Centre for Youth Mental Health - Research Publications

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    Plasma neurofilament light chain is not elevated in people with first-episode psychosis or those at ultra-high risk for psychosis.
    Kang, MJY ; Eratne, D ; Wannan, C ; Santillo, AF ; Velakoulis, D ; Pantelis, C ; Cropley, V (Elsevier BV, 2024-04-05)
    INTRODUCTION: Neurofilament light chain (NfL), a blood biomarker of neuronal injury, shows promise in distinguishing neurodegenerative disorders from psychiatric conditions. This is especially relevant in psychosis, given neurological conditions such as autoimmune encephalitis and Niemann Pick Type C disease (NPC) may initially present with psychotic symptoms. Whilst NfL levels have been studied in established schizophrenia cases, their levels in first-episode psychosis (FEP) and ultra-high risk (UHR) for psychosis individuals remain largely unexplored. This study aimed to compare plasma NfL in people with FEP or UHR with healthy controls, as well as explore its associations with clinical data. METHOD: We retrospectively analysed plasma NfL in 63 participants, consisting of 29 individuals with FEP, 10 individuals with UHR, and 24 healthy controls. We used general linear models (GLM), which were bootstrapped, to compute bias-corrected and accelerated (BCa) 95 % confidence intervals (CIs). RESULTS: Mean NfL levels were 5.2 pg/mL in FEP, 4.9 pg/mL in UHR, and 5.9 pg/mL in healthy controls. Compared to healthy controls, there were no significant differences in NfL levels in the FEP group (β = -0.22, 95 % CI [-0.86, 0.39], p = 0.516) nor UHR group (β = -0.37, 95 % CI [-0.90, 0.19], p = 0.182). There were no significant associations between NfL levels and clinical variables in the FEP group. DISCUSSION: Our study is the first to demonstrate that plasma NfL levels are not significantly elevated in individuals at UHR for psychosis compared to healthy controls, a finding also observed in the FEP cohort. These findings bolster the potential diagnostic utility of NfL in differentiating between psychiatric and neurodegenerative disorders.
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    A Novel Blended Transdiagnostic Intervention (eOrygen) for Youth Psychosis and Borderline Personality Disorder: Uncontrolled Single-Group Pilot Study
    O'Sullivan, S ; McEnery, C ; Cagliarini, D ; Hinton, JDX ; Valentine, L ; Nicholas, J ; Chen, NA ; Castagnini, E ; Lester, J ; Kanellopoulos, E ; D'Alfonso, S ; Gleeson, JF ; Alvarez-Jimenez, M (JMIR PUBLICATIONS, INC, 2024)
    BACKGROUND: Integrating innovative digital mental health interventions within specialist services is a promising strategy to address the shortcomings of both face-to-face and web-based mental health services. However, despite young people's preferences and calls for integration of these services, current mental health services rarely offer blended models of care. OBJECTIVE: This pilot study tested an integrated digital and face-to-face transdiagnostic intervention (eOrygen) as a blended model of care for youth psychosis and borderline personality disorder. The primary aim was to evaluate the feasibility, acceptability, and safety of eOrygen. The secondary aim was to assess pre-post changes in key clinical and psychosocial outcomes. An exploratory aim was to explore the barriers and facilitators identified by young people and clinicians in implementing a blended model of care into practice. METHODS: A total of 33 young people (aged 15-25 years) and 18 clinicians were recruited over 4 months from two youth mental health services in Melbourne, Victoria, Australia: (1) the Early Psychosis Prevention and Intervention Centre, an early intervention service for first-episode psychosis; and (2) the Helping Young People Early Clinic, an early intervention service for borderline personality disorder. The feasibility, acceptability, and safety of eOrygen were evaluated via an uncontrolled single-group study. Repeated measures 2-tailed t tests assessed changes in clinical and psychosocial outcomes between before and after the intervention (3 months). Eight semistructured qualitative interviews were conducted with the young people, and 3 focus groups, attended by 15 (83%) of the 18 clinicians, were conducted after the intervention. RESULTS: eOrygen was found to be feasible, acceptable, and safe. Feasibility was established owing to a low refusal rate of 25% (15/59) and by exceeding our goal of young people recruited to the study per clinician. Acceptability was established because 93% (22/24) of the young people reported that they would recommend eOrygen to others, and safety was established because no adverse events or unlawful entries were recorded and there were no worsening of clinical and social outcome measures. Interviews with the young people identified facilitators to engagement such as peer support and personalized therapy content, as well as barriers such as low motivation, social anxiety, and privacy concerns. The clinician focus groups identified evidence-based content as an implementation facilitator, whereas a lack of familiarity with the platform was identified as a barrier owing to clinicians' competing priorities, such as concerns related to risk and handling acute presentations, as well as the challenge of being understaffed. CONCLUSIONS: eOrygen as a blended transdiagnostic intervention has the potential to increase therapeutic continuity, engagement, alliance, and intensity. Future research will need to establish the effectiveness of blended models of care for young people with complex mental health conditions and determine how to optimize the implementation of such models into specialized services.
