Centre for Youth Mental Health - Research Publications

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    Broad clinical high-risk mental state (CHARMS): Methodology of a cohort study validating criteria for pluripotent risk
    Hartmann, JA ; Nelson, B ; Spooner, R ; Amminger, GP ; Chanen, A ; Davey, CG ; McHugh, M ; Ratheesh, A ; Treen, D ; Yuen, HP ; McGorry, PD (WILEY, 2019-06)
    AIM: The development of the ultra-high risk (UHR) criteria for psychosis created a new paradigm for the prevention research in psychiatry. Since (1) prevention research faces the challenge of achieving adequate statistical power when focusing on single low-incidence syndromes and (2) early clinical phenotypes are overlapping and non-specific, this study broadens the UHR state beyond psychosis as an outcome. The CHARMS (clinical high at-risk mental state) study aims to prospectively validate a set of trans-diagnostic criteria to identify help-seeking young people at risk of developing a range of serious mental illnesses. METHODS: This paper describes the methodology of the CHARMS study, which involves applying the CHARMS criteria to a cohort of help-seeking young people aged 12 to 25 attending youth mental health services in Melbourne. New referrals meeting the CHARMS criteria are allocated to the CHARMS+ group; referrals not meeting CHARMS threshold are allocated to CHARMS- group (control group); referrals meeting criteria for a full-threshold disorder are excluded. Transition status and clinical and functional outcomes are re-assessed at 6 and 12 months. CONCLUSIONS: This study will be the first to introduce and validate clinical criteria to identify a broader at-risk patient population, which may facilitate young people's access to clinical services and early treatment by reducing the reliance on "caseness" defined according to current diagnostic categories being required for service entry. These criteria may introduce a new, trans-diagnostic approach for understanding risk factors and pathogenic mechanisms that drive the onset of severe mental illness and the next generation of preventive intervention trials.
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    Staged Treatment in Early Psychosis: A sequential multiple assignment randomised trial of interventions for ultra high risk of psychosis patients
    Nelson, B ; Amminger, GP ; Yuen, HP ; Wallis, N ; Kerr, MJ ; Dixon, L ; Carter, C ; Loewy, R ; Niendam, TA ; Shumway, M ; Morris, S ; Blasioli, J ; McGorry, PD (WILEY, 2018-06)
    AIM: Previous research indicates that preventive intervention is likely to benefit patients "at risk" of psychosis, in terms of functional improvement, symptom reduction and delay or prevention of onset of threshold psychotic disorder. The primary aim of the current study is to test outcomes of ultra high risk (UHR) patients, primarily functional outcome, in response to a sequential intervention strategy consisting of support and problem solving (SPS), cognitive-behavioural case management and antidepressant medication. A secondary aim is to test biological and psychological variables that moderate and mediate response to this sequential treatment strategy. METHODS: This is a sequential multiple assignment randomised trial (SMART) consisting 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). The intervention is of 12 months duration in total and participants will be followed up at 18 months and 24 months post baseline. CONCLUSION: This paper reports on the rationale and protocol of the Staged Treatment in Early Psychosis (STEP) study. With a large sample of 500 UHR participants this study will investigate the most effective type and sequence of treatments for improving functioning and reducing the risk of developing psychotic disorder in this clinical population.
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    Youth mental health services in Italy: An achievable dream?
