Centre for Youth Mental Health - Research Publications

Permanent URI for this collection

Search Results

Now showing 1 - 10 of 25
  • Item
    No Preview Available
    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)
    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.
  • Item
    Thumbnail Image
    Migrant status and identification as ultra-high risk for psychosis and transitioning to a psychotic disorder
    Geros, H ; Sizer, H ; Mifsud, N ; Reynolds, S ; Kim, DJ ; Eaton, S ; McGorry, P ; Nelson, B ; O'Donoghue, B (WILEY, 2020-01)
    BACKGROUND: Certain migrant groups are more likely to develop a psychotic disorder compared to the native-born populations, and a younger age at migration is associated with greater risk. However, it is not known at which stage migration has an effect on the development of psychotic disorders. We examined whether migrants were more likely to be identified as ultra-high risk for psychosis (UHR) compared to native-born young people and whether migrant status was associated with the risk of transition to a full-threshold psychotic disorder. METHODS: The cohort included all young people aged 15-24 who were identified as UHR at a specialist clinic over a five-year period (2012-16). Australian census data were used to obtain the at-risk population. Poisson regression was used to calculate rate ratios and Cox regression analysis determined hazard ratios. RESULTS: 467 young people were identified as UHR, of which 13.5% (n = 63) were born overseas. First-generation migrants were 2.6-fold less likely to be identified as UHR compared to Australian-born young people (IRR = 0.39, 95% CI [0.30, 0.51], P < 0.001). There was no difference between migrant and native-born young people in their risk of transitioning to a psychotic disorder (HR = 0.90, 95% CI [0.39, 2.08], P = 0.81). CONCLUSIONS: UHR first-generation migrants may be under-accessing mental health services.
  • Item
    No Preview Available
    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.
  • Item
    Thumbnail Image
    S166. EFFECTIVE CONNECTIVITY OF FRONTOSTRIATAL SYSTEMS IN FIRST-EPISODE PSYCHOSIS
    Sabaroedin, K ; Razi, A ; Aquino, K ; Chopra, S ; Finlay, A ; Nelson, B ; Allott, K ; Alvarez-Jimenez, M ; Graham, J ; Baldwin, L ; Tahtalian, S ; Yuen, HP ; Harrigan, S ; Cropley, V ; Pantelis, C ; Wood, S ; O’Donoghue, B ; Francey, S ; McGorry, P ; Fornito, A (Oxford University Press (OUP), 2020-05-18)
    Abstract Background Neuroimaging studies have found dysconnectivity of frontostriatal circuits across a broad spectrum of psychotic symptoms. However, it is unknown whether dysconnectivity within frontostriatal circuits originates from disrupted bottom-up or top-down control signaling within these systems. Here, we used dynamic causal modelling (DCM) to examine the effective connectivity of frontostriatal systems in first-episode psychosis (FEP). Methods A total of 55 FEP patients (26 males; mean [SD] age = 19.24 [2.89]) and 24 healthy controls (15 males; mean [SD] age = 21.83 [1.93]) underwent a resting-state functional magnetic resonance imaging protocol. Biologically plausible connections between eight left hemisphere regions encompassing the dorsal and ventral frontostriatal systems were modelled using spectral DCM. The regions comprise dorsolateral prefrontal cortex, ventromedial prefrontal cortex, anterior hippocampus, amygdala, dorsal caudate, nucleus accumbens, thalamus, and the midbrain. Effective connectivity between groups were assessed using a parametric Bayesian model. Associations between effective connectivity parameters and positive symptoms, measured by the Brief Psychiatric Rating Scale positive subscale, was assessed in the patient group in a separate Bayesian general linear model. Results DCM shows evidence for differences in effective connectivity between patients and healthy controls, namely in the bottom-down connections distributed in the frontostriatal system encompassing the hippocampus, amygdala, striatum, and midbrain. Compared to healthy controls, patients also demonstrated increased disinhibition of the midbrain. In patients, positive symptoms are associated with increased top-down connections to the midbrain. Outgoing connection from the midbrain to the nucleus accumbens is also increased in association with positive symptoms. Discussion Aberrant top-down connectivity in the frontostriatal system in patients is consistent with top-down dysregulation of dopamine function in FEP, as dopaminergic activity in the midbrain is proposed to be under the control of higher brain areas. In patients, increased self-inhibition of the midbrain, as well as symptom associations in both ingoing and outgoing connections of this region, are congruous with hyperactivity of the midbrain as proposed by the dopamine dysregulation hypothesis. Here, we demonstrate that mathematical models of brain imaging signals can be used to identify the key disruptions driving brain circuit dysfunction, identifying new targets for treatment.
