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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ItemRelationship Between Polyunsaturated Fatty Acids and Psychopathology in the NEURAPRO Clinical Trial(FRONTIERS MEDIA SA, 2019-06-06)Background: Deficiencies in membrane polyunsaturated fatty acids (PUFA) such as omega-3 (n-3) fatty acids are thought to contribute to the pathophysiological processes underlying psychotic disorders. Emerging evidence suggests that the levels of PUFA are related to clinical symptoms but significant heterogeneity exists between studies. Here, we investigated associations of membrane PUFA with clinical symptoms and functioning in a large sample of individuals at ultra-high risk (UHR) for psychosis. Methods: A total of 285 participants of the NEURAPRO clinical trial were investigated for erythrocyte PUFA levels, including the n-3 index, n-6/n-3 PUFA ratio, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). Severity of general psychopathology [Brief Psychiatric Rating Scale (BPRS)], psychotic symptoms (BPRS psychosis subscale), negative symptoms [Scale for the Assessment of Negative Symptoms (SANS)], manic symptoms [Young Mania Rating Scale (YMRS)], depressive symptoms [Montgomery Asberg Depression Rating Scale (MADRS)], and functioning [Social and Occupational Functioning Scale (SOFAS), Global Functioning Social (GF-S) and Role (GF-R) scales] were assessed concurrently. Partial correlation taking into account the effects of gender, age, and smoking was used to examine the relationship between PUFAs and symptoms severity. Results: The n-3 index negatively correlated with the severity of general psychopathology, psychotic symptoms, depressive symptoms, and manic symptoms. The n-6/n-3 PUFA ratio positively correlated with severity of psychotic and depressive symptoms. The n-3 PUFA DHA negatively correlated with the severity of general psychopathology, positive, manic, and depressive symptoms. EPA negatively correlated with manic symptoms. Nervonic acid, an n-9 monounsaturated fatty acid, positively correlated with general psychopathology, positive and negative symptoms, depressive symptoms, and manic symptoms. The long-chain saturated fatty acid tetracosanoic acid positively correlated with general psychopathology, positive, manic, and depressive symptoms. Conclusions: Partially consistent with a previous study, psychotic symptoms, depressive symptoms, and symptoms of mania were associated with several classes of FAs in the present study. These findings support the relevance of membrane fatty acids for the onset of psychotic symptoms and indicate that FAs should be further evaluated as biomarkers in the UHR for psychosis group. Clinical Trial Registration: ANZCTR, identifier: 12608000475347.
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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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ItemNEURAPRO: a multi-centre RCT of omega-3 polyunsaturated fatty acids versus placebo in young people at ultra-high risk of psychotic disorders-medium-term follow-up and clinical course.(Springer Science and Business Media LLC, 2018-06-25)This study reports a medium-term follow-up of a randomised, double-blind, placebo-controlled trial of omega-3 polyunsaturated fatty acids (PUFA) in ultra-high risk for psychosis (UHR) patients. Primary outcomes of interest were transition to psychosis and symptomatic and functional outcome. A secondary aim was to investigate clinical predictors of medium-term outcome. Three hundred four UHR participants were recruited across 10 specialised early psychosis services in Australia, Asia, and Europe. The intervention consisted of 1.4 g/daily of omega-3 PUFA or placebo, plus up to 20 sessions of cognitive-behavioural case management (CBCM), over the 6-month study period, with participants receiving further CBCM sessions on basis of need between months 6-12. Mean time to follow-up was 3.4 (median = 3.3; SD = 0.9) years. There was a modest increase in transitions between 12-month and medium-term follow-up (11-13%) and substantial improvement in symptoms and functioning between baseline and follow-up, with no differences between the treatment groups. Most improvement had been achieved by end of the intervention. 55% of the sample received mental health treatment between end of intervention and follow-up. Omega-3 PUFA did not provide additional benefits to good quality psychosocial intervention over the medium term. Although most improvement had been achieved by end of intervention the substantial rates of post-intervention mental health service use indicate longer-term clinical need in UHR patients. The post-intervention phase treatment or the longer-term effect of CBCM, or a combination of the two, may have contributed to maintaining the gains achieved during the intervention phase and prevented significant deterioration after this time.
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ItemLongitudinal determinants of client treatment satisfaction in an intensive first-episode psychosis treatment programme(WILEY, 2017-08)AIM: Previous evidence demonstrates that higher treatment satisfaction is strongly associated with improved clinical outcomes and functioning. The aim of the current study is to explore potential associations between clinical and demographic attributes, as well as changes in role, social and cognitive functioning occurring over the course of treatment, on self-reported treatment satisfaction within the context of an intensive first-episode psychosis intervention programme. METHODS: Forty-four young adults attending a first-episode psychosis treatment programme completed a battery of clinical and neuropsychological measures at intake to the programme and again after 6 months of treatment. A modified version of the Client Satisfaction Questionnaire was administered at 6 months. Baseline, 6-month and change scores across the clinical and demographic measures were examined relative to the satisfaction questionnaire to evaluate determinants of treatment satisfaction. RESULTS: Better premorbid adjustment during childhood and early adolescence was associated with higher treatment satisfaction, as did positive changes in clients' cognitive performance and their use of humour as a coping strategy. Clients' use of emotional support as a coping strategy at 6 months was also positively associated with treatment satisfaction. Although clients' social and role functioning improved significantly during the 6-month treatment window, changes in functional outcomes were not significantly associated with treatment satisfaction. CONCLUSIONS: The current study highlights the role of premorbid adjustment and changes in coping and neurocognition as factors influencing treatment satisfaction. Future research designs might be able to more specifically ascertain causal relationships between patient characteristics, treatment components, client satisfaction and clinical effects.
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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.
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ItemNo Preview AvailableOmega-3 Fatty Acid Supplementation in Adolescents With Borderline Personality Disorder and Ultra-High Risk Criteria for Psychosis: A Post Hoc Subgroup Analysis of a Double-Blind, Randomized Controlled Trial(CANADIAN PSYCHIATRIC ASSOC, 2013-07)OBJECTIVE: To investigate whether long-chain omega-3 (n-3) polyunsaturated fatty acids (PUFAs) improve functioning and psychiatric symptoms in young people with borderline personality disorder (BPD) who also meet ultra-high risk criteria for psychosis. METHODS: We conducted a post hoc subgroup analysis of a double-blind, randomized controlled trial. Fifteen adolescents with BPD (mean age 16.2 years, [SD 2.1]) were randomized to either 1.2 g/day n-3 PUFAs or placebo. The intervention period was 12 weeks. Study measures included the Positive and Negative Syndrome Scale, the Montgomery-Åsberg Depression Rating Scale, and the Global Assessment of Functioning. Side effects were documented with the Udvalg for Kliniske Undersøgelser. Fatty acids in erythrocytes were analyzed using capillary gas chromatography. RESULTS: At baseline, erythrocyte n-3 PUFA levels correlated positively with psychosocial functioning and negatively with psychopathology. By the end of the intervention, n-3 PUFAs significantly improved functioning and reduced psychiatric symptoms, compared with placebo. Side effects did not differ between the treatment groups. CONCLUSIONS: Long-chain n-3 PUFAs should be further explored as a viable treatment strategy with minimal associated risk in young people with BPD. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT00396643).