Centre for Youth Mental Health - Research Publications
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ItemBroad clinical high-risk mental state (CHARMS): Methodology of a cohort study validating criteria for pluripotent risk(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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ItemStaged Treatment in Early Psychosis: A sequential multiple assignment randomised trial of interventions for ultra high risk of psychosis patients(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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ItemYouth mental health services in Italy: An achievable dream?(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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ItemNo Preview AvailableImpaired olfactory ability associated with larger left hippocampus and rectus volumes at earliest stages of schizophrenia: A sign of neuroinflammation?(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.
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ItemMigrant status and identification as ultra-high risk for psychosis and transitioning to a psychotic disorder(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.
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ItemAripiprazole compared with placebo for auditory verbal hallucinations in youth with borderline personality disorder: Protocol for the VERBATIM randomized controlled trial(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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ItemStaging model in psychiatry: Review of the evolution of electroencephalography abnormalities in major psychiatric disorders(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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ItemStaged 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(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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ItemDoes reason for referral to an ultra-high risk clinic predict transition to psychosis?(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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ItemS166. EFFECTIVE CONNECTIVITY OF FRONTOSTRIATAL SYSTEMS IN FIRST-EPISODE PSYCHOSIS(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.
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