  • Item
    Thumbnail Image
    T34. THE IMPACT OF ANTIDEPRESSANT USE ON THE TRANSITION TO PSYCHOSIS RATE IN THE NEURAPRO TRIAL
    Schlögelhofer, M ; McGorry, PD ; Nelson, B ; Berger, M ; Markulev, C ; Pan Yuen, H ; Schäfer, MR ; Mossaheb, N ; Smesny, S ; Hickie, IB ; Berger, G ; Chen, EYH ; De Haan, L ; Nieman, D ; Nordentoft, M ; Riecher-Rössler, A ; Verma, S ; Thompson, A ; Yung, A ; Amminger, GP (Oxford University Press (OUP), 2020-05-18)
    Abstract Background Over the last two decades, several randomised controlled trials (RCTs) have indicated that preventive psychosocial, pharmacologic (Van der Gaag et al. 2013), and nutritional interventions (Amminger et al. 2010) are likely to be beneficial in people at ultra-high risk (UHR) of psychosis, in terms of delaying or preventing a transition to psychosis. Antidepressant medication is commonly prescribed in young people at UHR for psychosis; however, the evidence regarding its efficacy for psychosis prevention is limited (Fusar-Poli et al. 2007; Cornblatt et al. 2007; Fusar-Poli et al. 2015). The main aim of the present study is to investigate the impact of concomitant AD medication on the transition to psychosis rate in young people at ultra-high risk of psychosis who participated in the NEURAPRO trial (McGorry et al. 2017). Methods In this secondary analysis, data from 304 participants of a multicenter, double-blind, placebo-controlled, randomized clinical trial (NEURAPRO) of omega-3 polyunsaturated fatty acids (omega-3 PUFAs) were included. During the trial, concomitant antidepressant medication was permitted for treatment of moderate to severe major depressive disorder (a score of ≥ 21 on the Montgomery-Asberg Depression Rating Scale, MADRS) in all participants. Results Of 304 participants, 189 (62.2%) were treated with ADs. 98 (64.1%) of those were in the omega-3 group and 91 (60.3%) in the placebo group. The transition rate to psychosis was higher in individuals who received AD treatment (13.2%; 25 of 189) as in individuals without ADs (6.1%; 7 of 115). The Kaplan-Meier survival curve estimated a group difference of X2 = 3.237, P = .072 (log rank test). Discussion Antidepressants are widely used in early psychosis. This analysis does not support the view that antidepressants may have reduced the transition to psychosis rate in this cohort. The findings are limited by the fact that antidepressants were prescribed based on clinical discretion. A randomised controlled trial is needed to determine whether antidepressants have a role in prevention of transition to psychosis.
