scores to compare profiles between groups. Results Of those prescribed metformin, 83% were overweight or obese and 72% had elevated HOMA2-IR scores. Of those not receiving metformin treatment, 41% were overweight or obese and 22% had elevated HOMA2-IR scores. Youth prescribed metformin had significantly higher BMI, and elevated markers of insulin resistance, but did not differ to those not prescribed metformin on other demographic, clinical or metabolic factors. Conclusions While metformin is prescribed to some youth with mood or psychotic disorders displaying markers of cardiometabolic disturbance, there is a need to develop clearer treatment guidelines for metformin in these youth.

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.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.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.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.

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.

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.

Atypical sensory processing occurs in up to 97% of children on the autism spectrum. Children who are on the autism spectrum also commonly demonstrate challenging behaviors, and their caregivers report increased levels of strain in daily life. The aim of this study was to explore four sensory processing features; seeking, avoiding, sensitivity, and registration, and their relationships with maladaptive behaviors in children with autism, as well as with caregiver strain. Participants comprised 75 children with autism aged 7-12 years (M = 7.81). Caregivers completed three questionnaire measures examining child sensory processing, maladaptive behaviors, and perceptions of caregiver strain. We found avoiding significantly associated with irritability. Avoiding also displayed the strongest relationship with global caregiver strain. Avoiding and seeking were strongly related to hyperactivity/noncompliance (components of maladaptive behavior). A multiple regression was performed to explore how atypical sensory processing features and maladaptive behaviors together predicted caregiver strain. Together, maladaptive behaviors and sensory features accounted for 58% of the variance in total caregiver strain. The only significant individual predictor of total caregiver strain was sensory avoiding, which uniquely accounted for 5.76% of the variation. The findings suggest that atypical sensory processing is associated with overall caregiver strain, above that explained by maladaptive behaviors. Implications for targeted support for the benefit of the child, parents and family unit are discussed. LAY SUMMARY: Children who are on the autism spectrum often have differences in sensory processing. These children also tend to show challenging behaviors, and their caregivers can experience increased stress. This study looked at how sensory processing difficulties relate to such behaviors and caregiver stress. We found that both sensory processing and challenging behaviors were related to the amount of stress caregivers felt. This suggests that interventions may benefit from looking at sensory processing features when considering how to help reduce challenging behaviors and caregiver stress.

Background Variation within the CYP2C19 gene has been linked to differential metabolism of selective serotonin reuptake inhibitors (SSRIs). Pharmacogenetic recommendations based on the effect of CYP2C19 variants have been made available and are used increasingly by clinical practitioners. Nonetheless, the underlying assumption linking differential metabolism to efficacy or adverse side effects remains understudied. Here, we aim to fill this gap by studying CYP2C19 polymorphisms and inferred metabolism and patient-reported antidepressant response in a sample of 9531 Australian adults who have taken SSRIs. Methods Metaboliser status was inferred for participants based on CYP2C19 alleles. Primary analysis consisted of assessing differences in treatment efficacy and tolerability between normal (reference) and: ultrarapid, rapid, intermediate and poor metabolisers. Results Across medications, poor metabolisers reported a higher efficacy, whereas rapid metabolisers reported higher tolerability. When stratified by drug, associations between metaboliser status and efficacy did not survive multiple testing correction. Intermediate metabolisers were at greater odds of reporting any side effect for sertraline and higher number of side effects across medications and for sertraline. Conclusions The effects between metaboliser status and treatment efficacy, tolerability and side effects were in the expected direction. Our power analysis suggests we would detect moderate to large effects, at least nominally. Reduced power may also be explained by heterogeneity in antidepressant dosages or concomitant medications, which we did not measure. The fact that we identify slower metabolisers to be at higher risk of side effects even without adjusting for clinical titration, and the nominally significant associations consistent with the expected metabolic effects provide new evidence for the link between CYP2C19 metabolism and SSRI response. Nonetheless, longitudinal and interventional designs such as randomized clinical trials that stratify by metaboliser status are necessary to establish the effects of CYP2C19 metabolism on SSRI treatment efficacy or adverse effects.

Distinctions between major depressive disorder (MDD) and perinatal depression (PND) reflect varying views of PND, from a unique etiological subtype of MDD to an MDD episode that happens to coincide with childbirth. This case-control study investigated genetic differences between PND and MDD outside the perinatal period (non-perinatal depression or NPD).We conducted a genome-wide association study using PND cases (Edinburgh Postnatal Depression Scale score ≥ 13) from the Australian Genetics of Depression Study 2018 data (n = 3804) and screened controls (n = 6134). Results of gene-set enrichment analysis were compared with those of women with non-PND. For six psychiatric disorders/traits, genetic correlations with PND were evaluated, and logistic regression analysis reported polygenic score (PGS) association with both PND and NPD.Genes differentially expressed in ovarian tissue were significantly enriched (stdBeta = 0.07, p = 3.3e-04), but were not found to be associated with NPD. The genetic correlation between PND and MDD was 0.93 (SE = 0.07; p = 3.5e-38). Compared with controls, PGS for MDD are higher for PND cases (odds ratio [OR] = 1.8, confidence interval [CI] = [1.7-1.8], p = 9.5e-140) than for NPD cases (OR = 1.6, CI = [1.5-1.7], p = 1.2e-49). Highest risk is for those reporting both antenatal and postnatal depression, irrespective of prior MDD history.PND has a high genetic overlap with MDD, but points of distinction focus on differential expression in ovarian tissue and higher MDD PGS, particularly for women experiencing both antenatal and postpartum PND.

