Centre for Youth Mental Health - Research Publications

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    The association of plasma inflammatory markers with omega-3 fatty acids and their mediating role in psychotic symptoms and functioning: An analysis of the NEURAPRO clinical trial
    Susai, SR ; Mongan, D ; Healy, C ; Cannon, M ; Nelson, B ; Markulev, C ; Schafer, MR ; Berger, M ; Mossaheb, N ; Schloegelhofer, M ; Smesny, S ; Hickie, IB ; Berger, GE ; Chen, EYH ; de Haan, L ; Nieman, DH ; Nordentoft, M ; Riecher-Roessler, A ; Verma, S ; Thompson, A ; Yung, AR ; McGorry, PD ; Focking, M ; Cotter, D ; Amminger, GP (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2021-10-08)
    BACKGROUND: There is increasing evidence that dysregulation of polyunsaturated fatty acids (FAs) mediated membrane function plays a role in the pathophysiology of schizophrenia. Even though preclinical findings have supported the anti-inflammatory properties of omega-3 FAs on brain health, their biological roles as anti-inflammatory agents and their therapeutic role on clinical symptoms of psychosis risk are not well understood. In the current study, we investigated the relationship of erythrocyte omega-3 FAs with plasma immune markers in a clinical high risk for psychosis (CHR) sample. In addition, a mediation analysis was performed to examine whether previously reported associations between omega-3 FAs and clinical outcomes were mediated via plasma immune markers. Clinical outcomes for CHR participants in the NEURAPRO clinical trial were measured using the Brief Psychiatric Rating Scale (BPRS), Schedule for the Scale of Assessment of Negative Symptoms (SANS) and Social and Occupational Functioning Assessment Scale (SOFAS) scales. The erythrocyte omega-3 index [eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA)] and plasma concentrations of inflammatory markers were quantified at baseline (n = 268) and 6 month follow-up (n = 146) by gas chromatography and multiplex immunoassay, respectively. In linear regression models, the baseline plasma concentrations of Interleukin (IL)-15, Intercellular adhesion molecule (ICAM)-1 and Vascular cell adhesion molecule (VCAM)-1 were negatively associated with baseline omega-3 index. In addition, 6-month change in IL-12p40 and TNF-α showed a negative association with change in omega-3 index. In longitudinal analyses, the baseline and 6 month change in omega-3 index was negatively associated with VCAM-1 and TNF-α respectively at follow-up. Mediation analyses provided little evidence for mediating effects of plasma immune markers on the relationship between omega-3 FAs and clinical outcomes (psychotic symptoms and functioning) in CHR participants. Our results indicate a predominantly anti-inflammatory relationship of omega-3 FAs on plasma inflammatory status in CHR individuals, but this did not appear to convey clinical benefits at 6 month and 12 month follow-up. Both immune and non-immune biological effects of omega-3 FAs would be resourceful in understanding the clinical benefits of omega-3 FAs in CHR papulation.
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    Association of Structural Magnetic Resonance Imaging Measures With Psychosis Onset in Individuals at Clinical High Risk for Developing Psychosis An ENIGMA Working Group Mega-analysis
    Jalbrzikowski, M ; Hayes, RA ; Wood, SJ ; Nordholm, D ; Zhou, JH ; Fusar-Poli, P ; Uhlhaas, PJ ; Takahashi, T ; Sugranyes, G ; Kwak, YB ; Mathalon, DH ; Katagiri, N ; Hooker, CI ; Smigielski, L ; Colibazzi, T ; Via, E ; Tang, J ; Koike, S ; Rasser, PE ; Michel, C ; Lebedeva, I ; Hegelstad, WTV ; de la Fuente-Sandoval, C ; Waltz, JA ; Mizrahi, R ; Corcoran, CM ; Resch, F ; Tamnes, CK ; Haas, SS ; Lemmers-Jansen, ILJ ; Agartz, I ; Allen, P ; Amminger, GP ; Andreassen, OA ; Atkinson, K ; Bachman, P ; Baeza, I ; Baldwin, H ; Bartholomeusz, CF ; Borgwardt, S ; Catalano, S ; Chee, MWL ; Chen, X ; Cho, KIK ; Cooper, RE ; Cropley, VL ; Dolz, M ; Ebdrup, BH ; Fortea, A ; Glenthoj, LB ; Glenthoj, BY ; de Haan, L ; Hamilton, HK ; Harris, MA ; Haut, KM ; He, Y ; Heekeren, K ; Heinz, A ; Hubl, D ; Hwang, WJ ; Kaess, M ; Kasai, K ; Kim, M ; Kindler, J ; Klaunig, MJ ; Koppel, A ; Kristensen, TD ; Kwon, JS ; Lawrie, SM ; Lee, J ; Leon-Ortiz, P ; Lin, A ; Loewy, RL ; Ma, X ; McGorry, P ; McGuire, P ; Mizuno, M ; Moller, P ; Moncada-Habib, T ; Munoz-Samons, D ; Nelson, B ; Nemoto, T ; Nordentoft, M ; Omelchenko, MA ; Oppedal, K ; Ouyang, L ; Pantelis, C ; Pariente, JC ; Raghava, JM ; Reyes-Madrigal, F ; Roach, BJ ; Rossberg, JI ; Rossler, W ; Salisbury, DF ; Sasabayashi, D ; Schall, U ; Schiffman, J ; Schlagenhauf, F ; Schmidt, A ; Sorensen, ME ; Suzuki, M ; Theodoridou, A ; Tomyshev, AS ; Tor, J ; Vaernes, TG ; Velakoulis, D ; Venegoni, GD ; Vinogradov, S ; Wenneberg, C ; Westlye, LT ; Yamasue, H ; Yuan, L ; Yung, AR ; van Amelsvoort, TAMJ ; Turner, JA ; van Erp, TGM ; Thompson, PM ; Hernaus, D (AMER MEDICAL ASSOC, 2021-05-05)
    Importance: The ENIGMA clinical high risk (CHR) for psychosis initiative, the largest pooled neuroimaging sample of individuals at CHR to date, aims to discover robust neurobiological markers of psychosis risk. Objective: To investigate baseline structural neuroimaging differences between individuals at CHR and healthy controls as well as between participants at CHR who later developed a psychotic disorder (CHR-PS+) and those who did not (CHR-PS-). Design, Setting, and Participants: In this case-control study, baseline T1-weighted magnetic resonance imaging (MRI) data were pooled from 31 international sites participating in the ENIGMA Clinical High Risk for Psychosis Working Group. CHR status was assessed using the Comprehensive Assessment of At-Risk Mental States or Structured Interview for Prodromal Syndromes. MRI scans were processed using harmonized protocols and analyzed within a mega-analysis and meta-analysis framework from January to October 2020. Main Outcomes and Measures: Measures of regional cortical thickness (CT), surface area, and subcortical volumes were extracted from T1-weighted MRI scans. Independent variables were group (CHR group vs control group) and conversion status (CHR-PS+ group vs CHR-PS- group vs control group). Results: Of the 3169 included participants, 1428 (45.1%) were female, and the mean (SD; range) age was 21.1 (4.9; 9.5-39.9) years. This study included 1792 individuals at CHR and 1377 healthy controls. Using longitudinal clinical information, 253 in the CHR-PS+ group, 1234 in the CHR-PS- group, and 305 at CHR without follow-up data were identified. Compared with healthy controls, individuals at CHR exhibited widespread lower CT measures (mean [range] Cohen d = -0.13 [-0.17 to -0.09]), but not surface area or subcortical volume. Lower CT measures in the fusiform, superior temporal, and paracentral regions were associated with psychosis conversion (mean Cohen d = -0.22; 95% CI, -0.35 to 0.10). Among healthy controls, compared with those in the CHR-PS+ group, age showed a stronger negative association with left fusiform CT measures (F = 9.8; P < .001; q < .001) and left paracentral CT measures (F = 5.9; P = .005; q = .02). Effect sizes representing lower CT associated with psychosis conversion resembled patterns of CT differences observed in ENIGMA studies of schizophrenia (ρ = 0.35; 95% CI, 0.12 to 0.55; P = .004) and individuals with 22q11.2 microdeletion syndrome and a psychotic disorder diagnosis (ρ = 0.43; 95% CI, 0.20 to 0.61; P = .001). Conclusions and Relevance: This study provides evidence for widespread subtle, lower CT measures in individuals at CHR. The pattern of CT measure differences in those in the CHR-PS+ group was similar to those reported in other large-scale investigations of psychosis. Additionally, a subset of these regions displayed abnormal age associations. Widespread disruptions in CT coupled with abnormal age associations in those at CHR may point to disruptions in postnatal brain developmental processes.