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    Development of the PSYCHS: Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS.
    Woods, SW ; Parker, S ; Kerr, MJ ; Walsh, BC ; Wijtenburg, SA ; Prunier, N ; Nunez, AR ; Buccilli, K ; Mourgues-Codern, C ; Brummitt, K ; Kinney, KS ; Trankler, C ; Szacilo, J ; Colton, B-L ; Ali, M ; Haidar, A ; Billah, T ; Huynh, K ; Ahmed, U ; Adery, LL ; Corcoran, CM ; Perkins, DO ; Schiffman, J ; Perez, J ; Mamah, D ; Ellman, LM ; Powers, AR ; Coleman, MJ ; Anticevic, A ; Fusar-Poli, P ; Kane, JM ; Kahn, RS ; McGorry, PD ; Bearden, CE ; Shenton, ME ; Nelson, B ; Calkins, ME ; Hendricks, L ; Bouix, S ; Addington, J ; McGlashan, TH ; Yung, AR ; Accelerating Medicines Partnership Schizophrenia, ( 2023-05-02)
    AIM: To harmonize two ascertainment and severity rating instruments commonly used for the clinical high risk syndrome for psychosis (CHR-P): the Structured Interview for Psychosis-risk Syndromes (SIPS) and the Comprehensive Assessment of At-Risk Mental States (CAARMS). METHODS: The initial workshop is described in the companion report from Addington et al. After the workshop, lead experts for each instrument continued harmonizing attenuated positive symptoms and criteria for psychosis and CHR-P through an intensive series of joint videoconferences. RESULTS: Full harmonization was achieved for attenuated positive symptom ratings and psychosis criteria, and partial harmonization for CHR-P criteria. The semi-structured interview, named P ositive SY mptoms and Diagnostic Criteria for the C AARMS H armonized with the S IPS (PSYCHS), generates CHR-P criteria and severity scores for both CAARMS and SIPS. CONCLUSION: Using the PSYCHS for CHR-P ascertainment, conversion determination, and attenuated positive symptom severity rating will help in comparing findings across studies and in meta-analyses.
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    Cortical profiles of numerous psychiatric disorders and normal development share a common pattern.
    Cao, Z ; Cupertino, RB ; Ottino-Gonzalez, J ; Murphy, A ; Pancholi, D ; Juliano, A ; Chaarani, B ; Albaugh, M ; Yuan, D ; Schwab, N ; Stafford, J ; Goudriaan, AE ; Hutchison, K ; Li, C-SR ; Luijten, M ; Groefsema, M ; Momenan, R ; Schmaal, L ; Sinha, R ; van Holst, RJ ; Veltman, DJ ; Wiers, RW ; Porjesz, B ; Lett, T ; Banaschewski, T ; Bokde, ALW ; Desrivières, S ; Flor, H ; Grigis, A ; Gowland, P ; Heinz, A ; Brühl, R ; Martinot, J-L ; Martinot, M-LP ; Artiges, E ; Nees, F ; Orfanos, DP ; Paus, T ; Poustka, L ; Hohmann, S ; Millenet, S ; Fröhner, JH ; Robinson, L ; Smolka, MN ; Walter, H ; Winterer, J ; Schumann, G ; Whelan, R ; Bhatt, RR ; Zhu, A ; Conrod, P ; Jahanshad, N ; Thompson, PM ; Mackey, S ; Garavan, H ; IMAGEN Consortium, ; ENIGMA Addiction Working Group, (Springer Science and Business Media LLC, 2023-02)
    The neurobiological bases of the association between development and psychopathology remain poorly understood. Here, we identify a shared spatial pattern of cortical thickness (CT) in normative development and several psychiatric and neurological disorders. Principal component analysis (PCA) was applied to CT of 68 regions in the Desikan-Killiany atlas derived from three large-scale datasets comprising a total of 41,075 neurotypical participants. PCA produced a spatially broad first principal component (PC1) that was reproducible across datasets. Then PC1 derived from healthy adult participants was compared to the pattern of CT differences associated with psychiatric and neurological disorders comprising a total of 14,886 cases and 20,962 controls from seven ENIGMA disease-related working groups, normative maturation and aging comprising a total of 17,697 scans from the ABCD Study® and the IMAGEN developmental study, and 17,075 participants from the ENIGMA Lifespan working group, as well as gene expression maps from the Allen Human Brain Atlas. Results revealed substantial spatial correspondences between PC1 and widespread lower CT observed in numerous psychiatric disorders. Moreover, the PC1 pattern was also correlated with the spatial pattern of normative maturation and aging. The transcriptional analysis identified a set of genes including KCNA2, KCNS1 and KCNS2 with expression patterns closely related to the spatial pattern of PC1. The gene category enrichment analysis indicated that the transcriptional correlations of PC1 were enriched to multiple gene ontology categories and were specifically over-represented starting at late childhood, coinciding with the onset of significant cortical maturation and emergence of psychopathology during the prepubertal-to-pubertal transition. Collectively, the present study reports a reproducible latent pattern of CT that captures interregional profiles of cortical changes in both normative brain maturation and a spectrum of psychiatric disorders. The pubertal timing of the expression of PC1-related genes implicates disrupted neurodevelopment in the pathogenesis of the spectrum of psychiatric diseases emerging during adolescence.