Background There is increasing evidence that dysregulation of polyunsaturated fatty acids (FAs) mediated membrane function plays a role in the pathophysiology of schizophrenia. Even though preclinical findings have supported the anti-inflammatory properties of omega-3 FAs on brain health, their biological roles as anti-inflammatory agents and their therapeutic role on clinical symptoms of psychosis risk are not well understood. In the current study, we investigated the relationship of erythrocyte omega-3 FAs with plasma immune markers in a clinical high risk for psychosis (CHR) sample. In addition, a mediation analysis was performed to examine whether previously reported associations between omega-3 FAs and clinical outcomes were mediated via plasma immune markers. Clinical outcomes for CHR participants in the NEURAPRO clinical trial were measured using the Brief Psychiatric Rating Scale (BPRS), Schedule for the Scale of Assessment of Negative Symptoms (SANS) and Social and Occupational Functioning Assessment Scale (SOFAS) scales. The erythrocyte omega-3 index [eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA)] and plasma concentrations of inflammatory markers were quantified at baseline (n = 268) and 6 month follow-up (n = 146) by gas chromatography and multiplex immunoassay, respectively. In linear regression models, the baseline plasma concentrations of Interleukin (IL)-15, Intercellular adhesion molecule (ICAM)-1 and Vascular cell adhesion molecule (VCAM)-1 were negatively associated with baseline omega-3 index. In addition, 6-month change in IL-12p40 and TNF-α showed a negative association with change in omega-3 index. In longitudinal analyses, the baseline and 6 month change in omega-3 index was negatively associated with VCAM-1 and TNF-α respectively at follow-up. Mediation analyses provided little evidence for mediating effects of plasma immune markers on the relationship between omega-3 FAs and clinical outcomes (psychotic symptoms and functioning) in CHR participants. Our results indicate a predominantly anti-inflammatory relationship of omega-3 FAs on plasma inflammatory status in CHR individuals, but this did not appear to convey clinical benefits at 6 month and 12 month follow-up. Both immune and non-immune biological effects of omega-3 FAs would be resourceful in understanding the clinical benefits of omega-3 FAs in CHR papulation.

Special Issue: The ENIGMA Consortium: the first 10 years., Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3–90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes., European Community's Seventh Framework Programme, Grant/Award Numbers: 278948, 602450, 603016, 602805; US National Institute of Child Health and Human Development, Grant/Award Numbers: RO1HD050735, 1009064, 496682; QIMR Berghofer Medical Research Institute and the Centre for Advanced Imaging, University of Queensland; ICTSI NIH/NCRR, Grant/Award Number: RR025761; European Community's Horizon 2020 Programme, Grant/Award Numbers: 667302, 643051; Vici Innovation Program, Grant/Award Numbers: #91619115, 016-130-669; NWO Brain & Cognition Excellence Program, Grant/Award Number: 433-09-229; Biobanking and Biomolecular Resources Research Infrastructure (Netherlands) (BBMRI-NL); Spinozapremie, Grant/Award Number: NWO-56-464-14192; Biobanking and Biomolecular Resources Research Infrastructure, Grant/Award Numbers: 184.033.111, 184.021.007; Netherlands Organization for Health Research and Development (ZonMW), Grant/Award Numbers: 480-15-001/674, 024.001.003, 911-09-032, 056-32-010, 481-08-011, 016-115-035, 31160008, 400-07-080, 400-05-717, 451-04-034, 463-06-001, 480-04-004, 904-61-193, 912-10-020, 985-10-002, 904-61-090; NIMH, Grant/Award Number: R01 MH090553; Geestkracht programme of the Dutch Health Research Council, Grant/Award Number: 10-000-1001; FP7 Ideas: European Research Council; Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Grant/Award Numbers: NWO/SPI 56-464-14192, NWO-MagW 480-04-004, 433-09-220, NWO 51.02.062, NWO 51.02.061; National Center for Advancing Translational Sciences, National Institutes of Health, Grant/Award Number: UL1 TR000153; National Center for Research Resources; National Center for Research Resources at the National Institutes of Health, Grant/Award Numbers: NIH 1U24 RR025736-01, NIH 1U24 RR021992; NIH Institutes contributing to the Big Data to Knowledge; U.S. National Institutes of Health, Grant/Award Numbers: R01 CA101318, P30 AG10133, R01 AG19771; Medical Research Council, Grant/Award Numbers: U54EB020403, G0500092; National Institute of Mental Health, Grant/Award Numbers: R01MH117014, R01MH042191; Fundación Instituto de Investigación Marqués de Valdecilla, Grant/Award Numbers: API07/011, NCT02534363, NCT0235832; Instituto de Salud Carlos III, Grant/Award Numbers: PI14/00918, PI14/00639, PI060507, PI050427, PI020499; Swedish Research Council, Grant/Award Numbers: 523-2014-3467, 2017-00949, 521-2014-3487; South-Eastern Norway Health Authority; the Research Council of Norway, Grant/Award Number: 223273; South Eastern Norway Regional Health Authority, Grant/Award Numbers: 2017-112, 2019107; Icahn School of Medicine at Mount Sinai; Seventh Framework Programme (FP7/2007-2013), Grant/Award Number: 602450; National Institutes of Health, Grant/Award Numbers: R01 MH116147, R01 MH113619, R01 MH104284; South London and Maudsley NHS Foundation Trust; the National Institute for Health Research (NIHR)

Contains fulltext : 248376.pdf (Publisher’s version ) (Open Access) For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to 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 (β = -0.447 to −0.448, p < 0.001), depressive (β = -0.650, p < 0.001) and hypo/manic symptoms (β = -0.819, p < 0.001). Against our predictions, baseline chronotypes did not predict change in depressive (β = -0.016, p = 0.810) or hypo/manic symptoms (β = 0.077, p = 0.104). Similarly, the change in chronotype did not correlate with the change in depressive symptoms (β = -0.096, p = 0.295) nor did the change in chronotype and the change in hypo/manic symptoms (β = -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.

AIM Young people with common mood disorders face the prospect of shortened life expectancy largely due to premature cardiovascular disease. Metabolic dysfunction is a risk factor for premature cardiovascular disease. There is an ongoing debate whether metabolic dysfunction can be simply explained by weight gain secondary to psychotropic medications or whether shared genetic vulnerability, intrinsic immune-metabolic disturbances or other system perturbations (e.g. dysregulated sympathetic nervous system, circadian dysfunction) are more relevant determinants of premature cardiovascular disease. Thus, we aimed to investigate underlying drivers of metabolic dysfunction and premature cardiovascular disease in young people in the early phases of common mood disorders. METHODS We evaluated the relationships between insulin resistance (assessed by HOMA2-IR) and body mass index (BMI), sex, diagnosis, medication, inflammatory markers and hormonal factors in 327 inpatients with emerging affective and major mood disorders admitted to the Young Adult Mental Health Unit, St Vincent's Private Hospital, Sydney. RESULTS While HOMA2-IR scores were positively associated with BMI (rs = 0.465, p

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.

BACKGROUND As the demand for youth mental health care continues to rise, managing wait times and reducing treatment delays are key challenges to delivering timely and quality care. Clinical staging is a heuristic model for youth mental health that can stratify care allocation according to an individual’s risk of illness progression. The application of staging has been traditionally limited to trained clinicians, yet if digital technologies could be leveraged to apply clinical staging, then this could increase the scalability and utility of this model in services. OBJECTIVE The aim of this study is to validate a digital algorithm to accurately differentiate young people at lower and higher risk of developing mental disorders. METHODS The cohort comprised 131 young people, aged between 16 to 25 years, who presented to youth mental health services in Australia for the first time between November 2018 to March 2021. Clinical stages (either stage 1a or stage 1b+) were allocated independently by expert psychiatrists and compared to the digital algorithm based on a multidimensional self-report questionnaire. RESULTS Of the 131 participants, the mean (SD) age was 20.3 (2.4) years and 94 (71.8%) were female. Ninety-one percent of clinical stage ratings were concordant between the digital algorithm and the expert ratings with a substantial interrater agreement (κ=0.67, P CONCLUSIONS This novel digital algorithm is sufficiently robust to be used as an adjunctive decision support tool to stratify care and assist with demand management in youth mental health services. This work could transform care pathways and expedite care allocation for those in early stages of common anxiety and depressive disorders. Between 11% and 27% of young people presenting for care may be suitable for low intensity online or brief interventions, creating additional clinical capacity to be directed towards those who are in stage 1b+ for further assessment and intervention.

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.

