The Addition of Fish Oil to Cognitive Behavioral Case Management for Youth Depression: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Trial.

BACKGROUND: Clinical trials suggest that long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs) (fish oil) may reduce depressive symptoms in adults with major depressive disorder. Therefore, n-3 PUFAs may be a potential treatment for depression in youth. METHODS: Participants were 15- to-25 year-old individuals with major depressive disorder who sought care in one of three government-funded mental health services for young people in metropolitan Melbourne, Perth, or Sydney, Australia. Participants were randomly assigned in a double-blind, parallel-arm design to receive either fish oil (840 mg of eicosapentaenoic acid and 560 mg of docosahexaenoic acid) or placebo capsules as adjunct to cognitive behavioral case management. All participants were offered 50-minute cognitive behavioral case management sessions every 2 weeks delivered by qualified therapists (treatment as usual) at the study sites during the intervention period. The primary outcome was change in the interviewer-rated Quick Inventory of Depressive Symptomatology, Adolescent Version, score at 12 weeks. Erythrocyte n-3 PUFA levels were assessed pre-post intervention. RESULTS: A total of 233 young people were randomized to the treatment arms: 115 participants to the n-3 PUFA group and 118 to the placebo group. Mean change from baseline in the Quick Inventory of Depressive Symptomatology score was -5.8 in the n-3 PUFA group and -5.6 in the placebo group (mean difference, 0.2; 95% CI, -1.1 to 1.5; p = .75). Erythrocyte PUFA levels were not associated with depression severity at any time point. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONS: This placebo-controlled trial and biomarker analysis found no evidence to support the use of fish oil for treatment in young people with major depressive disorder.

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.

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.

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.

Premature mortality in early-intervention mental health services: a data linkage study protocol to examine mortality and morbidity outcomes in a cohort of help-seeking young people.

INTRODUCTION: Understanding the risk of premature death from suicide, accident and injury and other physical health conditions in people seeking healthcare for mental disorders is essential for delivering targeted clinical interventions and secondary prevention strategies. It is not clear whether morbidity and mortality outcomes in hospital-based adult cohorts are applicable to young people presenting to early-intervention services. METHODS AND ANALYSIS: The current data linkage project will establish the Brain and Mind Patient Research Register-Mortality and Morbidity (BPRR-M&M) database. The existing Brain and Mind Research Institute Patient Research Register (BPRR) is a cohort of 6743 young people who have accessed primary care-based early-intervention services; subsets of the BPRR contain rich longitudinal clinical, neurobiological, social and functional data. The BPRR will be linked with the routinely collected health data from emergency department (ED), hospital admission and mortality databases in New South Wales from January 2010 to November 2020. Mortality will be the primary outcome of interest, while hospital presentations will be a secondary outcome. The established BPRR-M&M database will be used to establish mortality rates and rates of ED presentations and hospital admissions. Survival analysis will determine how time to death or hospital presentation varies by identified social, demographic and clinical variables. Bayesian modelling will be used to identify predictors of these morbidity and mortality outcomes. ETHICS AND DISSEMINATION: The study has been reviewed and approved by the human research ethics committee of the Sydney Local Health District (2019/ETH00469). All data will be non-identifiable, and research findings will be disseminated through peer-reviewed journals and scientific conference presentations.

Social and occupational outcomes for young people who attend early intervention mental health services: a longitudinal study.

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.

Effects of adjunctive brexpiprazole on sleep-wake and circadian parameters in youth with depressive disorders: study protocol for a clinical trial.

