Centre for Youth Mental Health - Research Publications

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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.
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    Combining Clinical With Cognitive or Magnetic Resonance Imaging Data for Predicting Transition to Psychosis in Ultra High-Risk Patients: Data From the PACE 400 Cohort.
    Hartmann, S ; Cearns, M ; Pantelis, C ; Dwyer, D ; Cavve, B ; Byrne, E ; Scott, I ; Yuen, HP ; Gao, C ; Allott, K ; Lin, A ; Wood, SJ ; Wigman, JTW ; Amminger, GP ; McGorry, PD ; Yung, AR ; Nelson, B ; Clark, SR (Elsevier BV, 2023-12-03)
    BACKGROUND: Multimodal modeling that combines biological and clinical data shows promise in predicting transition to psychosis in individuals who are at ultra-high risk. Individuals who transition to psychosis are known to have deficits at baseline in cognitive function and reductions in gray matter volume in multiple brain regions identified by magnetic resonance imaging. METHODS: In this study, we used Cox proportional hazards regression models to assess the additive predictive value of each modality-cognition, cortical structure information, and the neuroanatomical measure of brain age gap-to a previously developed clinical model using functioning and duration of symptoms prior to service entry as predictors in the Personal Assessment and Crisis Evaluation (PACE) 400 cohort. The PACE 400 study is a well-characterized cohort of Australian youths who were identified as ultra-high risk of transitioning to psychosis using the Comprehensive Assessment of At Risk Mental States (CAARMS) and followed for up to 18 years; it contains clinical data (from N = 416 participants), cognitive data (n = 213), and magnetic resonance imaging cortical parameters extracted using FreeSurfer (n = 231). RESULTS: The results showed that neuroimaging, brain age gap, and cognition added marginal predictive information to the previously developed clinical model (fraction of new information: neuroimaging 0%-12%, brain age gap 7%, cognition 0%-16%). CONCLUSIONS: In summary, adding a second modality to a clinical risk model predicting the onset of a psychotic disorder in the PACE 400 cohort showed little improvement in the fit of the model for long-term prediction of transition to psychosis.
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    The self, neuroscience and psychosis study: Testing a neurophenomenological model of the onset of psychosis
    Krcmar, M ; Wannan, CMJ ; Lavoie, S ; Allott, K ; Davey, CGG ; Yuen, HP ; Whitford, T ; Formica, M ; Youn, S ; Shetty, J ; Beedham, R ; Rayner, V ; Murray, G ; Polari, A ; Gaweda, L ; Koren, D ; Sass, L ; Parnas, J ; Rasmussen, ARR ; McGorry, P ; Hartmann, JAA ; Nelson, B (WILEY, 2024-02)
    AIM: Basic self disturbance is a putative core vulnerability marker of schizophrenia spectrum disorders. The primary aims of the Self, Neuroscience and Psychosis (SNAP) study are to: (1) empirically test a previously described neurophenomenological self-disturbance model of psychosis by examining the relationship between specific clinical, neurocognitive, and neurophysiological variables in UHR patients, and (2) develop a prediction model using these neurophenomenological disturbances for persistence or deterioration of UHR symptoms at 12-month follow-up. METHODS: SNAP is a longitudinal observational study. Participants include 400 UHR individuals, 100 clinical controls with no attenuated psychotic symptoms, and 50 healthy controls. All participants complete baseline clinical and neurocognitive assessments and electroencephalography. The UHR sample are followed up for a total of 24 months, with clinical assessment completed every 6 months. RESULTS: This paper presents the protocol of the SNAP study, including background rationale, aims and hypotheses, design, and assessment procedures. CONCLUSIONS: The SNAP study will test whether neurophenomenological disturbances associated with basic self-disturbance predict persistence or intensification of UHR symptomatology over a 2-year follow up period, and how specific these disturbances are to a clinical population with attenuated psychotic symptoms. This may ultimately inform clinical care and pathoaetiological models of psychosis.