BACKGROUND As the demand for youth mental health care continues to rise, managing wait times and reducing treatment delays are key challenges to delivering timely and quality care. Clinical staging is a heuristic model for youth mental health that can stratify care allocation according to an individual’s risk of illness progression. The application of staging has been traditionally limited to trained clinicians, yet if digital technologies could be leveraged to apply clinical staging, then this could increase the scalability and utility of this model in services. OBJECTIVE The aim of this proof-of-concept study is to validate a digital algorithm to accurately differentiate young people at lower and higher risk of developing mental disorders. METHODS The cohort comprised 131 young people, aged between 16 to 25 years, who presented to youth mental health services in Australia for the first time between November 2018 to March 2021. Clinical stages (either stage 1a or stage 1b+) were allocated independently by expert psychiatrists and compared to the digital algorithm based on a multidimensional self-report questionnaire. RESULTS Of the 131 participants, the mean (SD) age was 20.3 (2.4) years and 94 (71.8%) were female. Ninety-one percent of clinical stage ratings were concordant between the digital algorithm and the expert ratings with a substantial interrater agreement (κ=0.67, P CONCLUSIONS This novel digital algorithm is sufficiently robust to be used as an adjunctive decision support tool to stratify care and assist with demand management in youth mental health services. This work could transform care pathways and expedite care allocation for those in early stages of common anxiety and depressive disorders. Between 11% and 27% of young people presenting for care may be suitable for low intensity online or brief interventions, creating additional clinical capacity to be directed towards those who are stage 1b+ for further assessment and intervention.

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.

Objective To identify trajectories of social and occupational functioning in young people during the two years after presenting for early intervention mental health care; to identify demographic and clinical factors that influence these trajectories. Design Longitudinal, observational study of young people presenting for mental health care. Setting Two primary care-based early intervention mental health services at the Brain and Mind Centre (University of Sydney), 1 June 2008 - 31 July 2018. Participants 1510 people aged 12-25 years who had presented with anxiety, mood, or psychotic disorders, for whom two years' follow-up data were available for analysis. Main outcome measures Latent class trajectories of social and occupational functioning based on growth mixture modelling of Social and Occupational Assessment Scale (SOFAS) scores. Results We identified four trajectories of functioning during the first two years of care: deteriorating and volatile (733 participants, 49%); persistent impairment (237, 16%); stable good functioning (291, 19%); and improving, but late recurrence (249, 16%). The less favourable trajectories (deteriorating and volatile; persistent impairment) were associated with physical comorbidity, not being in education, employment, or training, having substance-related disorders, having been hospitalised, and having a childhood onset mental disorder, psychosis-like experiences, or a history of self-harm or suicidality. Conclusions Two in three young people with emerging mental disorders did not experience meaningful improvement in social and occupational functioning during two years of early intervention care. Most functional trajectories were also quite volatile, indicating the need for dynamic service models that emphasise multidisciplinary interventions and measurement-based care.

Combine economic, social and medical data to forecast need and design services to address the growing crisis. Combine economic, social and medical data to forecast need and design services to address the growing crisis.

A rate-limiting step in the prevention and early intervention of depressive disorders in young people is our insufficient understanding of causal mechanisms. One plausible pathophysiological pathway is disturbance in the 24 h sleep-wake cycle and the underlying circadian system. Abnormalities in circadian rhythms are well documented in adults with various depressive disorders and have been linked to core clinical features, including unstable mood, daytime fatigue, non-restorative sleep, reduced motor activity, somatic symptoms, and appetite and weight change. In this Review, we summarise four areas of research: basic circadian biology and animal models of circadian disturbances; developmental changes in circadian rhythms during adolescence and implications for the emergence of adolescent-onset depressive syndromes; community and clinical studies linking 24 h sleep-wake cycle disturbances and depressive disorders; and clinical trials of circadian-based treatments. We present recommendations based on a highly personalised, early intervention model for circadian-linked depression in young people.

Emerging evidence suggests that obesity impacts brain physiology at multiple levels. Here we aimed to clarify the relationship between obesity and brain structure using structural MRI (n = 6420) and genetic data (n = 3907) from the ENIGMA Major Depressive Disorder (MDD) working group. Obesity (BMI > 30) was significantly associated with cortical and subcortical abnormalities in both mass-univariate and multivariate pattern recognition analyses independent of MDD diagnosis. The most pronounced effects were found for associations between obesity and lower temporo-frontal cortical thickness (maximum Cohen´s d (left fusiform gyrus) = −0.33). The observed regional distribution and effect size of cortical thickness reductions in obesity revealed considerable similarities with corresponding patterns of lower cortical thickness in previously published studies of neuropsychiatric disorders. A higher polygenic risk score for obesity significantly correlated with lower occipital surface area. In addition, a significant age-by-obesity interaction on cortical thickness emerged driven by lower thickness in older participants. Our findings suggest a neurobiological interaction between obesity and brain structure under physiological and pathological brain conditions.

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.