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    A supported education programme implemented in youth mental health services: Outcomes and lessons from the first year of COVID-disrupted delivery
    Nicholas, J (Wiley, 2024)
    AIM: Educational attainment is consistently highly valued by young people with mental ill health, yet maintenance and completion of education is a challenge. This paper reports on the implementation of a supported education programme for youth mental health. METHODS: Between 10 October 2019 and 10 October 2020, a supported education programme was delivered within primary and tertiary youth mental health services. A description of the programme, context, and adjustments required due to COVID-19 is presented, and the educational outcomes of young people referred to the programme were explored. Two case studies are also presented. RESULTS: The programme received 71 referrals over this period, of which 70.4% had not yet completed secondary school and 68% were experiencing multiple mental health conditions. Overall outcomes were positive, with 47.5% of the 40 young people who chose to engage with the programme maintaining or re-engaging with education. However, the remainder of those who engaged withdrew from the programme, often reporting challenges due to COVID-19 such as social isolation or increased uncertainty. Additionally, a number of young people declined or disengaged from the programme to focus on employment. CONCLUSION: This report of the experience of integrating a supported employment programme in Australian youth mental health services reinforces the need for such support, and provides preliminary evidence for its successful implementation as part of routine care. The disengagement in response to COVID-19 highlights the real-world challenges of the pandemic, while young people's voicing of employment goals indicates the need for combined educational and vocational support-to assist transition and progression between these goals.
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    Proteomic Biomarkers for the Prediction of Transition to Psychosis in Individuals at Clinical High Risk: A Multi-cohort Model Development Study
    Byrne, JF ; Healy, C ; Focking, M ; Susai, SR ; Mongan, D ; Wynne, K ; Kodosaki, E ; Heurich, M ; de Haan, L ; Hickie, IB ; Smesny, S ; Thompson, A ; Markulev, C ; Young, AR ; Schafer, MR ; Riecher-Rossler, A ; Mossaheb, N ; Berger, G ; Schlogelhofer, M ; Nordentoft, M ; Chen, EYH ; Verma, S ; Nieman, DH ; Woods, SW ; Cornblatt, BA ; Stone, WS ; Mathalon, DH ; Bearden, CE ; Cadenhead, KS ; Addington, J ; Walker, EF ; Cannon, TD ; Cannon, M ; McGorry, P ; Amminger, P ; Cagney, G ; Nelson, B ; Jeffries, C ; Perkins, D ; Cotter, DR (OXFORD UNIV PRESS, 2024-04-30)
    Psychosis risk prediction is one of the leading challenges in psychiatry. Previous investigations have suggested that plasma proteomic data may be useful in accurately predicting transition to psychosis in individuals at clinical high risk (CHR). We hypothesized that an a priori-specified proteomic prediction model would have strong predictive accuracy for psychosis risk and aimed to replicate longitudinal associations between plasma proteins and transition to psychosis. This study used plasma samples from participants in 3 CHR cohorts: the North American Prodrome Longitudinal Studies 2 and 3, and the NEURAPRO randomized control trial (total n = 754). Plasma proteomic data were quantified using mass spectrometry. The primary outcome was transition to psychosis over the study follow-up period. Logistic regression models were internally validated, and optimism-corrected performance metrics derived with a bootstrap procedure. In the overall sample of CHR participants (age: 18.5, SD: 3.9; 51.9% male), 20.4% (n = 154) developed psychosis within 4.4 years. The a priori-specified model showed poor risk-prediction accuracy for the development of psychosis (C-statistic: 0.51 [95% CI: 0.50, 0.59], calibration slope: 0.45). At a group level, Complement C8B, C4B, C5, and leucine-rich α-2 glycoprotein 1 (LRG1) were associated with transition to psychosis but did not surpass correction for multiple comparisons. This study did not confirm the findings from a previous proteomic prediction model of transition from CHR to psychosis. Certain complement proteins may be weakly associated with transition at a group level. Previous findings, derived from small samples, should be interpreted with caution.
