Centre for Youth Mental Health - Research Publications

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    Combining Clinical With Cognitive or Magnetic Resonance Imaging Data for Predicting Transition to Psychosis in Ultra High-Risk Patients: Data From the PACE 400 Cohort.
    Hartmann, S ; Cearns, M ; Pantelis, C ; Dwyer, D ; Cavve, B ; Byrne, E ; Scott, I ; Yuen, HP ; Gao, C ; Allott, K ; Lin, A ; Wood, SJ ; Wigman, JTW ; Amminger, GP ; McGorry, PD ; Yung, AR ; Nelson, B ; Clark, SR (Elsevier BV, 2023-12-03)
    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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    Effects of risperidone/paliperidone versus placebo on cognitive functioning over the first 6 months of treatment for psychotic disorder: secondary analysis of a triple-blind randomised clinical trial
    Allott, K ; Yuen, HP ; Baldwin, L ; O'Donoghue, B ; Fornito, A ; Chopra, S ; Nelson, B ; Graham, J ; Kerr, MJJ ; Proffitt, T-M ; Ratheesh, A ; Alvarez-Jimenez, M ; Harrigan, S ; Brown, E ; Thompson, ADD ; Pantelis, C ; Berk, M ; McGorry, PDD ; Francey, SMM ; Wood, SJJ (SPRINGERNATURE, 2023-06-10)
    The drivers of cognitive change following first-episode psychosis remain poorly understood. Evidence regarding the role of antipsychotic medication is primarily based on naturalistic studies or clinical trials without a placebo arm, making it difficult to disentangle illness from medication effects. A secondary analysis of a randomised, triple-blind, placebo-controlled trial, where antipsychotic-naive patients with first-episode psychotic disorder were allocated to receive risperidone/paliperidone or matched placebo plus intensive psychosocial therapy for 6 months was conducted. A healthy control group was also recruited. A cognitive battery was administered at baseline and 6 months. Intention-to-treat analysis involved 76 patients (antipsychotic medication group: 37; 18.6Mage [2.9] years; 21 women; placebo group: 39; 18.3Mage [2.7]; 22 women); and 42 healthy controls (19.2Mage [3.0] years; 28 women). Cognitive performance predominantly remained stable (working memory, verbal fluency) or improved (attention, processing speed, cognitive control), with no group-by-time interaction evident. However, a significant group-by-time interaction was observed for immediate recall (p = 0.023), verbal learning (p = 0.024) and delayed recall (p = 0.005). The medication group declined whereas the placebo group improved on each measure (immediate recall: p = 0.024; ηp2 = 0.062; verbal learning: p = 0.015; ηp2 = 0.072 both medium effects; delayed recall: p = 0.001; ηp2 = 0.123 large effect). The rate of change for the placebo and healthy control groups was similar. Per protocol analysis (placebo n = 16, medication n = 11) produced similar findings. Risperidone/paliperidone may worsen verbal learning and memory in the early months of psychosis treatment. Replication of this finding and examination of various antipsychotic agents are needed in confirmatory trials. Antipsychotic effects should be considered in longitudinal studies of cognition in psychosis.Trial registration: Australian New Zealand Clinical Trials Registry ( http://www.anzctr.org.au/ ; ACTRN12607000608460).
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    The relationship between subjective sleep disturbance and attenuated psychotic symptoms after accounting for anxiety and depressive symptoms
    Formica, MJC ; Fuller-Tyszkiewicz, M ; Hickie, I ; Olive, L ; Wood, SJ ; Purcell, R ; Yung, AR ; Phillips, LJ ; Nelson, B ; Pantelis, C ; Mcgorry, PD ; Hartmann, JA (ELSEVIER, 2023-08)
    BACKGROUND AND HYPOTHESES: Sleep disturbances are increasingly recognized as cooccurring with psychotic symptoms. The potential importance of this relationship is complicated when considering the effects of anxiety and depressive symptoms which commonly present in early-stage illness states. This study aimed to investigate the relationship between self-reported sleep disturbance on the development of attenuated psychotic symptoms (APS) cross-sectionally and longitudinally while adjusting for roles of anxiety and depressive symptoms. DESIGN: Eight-hundred and two help-seeking young people aged 12 to 25 years who engaged with our Australian early intervention services were included in the study (the "Transitions" cohort). Cross sectional mediation and cross-lagged longitudinal (12-month) mediation models were developed with outcomes being different APS domains. RESULTS: Only baseline excessive daytime sleepiness predicted later APS when accounting for previous APS, anxiety and depressive symptomatology. Cross sectionally, self-reported sleep disturbance showed both direct and indirect predictive relationships with all APS domains. Partial mediation through anxiety and depression was shown for unusual thought content, perceptual abnormalities, and disorganised speech, while full mediation through depression was shown for non-bizarre ideas. CONCLUSIONS: The specificity of the relationship between self-reported sleep disturbance on APS highlights the potential for different roles in mechanistic models of psychotic symptom expression. This further indicates the need for further experimental research to illuminate potential causal pathways. Future research should continue to use continuous, symptom level approaches across a range of timeframes to more accurately model the complex dynamics present in the sleep-psychosis relationship.
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    Network-Based Spreading of Gray Matter Changes Across Different Stages of Psychosis
    Chopra, S ; Segal, A ; Oldham, S ; Holmes, A ; Sabaroedin, K ; Orchard, ER ; Francey, SM ; O'Donoghue, B ; Cropley, V ; Nelson, B ; Graham, J ; Baldwin, L ; Tiego, J ; Yuen, HP ; Allott, K ; Alvarez-Jimenez, M ; Harrigan, S ; Fulcher, BD ; Aquino, K ; Pantelis, C ; Wood, SJ ; Bellgrove, M ; Mcgorry, PD ; Fornito, A (AMER MEDICAL ASSOC, 2023-12)
    IMPORTANCE: Psychotic illness is associated with anatomically distributed gray matter reductions that can worsen with illness progression, but the mechanisms underlying the specific spatial patterning of these changes is unknown. OBJECTIVE: To test the hypothesis that brain network architecture constrains cross-sectional and longitudinal gray matter alterations across different stages of psychotic illness and to identify whether certain brain regions act as putative epicenters from which volume loss spreads. DESIGN, SETTINGS, AND PARTICIPANTS: This case-control study included 534 individuals from 4 cohorts, spanning early and late stages of psychotic illness. Early-stage cohorts included patients with antipsychotic-naive first-episode psychosis (n = 59) and a group of patients receiving medications within 3 years of psychosis onset (n = 121). Late-stage cohorts comprised 2 independent samples of people with established schizophrenia (n = 136). Each patient group had a corresponding matched control group (n = 218). A sample of healthy adults (n = 356) was used to derive representative structural and functional brain networks for modeling of network-based spreading processes. Longitudinal illness-related and antipsychotic-related gray matter changes over 3 and 12 months were examined using a triple-blind randomized placebo-control magnetic resonance imaging study of the antipsychotic-naive patients. All data were collected between April 29, 2008, and January 15, 2020, and analyses were performed between March 1, 2021, and January 14, 2023. MAIN OUTCOMES AND MEASURES: Coordinated deformation models were used to estimate the extent of gray matter volume (GMV) change in each of 332 parcellated areas by the volume changes observed in areas to which they were structurally or functionally coupled. To identify putative epicenters of volume loss, a network diffusion model was used to simulate the spread of pathology from different seed regions. Correlations between estimated and empirical spatial patterns of GMV alterations were used to quantify model performance. RESULTS: Of 534 included individuals, 354 (66.3%) were men, and the mean (SD) age was 28.4 (7.4) years. In both early and late stages of illness, spatial patterns of cross-sectional volume differences between patients and controls were more accurately estimated by coordinated deformation models constrained by structural, rather than functional, network architecture (r range, >0.46 to <0.57; P < .01). The same model also robustly estimated longitudinal volume changes related to illness (r ≥ 0.52; P < .001) and antipsychotic exposure (r ≥ 0.50; P < .004). Network diffusion modeling consistently identified, across all 4 data sets, the anterior hippocampus as a putative epicenter of pathological spread in psychosis. Epicenters of longitudinal GMV loss were apparent in posterior cortex early in the illness and shifted to the prefrontal cortex with illness progression. CONCLUSION AND RELEVANCE: These findings highlight a central role for white matter fibers as conduits for the spread of pathology across different stages of psychotic illness, mirroring findings reported in neurodegenerative conditions. The structural connectome thus represents a fundamental constraint on brain changes in psychosis, regardless of whether these changes are caused by illness or medication. Moreover, the anterior hippocampus represents a putative epicenter of early brain pathology from which dysfunction may spread to affect connected areas.
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    Normative Modeling of Brain Morphometry in Clinical High Risk for Psychosis
    Haas, SS ; Ge, R ; Agartz, I ; Amminger, GP ; Andreassen, OA ; Bachman, P ; Baeza, I ; Choi, S ; Colibazzi, T ; Cropley, VL ; de la Fuente-Sandoval, C ; Ebdrup, BH ; Fortea, A ; Fusar-Poli, P ; Glenthoj, BY ; Glenthoj, LB ; Haut, KM ; Hayes, RA ; Heekeren, K ; Hooker, CI ; Hwang, WJ ; Jahanshad, N ; Kaess, M ; Kasai, K ; Katagiri, N ; Kim, M ; Kindler, J ; Koike, S ; Kristensen, TD ; Kwon, JS ; Lawrie, SM ; Lebedeva, I ; Lee, J ; Lemmers-Jansen, ILJ ; Lin, A ; Ma, X ; Mathalon, DH ; McGuire, P ; Michel, C ; Mizrahi, R ; Mizuno, M ; Moller, P ; Mora-Duran, R ; Nelson, B ; Nemoto, T ; Nordentoft, M ; Nordholm, D ; Omelchenko, MA ; Pantelis, C ; Pariente, JC ; