Centre for Youth Mental Health - Research Publications
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ItemAn open label pilot trial of low-dose lithium for young people at ultra-high risk for psychosis(WILEY, 2024-04-10)AIM: Lithium, even at low doses, appears to offer neuroprotection against a wide variety of insults. In this controlled pilot, we examined the safety (i.e., side-effect profile) of lithium in a sample of young people identified at ultra-high risk (UHR) for psychosis. The secondary aim was to explore whether lithium provided a signal of clinical efficacy in reducing transition to psychosis compared with treatment as usual (TAU). METHODS: Young people attending the PACE clinic at Orygen, Melbourne, were prescribed a fixed dose (450 mg) of lithium (n = 25) or received TAU (n = 78). The primary outcome examined side-effects, with transition to psychosis, functioning and measures of psychopathology assessed as secondary outcomes. RESULTS: Participants in both groups were functionally compromised (lithium group GAF = 56.6; monitoring group GAF = 56.9). Side-effect assessment indicated that lithium was well-tolerated. 64% (n = 16) of participants in the lithium group were lithium-adherent to week 12. Few cases transitioned to psychosis across the study period; lithium group 4% (n = 1); monitoring group 7.7% (n = 6). There was no difference in time to transition to psychosis between the groups. No group differences were observed in other functioning and symptom domains, although all outcomes improved over time. CONCLUSIONS: With a side-effect profile either comparable to, or better than UHR antipsychotic trials, lithium might be explored for further research with UHR young people. A definitive larger trial is needed to determine the efficacy of lithium in this cohort.
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ItemDevelopment of the PSYCHS: Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS(Wiley, 2024-04)AIM: To harmonize two ascertainment and severity rating instruments commonly used for the clinical high risk syndrome for psychosis (CHR-P): the Structured Interview for Psychosis-risk Syndromes (SIPS) and the Comprehensive Assessment of At-Risk Mental States (CAARMS). METHODS: The initial workshop is described in the companion report from Addington et al. After the workshop, lead experts for each instrument continued harmonizing attenuated positive symptoms and criteria for psychosis and CHR-P through an intensive series of joint videoconferences. RESULTS: Full harmonization was achieved for attenuated positive symptom ratings and psychosis criteria, and modest harmonization for CHR-P criteria. The semi-structured interview, named Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS (PSYCHS), generates CHR-P criteria and severity scores for both CAARMS and SIPS. CONCLUSIONS: Using the PSYCHS for CHR-P ascertainment, conversion determination, and attenuated positive symptom severity rating will help in comparing findings across studies and in meta-analyses.
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ItemAccelerating Medicines Partnership® Schizophrenia (AMP® SCZ): Rationale and Study Design of the Largest Global Prospective Cohort Study of Clinical High Risk for Psychosis(OXFORD UNIV PRESS, 2024-04-30)This article describes the rationale, aims, and methodology of the Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ). This is the largest international collaboration to date that will develop algorithms to predict trajectories and outcomes of individuals at clinical high risk (CHR) for psychosis and to advance the development and use of novel pharmacological interventions for CHR individuals. We present a description of the participating research networks and the data processing analysis and coordination center, their processes for data harmonization across 43 sites from 13 participating countries (recruitment across North America, Australia, Europe, Asia, and South America), data flow and quality assessment processes, data analyses, and the transfer of data to the National Institute of Mental Health (NIMH) Data Archive (NDA) for use by the research community. In an expected sample of approximately 2000 CHR individuals and 640 matched healthy controls, AMP SCZ will collect clinical, environmental, and cognitive data along with multimodal biomarkers, including neuroimaging, electrophysiology, fluid biospecimens, speech and facial expression samples, novel measures derived from digital health technologies including smartphone-based daily surveys, and passive sensing as well as actigraphy. The study will investigate a range of clinical outcomes over a 2-year period, including transition to psychosis, remission or persistence of CHR status, attenuated positive symptoms, persistent negative symptoms, mood and anxiety symptoms, and psychosocial functioning. The global reach of AMP SCZ and its harmonized innovative methods promise to catalyze the development of new treatments to address critical unmet clinical and public health needs in CHR individuals.