  • Item
    Thumbnail Image
    T21. DEVELOPMENT OF PROTEOMIC PREDICTION MODELS FOR OUTCOMES IN THE CLINICAL HIGH RISK STATE AND PSYCHOTIC EXPERIENCES IN ADOLESCENCE: MACHINE LEARNING ANALYSES IN TWO NESTED CASE-CONTROL STUDIES
    Mongan, D ; Föcking, M ; Healy, C ; Raj Susai, S ; Cagney, G ; Cannon, M ; Zammit, S ; Nelson, B ; McGorry, P ; Nordentoft, M ; Krebs, M-O ; Riecher-Rössler, A ; Bressan, R ; Barrantes-Vidal, N ; Borgwardt, S ; Ruhrmann, S ; Sachs, G ; Van der Gaag, M ; Rutten, B ; Pantelis, C ; De Haan, L ; Valmaggia, L ; Kempton, M ; McGuire, P ; Cotter, D (Oxford University Press (OUP), 2020-05-18)
    Abstract Background Individuals at clinical high risk (CHR) of psychosis have an approximately 20% probability of developing psychosis within 2 years, as well as an associated risk of non-psychotic disorders and functional impairment. People with subclinical psychotic experiences (PEs) are also at risk of future psychotic and non-psychotic disorders and decreased functioning. It is difficult to accurately predict outcomes in individuals at risk of psychosis on the basis of symptoms alone. Biomarkers for accurate prediction of outcomes could inform the clinical management of this group. Methods We conducted two nested case-control studies. We employed discovery-based proteomic methods to analyse protein expression in baseline plasma samples in EU-GEI and age 12 plasma samples in ALSPAC using liquid chromatography mass spectrometry. Differential expression of quantified proteomic markers was determined by analyses of covariance (with false discovery rate of 5%) comparing expression levels for each marker between those who did not and did not develop psychosis in Study 1 (adjusting for age, gender, body mass index and years in education), and between those who did and did not develop PEs in Study 2 (adjusting for gender, body mass index and maternal social class). Support vector machine algorithms were used to develop models for prediction of transition vs. non-transition (as determined by the Comprehensive Assessment of At Risk Mental States) and poor vs. good functional outcome at 2 years in Study 1 (General Assessment of Functioning: Disability subscale score &lt;/=60 vs. &gt;60). Similar algorithms were used to develop a model for prediction of PEs vs. no PEs at age 18 in Study 2 (as determined by the Psychosis Like Symptoms Interview). Results In Study 1, 35 of 166 quantified proteins were significantly differentially expressed between CHR participants who did and did not develop psychosis. Functional enrichment analysis provided evidence for particular implication of the complement and coagulation cascade (false discovery rate-adjusted Fisher’s exact test p=2.23E-21). Using 65 clinical and 166 proteomic features a model demonstrated excellent performance for prediction of transition status (area under the receiver-operating curve [AUC] 0.96, positive predictive value [PPV] 83.0%, negative predictive value [NPV] 93.8%). A model based on the ten most predictive proteins accurately predicted transition status in training (AUC 0.96, PPV 87.5%, NPV 95.8%) and withheld data (AUC 0.92, PPV 88.9%, NPV 91.4%). A model using the same 65 clinical and 166 proteomic features predicted 2-year functional outcome with AUC 0.72 (PPV 67.6%, NPV 47.6%). In Study 2, 5 of 265 quantified proteins were significantly differentially expressed between participants who did and did not report PEs at age 18. A model using 265 proteomic features predicted PEs at age 18 with AUC 0.76 (PPV 69.1%, NPV 74.2%). Discussion With external validation, models incorporating proteomic data may contribute to improved prediction of clinical outcomes in individuals at risk of psychosis.
