Centre for Youth Mental Health - Research Publications
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ItemEffects of NRG1 and DAOA genetic variation on transition to psychosis in individuals at ultra-high risk for psychosis(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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ItemIndividualized Prediction of Transition to Psychosis in 1,676 Individuals at Clinical High Risk: Development and Validation of a Multivariable Prediction Model Based on Individual Patient Data Meta-Analysis(FRONTIERS MEDIA SA, 2019-05-21)Background: The Clinical High Risk state for Psychosis (CHR-P) has become the cornerstone of modern preventive psychiatry. The next stage of clinical advancements rests on the ability to formulate a more accurate prognostic estimate at the individual subject level. Individual Participant Data Meta-Analyses (IPD-MA) are robust evidence synthesis methods that can also offer powerful approaches to the development and validation of personalized prognostic models. The aim of the study was to develop and validate an individualized, clinically based prognostic model for forecasting transition to psychosis from a CHR-P stage. Methods: A literature search was performed between January 30, 2016, and February 6, 2016, consulting PubMed, Psychinfo, Picarta, Embase, and ISI Web of Science, using search terms ("ultra high risk" OR "clinical high risk" OR "at risk mental state") AND [(conver* OR transition* OR onset OR emerg* OR develop*) AND psychosis] for both longitudinal and intervention CHR-P studies. Clinical knowledge was used to a priori select predictors: age, gender, CHR-P subgroup, the severity of attenuated positive psychotic symptoms, the severity of attenuated negative psychotic symptoms, and level of functioning at baseline. The model, thus, developed was validated with an extended form of internal validation. Results: Fifteen of the 43 studies identified agreed to share IPD, for a total sample size of 1,676. There was a high level of heterogeneity between the CHR-P studies with regard to inclusion criteria, type of assessment instruments, transition criteria, preventive treatment offered. The internally validated prognostic performance of the model was higher than chance but only moderate [Harrell's C-statistic 0.655, 95% confidence interval (CIs), 0.627-0.682]. Conclusion: This is the first IPD-MA conducted in the largest samples of CHR-P ever collected to date. An individualized prognostic model based on clinical predictors available in clinical routine was developed and internally validated, reaching only moderate prognostic performance. Although personalized risk prediction is of great value in the clinical practice, future developments are essential, including the refinement of the prognostic model and its external validation. However, because of the current high diagnostic, prognostic, and therapeutic heterogeneity of CHR-P studies, IPD-MAs in this population may have an limited intrinsic power to deliver robust prognostic models.
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ItemNo Preview AvailableUsing clinical information to make individualized prognostic predictions in people at ultra high risk for psychosis(ELSEVIER, 2017-06)Recent studies have reported an association between psychopathology and subsequent clinical and functional outcomes in people at ultra-high risk (UHR) for psychosis. This has led to the suggestion that psychopathological information could be used to make prognostic predictions in this population. However, because the current literature is based on inferences at group level, the translational value of the findings for everyday clinical practice is unclear. Here we examined whether psychopathological information could be used to make individualized predictions about clinical and functional outcomes in people at UHR. Participants included 416 people at UHR followed prospectively at the Personal Assessment and Crisis Evaluation (PACE) Clinic in Melbourne, Australia. The data were analysed using Support Vector Machine (SVM), a supervised machine learning technique that allows inferences at the individual level. SVM predicted transition to psychosis with a specificity of 60.6%, a sensitivity of 68.6% and an accuracy of 64.6% (p<0.001). In addition, SVM predicted functioning with a specificity of 62.5%, a sensitivity of 62.5% and an accuracy of 62.5% (p=0.008). Prediction of transition was driven by disorder of thought content, attenuated positive symptoms and functioning, whereas functioning was best predicted by attention disturbances, anhedonia-asociality and disorder of thought content. These results indicate that psychopathological information allows individualized prognostic predictions with statistically significant accuracy. However, this level of accuracy may not be sufficient for clinical translation in real-world clinical practice. Accuracy might be improved by combining psychopathological information with other types of data using a multivariate machine learning framework.
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ItemNo Preview AvailableOutcomes of Nontransitioned Cases in a Sample at Ultra-High Risk for Psychosis(AMER PSYCHIATRIC PUBLISHING, INC, 2015-03)OBJECTIVE: Two-thirds of individuals identified as at ultra-high risk for psychosis do not develop psychotic disorder over the medium term. The authors examined outcomes in a group of such patients. METHOD: Participants were help-seeking individuals identified as being at ultra-high risk for psychosis 2-14 years previously. The 226 participants (125 female, 101 male) completed a follow-up assessment and had not developed psychosis. Their mean age at follow-up was 25.5 years (SD=4.8). RESULTS: At follow-up, 28% of the participants reported attenuated psychotic symptoms. Over the follow-up period, 68% experienced nonpsychotic disorders: mood disorder in 49%, anxiety disorder in 35%, and substance use disorder in 29%. For the majority (90%), nonpsychotic disorder was present at baseline, and it persisted for 52% of them. During follow-up, 26% of the cohort had remission of a disorder, but 38% developed a new disorder. Only 7% did not experience any disorder at baseline or during follow up. The incidence of nonpsychotic disorder was associated with more negative symptoms at baseline. Female participants experienced higher rates of persistent or recurrent disorder. Meeting criteria for brief limited intermittent psychotic symptoms at intake was associated with lower risk for persistent or recurrent disorder. CONCLUSIONS: Individuals at ultra-high risk for psychosis who do not transition to psychosis are at significant risk for continued attenuated psychotic symptoms, persistent or recurrent disorders, and incident disorders. Findings have implications for ongoing clinical care.
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ItemNo Preview AvailableSexual Trauma Increases the Risk of Developing Psychosis in an Ultra High-Risk "Prodromal" Population(OXFORD UNIV PRESS, 2014-05)Studies indicate a high prevalence of childhood trauma in patient cohorts with established psychotic disorder and in those at risk of developing psychosis. A causal link between childhood trauma and development of psychosis has been proposed. We aimed to examine the association between experience of childhood trauma and the development of a psychotic disorder in a large "Ultra High Risk" (UHR) for psychosis cohort. The data were collected as part of a longitudinal cohort study of all UHR patients recruited to research studies at the Personal Assessment and Clinical Evaluation clinic between 1993 and 2006. Baseline data were collected at recruitment to these studies. The participants completed a comprehensive follow-up assessment battery (mean time to follow-up 7.5 years, range 2.4-14.9 years), which included the Childhood Trauma Questionnaire (CTQ), a self-report questionnaire that assesses experience of childhood trauma. The outcome of interest was transition to a psychotic disorder during the follow-up period. Data were available on 233 individuals. Total CTQ trauma score was not associated with transition to psychosis. Of the individual trauma types, only sexual abuse was associated with transition to psychosis (P = .02). The association remained when adjusting for potential confounding factors. Those with high sexual abuse scores were estimated to have a transition risk 2-4 times that of those with low scores. The findings suggest that sexual trauma may be an important contributing factor in development of psychosis for some individuals.
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ItemNo Preview AvailablePhenylthiocarbamide (PTC) perception in ultra-high risk for psychosis participants who develop schizophrenia: Testing the evidence for an endophenotypic marker(ELSEVIER IRELAND LTD, 2012-08-30)Reports suggesting that schizophrenia participants are more likely to be phenylthiocarbamide (PTC) non-tasters when compared to controls have recently been controversial. If supported, a genetic-based phenotypic variation in PTC taster status is implicated, suggesting a greater illness risk for those participants with recessive alleles for the TAS2R38 receptor. Should PTC insensitivity be a schizophrenia endophenotype, then it would be expected in follow-up of ultra high-risk for psychosis participants who later develop schizophrenia (UHR-S). UHR-S was hypothesised to show reduced PTC sensitivity compared to those who were previously at risk, but did not transition (UHR-NP). PTC perception was assessed in 219 UHR participants at long-term follow-up, of whom 53 had transitioned to psychosis (UHR-P) during the follow-up period. Fifteen of the 219 participants were diagnosed with schizophrenia. Seventy-eight had a family history of psychotic disorder. No differences in PTC taster status were found in UHR participants based upon transition to psychosis status, schizophrenia diagnosis, or family history of schizophrenia. This report indicates that schizophrenia development among UHR participants is not associated with PTC tasting deficits and fails to support previous findings that inability to detect the bitter taste of PTC is a schizophrenia endophenotype.