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ItemNo Preview AvailableDevelopment of the PSYCHS: Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS.( 2023-05-02)AIM: To harmonize two ascertainment and severity rating instruments commonly used for the clinical high risk syndrome for psychosis (CHR-P): the Structured Interview for Psychosis-risk Syndromes (SIPS) and the Comprehensive Assessment of At-Risk Mental States (CAARMS). METHODS: The initial workshop is described in the companion report from Addington et al. After the workshop, lead experts for each instrument continued harmonizing attenuated positive symptoms and criteria for psychosis and CHR-P through an intensive series of joint videoconferences. RESULTS: Full harmonization was achieved for attenuated positive symptom ratings and psychosis criteria, and partial harmonization for CHR-P criteria. The semi-structured interview, named P ositive SY mptoms and Diagnostic Criteria for the C AARMS H armonized with the S IPS (PSYCHS), generates CHR-P criteria and severity scores for both CAARMS and SIPS. CONCLUSION: Using the PSYCHS for CHR-P ascertainment, conversion determination, and attenuated positive symptom severity rating will help in comparing findings across studies and in meta-analyses.
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ItemProteomic Biomarkers for the Prediction of Transition to Psychosis in Individuals at Clinical High Risk: A Multi-cohort Model Development Study(OXFORD UNIV PRESS, 2024-04-30)Psychosis risk prediction is one of the leading challenges in psychiatry. Previous investigations have suggested that plasma proteomic data may be useful in accurately predicting transition to psychosis in individuals at clinical high risk (CHR). We hypothesized that an a priori-specified proteomic prediction model would have strong predictive accuracy for psychosis risk and aimed to replicate longitudinal associations between plasma proteins and transition to psychosis. This study used plasma samples from participants in 3 CHR cohorts: the North American Prodrome Longitudinal Studies 2 and 3, and the NEURAPRO randomized control trial (total n = 754). Plasma proteomic data were quantified using mass spectrometry. The primary outcome was transition to psychosis over the study follow-up period. Logistic regression models were internally validated, and optimism-corrected performance metrics derived with a bootstrap procedure. In the overall sample of CHR participants (age: 18.5, SD: 3.9; 51.9% male), 20.4% (n = 154) developed psychosis within 4.4 years. The a priori-specified model showed poor risk-prediction accuracy for the development of psychosis (C-statistic: 0.51 [95% CI: 0.50, 0.59], calibration slope: 0.45). At a group level, Complement C8B, C4B, C5, and leucine-rich α-2 glycoprotein 1 (LRG1) were associated with transition to psychosis but did not surpass correction for multiple comparisons. This study did not confirm the findings from a previous proteomic prediction model of transition from CHR to psychosis. Certain complement proteins may be weakly associated with transition at a group level. Previous findings, derived from small samples, should be interpreted with caution.
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ItemNo Preview AvailableNon-psychotic Outcomes in Young People at Ultra-High Risk of Developing a Psychotic Disorder: A Long-Term Follow-up Study(OXFORD UNIV PRESS, 2024-02-16)BACKGROUND: The majority of individuals at ultra-high risk (UHR) for psychosis do not transition to a full threshold psychotic disorder. It is therefore important to understand their longer-term clinical and functional outcomes, particularly given the high prevalence of comorbid mental disorders in this population at baseline. AIMS: This study investigated the prevalence of non-psychotic disorders in the UHR population at entry and long-term follow-up and their association with functional outcomes. Persistence of UHR status was also investigated. STUDY DESIGN: The sample comprised 102 UHR young people from the Personal Assessment and Crisis Evaluation (PACE) Clinic who had not transitioned to psychosis by long-term follow-up (mean = 8.8 years, range = 6.8-12.1 years since baseline). RESULTS: Eighty-eight percent of participants at baseline were diagnosed with at least one mental disorder, the majority of which were mood disorders (78%), anxiety disorders (35%), and substance use disorders (SUDs) (18%). This pattern of disorder prevalence continued at follow-up, though prevalence was reduced, with 52% not meeting criteria for current non-psychotic mental disorder. However, 35% of participants developed a new non-psychotic mental disorder by follow-up. Presence of a continuous non-psychotic mental disorder was associated with poorer functional outcomes at follow-up. 28% of participants still met UHR criteria at follow-up. CONCLUSIONS: The study adds to the evidence base that a substantial proportion of UHR individuals who do not transition to psychosis experience persistent attenuated psychotic symptoms and persistent and incident non-psychotic disorders over the long term. Long-term treatment and re-entry into services is indicated.