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    Multi-site benchmark classification of major depressive disorder using machine learning on cortical and subcortical measures.
    Belov, V ; Erwin-Grabner, T ; Aghajani, M ; Aleman, A ; Amod, AR ; Basgoze, Z ; Benedetti, F ; Besteher, B ; Bülow, R ; Ching, CRK ; Connolly, CG ; Cullen, K ; Davey, CG ; Dima, D ; Dols, A ; Evans, JW ; Fu, CHY ; Gonul, AS ; Gotlib, IH ; Grabe, HJ ; Groenewold, N ; Hamilton, JP ; Harrison, BJ ; Ho, TC ; Mwangi, B ; Jaworska, N ; Jahanshad, N ; Klimes-Dougan, B ; Koopowitz, S-M ; Lancaster, T ; Li, M ; Linden, DEJ ; MacMaster, FP ; Mehler, DMA ; Melloni, E ; Mueller, BA ; Ojha, A ; Oudega, ML ; Penninx, BWJH ; Poletti, S ; Pomarol-Clotet, E ; Portella, MJ ; Pozzi, E ; Reneman, L ; Sacchet, MD ; Sämann, PG ; Schrantee, A ; Sim, K ; Soares, JC ; Stein, DJ ; Thomopoulos, SI ; Uyar-Demir, A ; van der Wee, NJA ; van der Werff, SJA ; Völzke, H ; Whittle, S ; Wittfeld, K ; Wright, MJ ; Wu, M-J ; Yang, TT ; Zarate, C ; Veltman, DJ ; Schmaal, L ; Thompson, PM ; Goya-Maldonado, R ; ENIGMA Major Depressive Disorder working group, (Springer Science and Business Media LLC, 2024-01-11)
    Machine learning (ML) techniques have gained popularity in the neuroimaging field due to their potential for classifying neuropsychiatric disorders. However, the diagnostic predictive power of the existing algorithms has been limited by small sample sizes, lack of representativeness, data leakage, and/or overfitting. Here, we overcome these limitations with the largest multi-site sample size to date (N = 5365) to provide a generalizable ML classification benchmark of major depressive disorder (MDD) using shallow linear and non-linear models. Leveraging brain measures from standardized ENIGMA analysis pipelines in FreeSurfer, we were able to classify MDD versus healthy controls (HC) with a balanced accuracy of around 62%. But after harmonizing the data, e.g., using ComBat, the balanced accuracy dropped to approximately 52%. Accuracy results close to random chance levels were also observed in stratified groups according to age of onset, antidepressant use, number of episodes and sex. Future studies incorporating higher dimensional brain imaging/phenotype features, and/or using more advanced machine and deep learning methods may yield more encouraging prospects.
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    Best practice for integrating digital interventions into clinical care for young people at risk of suicide: a Delphi study
    Bailey, E ; Bellairs-Walsh, I ; Reavley, N ; Gooding, P ; Hetrick, S ; Rice, S ; Boland, A ; Robinson, J (BMC, 2024-01-24)
    BACKGROUND: Digital tools have the capacity to complement and enhance clinical care for young people at risk of suicide. Despite the rapid rise of digital tools, their rate of integration into clinical practice remains low. The poor uptake of digital tools may be in part due to the lack of best-practice guidelines for clinicians and services to safely apply them with this population. METHODS: A Delphi study was conducted to produce a set of best-practice guidelines for clinicians and services on integrating digital tools into clinical care for young people at risk of suicide. First, a questionnaire was developed incorporating action items derived from peer-reviewed and grey literature, and stakeholder interviews with 17 participants. Next, two independent expert panels comprising professionals (academics and clinical staff; n = 20) and young people with lived experience of using digital technology for support with suicidal thoughts and behaviours (n = 29) rated items across two consensus rounds. Items reaching consensus (rated as "essential" or "important" by at least 80% of panel members) at the end of round two were collated into a set of guidelines. RESULTS: Out of 326 individual items rated by the panels, 188 (57.7%) reached consensus for inclusion in the guidelines. The endorsed items provide guidance on important topics when working with young people, including when and for whom digital tools should be used, how to select a digital tool and identify potentially harmful content, and identifying and managing suicide risk conveyed via digital tools. Several items directed at services (rather than individual clinicians) were also endorsed. CONCLUSIONS: This study offers world-first evidence-informed guidelines for clinicians and services to integrate digital tools into clinical care for young people at risk of suicide. Implementation of the guidelines is an important next step and will hopefully lead to improved uptake of potentially helpful digital tools in clinical practice.