    Masillo, A ; Brandizzi, M ; Nelson, B ; Lo Cascio, N ; Saba, R ; Lindau, JF ; Telesforo, L ; Montanaro, D ; D'Alema, M ; Girardi, P ; McGorry, P ; Nastro, PF (WILEY, 2018-06)
    AIM: "Liberiamo il futuro" (LIF) project was designed to assess psychological problems of adolescents and young adults and to identify individuals at high-risk for developing a psychosis through a collaboration between a University team, Child and Adolescent Mental Health Services and Adult Mental Health Services. This paper presents the baseline demographic and clinical characteristics of the cohort, particularly the nature and severity of psychopathology. METHOD: All help-seeking young people aged 12-35 years residing in the health district involved in LIF were invited to participate in the study and completed a battery of self- report and interviewer-administered measures of psychopathology and functioning at baseline. RESULTS: A total of 338 adolescents and young people (mean age 17.42) participated in the study. The majority of the sample (n = 107, 35%) had an anxiety disorder, followed by mood disorders (n = 62, 21%). Only 35 (12%) participants had no psychiatric diagnosis. After a screening phase, 166 (52%) individuals were assessed to detect the presence of an Ultra High Risk (UHR) state. Of these, 38.60% (n = 64) met UHR criteria. Overall, the majority of the sample resulted moderately functionally impaired at baseline. CONCLUSIONS: LIF project showed that psychological problems, associated with impaired psychosocial functioning, are very common among help-seeking young people. The help-seeking behaviour of young people is in contrast with the barriers presented by the Italian community mental health system that is modelled around adults' requirements. A need of a strong, stigma-free, young oriented system of care for young people up to the mid-20s emerged.
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    Aripiprazole compared with placebo for auditory verbal hallucinations in youth with borderline personality disorder: Protocol for the VERBATIM randomized controlled trial
    Chanen, AM ; Betts, J ; Jackson, H ; McGorry, P ; Nelson, B ; Cotton, SM ; Bartholomeusz, C ; Jovev, M ; Ratheesh, A ; Davey, C ; Pantelis, C ; McCutcheon, L ; Francey, S ; Bhaduri, A ; Lowe, D ; Rayner, V ; Thompson, K (WILEY, 2019-12)
    AIM: Up to half of patients with borderline personality disorder report auditory verbal hallucinations that are phenomenologically indistinguishable from those in schizophrenia, occur early in the course of the disorder, and are enduring, distressing and disabling. In clinical practice, this symptom is widely assumed to be unresponsive to treatment with antipsychotic medication and early intervention is rarely offered. The Verbal Experiences Response in Borderline personality disorder to Aripiprazole TrIal Medication (VERBATIM) study aims to be the first controlled trial to investigate the effectiveness of conventional pharmacotherapy for this symptom in this patient group. METHOD: VERBATIM is a 12-week, triple-blind, single-centre, parallel groups randomised controlled trial, with a 27-week follow-up period. Participants between the ages of 15 and 25 years receive either aripiprazole or placebo daily, commencing at 2 mg and increasing to 10 mg by day 15. Further dose escalations (up to 30 mg) may occur, as clinically indicated. This trial was prospectively registered with the Australian and New Zealand Clinical Trials Registry ACTRN12616001192471 on 30/08/2016. RESULTS: The primary outcome is severity of auditory verbal hallucinations assessed using the Psychotic Symptom Rating Scale. Secondary outcomes include the severity of general psychopathology, borderline personality pathology, social and occupational functioning and change in brain resting state connectivity. The primary endpoint is week 12 and secondary endpoint is week 39. CONCLUSION: The results will inform treatment decisions for individuals with borderline personality disorder who present with auditory verbal hallucinations.
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    Staging model in psychiatry: Review of the evolution of electroencephalography abnormalities in major psychiatric disorders
    Lavoie, S ; Polari, AR ; Goldstone, S ; Nelson, B ; McGorry, PD (WILEY, 2019-12)
    AIM: Clinical staging in psychiatry aims to classify patients according to the severity of their symptoms, from stage 0 (increased risk, asymptomatic) to stage 4 (severe illness), enabling adapted treatment at each stage of the illness. The staging model would gain specificity if one or more quantifiable biological markers could be identified. Several biomarkers reflecting possible causal mechanisms and/or consequences of the pathophysiology are candidates for integration into the clinical staging model of psychiatric illnesses. METHODS: This review covers the evolution (from stage 0 to stage 4) of the most important brain functioning impairments as measured with electroencephalography (EEG), in psychosis spectrum and in severe mood disorders. RESULTS: The present review of the literature demonstrates that it is currently not possible to draw any conclusion with regard to the state or trait character of any of the EEG impairments in both major depressive disorder and bipolar disorder. As for schizophrenia, the most promising markers of the stage of the illness are the pitch mismatch negativity as well as the p300 event-related potentials, as these components seem to deteriorate with increasing severity of the illness. CONCLUSIONS: Given the complexity of major psychiatric disorders, and that not a single impairment can be observed in all patients, future research should most likely consider combinations of markers in the quest for a better identification of the stages of the psychiatric illnesses.
