Centre for Youth Mental Health - Research Publications

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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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    Intelligence trajectories in individuals at ultra-high risk for psychosis: An 8-year longitudinal analysis
    Cheng, N ; Lin, A ; Bowden, S ; Gao, C ; Yung, AR ; Nelson, B ; Thompson, A ; Yuen, HP ; Brewer, WJ ; Cagliarini, D ; Bruxner, A ; Simmons, M ; Broussard, C ; Pantelis, C ; McGorry, PD ; Allott, K ; Wood, SJ (ELSEVIER, 2022-10)
    Cognitive impairment is a well-documented predictor of transition to a full-threshold psychotic disorder amongst individuals at ultra-high risk (UHR) for psychosis. However, less is known about whether change in cognitive functioning differs between those who do and do not transition. Studies to date have not examined trajectories in intelligence constructs (e.g., acquired knowledge and fluid intelligence), which have demonstrated marked impairments in individuals with schizophrenia. This study aimed to examine intelligence trajectories using longitudinal data spanning an average of eight years, where some participants completed assessments over three time-points. Participants (N = 139) at UHR for psychosis completed the Wechsler Abbreviated Scale of Intelligence (WASI) at each follow-up. Linear mixed-effects models mapped changes in WASI Full-Scale IQ (FSIQ) and T-scores on Vocabulary, Similarities, Block Design, and Matrix Reasoning subtests. The sample showed stable and improving trajectories for FSIQ and all subtests. There were no significant differences in trajectories between those who did and did not transition to psychosis and between individuals with good and poor functional outcomes. However, although not significant, the trajectories of the acquired knowledge subtests diverged between transitioned and non-transitioned individuals (β = -0.12, 95 % CI [-0.29, 0.05] for Vocabulary and β = -0.14, 95 % CI [-0.33, 0.05] for Similarities). Overall, there was no evidence for long-term deterioration in intelligence trajectories in this UHR sample. Future studies with a larger sample of transitioned participants may be needed to explore potential differences in intelligence trajectories between UHR transition groups and other non-psychosis outcomes.
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    Pineal morphology of the clinical high-risk state for psychosis and different psychotic disorders
    Takahashi, T ; Wood, SJ ; Yung, AR ; Nelson, B ; Lin, A ; Yuen, HP ; Phillips, LJ ; Suzuki, M ; McGorry, PD ; Velakoulis, D ; Pantelis, C (ELSEVIER, 2022-06)
    BACKGROUND: Pineal volume reductions have been reported in schizophrenia and clinical high-risk states for the development of psychosis, supporting the role of melatonin dysregulation in the pathophysiology of psychosis. However, it remains unclear whether pineal volume is associated with the later onset of psychosis in individuals at clinical high-risk (CHR) of psychosis or if pineal atrophy is specific to schizophrenia among different psychotic disorders. METHODS: This magnetic resonance imaging study examined the volume of and cyst prevalence in the pineal gland in 135 individuals at CHR of psychosis [52 (38.5%) subsequently developed psychosis], 162 with first-episode psychosis (FEP), 89 with chronic schizophrenia, and 87 healthy controls. The potential contribution of the pineal morphology to clinical characteristics was also examined in the CHR and FEP groups. RESULTS: Pineal volumes did not differ significantly between the CHR, FEP, and chronic schizophrenia groups, but were significantly smaller than that in healthy controls. However, pineal volumes were not associated with the later onset of psychosis in the CHR group or FEP sub-diagnosis (i.e., schizophrenia, schizophreniform disorder, affective psychosis, and other psychoses). No significant differences were observed in the prevalence of pineal cysts between the groups, and it also did not correlate with clinical characteristics in the CHR and FEP groups. CONCLUSION: These results suggest that pineal atrophy is a general vulnerability marker of psychosis, while pineal cysts do not appear to contribute to the pathophysiology of psychosis.