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ItemNo Preview AvailableCombining Clinical With Cognitive or Magnetic Resonance Imaging Data for Predicting Transition to Psychosis in Ultra High-Risk Patients: Data From the PACE 400 Cohort(Elsevier, 2024-04)BACKGROUND: Multimodal modeling that combines biological and clinical data shows promise in predicting transition to psychosis in individuals who are at ultra-high risk. Individuals who transition to psychosis are known to have deficits at baseline in cognitive function and reductions in gray matter volume in multiple brain regions identified by magnetic resonance imaging. METHODS: In this study, we used Cox proportional hazards regression models to assess the additive predictive value of each modality-cognition, cortical structure information, and the neuroanatomical measure of brain age gap-to a previously developed clinical model using functioning and duration of symptoms prior to service entry as predictors in the Personal Assessment and Crisis Evaluation (PACE) 400 cohort. The PACE 400 study is a well-characterized cohort of Australian youths who were identified as ultra-high risk of transitioning to psychosis using the Comprehensive Assessment of At Risk Mental States (CAARMS) and followed for up to 18 years; it contains clinical data (from N = 416 participants), cognitive data (n = 213), and magnetic resonance imaging cortical parameters extracted using FreeSurfer (n = 231). RESULTS: The results showed that neuroimaging, brain age gap, and cognition added marginal predictive information to the previously developed clinical model (fraction of new information: neuroimaging 0%-12%, brain age gap 7%, cognition 0%-16%). CONCLUSIONS: In summary, adding a second modality to a clinical risk model predicting the onset of a psychotic disorder in the PACE 400 cohort showed little improvement in the fit of the model for long-term prediction of transition to psychosis.
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ItemNo Preview AvailableThe Addition of Fish Oil to Cognitive Behavioral Case Management for Youth Depression: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Trial(ELSEVIER SCIENCE INC, 2024-03-01)BACKGROUND: Clinical trials suggest that long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs) (fish oil) may reduce depressive symptoms in adults with major depressive disorder. Therefore, n-3 PUFAs may be a potential treatment for depression in youth. METHODS: Participants were 15- to-25 year-old individuals with major depressive disorder who sought care in one of three government-funded mental health services for young people in metropolitan Melbourne, Perth, or Sydney, Australia. Participants were randomly assigned in a double-blind, parallel-arm design to receive either fish oil (840 mg of eicosapentaenoic acid and 560 mg of docosahexaenoic acid) or placebo capsules as adjunct to cognitive behavioral case management. All participants were offered 50-minute cognitive behavioral case management sessions every 2 weeks delivered by qualified therapists (treatment as usual) at the study sites during the intervention period. The primary outcome was change in the interviewer-rated Quick Inventory of Depressive Symptomatology, Adolescent Version, score at 12 weeks. Erythrocyte n-3 PUFA levels were assessed pre-post intervention. RESULTS: A total of 233 young people were randomized to the treatment arms: 115 participants to the n-3 PUFA group and 118 to the placebo group. Mean change from baseline in the Quick Inventory of Depressive Symptomatology score was -5.8 in the n-3 PUFA group and -5.6 in the placebo group (mean difference, 0.2; 95% CI, -1.1 to 1.5; p = .75). Erythrocyte PUFA levels were not associated with depression severity at any time point. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONS: This placebo-controlled trial and biomarker analysis found no evidence to support the use of fish oil for treatment in young people with major depressive disorder.