Autistic adults report concerns with social skills and unemployment. Despite anxiety and difficulty with executive cognitive skills being associated with autism, no studies to date have investigated relationships between anxiety or executive cognition with social and work functioning. This study aimed to investigate the associations between perceived social anxiety, perceived and objective executive function, and perceived social and work functioning in a sample of autistic people. A total of 62 participants completed self-report questionnaires of social anxiety (via the Liebowitz Social Anxiety Scale), mental health (via the Depression Anxiety Stress Scale), executive cognition (via the Behaviour Rating Inventory of Executive Function) and perceived social and work functioning (the Work and Social Adjustment Scale), and a smaller subset ( n = 36–40) completed performance-based executive function tasks (Trail Making Task and Rapid Visual Processing Task). Participants who reported having more social anxiety and more difficulty with executive cognition also perceived themselves as having poorer social and work functioning. Performance-based executive function was not related to social or work functioning. Our results suggest that perceived social anxiety and executive cognition are both areas that have potential to be targeted to investigate whether they improve social and vocational outcomes for autistic people. Lay abstract Many autistic adults have trouble in social situations and at work. Researchers do not know exactly why autistic people might find it difficult in these environments, and no studies to date have looked the way anxiety or other cognitive processes might affect autistic peoples’ ability to socialise and succeed in getting and keeping jobs. Anxiety (how much you worry) and difficulty with getting stuff done or switching attention (known as executive function) can be concerns for autistic people and may contribute to social and work difficulties. This study looked at the relationships between the way autistic people perceived their anxiety and executive functioning and their ability to socialise and work. Sixty-two autistic participants completed questionnaires related to their ability to socialise and work, their social anxiety and their executive function. We found that participants who thought that they had poorer ability to work also found themselves to have more difficulties with executive function and they were more socially anxious. Our results showed that how autistic participants perceived their social anxiety and executive function were important in their perception of their social skills and work ability. This study supports the idea that anxiety and executive function could be targeted in interventions to support autistic people and their social and work outcomes.

Major mood syndromes are among the most common and disabling mental disorders. However, a lack of clear delineation of their underlying pathophysiological mechanisms is a major barrier to prevention and optimised treatments. Dysfunction of the 24-h circadian system is a candidate mechanism that has genetic, behavioural, and neurobiological links to mood syndromes. Here, we outline evidence for a new clinical phenotype, which we have called ‘circadian depression’. We propose that key clinical characteristics of circadian depression include disrupted 24-h sleep-wake cycles, reduced motor activity, low subjective energy, and weight gain. The illness course includes early age-of-onset, phenomena suggestive of bipolarity (defined by bidirectional associations between objective motor and subjective energy/mood states), poor response to conventional antidepressant medications, and concurrent cardiometabolic and inflammatory disturbances. Identifying this phenotype could be clinically valuable, as circadian-targeted strategies show promise for reducing depressive symptoms and stabilising illness course. Further investigation of underlying circadian disturbances in mood syndromes is needed to evaluate the clinical utility of this phenotype and guide the optimal use of circadian-targeted interventions.

Sleep fragmentation and reductions in sleep spindles have been observed in individuals with depression. Sleep spindles are known to play a protective role for sleep, and there are indications that melatonin agents can enhance spindles in healthy people. Whether agomelatine, a melatonin agonist indicated for the treatment of depression, may increase spindle density sufficiently to impact sleep continuity in people with depression remains unknown. This proof-of-concept study investigated changes in spindles following agomelatine intake in young adults with depression and assessed how they may relate to potential changes in sleep continuity and depressive symptoms. This study was based on an open-label design. Fifteen participants between 17 and 28 years of age (mean = 22.2; standard deviation [SD] = 3.4) with a diagnosis of a depressive disorder underwent polysomnography before and after an intervention including a 1 hr psychoeducation session centered on sleep and circadian rhythms, and an 8-week course of agomelatine (25-50 mg) with a guided sleep phase advance. Fast spindle density significantly increased from pre- to post-intervention. This increase in spindle density significantly correlated with a reduction in wake after sleep onset, and a similar trend was found with increased sleep efficiency. There was no significant correlation between spindle parameters and depressive symptoms. These findings suggest that agomelatine may contribute to enhanced sleep consolidation, possibly in part through the modulation of spindle production. This should be confirmed by larger randomized control trials.

This paper presents a case study of an innovative direct-to-consumer preclinic triage system designed to reduce predicted peak demand for Australian mental health services as a result of COVID-19 and its associated socioeconomic consequences by guiding Australians to the right mental health care first time. Our innovative, digital health solution comprises two components: (1) a highly personalised and measurement-based model of care (Brain and Mind Centre model of care) that considers both the heterogeneity of mental disorders and other underlying comorbidities, as well as clinical staging; and (2) a health information technology (i.e. the InnoWell Platform). This digital health solution has been embedded as part of standard service delivery into a community-based intake service, thus resulting in a redesigned service model. The service model is currently being implemented as part of a pilot feasibility study, the marker of acceptability at the health professional and service level, and is now under active evaluation to determine its effect on outcomes for consumers, health professionals and the service. For the purposes of this paper, this model served as a prototype for the preclinic triage system that was conceptualised for national scalability at the primary health network level. When implemented at a national level, our direct-to-consumer preclinic triage system is expected to be an effective population health demand management strategy to address the rapidly emerging mental health demand crisis in Australia, and is aligned with the recent recommendation from the Productivity Commission to develop a sustainable national digital platform to facilitate the assessment and referral process to ensure access to mental health care matched to an individual’s level of need. What is known about the topic? Although there is increased recognition of the mental health demand crisis in Australia as a result of the COVID-19 pandemic, little has been done to ‘flatten’ the curve. The Australian Government committed additional funding to support the Better Access Pandemic Support measure; however, this approach to care fails to appreciate both the disparities in service availability across Australia and the gap fees that are prohibitive to some of those seeking help. Furthermore, the expansion of this program may only result in those in care remaining in care, thus further delaying access to those in need. What does this paper add? This paper describes a digital health solution, comprised of a highly personalised and measurement-based model of care coupled with a health information technology, that has been embedded as part of standard service delivery. Consumers seeking mental health care complete a multidimensional self-report assessment via the technology, the results of which are available in real-time and used to facilitate triage to pathways of care as indicated by the severity of the consumer’s illness and level of need to more effectively and efficiently allocate consumers to care. The redesigned service model is now under active evaluation to determine its effects on outcomes at consumer, health professional and service levels. What are the implications for practitioners? The redesigned local service model served as a prototype for our innovative direct-to-consumer preclinic triage system specifically designed to allocate consumers to self-management, ambulatory care or acute care based on clinical stage and level of need. It is our hypothesis that the preclinic triage system will be an effective population health demand management strategy. Importantly, the proposed preclinic triage system aligns with the recent recommendation from the Productivity Commission for the Australian Government to fund the development and sustained implementation of a digital platform to facilitate assessment and referral to evidence-based interventions matched to a consumer’s level of need.

headspace centres provide enhanced primary mental healthcare for young people. A priority is to provide services for all young people irrespective of a range of social disadvantages or social exclusion. The aims of this study were to: (i) delineate extent of social inclusion across domains of housing, studying/employment, functioning, alcohol, and other drug use; and (ii) map profiles of young people deemed vulnerable to experiencing additional barriers to accessing services based on their social inclusion domains (e.g., those living in unstable housing, not in employment/education, and/or experiencing intersecting or multiple forms of disadvantage or difficulties), including detailing their clinical characteristics. Young people were recruited from five headspace centres. Data relevant to social inclusion were examined. Multivariate logistic regression models were used to determine overlap between vulnerable groups, functional, social, clinical, and behavioural factors. 1107 young people participated, aged 12–25 years (M = 18.1 years, SD = 3.3), most living in stable housing (96.5%) and engaged in studying/employment (84.8%). Specific vulnerabilities were evident in young people with NEET status (15.2%); in unstable accommodation (3.5%); of culturally diverse backgrounds (CALD) (12.2%); living in regional areas (36.1%); and identifying as lesbian, gay, bisexual, transgender, intersex, queer/questioning, and asexual plus (LGBTIQA+; 28.2%). Higher levels of distress, substance use, functional impairment, and lower social support were reported by those who were NEET and/or in unstable housing. LGBTIQA+ status was associated with high distress, depressive symptoms, and suicidal ideation. Most participants reported good social support, stable housing, and engagement in work or education. Those deemed vulnerable were likely to experience social exclusion across multiple domains and reported more mental health problems. The co-occurrence of mental ill-health and social exclusion highlights the importance of integrated mental healthcare.

An ongoing need exists for innovation in service delivery to ensure that mental health services deliver high-quality treatment and prevention in the population. This Special Article proposes the adoption of “staged care” as a population health–oriented service delivery model for packages of specialized services delivered largely in ambulatory care settings for individuals with common affective disorders. Staged care integrates measures of clinical need alongside clinical stage and personal choice to select hierarchically arranged service packages for individuals. Packages then vary according to the intensity, duration, and mix of treatment options. This Special Article describes five levels of care in staged care: self- or family-directed monitoring and management, low-intensity services, moderate-intensity services, high-intensity services, and acute and specialist community mental health services. The care environment, treatment team, and length of treatment are also described, and provisional criteria are specified for assigning individuals to different care levels on the basis of current clinical need and clinical stage. Staged care is presented as a model that guides treatment selection and health service delivery to ensure that the high-quality care aims of “right care first time” and prevention are achieved and optimal use of available resources is considered.