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    Global prevalence of psychosocial assessment following hospital-treated self-harm: systematic review and meta-analysis
    Witt, K ; McGill, K ; Leckning, B ; Hill, NTM ; Davies, BM ; Robinson, J ; Carter, G (CAMBRIDGE UNIV PRESS, 2024-01-11)
    BACKGROUND: Hospital-treated self-harm is common, costly and associated with repeated self-harm and suicide. Providing a comprehensive psychosocial assessment following self-harm is recommended by professional bodies and may improve outcomes. AIMS: To review the provision of psychosocial assessments after hospital-presenting self-harm and the extent to which macro-level factors indicative of service provision explain variability in these estimates. METHOD: We searched five electronic databases to 3 January 2023 for studies reporting data on the proportion of patients and/or events that were provided a psychosocial assessment. Pooled weighted prevalence estimates were calculated with the random-effects model. Random-effects meta-regression was used to investigate between-study variability. RESULTS: 119 publications (69 unique samples) were included. Across ages, two-thirds of patients had a psychosocial assessment (0.67, 95% CI 0.58-0.76). The proportion was higher for young people and older adults (0.75, 95% CI 0.36-0.99 and 0.83, 95% CI 0.48-1.00, respectively) compared with adults (0.64, 95% CI 0.54-0.73). For events, around half of all presentations had these assessments across the age range. No macro-level factor explained between-study heterogeneity. CONCLUSIONS: There is room for improvement in the universal provision of psychosocial assessments for self-harm. This represents a missed opportunity to review and tailor aftercare supports for those at risk. Given the marked unexplained heterogeneity between studies, the person- and system-level factors that influence provision of psychosocial assessments after self-harm should be studied further.
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    Non-psychotic Outcomes in Young People at Ultra-High Risk of Developing a Psychotic Disorder: A Long-Term Follow-up Study
    Spiteri-Staines, AE ; Yung, AR ; Lin, A ; Hartmann, JA ; Amminger, P ; Mcgorry, PD ; Thompson, A ; Wood, SJ ; Nelson, B (OXFORD UNIV PRESS, 2024-02-16)
    BACKGROUND: The majority of individuals at ultra-high risk (UHR) for psychosis do not transition to a full threshold psychotic disorder. It is therefore important to understand their longer-term clinical and functional outcomes, particularly given the high prevalence of comorbid mental disorders in this population at baseline. AIMS: This study investigated the prevalence of non-psychotic disorders in the UHR population at entry and long-term follow-up and their association with functional outcomes. Persistence of UHR status was also investigated. STUDY DESIGN: The sample comprised 102 UHR young people from the Personal Assessment and Crisis Evaluation (PACE) Clinic who had not transitioned to psychosis by long-term follow-up (mean = 8.8 years, range = 6.8-12.1 years since baseline). RESULTS: Eighty-eight percent of participants at baseline were diagnosed with at least one mental disorder, the majority of which were mood disorders (78%), anxiety disorders (35%), and substance use disorders (SUDs) (18%). This pattern of disorder prevalence continued at follow-up, though prevalence was reduced, with 52% not meeting criteria for current non-psychotic mental disorder. However, 35% of participants developed a new non-psychotic mental disorder by follow-up. Presence of a continuous non-psychotic mental disorder was associated with poorer functional outcomes at follow-up. 28% of participants still met UHR criteria at follow-up. CONCLUSIONS: The study adds to the evidence base that a substantial proportion of UHR individuals who do not transition to psychosis experience persistent attenuated psychotic symptoms and persistent and incident non-psychotic disorders over the long term. Long-term treatment and re-entry into services is indicated.