INTRODUCTION: Sleep-wake and circadian disturbance is a key feature of mood disorders with a potential causal role and particular relevance to young people. Brexpiprazole is a second-generation antipsychotic medication with demonstrated efficacy as an adjunct to antidepressant treatment for major depressive disorder (MDD) in adults, with preliminary evidence suggesting greater effectiveness in subgroups of depressed patients with sleep disturbances. This clinical trial aims to evaluate the relationships between changes in sleep-wake and circadian parameters and changes in depressive symptoms following adjunctive brexpiprazole treatment in young adults with MDD and sleep-wake disturbance. METHODS AND ANALYSIS: This study is designed as a 16 week (8 weeks active treatment, 8 weeks follow-up) mechanistic, open-label, single-arm, phase IV clinical trial and aims to recruit 50 young people aged 18-30 with MDD and sleep-wake cycle disturbance through an early intervention youth mental health clinic in Sydney, Australia. At baseline, participants will undergo multidimensional outcome assessment and subsequently receive 8 weeks of open-label treatment with brexpiprazole as adjunctive to their stable psychotropic medication. Following 4 weeks of treatment, clinical and self-report measures will be repeated. Ambulatory sleep-wake monitoring will be conducted continuously for the duration of treatment. After 8 weeks of treatment, all multidimensional outcome assessments will be repeated. Follow-up visits will be conducted 4 and 8 weeks after trial completion (including sleep-wake, clinical and self-report assessments). Circadian rhythm biomarkers including salivary melatonin, cortisol and core body temperature will be collected during an in-lab assessment. Additionally, metabolic, inflammatory and genetic risk markers will be collected at baseline and after 8 weeks of treatment. ETHICS AND DISSEMINATION: This trial protocol has been approved by the Human Research Ethics Committee of the Sydney Local Health District (X19-0417 and 2019/ETH12986, Protocol Version 1-3, dated 25 February 2021). The results of this study, in deidentified form, will be disseminated through publication in peer-reviewed journals, scholarly book chapters, presentation at conferences and publication in conference proceedings. TRIAL REGISTRATION NUMBER: ACTRN12619001456145.

Effect of an online healthy lifestyle psychoeducation programme to improve cardiometabolic outcomes and affective symptoms in youth receiving mental health care: study protocol for a pilot clinical trial.

INTRODUCTION: Worsened cardiometabolic profiles in youth with mental ill health have been associated with a number of modifiable lifestyle risk factors. It is becoming increasingly evident that clinical interventions need to be multimodal in focus to improve mental health symptoms and the physical health symptoms in this already at-risk cohort. METHODS AND ANALYSIS: This 12-week pilot clinical trial examines the efficacy, feasibility and acceptability of an adjunctive online psychoeducation programme for improving cardiometabolic risk parameters and affective symptoms in a transdiagnostic sample of at least 44 young people aged 16-25 years presenting for mental healthcare for mood and/or psychotic syndromes (including anxiety, depression, bipolar disorder and psychosis). Individuals will be invited to participate in a pilot clinical trial for a structured online psychoeducation programme incorporating nutritional, physical activity, sleep-wake and healthy lifestyle information, delivered fortnightly over six online modules. Participants will undergo a series of assessments including: (1) self-report and clinician administered assessments determining mental health symptomatology; (2) fasting blood tests to assess cardiometabolic markers (fasting insulin, fasting glucose and blood lipids); (3) anthropometric assessments (height, weight, waist circumference and blood pressure); and (4) sleep-wake behaviours and circadian rhythm assessments. Changes in scores for all cardiometabolic and affective measures will be assessed via paired samples t-tests, and correlations between change scores will be assessed via Pearson's or Spearman's correlations. Feasibility will be assessed via completion rates, and the acceptability of the programme will be assessed via programme satisfaction measures. ETHICS AND DISSEMINATION: This pilot clinical trial has been approved by the Sydney Local Health District Research Ethics and Governance Office (X20-0228 & 2020/ETH01201). The results of this pilot clinical trial 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: ACTRN12620000772943, Date 28 August 2020.

Neurobiology Youth Follow-up Study: protocol to establish a longitudinal and prospective research database using multimodal assessments for current and past mental health treatment-seeking young people within an early intervention service.

INTRODUCTION: Approximately 75% of major mental illness occurs before the age of 25 years. Despite this, our capacity to provide effective, early and personalised interventions is limited by insufficient evidence for characterising early-stage, and less specific, presentations of major mental disorders in youth populations. This article describes the protocol for setting up a large-scale database that will collect longitudinal, prospective data that incorporate clinical, social and occupational function, neuropsychological, circadian, metabolic, family history and genetic metrics. By collecting data in a research-purposed, standardised manner, the 'Neurobiology Youth Follow-up Study' should improve identification, characterisation and profiling of youth attending mental healthcare, to better inform diagnosis and treatment at critical time points. The overall goal is enhanced long-term clinical and functional outcomes. METHODS AND ANALYSIS: This longitudinal clinical cohort study will invite participation from youth (12-30 years) who seek help for mental health-related issues at an early intervention service (headspace Camperdown) and linked services. Participants will be prospectively tracked over 3 years with a series of standardised multimodal assessments at baseline, 6, 12, 24 and 36 months. Evaluations will include: (1) clinician-administered and self-report assessments determining clinical stage, pathophysiological pathways to illness, diagnosis, symptomatology, social and occupational function; (2) neuropsychological profile; (3) sleep-wake patterns and circadian rhythms; (4) metabolic markers and (5) genetics. These data will be used to: (1) model the impact of demographic, phenomenological and treatment variables, on clinical and functional outcomes; (2) map neurobiological profiles and changes onto a transdiagnostic clinical stage and pathophysiological mechanisms framework. ETHICS AND DISSEMINATION: This study protocol has been approved by the Human Research Ethics Committee of the Sydney Local Health District (2020/ETH01272, protocol V.1.3, 14 October 2020). Research findings will be disseminated through peer-reviewed journals and presentations at scientific conferences and to user and advocacy groups. Participant data will be de-identified.

Neurocognitive functioning predicts suicidal behaviour in young people with affective disorders.

BACKGROUND: Neurocognitive impairment is recognised as a risk factor for suicidal behaviour in adults. The current study aims to determine whether neurocognitive deficits also predict ongoing or emergent suicidal behaviour in young people with affective disorders. METHODS: Participants were aged 12-30 years and presented to early intervention youth mental health clinics between 2008 and 2018. In addition to clinical assessment a standardised neurocognitive assessment was conducted at baseline. Clinical data was extracted from subsequent visits using a standardised proforma. RESULTS: Of the 635 participants who met inclusion criteria (mean age 19.6 years, 59% female, average follow up 476 days) 104 (16%) reported suicidal behaviour during care. In 5 of the 10 neurocognitive domains tested (cognitive flexibility, processing speed, working memory, verbal memory and visuospatial memory) those with suicidal behaviour during care were superior to clinical controls. Better general neurocognitive function remained a significant predictor (OR=1.94, 95% CI 1.29- 2.94) of suicidal behaviour in care after controlling for other risk factors. LIMITATIONS: The neurocognitive battery used was designed for use with affective and psychotic disorders and may not have detected some deficits more specific to suicidal behaviour. CONCLUSION: Contrary to expectations, better neurocognitive functioning predicts suicidal behaviour during care in young people with affective disorders. While other populations with suicidal behaviour, such as adults with affective disorders or young people with psychotic disorders, tend to experience neurocognitive deficits which may limit their capacity to engage in some interventions, this does not appear to be the case for young people with affective disorders.

Predicting self-harm within six months after initial presentation to youth mental health services: A machine learning study.

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

Youth Mental Health Tracker: protocol to establish a longitudinal cohort and research database for young people attending Australian mental health services.

INTRODUCTION: Mental disorders are a leading cause of long-term disability worldwide. Much of the burden of mental ill-health is mediated by early onset, comorbidities with physical health conditions and chronicity of the illnesses. This study aims to track the early period of mental disorders among young people presenting to Australian mental health services to facilitate more streamlined transdiagnostic processes, highly personalised and measurement-based care, secondary prevention and enhanced long-term outcomes. METHODS AND ANALYSIS: Recruitment to this large-scale, multisite, prospective, transdiagnostic, longitudinal clinical cohort study ('Youth Mental Health Tracker') will be offered to all young people between the ages of 12 and 30 years presenting to participating services with proficiency in English and no history of intellectual disability. Young people will be tracked over 3 years with standardised assessments at baseline and 3, 6, 12, 24 and 36 months. Assessments will include self-report and clinician-administered measures, covering five key domains including: (1) social and occupational function; (2) self-harm, suicidal thoughts and behaviour; (3) alcohol or other substance misuse; (4) physical health; and (5) illness type, clinical stage and trajectory. Data collection will be facilitated by the use of health information technology. The data will be used to: (1) determine prospectively the course of multidimensional functional outcomes, based on the differential impact of demographics, medication, psychological interventions and other key potentially modifiable moderator variables and (2) map pathophysiological mechanisms and clinical illness trajectories to determine transition rates of young people to more severe illness forms. ETHICS AND DISSEMINATION: The study has been reviewed and approved by the Human Research Ethics Committee of the Sydney Local Health District (2019/ETH00469). All data will be non-identifiable, and research findings will be disseminated through peer-reviewed journals and scientific conference presentations.

Cohort profile: the Brain and Mind Centre Optymise cohort: tracking multidimensional outcomes in young people presenting for mental healthcare.