ObjectivesThe aim of this study was to determine the prevalence of disordered eating in young people attending a headspace centre, an enhanced primary care centre providing early intervention services for mental health disorders for young people aged 12–25 years, in metropolitan Sydney.DesignCross-sectional assessment of disordered eating symptoms and behaviours.SettingAn enhanced primary care youth mental health service in inner urban Sydney, Australia.ParticipantsA sequential cohort of 530 young people aged 14–26 years presenting to headspace Camperdown for support with mental health concerns.Outcome measuresParticipants completed a series of questionnaires online which included items assessing the presence of eating disorder symptoms and behaviours.ResultsOver one-third of young people aged 14–26 years presenting to headspace Camperdown in a 22-month period reported symptoms of disordered eating. Of these, 32% endorsed overeating behaviours, 25% endorsed dietary restriction and 8% reported purging behaviours. In total, 44% reported engaging in one of more of these behaviours on a regular basis. Almost half reported experiencing significant shape and weight concerns. Eating disorder behaviours were particularly prevalent among female and gender-diverse participants (48% of females and 46% of gender-diverse participants compared with 35% of males) and overall scores across all of the eating disorder and body image items assessed were significantly higher for female participants compared with males.ConclusionsDisordered eating behaviours and symptoms are common among those presenting to youth mental health primary care services. Proactive screening for these behaviours presents opportunities for early detection and specific interventions.Trial registration numberACTRN12618001676202; Results.

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.

BackgroundSubthreshold/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.MethodsWe 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.ResultsThe 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.ConclusionsThese probabilistic models identify symptoms and personal/lifestyle factors that might prove useful targets for indicated preventative strategies.

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.

Background Reducing suicidal behaviour (SB) is a critical public health issue globally. The complex interplay of social determinants, service system factors, population demographics, and behavioural dynamics makes it extraordinarily difficult for decision makers to determine the nature and balance of investments required to have the greatest impacts on SB. Real-world experimentation to establish the optimal targeting, timing, scale, frequency, and intensity of investments required across the determinants is unfeasible. Therefore, this study harnesses systems modelling and simulation to guide population-level decision making that represent best strategic allocation of limited resources. Methods Using a participatory approach, and informed by a range of national, state, and local datasets, a system dynamics model was developed, tested, and validated for a regional population catchment. The model incorporated defined pathways from social determinants of mental health to psychological distress, mental health care, and SB. Intervention scenarios were investigated to forecast their impact on SB over a 20-year period. Results A combination of social connectedness programs, technology-enabled coordinated care, post-attempt assertive aftercare, reductions in childhood adversity, and increasing youth employment projected the greatest impacts on SB, particularly in a youth population, reducing self-harm hospitalisations (suicide attempts) by 28.5% (95% interval 26.3–30.8%) and suicide deaths by 29.3% (95% interval 27.1–31.5%). Introducing additional interventions beyond the best performing suite of interventions produced only marginal improvement in population level impacts, highlighting that ‘more is not necessarily better.’ Conclusion Results indicate that targeted investments in addressing the social determinants and in mental health services provides the best opportunity to reduce SB and suicide. Systems modelling and simulation offers a robust approach to leveraging best available research, data, and expert knowledge in a way that helps decision makers respond to the unique characteristics and drivers of SB in their catchments and more effectively focus limited health resources.

Australia’s Fifth National Mental Health Plan required governments to report, not only on the progress of changes to mental health service delivery, but to also plan for services that should be provided. Future population demand for treatment and care is challenging to predict and one solution involves modelling the uncertain demands on the system. Modelling can help decision-makers understand likely future changes in mental health service demand and more intelligently choose appropriate responses. It can also support greater scrutiny, accountability and transparency of these processes. Australia has an emerging national capacity for systems modelling in mental health which can enhance the next phase of mental health reform. This paper introduces concepts useful for understanding mental health modelling and identifies where modelling approaches can support health service planners to make evidence-informed decisions regarding planning and investment for the Australian population.

ObjectiveMany 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 theThrive by Five International Program, localised for nine countries in Asia and Africa.DesignBetween 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 theThrive by Fiveapp and its content. Detailed notes from the workshops and written feedback were coded and analysed using established thematic techniques.ResultsFour 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.ConclusionsThe 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.

Objective This study utilised digital technology to assess the clinical needs of young people presenting for care at headspace centres across Australia. Method 1490 young people (12–25 years) who presented to one of 11 headspace services from four geographical locations (urban New South Wales, urban South Australia, regional New South Wales, and regional Queensland) completed a digital multidimensional assessment at initial presentation. Characteristics were compared between services and geographical locations. Results We identified major variation in the demographics, and the type and severity of needs across different services. Individuals from regional services were more likely to be younger, of Aboriginal and Torres Strait Islander origin, and present with psychotic-like symptoms and suicidality, while those in urban areas were more likely to have previously sought help and have problematic alcohol use. Further differences in age, distress, depressive symptoms, psychotic-like experiences, trauma, family history, alcohol use, education/employment engagement, and days out of role were identified between different urban sites. Conclusions The variability between services provides insight into the heterogeneity of youth mental health populations which has implications for appropriate early intervention and prevention service provisions. We propose that integrating digital technologies has the potential to provide insights for smarter service planning and evaluation.