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ItemNo Preview AvailableA Sequential Adaptive Intervention Strategy Targeting Remission and Functional Recovery in Young People at Ultrahigh Risk of Psychosis The Staged Treatment in Early Psychosis (STEP) Sequential Multiple Assignment Randomized Trial(AMER MEDICAL ASSOC, 2023-09)IMPORTANCE: Clinical trials have not established the optimal type, sequence, and duration of interventions for people at ultrahigh risk of psychosis. OBJECTIVE: To determine the effectiveness of a sequential and adaptive intervention strategy for individuals at ultrahigh risk of psychosis. DESIGN, SETTING, AND PARTICIPANTS: The Staged Treatment in Early Psychosis (STEP) sequential multiple assignment randomized trial took place within the clinical program at Orygen, Melbourne, Australia. Individuals aged 12 to 25 years who were seeking treatment and met criteria for ultrahigh risk of psychosis according to the Comprehensive Assessment of At-Risk Mental States were recruited between April 2016 and January 2019. Of 1343 individuals considered, 342 were recruited. INTERVENTIONS: Step 1: 6 weeks of support and problem solving (SPS); step 2: 20 weeks of cognitive-behavioral case management (CBCM) vs SPS; and step 3: 26 weeks of CBCM with fluoxetine vs CBCM with placebo with an embedded fast-fail option of ω-3 fatty acids or low-dose antipsychotic medication. Individuals who did not remit progressed through these steps; those who remitted received SPS or monitoring for up to 12 months. MAIN OUTCOMES AND MEASURES: Global Functioning: Social and Role scales (primary outcome), Brief Psychiatric Rating Scale, Scale for the Assessment of Negative Symptoms, Montgomery-Åsberg Depression Rating Scale, quality of life, transition to psychosis, and remission and relapse rates. RESULTS: The sample comprised 342 participants (198 female; mean [SD] age, 17.7 [3.1] years). Remission rates, reflecting sustained symptomatic and functional improvement, were 8.5%, 10.3%, and 11.4% at steps 1, 2, and 3, respectively. A total of 27.2% met remission criteria at any step. Relapse rates among those who remitted did not significantly differ between SPS and monitoring (step 1: 65.1% vs 58.3%; step 2: 37.7% vs 47.5%). There was no significant difference in functioning, symptoms, and transition rates between SPS and CBCM and between CBCM with fluoxetine and CBCM with placebo. Twelve-month transition rates to psychosis were 13.5% (entire sample), 3.3% (those who ever remitted), and 17.4% (those with no remission). CONCLUSIONS AND RELEVANCE: In this sequential multiple assignment randomized trial, transition rates to psychosis were moderate, and remission rates were lower than expected, partly reflecting the ambitious criteria set and challenges with real-world treatment fidelity and adherence. While all groups showed mild to moderate functional and symptomatic improvement, this was typically short of remission. While further adaptive trials that address these challenges are needed, findings confirm substantial and sustained morbidity and reveal relatively poor responsiveness to existing treatments. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02751632.
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ItemBaseline data of a sequential multiple assignment randomized trial (STEP study)(WILEY, 2022-10)AIM: Research has shown that preventative intervention in individuals at ultra-high risk of psychosis (UHR) improves symptomatic and functional outcomes. The staged treatment in early psychosis (STEP) trial aims to determine the most effective type, timing and sequence of interventions in the UHR population by sequentially studying the effectiveness of (1) support and problem solving, (2) cognitive-behavioural case management and (3) antidepressant medication with an embedded fast-fail option of (4) omega-3 fatty acids or low-dose antipsychotic medication. This paper presents the recruitment flow and baseline clinical characteristics of the sample. METHODS: STEP is a sequential multiple assignment randomized trial. We present the baseline demographics, clinical characteristics and acceptability and feasibility of this treatment approach as indicated by the flow of participants from first contact up until enrolment into the trial. Recruitment took place between April 2016 and January 2019. RESULTS: Of 1343, help-seeking young people who were considered for participation, 402 participants were not eligible and 599 declined/disengaged, resulting in a total of 342 participants enrolled in the study. The most common reason for exclusion was an active prescription of antidepressant medication. Eighty-five percent of the enrolled sample had a non-psychotic DSM-5 diagnosis and symptomatic/functional measures showed a moderate level of clinical severity and functional impairment. DISCUSSION: The present study demonstrates the acceptability and participant's general positive appraisal of sequential treatment. It also shows, in line with other trials in UHR individuals, a significant level of psychiatric morbidity and impairment, demonstrating the clear need for care in this group and that treatment is appropriate.