Centre for Youth Mental Health - Research Publications
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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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ItemOmega-3 fatty acids and neurocognitive ability in young people at ultra-high risk for psychosis(WILEY, 2020-09-06)BACKGROUND: Neurocognitive impairments are core early features of psychosis and are observed in those at ultra-high risk (UHR) for psychosis. The aim of the present study was to explore whether neurocognition is associated with polyunsaturated fatty acids (PUFAs), as has been observed in other clinical populations. METHOD: Erythrocyte levels of total omega-3-and omega-6 PUFAs the omega-3/omega-6 ratio, were measured in 265 UHR individuals. Six domains of neurocognition as well a Composite Score, were assessed using the Brief Assessment of Cognition in Schizophrenia. Pearson's correlations were used to assess the relationship between PUFAs and neurocognition. All analyses were controlled for tobacco smoking. RESULTS: Verbal Fluency correlated positively with eicosapentaenoic acid (P = .024) and alpha-linolenic acid (P = .01), and negatively with docosahexanoic acid (P = .007) and Working Memory positively correlated with omega-3/omega-6 ratio (P = .007). CONCLUSIONS: The current results provide support for a relationship between Verbal Fluency and omega-3 PUFAs in UHR. Further investigation is required to elucidate whether these biomarkers are useful as risk markers or in understanding the biological underpinning of neurocognitive impairment in this population.
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ItemPrediction of clinical outcomes beyond psychosis in theultra-highrisk for psychosis population(WILEY, 2020-06-17)AIM: Several prediction models have been introduced to identify young people at greatest risk of transitioning to psychosis. To date, none has examined the possibility of developing a clinical prediction model of outcomes other than transition. The aims of this study were to examine the association between baseline clinical predictors and outcomes including, but not limited to, transition to psychosis in young people at risk for psychosis, and to develop a prediction model for these outcomes. METHODS: Several evidence-based variables previously associated with transition to psychosis and some important clinical comorbidities experienced by ultra-high risk (UHR) individuals were identified in 202 UHR individuals. Secondary analysis of the Neurapro clinical trial were conducted to investigate the associations between these variables and favourable (remission and recovery) or unfavourable (transition to psychosis, no remission, any recurrence and relapse) clinical outcomes. Logistic regression, best subset selection, Akaike Information Criterion and receiver operating characteristic curves were used to seek the best prediction model for clinical outcomes from all combinations of possible predictors. RESULTS: When considered individually, only higher general psychopathology levels (P = .023) was associated with the unfavourable outcomes. Prediction models suggest that general psychopathology and functioning are predictive of unfavourable outcomes. CONCLUSION: The predictive performance of the resulting models was modest and further research is needed. Nonetheless, when designing early intervention centres aiming to support individuals in the early phases of a mental disorder, the proper assessment of general psychopathology and functioning should be considered in order to inform interventions and length of care provided.
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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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ItemNo Preview AvailableEvidence for preventive treatments in young patients at clinical high risk of psychosis: the need for context(ELSEVIER SCI LTD, 2020-05-01)
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ItemAssociation of Adverse Outcomes With Emotion Processing and Its Neural Substrate in Individuals at Clinical High Risk for Psychosis(AMER MEDICAL ASSOC, 2020-02-01)IMPORTANCE: The development of adverse clinical outcomes in patients with psychosis has been associated with behavioral and neuroanatomical deficits related to emotion processing. However, the association between alterations in brain regions subserving emotion processing and clinical outcomes remains unclear. OBJECTIVE: To examine the association between alterations in emotion processing and regional gray matter volumes in individuals at clinical high risk (CHR) for psychosis, and the association with subsequent clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS: This naturalistic case-control study with clinical follow-up at 12 months was conducted from July 1, 2010, to August 31, 2016, and collected data from 9 psychosis early detection centers (Amsterdam, Basel, Cologne, Copenhagen, London, Melbourne, Paris, The Hague, and Vienna). Participants (213 individuals at CHR and 52 healthy controls) were enrolled in the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) project. Data were analyzed from October 1, 2018, to April 24, 2019. MAIN MEASURES AND OUTCOMES: Emotion recognition was assessed with the Degraded Facial Affect Recognition Task. Three-Tesla magnetic resonance imaging scans were acquired from all participants, and gray matter volume was measured in regions of interest (medial prefrontal cortex, amygdala, hippocampus, and insula). Clinical outcomes at 12 months were evaluated for transition to psychosis using the Comprehensive Assessment of At-Risk Mental States criteria, and the level of overall functioning was measured through the Global Assessment of Functioning [GAF] scale. RESULTS: A total of 213 individuals at CHR (105 women [49.3%]; mean [SD] age, 22.9 [4.7] years) and 52 healthy controls (25 women [48.1%]; mean [SD] age, 23.3 [4.0] years) were included in the study at baseline. At the follow-up within 2 years of baseline, 44 individuals at CHR (20.7%) had developed psychosis and 169 (79.3%) had not. Of the individuals at CHR reinterviewed with the GAF, 39 (30.0%) showed good overall functioning (GAF score, ≥65), whereas 91 (70.0%) had poor overall functioning (GAF score, <65). Within the CHR sample, better anger recognition at baseline was associated with worse functional outcome (odds ratio [OR], 0.88; 95% CI, 0.78-0.99; P = .03). In individuals at CHR with a good functional outcome, positive associations were found between anger recognition and hippocampal volume (ze = 3.91; familywise error [FWE] P = .02) and between fear recognition and medial prefrontal cortex volume (z = 3.60; FWE P = .02), compared with participants with a poor outcome. The onset of psychosis was not associated with baseline emotion recognition performance (neutral OR, 0.93; 95% CI, 0.79-1.09; P = .37; happy OR, 1.03; 95% CI, 0.84-1.25; P = .81; fear OR, 0.98; 95% CI, 0.85-1.13; P = .77; anger OR, 1.00; 95% CI, 0.89-1.12; P = .96). No difference was observed in the association between performance and regional gray matter volumes in individuals at CHR who developed or did not develop psychosis (FWE P < .05). CONCLUSIONS AND RELEVANCE: In this study, poor functional outcome in individuals at CHR was found to be associated with baseline abnormalities in recognizing negative emotion. This finding has potential implications for the stratification of individuals at CHR and suggests that interventions that target socioemotional processing may improve functional outcomes.