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    Effects of omega-3 polyunsaturated fatty acid supplementation on cognitive functioning in youth at ultra-high risk for psychosis: secondary analysis of the NEURAPRO randomised controlled trial
    Cheng, N ; McLaverty, A ; Nelson, B ; Markulev, C ; Schafer, MR ; Berger, M ; Mossaheb, N ; Schlogelhofer, M ; Smesny, S ; Hicikie, IB ; Berger, GE ; Chen, EYH ; de Haan, L ; Nieman, DH ; Nordentoft, M ; Riecher-Rossler, A ; Verma, S ; Street, R ; Thompson, A ; Yuen, HP ; Hester, R ; Yung, AR ; McGorry, PD ; Allott, K ; Amminger, GP (CAMBRIDGE UNIV PRESS, 2022-09-08)
    BACKGROUND: Cognitive impairments are well-established features of psychotic disorders and are present when individuals are at ultra-high risk for psychosis. However, few interventions target cognitive functioning in this population. AIMS: To investigate whether omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation improves cognitive functioning among individuals at ultra-high risk for psychosis. METHOD: Data (N = 225) from an international, multi-site, randomised controlled trial (NEURAPRO) were analysed. Participants were given omega-3 supplementation (eicosapentaenoic acid and docosahexaenoic acid) or placebo over 6 months. Cognitive functioning was assessed with the Brief Assessment of Cognition in Schizophrenia (BACS). Mixed two-way analyses of variance were computed to compare the change in cognitive performance between omega-3 supplementation and placebo over 6 months. An additional biomarker analysis explored whether change in erythrocyte n-3 PUFA levels predicted change in cognitive performance. RESULTS: The placebo group showed a modest greater improvement over time than the omega-3 supplementation group for motor speed (ηp2 = 0.09) and BACS composite score (ηp2 = 0.21). After repeating the analyses without individuals who transitioned, motor speed was no longer significant (ηp2 = 0.02), but the composite score remained significant (ηp2 = 0.02). Change in erythrocyte n-3 PUFA levels did not predict change in cognitive performance over 6 months. CONCLUSIONS: We found no evidence to support the use of omega-3 supplementation to improve cognitive functioning in ultra-high risk individuals. The biomarker analysis suggests that this finding is unlikely to be attributed to poor adherence or consumption of non-trial n-3 PUFAs.
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    Preventive interventions for individuals at ultra high risk for psychosis: An updated and extended meta-analysis
    Mei, C ; van der Gaag, M ; Nelson, B ; Smit, F ; Yuen, HP ; Berger, M ; Krcmar, M ; French, P ; Amminger, GP ; Bechdolf, A ; Cuijpers, P ; Yung, AR ; McGorry, PD (PERGAMON-ELSEVIER SCIENCE LTD, 2021-06)
    Intervention at the earliest illness stage, in ultra or clinical high-risk individuals, or indicated prevention, currently represents the most promising strategy to ameliorate, delay or prevent psychosis. We review the current state of evidence and conduct a broad-spectrum meta-analysis of various outcomes: transition to psychosis, attenuated positive and negative psychotic symptoms, mania, depression, anxiety, general psychopathology, symptom-related distress, functioning, quality of life, and treatment acceptability. 26 randomized controlled trials were included. Meta-analytically pooled interventions reduced transition rate (risk ratio [RR] = 0.57, 95%CI 0.41-0.81) and attenuated positive psychotic symptoms at 12-months (standardized mean difference = -0.15, 95%CI = -0.28--0.01). When stratified by intervention type (pharmacological, psychological), only the pooled effect of psychological interventions on transition rate was significant. Cognitive behavioral therapy (CBT) was associated with a reduction in incidence at 12-months (RR = 0.52, 95%CI = 0.33-0.82) and 18-48-months (RR = 0.60, 95%CI = 0.42-0.84), but not 6-months. Findings at 12-months and 18-48-months were robust in sensitivity and subgroup analyses. All other outcomes were non-significant. To date, effects of trialed treatments are specific to transition and, a lesser extent, attenuated positive symptoms, highlighting the future need to target other symptom domains and functional outcomes. Sound evidence supports CBT in reducing transition and the value of intervening at this illness stage. STUDY REGISTRATION: Research Registry ID: reviewregistry907.