  • Item
    Thumbnail Image
    M22. IGG ANTIBODIES TO TOXOPLASMA GONDII ARE ASSOCIATED WITH INCREASED LONG-TERM RISK FOR PSYCHOSIS IN INDIVIDUALS AT ULTRA-HIGH RISK FOR PSYCHOSIS
    Berger, M ; Burkhardt, E ; Yung, A ; Nelson, B ; Francey, S ; Lin, A ; Wood, S ; Thompson, A ; Berger, G ; Philipps, L ; Harrington, S ; McGorry, P ; Yolken, R ; Amminger, GP (Oxford University Press (OUP), 2020-05-18)
    Abstract Background The prevalence of antibodies to Toxoplasma gondii, a ubiquitous parasitic protozoan causing the infectious disease toxoplasmosis, is increased in patients with psychotic disorders compared to the general population. We have previously shown that antibody titers for T.gondii correlate with the severity of positive symptoms in young people at ultra-high risk (UHR) for psychosis, suggesting that infection with T. gondii may be relevant to the manifestation of psychosis. However, it is unclear if T. gondii antibodies represent a risk factor for psychosis onset or non-psychotic outcome in UHR individuals. The aim of the present study was to examine whether seropositivity for T.gondii is associated with transition to psychosis and other outcomes in young people at UHR for psychosis. Methods The study sample consisted of 96 individuals at UHR for psychosis who were referred to the Personal Assistance and Crisis Evaluation (PACE) clinic in Melbourne, Australia, between 2001 and 2004, consented to optional blood tests for infectious agents and were followed up for up to 10 years after baseline (median (interquartile range) duration of follow-up: 7.15 (3.14 – 7.72) years). Serum IgG antibodies to six viral and parasitic pathogens (Toxoplasma gondii, Herpes Simplex Virus Type 1 and 2, Cytomegalovirus, Epstein Barr Virus, Varicella-Zoster Virus) were measured at baseline. Outcome measures included transition to psychosis, general psychiatric symptomatology and positive psychotic symptoms (BPRS), negative symptoms (SANS), depressive symptoms (HAM-D), anxiety symptoms (HAM-A) and functioning (SOFAS and GAF). Cox proportional hazards regression and linear regression models were used to examine the associations of seropositivity and antibody titers at baseline and transition to psychosis and other outcomes at follow-up. Results A total of 17 individuals (17.7%) were seropositive for Toxoplasma gondii at baseline. The rate of transition to psychosis was higher among seropositive (35.7%) compared to seronegative participants (14.6%), although this was not statistically significant (p=0.101). Antibody titers (IgG) for Toxoplasma gondii were significantly higher at baseline in participants who later transitioned to psychosis (1.34 ± 1.36 vs. 0.79 ± 0.73, p=0.027). Seropositivity for T.gondii IgG at baseline significantly predicted transition to psychosis within the follow-up duration (hazard ratio [HR]=3.61, 95%CI 1.08 – 12.00, p=0.036). Toxoplasma IgG at baseline were significantly associated with higher BPRS scores at follow-up in participants who were seropositive at baseline (Beta=6.38, 95%CI 0.43 – 12.34, p=0.038). No significant associations were found between antibodies to other pathogens and outcome, or between antibodies to Toxoplasma gondii and any other outcomes. Discussion Our findings suggest that the presence of IgG class antibodies for Toxoplasma gondii is associated with a higher risk for psychosis transition in individuals at UHR for psychosis, but not with risk for other long-term outcomes. These observations provide support for the hypothesis that infection with Toxoplasma gondii may be an environmental risk factor for psychosis and suggest that IgG antibodies for Toxoplasma gondii in individuals at UHR for psychosis have prognostic relevance.
  • Item
    Thumbnail Image
    M21. THE STEP TRIAL: A SEQUENTIAL MULTIPLE ASSIGNMENT RANDOMISED TRIAL (SMART) OF INTERVENTIONS FOR PATIENTS AT ULTRA-HIGH RISK OF PSYCHOSIS - STUDY RATIONALE, DESIGN AND BASELINE DATA
    Nelson, B ; Amminger, GP ; Pan Yuen, H ; Kerr, M ; Spark, J ; Wallis, N ; Carter, C ; Niendam, T ; Loewy, R ; Shumway, M ; Dixon, L ; McGorry, P (Oxford University Press (OUP), 2020-05-18)
    Abstract Background Although approximately twenty randomised controlled trials have now been conducted with young people identified as being at high clinical risk of psychotic disorder, it remains unclear what the optimal type and sequence of treatments are for this clinical population. There has also been increased focus on clinical outcomes other than transition to psychotic disorder, such as psychosocial functioning, persistent attenuated psychotic symptoms and non-psychotic disorders. At Orygen, we are currently conducting a trial of a sequence of interventions consisting of two psychosocial therapies (support and problem solving [SPS] and cognitive-behavioural case management [CBCM]) and antidepressant medication. The primary outcome of the study is functional outcome after 6 months. This presentation will outline the background, rationale, design, recruitment and retention data and preliminary baseline results. Methods