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ItemClinical, cognitive and neuroanatomical associations of serum NMDAR autoantibodies in people at clinical high risk for psychosis(SPRINGERNATURE, 2020-10-19)Serum neuronal autoantibodies, such as those to the NMDA receptor (NMDAR), are detectable in a subgroup of patients with psychotic disorders. It is not known if they are present before the onset of psychosis or whether they are associated with particular clinical features or outcomes. In a case-control study, sera from 254 subjects at clinical high risk (CHR) for psychosis and 116 healthy volunteers were tested for antibodies against multiple neuronal antigens implicated in CNS autoimmune disorders, using fixed and live cell-based assays (CBAs). Within the CHR group, the relationship between NMDAR antibodies and symptoms, cognitive function and clinical outcomes over 24 month follow-up was examined. CHR subjects were not more frequently seropositive for neuronal autoantibodies than controls (8.3% vs. 5.2%; OR = 1.50; 95% CI: 0.58-3.90). The NMDAR was the most common target antigen and NMDAR IgGs were more sensitively detected with live versus fixed CBAs (p < 0.001). Preliminary phenotypic analyses revealed that within the CHR sample, the NMDAR antibody seropositive subjects had higher levels of current depression, performed worse on the Rey Auditory Verbal Learning Task (p < 0.05), and had a markedly lower IQ (p < 0.01). NMDAR IgGs were not more frequent in subjects who later became psychotic than those who did not. NMDAR antibody serostatus and titre was associated with poorer levels of functioning at follow-up (p < 0.05) and the presence of a neuronal autoantibody was associated with larger amygdala volumes (p < 0.05). Altogether, these findings demonstrate that NMDAR autoantibodies are detectable in a subgroup of CHR subjects at equal rates to controls. In the CHR group, they are associated with affective psychopathology, impairments in verbal memory, and overall cognitive function: these findings are qualitatively and individually similar to core features of autoimmune encephalitis and/or animal models of NMDAR antibody-mediated CNS disease. Overall the current work supports further evaluation of NMDAR autoantibodies as a possible prognostic biomarker and aetiological factor in a subset of people already meeting CHR criteria.
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ItemDistress related to attenuated psychotic symptoms: Static and dynamic association with transition to psychosis, non-remission and transdiagnostic symptomatology in clinical high-risk patients in an international intervention trial.(Oxford University Press (OUP), 2020-03-02)This study examined whether distress in relation to attenuated psychotic symptoms (DAPS) is associated with clinical outcomes in an ultra-high-risk (UHR) for psychosis sample. We also investigated whether DAPS is associated with cognitive style (attributional style and cognitive biases) and whether amount of psychosocial treatment provided is associated with reduction in DAPS. The study was a secondary analysis of the 'Neurapro' clinical trial of omega-3 fatty acids. 304 UHR patients were recruited across ten early intervention services. Data from baseline assessment, regular assessments over 12 months and medium term follow up (mean=3.4 years) were used for analysis. Findings indicated: a positive association between DAPS assessed over time and transition to psychosis; a significant positive association between baseline and longitudinal DAPS and transdiagnostic clinical and functional outcomes; a significant positive association between baseline and longitudinal DAPS and non-remission of UHR status. There was no relationship between severity of DAPS and cognitive style. A greater amount of psychosocial treatment (cognitive-behavioural case management) was associated with an increase in DAPS scores. The study indicates that UHR patients who are more distressed by their attenuated psychotic symptoms are more likely to have a poorer clinical trajectory transdiagnostically. Assessment of DAPS may therefore function as a useful marker of risk for a range of poor outcomes. The findings underline the value of repeated assessment of variables and incorporation of dynamic change into predictive modelling. More research is required into mechanisms driving distress associated with symptoms and the possible bidirectional relationship between symptom severity and associated distress.