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    Staged treatment and acceptability guidelines in early psychosis study (STAGES): A randomized placebo controlled trial of intensive psychosocial treatment plus or minus antipsychotic medication for first-episode psychosis with low-risk of self-harm or aggression. Study protocol and baseline characteristics of participants
    O'Donoghue, B ; Francey, SM ; Nelson, B ; Ratheesh, A ; Allott, K ; Grahann, J ; Baldwin, L ; Alvarez-Jinnenez, M ; Thonnpson, A ; Fornito, A ; Polari, A ; Berk, M ; Macneil, C ; Crisp, K ; Pantelis, C ; Yuen, HP ; Harrigan, S ; McGorry, P (WILEY, 2019-08)
    AIM: It is now necessary to investigate whether recovery in psychosis is possible without the use of antipsychotic medication. This study will determine (1) whether a first-episode psychosis (FEP) group receiving intensive psychosocial interventions alone can achieve symptomatic remission and functional recovery; (2) whether prolonging the duration of untreated psychosis (DUP) in a sub-group according to randomisation will be associated with a poorer outcome and thereby establish whether the relationship between DUP and outcome is causative; and (3) whether neurobiological changes observed in FEP are associated with the psychotic disorder or antipsychotic medication. Baseline characteristics of participants will be presented. METHODS: This study is a triple-blind randomized placebo-controlled non-inferiority trial. The primary outcome is the level of functioning measured by the Social and Occupational Functioning Assessment Scale at 6 months. This study is being conducted at the Early Psychosis Prevention and Intervention Centre, Melbourne and includes young people aged 15 to 24 years with a DSM-IV psychotic disorder, a DUP less than 6 months and not high risk for suicide or harm to others. Strict discontinuation criteria are being applied. Participants are also undergoing three 3-Tesla-MRI scans. RESULTS: Ninety participants have been recruited and baseline characteristics are presented. CONCLUSIONS: Staged treatment and acceptability guidelines in early psychosis will determine whether antipsychotic medications are indicated in all young people with a FEP and whether antipsychotic medication can be safely delayed. Furthermore, the relative contribution of psychotic illness and antipsychotic medication in terms of structural brain changes will also be elucidated. The findings will inform clinical practice guidelines.
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    Does reason for referral to an ultra-high risk clinic predict transition to psychosis?
    Rice, S ; Polari, A ; Thompson, A ; Hartmann, J ; McGorry, P ; Nelson, B (WILEY, 2019-04)
    AIM: To examine reasons for referral to a specialist ultra-high risk (UHR) for psychosis clinic and whether these reasons are associated with risk for subsequent transition to psychosis. METHODS: Data for 127 patients referred to the Personal Assessment and Crisis Evaluation clinic were collected by medical record audit. Time to transition to psychosis was calculated from date of referral to time at which the young person was judged by their treating team to be experiencing onset of first episode psychosis. RESULTS: Patients were primarily referred due to attenuated psychotic symptoms and depression (40.2%). There was an association with transition, with those in the attenuated psychotic-symptom-only category being more likely to transition. CONCLUSION: As well as attenuated psychotic symptoms, depression and anxiety were also important reasons for referral indicating that there is a broad clinical phenotype of young people presenting to UHR clinics. Clinical reason for referral may index level of risk for subsequent transition to psychosis.