STEP is a sequential multiple assignment randomised trial (SMART) of treatments for young people (12–25 year olds) who meet ultra high risk for psychosis (UHR) criteria. Participants were recruited from primary (headspace) and secondary/tertiary (Orygen Youth Health) mental health services in Melbourne, Australia. The trial consists of three steps: Step 1: SPS (1.5 months); Step 2: SPS vs Cognitive Behavioural Case Management (4.5 months); Step 3: Cognitive Behavioural Case Management + Antidepressant Medication vs Cognitive Behavioural Case Management + Placebo (6 months). Patients who do not respond by the end of each step graduate to the next step in treatment. Responders are randomised to SPS or monitoring. Treatment response is based a combination of reduced attenuated psychotic symptoms, rated using the Comprehensive Assessment of At-Risk Mental States (CAARMS), and functional improvement (Social and Occupational Functioning Assessment Scale [SOFAS]) at the end of the treatment step. A ‘fast fail’ option is built into Step 3, whereby patients who deteriorate or have not responded 3 months into Step 3 are offered a choice of continuing existing treatment or commencing omega-3 fatty acids or low-dose antipsychotic medication. The intervention is for 12 months, with follow up at 18 and 24 months. A pilot study using the same design is currently being conducted at The University of California Davis. Results Recruitment has recently completed, with 342 patients recruited over a 2.4 year period, representing the largest UHR treatment study conducted to date. Preliminary results indicate an 8% response rate to Step 1 and a 23% response rate to Step 2. Discontinuation rates are 15% (step 1), 43% (step 2), 32% (step 3), primarily due to participants being lost to follow up or not wanting to start medication. The current transition to psychosis rate is 10.2%. Baseline clinical data are currently being analysed and will be presented at the conference. Discussion Preliminary results indicate high non-response rates following SPS and moderate non-response rates following extended SPS or CBCM, possibly partly due to the stringent definition of response, which required substantial and persistent improvement in both attenuated psychotic symptoms and functioning. Discontinuation rates are low to moderate, reflecting the complexity and severity of this clinical population. The recruitment and retention data show that it is possible to conduct large-scale and complex stepped care trials with this high risk population in a primary mental health care setting (headspace services). Outcomes will inform the most effective type and sequence of treatments for improving psychosocial functioning, symptoms and reducing risk of developing psychotic disorder in this group, as well as identify predictors of treatment response.
  • Item
    No Preview Available
    Transcending false dichotomies and diagnostic silos to reduce disease burden in mental disorders
    McGorry, PD ; Nelson, B ; Wood, SJ ; Shah, JL ; Malla, A ; Yung, A (SPRINGER HEIDELBERG, 2020-09)
  • Item
    No Preview Available
    Transdiagnostic clinical staging in youth mental health: a first international consensus statement
    Shah, JL ; Scott, J ; McGorry, PD ; Cross, SPM ; Keshavan, MS ; Nelson, B ; Wood, SJ ; Marwaha, S ; Yung, AR ; Scott, EM ; Ongur, D ; Conus, P ; Henry, C ; Hickie, IB (WILEY, 2020-06-01)
    Recognizing that current frameworks for classification and treatment in psychiatry are inadequate, particularly for use in young people and early intervention services, transdiagnostic clinical staging models have gained prominence. These models aim to identify where individuals lie along a continuum of illness, to improve treatment selection and to better understand patterns of illness continuity, discontinuity and aetiopathogenesis. All of these factors are particularly relevant to help‐seeking and mental health needs experienced during the peak age range of onset, namely the adolescent and young adult developmental periods (i.e., ages 12‐25 years). To date, progressive stages in transdiagnostic models have typically been defined by traditional symptom sets that distinguish “sub‐threshold” from “threshold‐level” disorders, even though both require clinical assessment and potential interventions. Here, we argue that staging models must go beyond illness progression to capture additional dimensions of illness extension as evidenced by emergence of mental or physical comorbidity/complexity or a marked change in a linked biological construct. To develop further consensus in this nascent field, we articulate principles and assumptions underpinning transdiagnostic clinical staging in youth mental health, how these models can be operationalized, and the implications of these arguments for research and development of new service systems. We then propose an agenda for the coming decade, including knowledge gaps, the need for multi‐stakeholder input, and a collaborative international process for advancing both science and implementation.