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    The association between migrant status and transition in an ultra-high risk for psychosis population
    O'Donoghue, B ; Geros, H ; Sizer, H ; Addington, J ; Amminger, GP ; Beaden, CE ; Cadenhead, KS ; Cannon, TD ; Cornblatt, BA ; Berger, GE ; Chen, EYH ; de Haan, L ; Hartmann, JA ; Hickie, IB ; Ising, HK ; Lavoie, S ; Lin, A ; Markulev, C ; Mathalon, DH ; McGlashan, TH ; Mifsud, NG ; Mossaheb, N ; Nieman, DH ; Nordentoft, M ; Perkins, DO ; Riecher-Roessler, A ; Schaefer, MR ; Schloegelhofer, M ; Seidman, LJ ; Smesny, S ; Thompson, A ; Tsuang, MT ; van der Gaag, M ; Verma, S ; Walker, EF ; Wood, SJ ; Woods, SW ; Yuen, HP ; Yung, AR ; McGorry, PD ; Nelson, B (SPRINGER HEIDELBERG, 2021-06)
    PURPOSE: Migrant status is one of the most replicated and robust risk factors for developing a psychotic disorder. This study aimed to determine whether migrant status in people identified as Ultra-High Risk for Psychosis (UHR) was associated with risk of transitioning to a full-threshold psychotic disorder. METHODS: Hazard ratios for the risk of transition were calculated from five large UHR cohorts (n = 2166) and were used to conduct a meta-analysis using the generic inverse-variance method using a random-effects model. RESULTS: 2166 UHR young people, with a mean age of 19.1 years (SD ± 4.5) were included, of whom 221 (10.7%) were first-generation migrants. A total of 357 young people transitioned to psychosis over a median follow-up time of 417 days (I.Q.R.147-756 days), representing 17.0% of the cohort. The risk of transition to a full-threshold disorder was not increased for first-generation migrants, (HR = 1.08, 95% CI 0.62-1.89); however, there was a high level of heterogeneity between studies The hazard ratio for second-generation migrants to transition to a full-threshold psychotic disorder compared to the remainder of the native-born population was 1.03 (95% CI 0.70-1.51). CONCLUSIONS: This meta-analysis did not find a statistically significant association between migrant status and an increased risk for transition to a full-threshold psychotic disorder; however, several methodological issues could explain this finding. Further research should focus on examining the risk of specific migrant groups and also ensuring that migrant populations are adequately represented within UHR clinics.
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    Twelve-Month Cognitive Trajectories in Individuals at Ultra-High Risk for Psychosis: A Latent Class Analysis
    Allott, K ; Schmidt, SJ ; Yuen, HP ; Wood, SJ ; Nelson, B ; Markulev, C ; Lavoie, S ; Brewer, WJ ; Schäfer, MR ; Mossaheb, N ; Schlögelhofer, M ; Smesny, S ; Hickie, IB ; Berger, GE ; Chen, EYH ; De Haan, L ; Nieman, DH ; Nordentoft, M ; Riecher-Rössler, A ; Verma, S ; Thompson, A ; Yung, AR ; Amminger, P ; McGorry, PD ; Hartmann, J (Oxford University Press (OUP), 2022-01-01)
    Abstract Understanding longitudinal cognitive performance in individuals at ultra-high risk for psychosis (UHR) is important for informing theoretical models and treatment. A vital step in this endeavor is to determine whether there are UHR subgroups that have similar patterns of cognitive change over time. The aims were to: i) identify latent class trajectories of cognitive performance over 12-months in UHR individuals, ii) identify baseline demographic and clinical predictors of the resulting classes, and iii) determine whether trajectory classes were associated with transition to psychosis or functional outcomes. Cognition was assessed using the Brief Assessment of Cognition in Schizophrenia (BACS) at baseline, 6- and 12-months (N = 288). Using Growth Mixture Modeling, a single unimpaired improving trajectory class was observed for motor function, speed of processing, verbal fluency, and BACS composite. A two-class solution was observed for executive function and working memory, showing one unimpaired and a second impaired class. A three-class solution was found for verbal learning and memory: unimpaired, mildly impaired, and initially extremely impaired, but improved (“caught up”) to the level of the mildly impaired. IQ, omega-3 index, and premorbid adjustment were associated with class membership, whereas clinical variables (symptoms, substance use), including transition to psychosis, were not. Working memory and verbal learning and memory trajectory class membership was associated with functioning outcomes. These findings suggest there is no short-term progressive cognitive decline in help-seeking UHR individuals, including those who transition to psychosis. Screening of cognitive performance may be useful for identifying UHR individuals who may benefit from targeted cognitive interventions.
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    Greater preference for eveningness is associated with negative symptoms in an ultra-high risk for psychosis sample
    Shetty, JJ ; Nicholas, C ; Nelson, B ; McGorry, PD ; Lavoie, S ; Markulev, C ; Schafer, MR ; Thompson, A ; Yuen, HP ; Yung, AR ; Nieman, DH ; de Haan, L ; Amminger, GP ; Hartmann, JA (WILEY, 2021-12)
    AIM: Investigating biological processes in at-risk individuals may help elucidate the aetiological mechanisms underlying psychosis development, refine prediction models and improve intervention strategies. This study examined the associations between sleep disturbances, chronotype, depressive and psychotic symptoms in individuals at ultra-high risk for psychosis. METHODS: A sample of 81 ultra-high risk patients completed clinical interviews and self-report assessments of chronotype and sleep during the Neurapro clinical trial. Mixed regression was used to investigate the cross-sectional associations between symptoms and sleep disturbances/chronotype. RESULTS: Sleep disturbances were significantly associated with increased depressive and attenuated positive psychotic symptoms. Greater preference for eveningness was significantly associated with increased negative symptoms, but not with depressive or attenuated positive psychotic symptoms. CONCLUSION: Sleep disturbances and chronotype may impact the emerging psychopathology experienced by ultra-high risk individuals. Further, the preliminary relationship observed between greater preference for eveningness and negative symptoms offers a unique opportunity to treat negative symptoms through chronobiological approaches.