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    Effects of NRG1 and DAOA genetic variation on transition to psychosis in individuals at ultra-high risk for psychosis
    Bousman, CA ; Yung, AR ; Pantelis, C ; Ellis, JA ; Chavez, RA ; Nelson, B ; Lin, A ; Wood, SJ ; Amminger, GP ; Velakoulis, D ; McGorry, PD ; Everall, IP ; Foley, DL (NATURE PUBLISHING GROUP, 2013-04)
    Prospective studies have suggested genetic variation in the neuregulin 1 (NRG1) and D-amino-acid oxidase activator (DAOA) genes may assist in differentiating high-risk individuals who will or will not transition to psychosis. In a prospective cohort (follow-up=2.4-14.9 years) of 225 individuals at ultra-high risk (UHR) for psychosis, we assessed haplotype-tagging single-nucleotide polymorphisms (htSNPs) spanning NRG1 and DAOA for their association with transition to psychosis, using Cox regression analysis. Two NRG1 htSNPs (rs12155594 and rs4281084) predicted transition to psychosis. Carriers of the rs12155594 T/T or T/C genotype had a 2.34 (95% confidence interval (CI)=1.37-4.00) times greater risk of transition compared with C/C carriers. For every rs4281084 A-allele the risk of transition increased by 1.55 (95% CI=1.05-2.27). For every additional rs4281084-A and/or rs12155594-T allele carried the risk increased ∼1.5-fold, with 71.4% of those carrying a combination of 3 of these alleles transitioning to psychosis. None of the assessed DAOA htSNPs were associated with transition. Our findings suggest NRG1 genetic variation may improve our ability to identify UHR individuals at risk for transition to psychosis.
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    PET imaging of putative microglial activation in individuals at ultra-high risk for psychosis, recently diagnosed and chronically ill with schizophrenia
    Di Biase, MA ; Zalesky, A ; O'keefe, G ; Laskaris, L ; Baune, BT ; Weickert, CS ; Olver, J ; McGorry, PD ; Amminger, GP ; Nelson, B ; Scott, AM ; Hickie, I ; Banati, R ; Turkheimer, F ; Yaqub, M ; Everall, IP ; Pantelis, C ; Cropley, V (NATURE PUBLISHING GROUP, 2017-08-29)
    We examined putative microglial activation as a function of illness course in schizophrenia. Microglial activity was quantified using [11C](R)-(1-[2-chrorophynyl]-N-methyl-N-[1-methylpropyl]-3 isoquinoline carboxamide (11C-(R)-PK11195) positron emission tomography (PET) in: (i) 10 individuals at ultra-high risk (UHR) of psychosis; (ii) 18 patients recently diagnosed with schizophrenia; (iii) 15 patients chronically ill with schizophrenia; and, (iv) 27 age-matched healthy controls. Regional-binding potential (BPND) was calculated using the simplified reference-tissue model with four alternative reference inputs. The UHR, recent-onset and chronic patient groups were compared to age-matched healthy control groups to examine between-group BPND differences in 6 regions: dorsal frontal, orbital frontal, anterior cingulate, medial temporal, thalamus and insula. Correlation analysis tested for BPND associations with gray matter volume, peripheral cytokines and clinical variables. The null hypothesis of equality in BPND between patients (UHR, recent-onset and chronic) and respective healthy control groups (younger and older) was not rejected for any group comparison or region. Across all subjects, BPND was positively correlated to age in the thalamus (r=0.43, P=0.008, false discovery rate). No correlations with regional gray matter, peripheral cytokine levels or clinical symptoms were detected. We therefore found no evidence of microglial activation in groups of individuals at high risk, recently diagnosed or chronically ill with schizophrenia. While the possibility of 11C-(R)-PK11195-binding differences in certain patient subgroups remains, the patient cohorts in our study, who also displayed normal peripheral cytokine profiles, do not substantiate the assumption of microglial activation in schizophrenia as a regular and defining feature, as measured by 11C-(R)-PK11195 BPND.