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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, 2021-05-24)
    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, 2021-01-05)
    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, 2021-02-03)
    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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    Perceptual abnormalities in an ultra-high risk for psychosis population relationship to trauma and co-morbid disorder
    O' Connor, K ; Nelson, B ; Cannon, M ; Yung, A ; Thompson, A ; Ghose, P (WILEY, 2019-04-01)
    AIMS: The aims of this study were 3-fold. We wished to investigate whether at baseline entry to an ultra-high risk (UHR) clinic whether: (1) perceptual abnormalities are more prevalent in those young people with co-morbid psychiatric diagnoses, (2) perceptual abnormalities are more prevalent in those young people with histories of childhood adversity (childhood trauma, bullying) and (3) perceptual abnormality type is associated with co-morbid psychiatric diagnoses or histories of childhood adversity. METHODS: In a sample of 118 UHR patients we investigated the relationship between perceptual abnormalities and non-psychotic diagnoses and adverse life events at entry to a UHR clinic. RESULTS: Depressive disorder at baseline was associated with increased odds of experiencing perceptual abnormalities (OR 3.59, P = .004), particularly visual perceptual abnormalities (OR 2.36, P = .02). Borderline personality disorder at baseline was associated with increased odds of any auditory perceptual abnormalities (OR 3.44, P = .04) and specifically second person perceptual abnormalities (OR 2.69, P = .04). A history of childhood trauma and childhood bullying were both associated with increased odds of experiencing perceptual abnormalities at baseline (trauma OR 6.30, P < .001; bullying OR 5.00, P = .01). CONCLUSIONS: Our findings suggest that in the UHR population, certain types of perceptual abnormalities index risk for co-morbid non-psychotic disorder and indicate prior experience of childhood trauma. The use of detailed phenomenology of psychotic symptoms can help to shape our understanding of risk in UHR patients.
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    Impaired olfactory ability associated with larger left hippocampus and rectus volumes at earliest stages of schizophrenia: A sign of neuroinflammation?
    Masaoka, Y ; Velakoulis, D ; Brewer, WJ ; Cropley, VL ; Bartholomeusz, CF ; Yung, AR ; Nelson, B ; Dwyer, D ; Wannan, CMJ ; Izumizaki, M ; McGorry, PD ; Wood, SJ ; Pantelis, C (ELSEVIER IRELAND LTD, 2020-07-01)
    Impaired olfactory identification has been reported as a first sign of schizophrenia during the earliest stages of illness, including before illness onset. The aim of this study was to examine the relationship between volumes of these regions (amygdala, hippocampus, gyrus rectus and orbitofrontal cortex) and olfactory ability in three groups of participants: healthy control participants (Ctls), patients with first-episode schizophrenia (FE-Scz) and chronic schizophrenia patients (Scz). Exploratory analyses were performed in a sample of individuals at ultra-high risk (UHR) for psychosis in a co-submission paper (Masaoka et al., 2020). The relationship to brain structural measures was not apparent prior to psychosis onset, but was only evident following illness onset, with a different pattern of relationships apparent across illness stages (FE-Scz vs Scz). Path analysis found that lower olfactory ability was related to larger volumes of the left hippocampus and gyrus rectus in the FE-Scz group. We speculate that larger hippocampus and rectus in early schizophrenia are indicative of swelling, potentially caused by an active neurochemical or immunological process, such as inflammation or neurotoxicity, which is associated with impaired olfactory ability. The volumetric decreases in the chronic stage of Scz may be due to degeneration resulting from an active immune process and its resolution.
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    Omega-3 fatty acids and neurocognitive ability in young people at ultra-high risk for psychosis
    McLaverty, A ; Allott, KA ; Berger, M ; Hester, R ; McGorry, PD ; Nelson, B ; Markulev, C ; Yuen, HP ; Schaefer, MR ; Mossaheb, N ; Schloegelhofer, M ; Smesny, S ; Hickie, IB ; Berger, GE ; Chen, EYH ; de Haan, L ; Nieman, DH ; Nordentoft, M ; Riecher-Roessler, A ; Verma, S ; Thompson, A ; Yung, AR ; Amminger, GP (WILEY, 2020-09-06)
    BACKGROUND: Neurocognitive impairments are core early features of psychosis and are observed in those at ultra-high risk (UHR) for psychosis. The aim of the present study was to explore whether neurocognition is associated with polyunsaturated fatty acids (PUFAs), as has been observed in other clinical populations. METHOD: Erythrocyte levels of total omega-3-and omega-6 PUFAs the omega-3/omega-6 ratio, were measured in 265 UHR individuals. Six domains of neurocognition as well a Composite Score, were assessed using the Brief Assessment of Cognition in Schizophrenia. Pearson's correlations were used to assess the relationship between PUFAs and neurocognition. All analyses were controlled for tobacco smoking. RESULTS: Verbal Fluency correlated positively with eicosapentaenoic acid (P = .024) and alpha-linolenic acid (P = .01), and negatively with docosahexanoic acid (P = .007) and Working Memory positively correlated with omega-3/omega-6 ratio (P = .007). CONCLUSIONS: The current results provide support for a relationship between Verbal Fluency and omega-3 PUFAs in UHR. Further investigation is required to elucidate whether these biomarkers are useful as risk markers or in understanding the biological underpinning of neurocognitive impairment in this population.