PURPOSE: The Brain and Mind Centre (BMC) Optymise cohort assesses multiple clinical and functional domains longitudinally in young people presenting for mental health care and treatment. Longitudinal tracking of this cohort will allow investigation of the relationships between multiple outcome domains across the course of care. Subsets of Optymise have completed detailed neuropsychological and neurobiological assessments, permitting investigation of associations between these measures and longitudinal course. PARTICIPANTS: Young people (aged 12-30) presenting to clinics coordinated by the BMC were recruited to a research register (n=6743) progressively between June 2008 and July 2018. To date, 2767 individuals have been included in Optymise based on the availability of at least one detailed clinical assessment. MEASURES: Trained researchers use a clinical research proforma to extract key data from clinical files to detail social and occupational functioning, clinical presentation, self-harm and suicidal thoughts and behaviours, alcohol and other substance use, physical health comorbidities, personal and family history of mental illness, and treatment utilisation at the following time points: baseline, 3, 6, 12, 24, 36, 48, and 60 months, and time last seen. FINDINGS TO DATE: There is moderate to substantial agreement between raters for data collected via the proforma. While wide variations in individual illness course are clear, social and occupational outcomes suggest that the majority of cohort members show no improvement in functioning over time. Differential rates of longitudinal transition are reported between early and late stages of illness, with a number of baseline factors associated with these transitions. Furthermore, there are longitudinal associations between prior suicide attempts and inferior clinical and functional outcomes. FUTURE PLANS: Future reports will detail the longitudinal course of each outcome domain and examine multidirectional relationships between these domains both cross-sectionally and longitudinally, and explore in subsets the associations between detailed neurobiological measures and clinical, social and functional outcomes.

Transdiagnostic neurocognitive subgroups and functional course in young people with emerging mental disorders: a cohort study.

BACKGROUND: Neurocognitive impairments robustly predict functional outcome. However, heterogeneity in neurocognition is common within diagnostic groups, and data-driven analyses reveal homogeneous neurocognitive subgroups cutting across diagnostic boundaries. AIMS: To determine whether data-driven neurocognitive subgroups of young people with emerging mental disorders are associated with 3-year functional course. METHOD: Model-based cluster analysis was applied to neurocognitive test scores across nine domains from 629 young people accessing mental health clinics. Cluster groups were compared on demographic, clinical and substance-use measures. Mixed-effects models explored associations between cluster-group membership and socio-occupational functioning (using the Social and Occupational Functioning Assessment Scale) over 3 years, adjusted for gender, premorbid IQ, level of education, depressive, positive, negative and manic symptoms, and diagnosis of a primary psychotic disorder. RESULTS: Cluster analysis of neurocognitive test scores derived three subgroups described as 'normal range' (n = 243, 38.6%), 'intermediate impairment' (n = 252, 40.1%), and 'global impairment' (n = 134, 21.3%). The major mental disorder categories (depressive, anxiety, bipolar, psychotic and other) were represented in each neurocognitive subgroup. The global impairment subgroup had lower functioning for 3 years of follow-up; however, neither the global impairment (B = 0.26, 95% CI -0.67 to 1.20; P = 0.581) or intermediate impairment (B = 0.46, 95% CI -0.26 to 1.19; P = 0.211) subgroups differed from the normal range subgroup in their rate of change in functioning over time. CONCLUSIONS: Neurocognitive impairment may follow a continuum of severity across the major syndrome-based mental disorders, with data-driven neurocognitive subgroups predictive of functional course. Of note, the global impairment subgroup had longstanding functional impairment despite continuing engagement with clinical services.

Modelling associations between neurocognition and functional course in young people with emerging mental disorders: a longitudinal cohort study.

Neurocognitive impairment is commonly associated with functional disability in established depressive, bipolar and psychotic disorders. However, little is known about the longer-term functional implications of these impairments in early phase transdiagnostic cohorts. We aimed to examine associations between neurocognition and functioning at baseline and over time. We used mixed effects models to investigate associations between neurocognitive test scores and longitudinal social and occupational functioning ("Social and Occupational Functioning Assessment Scale") at 1-7 timepoints over five-years in 767 individuals accessing youth mental health services. Analyses were adjusted for age, sex, premorbid IQ, and symptom severity. Lower baseline functioning was associated with male sex (coefficient -3.78, 95% CI -5.22 to -2.34 p < 0.001), poorer verbal memory (coefficient 0.90, 95% CI 0.42 to 1.38, p < 0.001), more severe depressive (coefficient -0.28, 95% CI -0.41 to -0.15, p < 0.001), negative (coefficient -0.49, 95% CI -0.74 to -0.25, p < 0.001), and positive symptoms (coefficient -0.25, 95% CI -0.41 to -0.09, p = 0.002) and lower premorbid IQ (coefficient 0.13, 95% CI 0.07 to 0.19, p < 0.001). The rate of change in functioning over time varied among patients depending on their sex (male; coefficient 0.73, 95% CI 0.49 to 0.98, p < 0.001) and baseline level of cognitive flexibility (coefficient 0.14, 95% CI 0.06 to 0.22, p < 0.001), such that patients with the lowest scores had the least improvement in functioning. Impaired cognitive flexibility is common and may represent a meaningful and transdiagnostic target for cognitive remediation in youth mental health settings. Future studies should pilot cognitive remediation targeting cognitive flexibility while monitoring changes in functioning.

Clinical Stage Transitions in Persons Aged 12 to 25 Years Presenting to Early Intervention Mental Health Services With Anxiety, Mood, and Psychotic Disorders.

Importance: The large contribution of psychiatric disorders to premature death and persistent disability among young people means that earlier identification and enhanced long-term care for those who are most at risk of developing life-threatening or chronic disorders is critical. Clinical staging as an adjunct to diagnosis to address emerging psychiatric disorders has been proposed for young people presenting for care; however, the longer-term utility of this system has not been established. Objectives: To determine the rates of transition from earlier to later stages of anxiety, mood, psychotic, or comorbid disorders and to identify the demographic and clinical characteristics that are associated with the time course of these transitions. Design, Setting, and Participants: A longitudinal, observational study of 2254 persons aged 12 to 25 years who obtained mental health care at 2 early intervention mental health services in Sydney, Australia, and were recruited to a research register between June 18, 2008, and July 24, 2018 (the Brain and Mind Centre Optymise Cohort). Main Outcomes and Measures: The primary outcome of this study was transition from earlier to later clinical stages. A multistate Markov model was used to examine demographic (ie, age, sex, engagement in education, employment, or both) and clinical (ie, social and occupational function, clinical presentation, personal history of mental illness, physical health comorbidities, treatment use, self-harm, suicidal thoughts and behaviors) factors associated with these transitions. Results: Of the 2254 individuals included in the study, mean (SD) age at baseline was 18.18 (3.33) years and 1330 (59.0%) were female. Data on race/ethnicity were not available. Median (interquartile range) follow-up was 14 (5-33) months. Of 685 participants at stage 1a (nonspecific symptoms), 253 (36.9%) transitioned to stage 1b (attenuated syndromes). Transition was associated with lower social functioning (hazard ratio [HR], 0.77; 95% CI, 0.66-0.90), engagement with education, employment, or both (HR, 0.47; 95% CI, 0.25-0.91), manic-like experiences (HR, 2.12; 95% CI, 1.19-3.78), psychotic-like experiences (HR, 2.13; 95% CI, 1.38-3.28), self-harm (HR, 1.42; 95% CI, 1.01-1.99), and older age (HR, 1.27; 95% CI, 1.11-1.45). Of 1370 stage 1b participants, 176 (12.8%) transitioned to stage 2 (full-threshold) disorders. Transition was associated with psychotic-like experiences (HR, 2.31; 95% CI, 1.65-3.23), circadian disturbance (HR, 1.66; 95% CI, 1.17-2.35), psychiatric medication (HR, 1.43; 95% CI, 1.03-1.99), childhood psychiatric disorder (HR, 1.62; 95% CI, 1.03-2.54), and older age (HR, 1.24; 95% CI, 1.05-1.45). Conclusions and Relevance: Differential rates of progression from earlier to later stages of anxiety, mood, psychotic, or comorbid disorders were observed in young persons who presented for care at various stages. Understanding the rate and factors associated with transition assists planning of stage-specific clinical interventions and secondary prevention trials.

Exploring associations between early substance use and longitudinal socio-occupational functioning in young people engaged in a mental health service.

Neuropsychiatric disorders (including substance misuse) are associated with the greatest burden of functional disability in young people, and contributory factors remain poorly understood. Early-onset substance use is one candidate risk factor which may inform functional prognosis and facilitate direction of interventions aiming to curtail impairment. Accordingly, we modelled associations between early-onset use of alcohol, tobacco, cannabis and amphetamine-type stimulants (ATSs) and longitudinal socio-occupational functioning (indexed by the Social and Occupational Functioning Assessment Scale) in an observational cohort presenting to early intervention mental health services. A clinical proforma collated demographic, clinical, and socio-occupational information for up to 60-months from presentation to services in young people aged 17-30. Of the wider cohort (n = 2398), 446 participants were selected with complete alcohol and substance use data. Latent class analysis was used to derive an 'early-onset' (n = 243) and 'later-onset' class (n = 203) based on age of first use of alcohol, tobacco, cannabis and ATSs. Maximum-likelihood multilevel analyses modelled functioning over time in care and tested associations with substance use latent class, age, gender and diagnosis. Membership in the 'early-onset' class (B = -1.64, p = 0.05), male gender (B = -3.27, p<0.001) and psychotic disorder diagnosis (B = -7.62, p<0.001) were associated with poorer functioning at presentation and at least one other time-point. To our knowledge, this is the first study to explore associations of early-onset substance use and longitudinal functioning in a cohort of young people with mental disorders. The identified factors may be useful for directing specific social (e.g. Social Recovery Therapy) or occupational (e.g. Individual Placement and Support) interventions to at-risk individuals, early in illness course.

Prior suicide attempts predict worse clinical and functional outcomes in young people attending a mental health service.

BACKGROUND: Mental disorders and suicidal thoughts and behaviours are common in help-seeking youth. Few studies report the longitudinal associations between these phenomena and clinical and functional outcomes. This study examined whether prior suicide attempts predict poorer outcomes in mental health service attendees. METHODS: Clinical and functional data from 1143 individuals (aged 12-30) attending a primary care-based mental health service in Australia were collected over 3-60 months (median = 21 months). Odds ratios (OR) with 95% confidence intervals for the effect of a prior suicide attempt on follow-up outcomes were estimated (adjusted for confounders). RESULTS: Prior suicide attempts were common (n = 164; 14%) and prospectively associated with suicidal thoughts (OR = 1.71), suicide attempts (OR = 2.59), self-harm (OR = 1.71), an increased likelihood of being diagnosed with bipolar disorder (OR = 2.99), and the onset of an alcohol/substance use disorder (OR = 2.87). Over the course of care, no suicide attempts were reported in 1052 (92%) individuals, but 25 (2%) had recurrent attempts, and 66 (6%) had new onset of an attempt. New onset was associated with being female and previous suicidal ideation or self-harm; recurrent attempts were associated with being older and comorbid alcohol/substance use disorder. LIMITATIONS: The cohort includes only individuals who remained in clinical contact, and the consistency of their documentation varied (across clinicians and over time). CONCLUSIONS: Young people with prior suicide attempts are vulnerable to ongoing suicidal behaviours, and poorer clinical and functional outcomes. More intensive management strategies may be needed to directly address these behaviours and the long-term risks they confer. These behaviours also emerge over the course of care among those with no previous history, which has important implications for active service-level strategies that target these behaviours for all of those who present to such services.

Delineating the trajectories of social and occupational functioning of young people attending early intervention mental health services in Australia: a longitudinal study.

OBJECTIVES: Mental disorders typically emerge during adolescence and young adulthood and put young people at risk for prolonged socioeconomic difficulties. This study describes the longitudinal course of social and occupational functioning of young people attending primary care-based, early intervention services. DESIGN: A longitudinal study of young people receiving mental healthcare. SETTING: Data were collected between January 2005 and August 2017 from a designated primary care-based mental health service. PARTICIPANTS: 554 young people (54% women) aged 12-32 years. MEASURES: A systematic medical file audit collected clinical and functional information at predetermined time intervals (ie, 3 months to 5+ years) using a clinical pro forma. Group-based trajectory modelling (GBTM) was used to identify distinct trajectories of social and occupational functioning over time (median number of observations per person=4; median follow-up time=23 months). RESULTS: Between first clinical contact and time last seen, 15% of young people had reliably deteriorated, 23% improved and 62% did not demonstrate substantive change in function. Of the whole cohort, 69% had functional scores less than 70 at time last seen, indicative of ongoing and substantive impairment. GBTM identified six distinct functional trajectories whereby over 60% had moderate-to-serious functional impairment at entry and remained chronically impaired over time; 7% entered with serious impairment and deteriorated further; a quarter were mildly impaired at entry and functionally recovered and only a small minority (4%) presented with serious impairments and functionally improved over time. Not being in education, employment or training, previous hospitalisation and a younger age at baseline emerged as significant predictors of these functional trajectories. CONCLUSION: Young people with emerging mental disorders have significant functional impairment at presentation for care, and for the majority, it persists over the course of clinical care. In addition to providing clinical care earlier in the course of illness, these data suggest that more sophisticated and more intensive individual-level and organisational strategies may be required to achieve significant and sustained functional improvements.