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    Characterization and prediction of clinical pathways of vulnerability to psychosis through graph signal processing
    Sandini, C ; Zoller, D ; Schneider, M ; Tarun, A ; Armondo, M ; Nelson, B ; Amminger, PG ; Yuen, HP ; Markulev, C ; Schaffer, MR ; Mossaheb, N ; Schlogelhofer, M ; Smesny, S ; Hickie, IB ; Berger, GE ; Chen, EYH ; de Haan, L ; Nieman, DH ; Nordentoft, M ; Riecher-Rossler, A ; Verma, S ; Thompson, A ; Yung, AR ; McGorry, PD ; Van De Ville, D ; Eliez, S (eLIFE SCIENCES PUBL LTD, 2021-09-27)
    Causal interactions between specific psychiatric symptoms could contribute to the heterogenous clinical trajectories observed in early psychopathology. Current diagnostic approaches merge clinical manifestations that co-occur across subjects and could significantly hinder our understanding of clinical pathways connecting individual symptoms. Network analysis techniques have emerged as alternative approaches that could help shed light on the complex dynamics of early psychopathology. The present study attempts to address the two main limitations that have in our opinion hindered the application of network approaches in the clinical setting. Firstly, we show that a multi-layer network analysis approach, can move beyond a static view of psychopathology, by providing an intuitive characterization of the role of specific symptoms in contributing to clinical trajectories over time. Secondly, we show that a Graph-Signal-Processing approach, can exploit knowledge of longitudinal interactions between symptoms, to predict clinical trajectories at the level of the individual. We test our approaches in two independent samples of individuals with genetic and clinical vulnerability for developing psychosis. Novel network approaches can allow to embrace the dynamic complexity of early psychopathology and help pave the way towards a more a personalized approach to clinical care.
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    Characterization and Prediction of Clinical Pathways of Vulnerability to Psychosis through Graph Signal Processing
    Sandini, C ; Zöller, D ; Schneider, M ; Tarun, A ; Armando, M ; Nelson, B ; Nelson, B ; Mallawaarachchi, SR ; Amminger, P ; Farhall, J ; Bolt, L ; Yuen, HP ; Markulev, C ; Schäfer, M ; Mossaheb, N ; Schlögelhofer, M ; Smesny, S ; Hickie, I ; Berger, GE ; Chen, EYH ; de Haan, L ; Nieman, D ; Nordentoft, M ; Riecher-Rössler, A ; Verma, S ; Thompson, A ; Yung, AR ; Allott, K ; McGorry, P ; Van De Ville, D ; Eliez, S ( 2020)
    There is a growing recognition that psychiatric symptoms have the potential to causally interact with one another. Particularly in the earliest stages of psychopathology dynamic interactions between symptoms could contribute heterogeneous and cross-diagnostic clinical evolutions. Current clinical approaches attempt to merge clinical manifestations that co-occur across subjects and could therefore significantly hinder our understanding of clinical pathways connecting individual symptoms. Network approaches have the potential to shed light on the complex dynamics of early psychopathology. In the present manuscript we attempt to address 2 main limitations that have in our opinion hindered the application of network approaches in the clinical setting. The first limitation is that network analyses have mostly been applied to cross-sectional data, yielding results that often lack the intuitive interpretability of simpler categorical or dimensional approaches. Here we propose an approach based on multi-layer network analysis that offers an intuitive low-dimensional characterization of longitudinal pathways involved in the evolution of psychopathology, while conserving high-dimensional information on the role of specific symptoms. The second limitation is that network analyses typically characterize symptom connectivity at the level of a population, whereas clinical practice deals with symptom severity at the level of the individual. Here we propose an approach based on graph signal processing that exploits knowledge of network interactions between symptoms to predict longitudinal clinical evolution at the level of the individual. We test our approaches in two independent samples of individuals with genetic and clinical vulnerability for developing psychosis.