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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ItemCan youth at high risk of illness progression be identified by measures of rumination and sleep-wake disturbance(WILEY, 2019-10)AIM: Clinical staging models offer a useful framework for understanding illness trajectories, where individuals are located on a continuum of illness progression from stage 0 (at-risk but asymptomatic) to stage 4 (end-stage disease). Importantly, clinical staging allows investigation of risk factors for illness progression with the potential to target trans-diagnostic mechanisms at an early stage, especially in help-seeking youth who often present with sub-threshold syndromes. While depressive symptoms, rumination and sleep-wake disturbances may worsen syndrome outcomes, the role of these related phenomena has yet to be examined as risk factors for trans-diagnostic illness progression in at-risk youth. METHODS: This study is a prospective follow-up of 248 individuals aged 12 to 25 years presenting to headspace services with sub-threshold syndromes (stage 1) classified under the clinical staging model to determine transition to threshold syndromes (stage 2). Factor analysis of depression, rumination and sleep-wake patterns was used to identify key dimensions and any associations between factors and transition to stage 2 at follow-up. RESULTS: At 1 year, 9% of cases met criteria for stage 2 (n = 22). One of three identified factors, namely the factor reflecting the commonalities shared between rumination and sleep-wake disturbance, significantly differentiated cases that transitioned to stage 2 vs those that did not demonstrate transition. Items loading onto this factor, labelled Anergia, included depression severity and aspects of rumination and sleep-wake disturbance that were characterized as introceptive. CONCLUSIONS: Common dimensions between rumination and sleep-wake disturbance present a detectable trans-diagnostic marker of illness progression in youth, and may represent a target for early intervention.
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ItemNo Preview AvailableCharacterization and Prediction of Clinical Pathways of Vulnerability to Psychosis through Graph Signal Processing( 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.
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ItemGlobal research priorities for youth mental health(WILEY, 2020-02)AIM: Over the past two decades, the youth mental health field has expanded and advanced considerably. Yet, mental disorders continue to disproportionately affect adolescents and young adults. Their prevalence and associated morbidity and mortality in young people have not substantially reduced, with high levels of unmet need and poor access to evidence-based treatments even in high-income countries. Despite the potential return on investment, youth mental disorders receive insufficient funding. Motivated by these continual disparities, we propose a strategic agenda for youth mental health research. METHOD: Youth mental health experts and funders convened to develop youth mental health research priorities, via thematic roundtable discussions, that address critical evidence-based gaps. RESULTS: Twenty-one global youth mental health research priorities were developed, including population health, neuroscience, clinical staging, novel interventions, technology, socio-cultural factors, service delivery, translation and implementation. CONCLUSIONS: These priorities will focus attention on, and provide a basis for, a systematic and collaborative strategy to globally improve youth mental health outcomes.
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ItemT34. THE IMPACT OF ANTIDEPRESSANT USE ON THE TRANSITION TO PSYCHOSIS RATE IN THE NEURAPRO TRIAL(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.
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ItemM22. IGG ANTIBODIES TO TOXOPLASMA GONDII ARE ASSOCIATED WITH INCREASED LONG-TERM RISK FOR PSYCHOSIS IN INDIVIDUALS AT ULTRA-HIGH RISK FOR PSYCHOSIS(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.
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ItemM21. 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(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.
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ItemFrom Speech Illusions to Onset of Psychotic Disorder: Applying Network Analysis to an Experimental Measure of Aberrant Experiences(Oxford University Press (OUP), 2020-01-01)Abstract Aberrant perceptional experiences are a potential early marker of psychosis development. Earlier studies have found experimentally assessed speech illusions to be associated with positive symptoms in patients with psychotic disorders, but findings for attenuated symptoms in individuals without psychotic disorders have been inconsistent. Also, the role of affect is unclear. The aim of this study was to use the network approach to investigate how speech illusions relate to individual symptoms and onset of a psychotic disorder. We estimated a network model based on data from 289 Clinical High-Risk (CHR) subjects, participating in the EU-GEI project. The network structure depicts statistical associations between (affective and all) speech illusions, cross-sectional individual attenuated positive and affective symptoms, and transition to psychotic disorder after conditioning on all other variables in the network. Speech illusions were assessed with the White Noise Task, symptoms with the BPRS and transition during 24-month follow-up with the CAARMS. Affective, not all, speech illusions were found to be directly, albeit weakly, associated with hallucinatory experiences. Hallucinatory experiences, in turn, were associated with delusional ideation. Bizarre behavior was the only symptom in the network steadily predictive of transition. Affective symptoms were highly interrelated, with depression showing the highest overall strength of connections to and predictability by other symptoms. Both speech illusions and transition showed low overall predictability by symptoms. Our findings suggest that experimentally assessed speech illusions are not a mere consequence of psychotic symptoms or disorder, but that their single assessment is likely not useful for assessing transition risk.
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