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    Effects of risperidone/paliperidone versus placebo on cognitive functioning over the first 6 months of treatment for psychotic disorder: secondary analysis of a triple-blind randomised clinical trial
    Allott, K ; Yuen, HP ; Baldwin, L ; O'Donoghue, B ; Fornito, A ; Chopra, S ; Nelson, B ; Graham, J ; Kerr, MJJ ; Proffitt, T-M ; Ratheesh, A ; Alvarez-Jimenez, M ; Harrigan, S ; Brown, E ; Thompson, ADD ; Pantelis, C ; Berk, M ; McGorry, PDD ; Francey, SMM ; Wood, SJJ (SPRINGERNATURE, 2023-06-10)
    The drivers of cognitive change following first-episode psychosis remain poorly understood. Evidence regarding the role of antipsychotic medication is primarily based on naturalistic studies or clinical trials without a placebo arm, making it difficult to disentangle illness from medication effects. A secondary analysis of a randomised, triple-blind, placebo-controlled trial, where antipsychotic-naive patients with first-episode psychotic disorder were allocated to receive risperidone/paliperidone or matched placebo plus intensive psychosocial therapy for 6 months was conducted. A healthy control group was also recruited. A cognitive battery was administered at baseline and 6 months. Intention-to-treat analysis involved 76 patients (antipsychotic medication group: 37; 18.6Mage [2.9] years; 21 women; placebo group: 39; 18.3Mage [2.7]; 22 women); and 42 healthy controls (19.2Mage [3.0] years; 28 women). Cognitive performance predominantly remained stable (working memory, verbal fluency) or improved (attention, processing speed, cognitive control), with no group-by-time interaction evident. However, a significant group-by-time interaction was observed for immediate recall (p = 0.023), verbal learning (p = 0.024) and delayed recall (p = 0.005). The medication group declined whereas the placebo group improved on each measure (immediate recall: p = 0.024; ηp2 = 0.062; verbal learning: p = 0.015; ηp2 = 0.072 both medium effects; delayed recall: p = 0.001; ηp2 = 0.123 large effect). The rate of change for the placebo and healthy control groups was similar. Per protocol analysis (placebo n = 16, medication n = 11) produced similar findings. Risperidone/paliperidone may worsen verbal learning and memory in the early months of psychosis treatment. Replication of this finding and examination of various antipsychotic agents are needed in confirmatory trials. Antipsychotic effects should be considered in longitudinal studies of cognition in psychosis.Trial registration: Australian New Zealand Clinical Trials Registry ( http://www.anzctr.org.au/ ; ACTRN12607000608460).
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    The relationship between subjective sleep disturbance and attenuated psychotic symptoms after accounting for anxiety and depressive symptoms
    Formica, MJC ; Fuller-Tyszkiewicz, M ; Hickie, I ; Olive, L ; Wood, SJ ; Purcell, R ; Yung, AR ; Phillips, LJ ; Nelson, B ; Pantelis, C ; Mcgorry, PD ; Hartmann, JA (ELSEVIER, 2023-08)
    BACKGROUND AND HYPOTHESES: Sleep disturbances are increasingly recognized as cooccurring with psychotic symptoms. The potential importance of this relationship is complicated when considering the effects of anxiety and depressive symptoms which commonly present in early-stage illness states. This study aimed to investigate the relationship between self-reported sleep disturbance on the development of attenuated psychotic symptoms (APS) cross-sectionally and longitudinally while adjusting for roles of anxiety and depressive symptoms. DESIGN: Eight-hundred and two help-seeking young people aged 12 to 25 years who engaged with our Australian early intervention services were included in the study (the "Transitions" cohort). Cross sectional mediation and cross-lagged longitudinal (12-month) mediation models were developed with outcomes being different APS domains. RESULTS: Only baseline excessive daytime sleepiness predicted later APS when accounting for previous APS, anxiety and depressive symptomatology. Cross sectionally, self-reported sleep disturbance showed both direct and indirect predictive relationships with all APS domains. Partial mediation through anxiety and depression was shown for unusual thought content, perceptual abnormalities, and disorganised speech, while full mediation through depression was shown for non-bizarre ideas. CONCLUSIONS: The specificity of the relationship between self-reported sleep disturbance on APS highlights the potential for different roles in mechanistic models of psychotic symptom expression. This further indicates the need for further experimental research to illuminate potential causal pathways. Future research should continue to use continuous, symptom level approaches across a range of timeframes to more accurately model the complex dynamics present in the sleep-psychosis relationship.