GABA is the primary inhibitory neurotransmitter in the brain, and is essential to the balance of cortical excitation and inhibition. Reductions in GABA are proposed to result in an overly excitatory cortex that may cause, or contribute to, symptoms of autism spectrum disorder (ASD). This study employed a cross-sectional design to explore GABA+ differences in ASD and the impact of age, comparing 4-12 year olds with ASD (N = 24) to typically developing children (N = 35). GABA+ concentration was measured using edited magnetic resonance spectroscopy in the left parietal lobe. This study used a mixed model to investigate group differences between children with ASD and typically developing children. There was a significant difference in GABA+ levels between the groups, a significant effect of age and interaction between age and diagnostic group. The ASD group showed an association between GABA+ and age, with GABA+ levels gradually increasing with age (r = 0.59, p = 0.003). Typically developing children did not show age-related change in GABA+ concentration (r = 0.09, p = 0.60). By the age of 9, children with ASD showed GABA+ levels that were comparable to their typically developing peers. This study suggests that children with ASD have initially lower levels of GABA+ in the left parietal lobe compared to typically developing children, and that these initially lower levels of GABA+ increase with age in ASD within this region. It is suggested that this developmental shift of GABA+ levels within the left parietal lobe provides a possible explanation for the previously found reductions in childhood that does not persist in adults. LAY SUMMARY: This study measured levels of GABA in the left parietal lobe using magnetic resonance spectroscopy in children with ASD and typically developing children. GABA levels were initially lower in the ASD group, and increased with age, while GABA did not change with age in the typically developing group. This suggests that alterations in GABA signaling may be associated with ASD in childhood. Autism Res 2021, 14: 859-872. © 2021 International Society for Autism Research, Wiley Periodicals LLC.

One hundred and eleven youth with mental ill-health underwent systematic clinical, laboratory and actigraphy monitoring to report associations between 24-h sleep–wake patterns and cardiometabolic risk factors. Multiple linear regression analyses, controlling for medication usage and class, age and sex, found significant associations between: later sleep onset and BMI; standard variation (SV) in the sleep offset with both insulin values and the updated homeostatic model assessment of insulin resistance (HOMA2-IR) values; and the SV of the sleep midpoint with both poorer fasting insulin, and HOMA2-IR values. Further longitudinal research is required to determine the causative relationships between 24-h sleep–wake cycle patterns, and cardiometabolic outcomes.

Disturbed sleep and irregular sleep-wake patterns have been associated with poor outcomes in older adults. Sleep regularity however has not been studied in a sample with current or remitted major depression.138 participants (63.8±8.6 years; n=27 current major depression, n=64 remitted, and n=47 healthy controls) were monitored using wrist-worn actigraphy. The Sleep Regularity Index (SRI), sleep-wake fragmentation and stability, sleep onset and offset timing, number of awakenings and measures from cosinor analysis were computed.Compared with controls, older adults with current depression had lower SRI (p0.01), lower relative amplitude (p0.05), and higher activity during sleeping and post-midnight hours (p0.05). Older adults with remitted depression displayed lower activity during the day (p0.05), showed reduced average activity and lower amplitude than controls. Total sleep time, sleep timing, and number of awakenings did not differ between groups. All groups differed significantly in self-reported sleep quality and depression severity.Longitudinal studies which examine how sleep-wake patterns change based on depressive episode recency, severity and how medications may influence these patterns are needed.Older adults with current or remitted major depression do not differ from controls on traditional sleep metrics but do report poor quality sleep and show differences in sleep regularity and rest-activity patterns. Reducing the risk of poor outcomes in both groups may be aided by interventions that help promote sleep regularity and increased activity.

Background The acute sickness response to infection is a stereotyped set of illness manifestations initiated by proinflammatory signals in the periphery but mediated centrally. P2RX7 is a highly polymorphic gene encoding an ATP-gated cationic pore, widely expressed on immune cells and the brain, and regulating the NLRP3 inflammasome, as well as diverse neural functions. Methods Associations between P2RX7 genotype, pore activity, and illness manifestations were examined in a cohort with acute viral and bacterial infections (n = 484). Genotyping of 12 P2RX7 function-modifying single-nucleotide polymorphisms (SNPs) was used to identify haplotypes and diplotypes. Leucocyte pore activity was measured by uptake of the fluorescent dye, YO-PRO-1, and by ATP-induced interleukin-1β (IL-1β) release. Associations were sought with scores describing the symptom domains, or endophenotypes, derived from principal components analysis. Results Among the 12 SNPs, a 4-SNP haplotype block with 5 variants was found in 99.5% of the subjects. These haplotypes and diplotypes were closely associated with variations in pore activity and IL-1β production. Homozygous diplotypes were associated with overall illness severity as well as fatigue, pain, and mood disturbances. Conclusions P2RX7 signaling plays a significant role in the acute sickness response to infection, likely acting in both the immune system and the brain.