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    Network-Based Spreading of Gray Matter Changes Across Different Stages of Psychosis
    Chopra, S ; Segal, A ; Oldham, S ; Holmes, A ; Sabaroedin, K ; Orchard, ER ; Francey, SM ; O'Donoghue, B ; Cropley, V ; Nelson, B ; Graham, J ; Baldwin, L ; Tiego, J ; Yuen, HP ; Allott, K ; Alvarez-Jimenez, M ; Harrigan, S ; Fulcher, BD ; Aquino, K ; Pantelis, C ; Wood, SJ ; Bellgrove, M ; Mcgorry, PD ; Fornito, A (AMER MEDICAL ASSOC, 2023-12)
    IMPORTANCE: Psychotic illness is associated with anatomically distributed gray matter reductions that can worsen with illness progression, but the mechanisms underlying the specific spatial patterning of these changes is unknown. OBJECTIVE: To test the hypothesis that brain network architecture constrains cross-sectional and longitudinal gray matter alterations across different stages of psychotic illness and to identify whether certain brain regions act as putative epicenters from which volume loss spreads. DESIGN, SETTINGS, AND PARTICIPANTS: This case-control study included 534 individuals from 4 cohorts, spanning early and late stages of psychotic illness. Early-stage cohorts included patients with antipsychotic-naive first-episode psychosis (n = 59) and a group of patients receiving medications within 3 years of psychosis onset (n = 121). Late-stage cohorts comprised 2 independent samples of people with established schizophrenia (n = 136). Each patient group had a corresponding matched control group (n = 218). A sample of healthy adults (n = 356) was used to derive representative structural and functional brain networks for modeling of network-based spreading processes. Longitudinal illness-related and antipsychotic-related gray matter changes over 3 and 12 months were examined using a triple-blind randomized placebo-control magnetic resonance imaging study of the antipsychotic-naive patients. All data were collected between April 29, 2008, and January 15, 2020, and analyses were performed between March 1, 2021, and January 14, 2023. MAIN OUTCOMES AND MEASURES: Coordinated deformation models were used to estimate the extent of gray matter volume (GMV) change in each of 332 parcellated areas by the volume changes observed in areas to which they were structurally or functionally coupled. To identify putative epicenters of volume loss, a network diffusion model was used to simulate the spread of pathology from different seed regions. Correlations between estimated and empirical spatial patterns of GMV alterations were used to quantify model performance. RESULTS: Of 534 included individuals, 354 (66.3%) were men, and the mean (SD) age was 28.4 (7.4) years. In both early and late stages of illness, spatial patterns of cross-sectional volume differences between patients and controls were more accurately estimated by coordinated deformation models constrained by structural, rather than functional, network architecture (r range, >0.46 to <0.57; P < .01). The same model also robustly estimated longitudinal volume changes related to illness (r ≥ 0.52; P < .001) and antipsychotic exposure (r ≥ 0.50; P < .004). Network diffusion modeling consistently identified, across all 4 data sets, the anterior hippocampus as a putative epicenter of pathological spread in psychosis. Epicenters of longitudinal GMV loss were apparent in posterior cortex early in the illness and shifted to the prefrontal cortex with illness progression. CONCLUSION AND RELEVANCE: These findings highlight a central role for white matter fibers as conduits for the spread of pathology across different stages of psychotic illness, mirroring findings reported in neurodegenerative conditions. The structural connectome thus represents a fundamental constraint on brain changes in psychosis, regardless of whether these changes are caused by illness or medication. Moreover, the anterior hippocampus represents a putative epicenter of early brain pathology from which dysfunction may spread to affect connected areas.
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    A Sequential Adaptive Intervention Strategy Targeting Remission and Functional Recovery in Young People at Ultrahigh Risk of Psychosis The Staged Treatment in Early Psychosis (STEP) Sequential Multiple Assignment Randomized Trial
    McGorry, PD ; Mei, C ; Amminger, GP ; Yuen, HP ; Kerr, M ; Spark, J ; Wallis, N ; Polari, A ; Baird, S ; Buccilli, K ; Dempsey, S-JA ; Ferguson, N ; Formica, M ; Krcmar, M ; Quinn, AL ; Mebrahtu, Y ; Ruslins, A ; Street, R ; Wannan, C ; Dixon, L ; Carter, C ; Loewy, R ; Niendam, TA ; Shumway, M ; Nelson, B (AMER MEDICAL ASSOC, 2023-09)
    IMPORTANCE: Clinical trials have not established the optimal type, sequence, and duration of interventions for people at ultrahigh risk of psychosis. OBJECTIVE: To determine the effectiveness of a sequential and adaptive intervention strategy for individuals at ultrahigh risk of psychosis. DESIGN, SETTING, AND PARTICIPANTS: The Staged Treatment in Early Psychosis (STEP) sequential multiple assignment randomized trial took place within the clinical program at Orygen, Melbourne, Australia. Individuals aged 12 to 25 years who were seeking treatment and met criteria for ultrahigh risk of psychosis according to the Comprehensive Assessment of At-Risk Mental States were recruited between April 2016 and January 2019. Of 1343 individuals considered, 342 were recruited. INTERVENTIONS: Step 1: 6 weeks of support and problem solving (SPS); step 2: 20 weeks of cognitive-behavioral case management (CBCM) vs SPS; and step 3: 26 weeks of CBCM with fluoxetine vs CBCM with placebo with an embedded fast-fail option of ω-3 fatty acids or low-dose antipsychotic medication. Individuals who did not remit progressed through these steps; those who remitted received SPS or monitoring for up to 12 months. MAIN OUTCOMES AND MEASURES: Global Functioning: Social and Role scales (primary outcome), Brief Psychiatric Rating Scale, Scale for the Assessment of Negative Symptoms, Montgomery-Åsberg Depression Rating Scale, quality of life, transition to psychosis, and remission and relapse rates. RESULTS: The sample comprised 342 participants (198 female; mean [SD] age, 17.7 [3.1] years). Remission rates, reflecting sustained symptomatic and functional improvement, were 8.5%, 10.3%, and 11.4% at steps 1, 2, and 3, respectively. A total of 27.2% met remission criteria at any step. Relapse rates among those who remitted did not significantly differ between SPS and monitoring (step 1: 65.1% vs 58.3%; step 2: 37.7% vs 47.5%). There was no significant difference in functioning, symptoms, and transition rates between SPS and CBCM and between CBCM with fluoxetine and CBCM with placebo. Twelve-month transition rates to psychosis were 13.5% (entire sample), 3.3% (those who ever remitted), and 17.4% (those with no remission). CONCLUSIONS AND RELEVANCE: In this sequential multiple assignment randomized trial, transition rates to psychosis were moderate, and remission rates were lower than expected, partly reflecting the ambitious criteria set and challenges with real-world treatment fidelity and adherence. While all groups showed mild to moderate functional and symptomatic improvement, this was typically short of remission. While further adaptive trials that address these challenges are needed, findings confirm substantial and sustained morbidity and reveal relatively poor responsiveness to existing treatments. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02751632.
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    Baseline data of a sequential multiple assignment randomized trial (STEP study)
    Hartmann, JA ; Nelson, B ; Amminger, GP ; Spark, J ; Yuen, HP ; Kerr, MJ ; Polari, A ; Wallis, N ; Blasioli, J ; Dixon, L ; Carter, C ; Loewy, R ; Niendam, TA ; Shumway, M ; McGorry, PD (WILEY, 2022-10)
    AIM: Research has shown that preventative intervention in individuals at ultra-high risk of psychosis (UHR) improves symptomatic and functional outcomes. The staged treatment in early psychosis (STEP) trial aims to determine the most effective type, timing and sequence of interventions in the UHR population by sequentially studying the effectiveness of (1) support and problem solving, (2) cognitive-behavioural case management and (3) antidepressant medication with an embedded fast-fail option of (4) omega-3 fatty acids or low-dose antipsychotic medication. This paper presents the recruitment flow and baseline clinical characteristics of the sample. METHODS: STEP is a sequential multiple assignment randomized trial. We present the baseline demographics, clinical characteristics and acceptability and feasibility of this treatment approach as indicated by the flow of participants from first contact up until enrolment into the trial. Recruitment took place between April 2016 and January 2019. RESULTS: Of 1343, help-seeking young people who were considered for participation, 402 participants were not eligible and 599 declined/disengaged, resulting in a total of 342 participants enrolled in the study. The most common reason for exclusion was an active prescription of antidepressant medication. Eighty-five percent of the enrolled sample had a non-psychotic DSM-5 diagnosis and symptomatic/functional measures showed a moderate level of clinical severity and functional impairment. DISCUSSION: The present study demonstrates the acceptability and participant's general positive appraisal of sequential treatment. It also shows, in line with other trials in UHR individuals, a significant level of psychiatric morbidity and impairment, demonstrating the clear need for care in this group and that treatment is appropriate.
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    Has improved treatment contributed to the declining rate of transition to psychosis in ultra-high-risk cohorts?
    Formica, MJC ; Phillips, LJ ; Hartmann, JA ; Yung, AR ; Wood, SJ ; Lin, A ; Amminger, GP ; McGorry, PD ; Nelson, B (ELSEVIER, 2022-05)
    BACKGROUND: The factors contributing to declining psychotic disorder transition rates in ultra-high-risk populations remain unclear. We examined the contribution of longitudinal changes in standard clinical treatment ('treatment as usual') to this decline. METHOD: An audit was conducted on 105 clinical files of patients who received standard care at a specialised ultra-high-risk service. The session notes of these files were quantified, allowing examination of treatment quantity, targets, psychotherapy, and medication. Differences in these aspects across patients' year of clinic entry were assessed. Variables with significant differences across years were examined using cox regression to assess their contribution to psychosis transition rates. RESULTS: Findings were that, as a function of patients' year of clinic entry, there were increases in: patients' number of sessions, cognitive behavioural therapy (CBT), problem and solving therapy. There was a relationship between baseline year cohort and psychosis transition rate, with lower rates observed in more recent cohorts. When changes in treatment between cohorts were adjusted for, the relationship between baseline year cohort and transition rate disappeared. The relationship between baseline year and transition rate was attenuated most by increases in CBT. CONCLUSION: Changes in standard treatment, particularly increases in CBT, may have contributed to the decline in psychosis risk observed in recent ultra-high-risk cohorts, although these variables do not fully explain this trend. Implications for clinical practice, prediction and intervention research are discussed. Future ultra-high-risk research should investigate the impact of other treatment factors, such as therapeutic alliance.
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    Outcomes for first-episode psychosis after entry via an at-risk mental state clinic compared to direct entry to a first episode of psychosis service: A systematic review and meta-analysis
    Sizer, H ; Brown, E ; Geros, H ; Yung, A ; Nelson, B ; McGorry, P ; O'Donoghue, B (ELSEVIER, 2022-02)
    OBJECTIVE: Early intervention for psychosis services have been established worldwide and consist of specialist services for those with the At-Risk Mental State (ARMS) and a first episode of psychosis (FEP). This systematic review identified the literature on the outcomes of people who initially presented via an ARMS clinic and later transitioned to a psychotic disorder (UHR-T), compared to those who presented directly to an EI service with a FEP (FEP-D). The outcomes examined were (i) symptomatic (ii) functional, (iii) morbidity and mortality (including physical health) and (iv) service-usage. METHOD: A systematic search strategy was employed using three databases: MEDLINE, PsycInfo, and EMBASE. Studies published in English and that compared any of the above outcomes in a cohort of people with a first episode of psychosis who initially presented via an ARMS clinic to those who presented directly to a FEP service were included. Meta-analysis was performed for any outcome data from at least two studies. RESULTS: A total of 988 unique articles were identified and of these, three studies fulfilled the inclusion criteria and these included a total of 78 UHR-T and 253 FEP-D individuals. In the one study examining remission rates, there was no difference observed after one year in the UHR-T and FEP-D groups. In the one study that examined neurocognition, no differences were observed in any of the neurocognitive domains between groups after one year. Two studies examined psychiatric admission rates within one year and one of these found that UHR-T individuals were less likely to have any psychiatric admission (46% vs 68%) and admissions were less likely to be involuntary (30% vs 74%), while the other study found no difference in admission rates. In the meta-analysis, UHR-T individuals had lower odds for any psychiatric hospital admission within one year compared to FEP-D individuals (OR = 0.54, 95% C.I. 0.32 - 0.94, p = .03). No studies examined functional outcomes or mortality and morbidity between the groups. CONCLUSION: The limited research indicates similar or superior outcomes for people with a FEP who present initially via an ARMS clinic. The reduced psychiatric admission rate is an important potential benefit of ARMS clinics that requires replication.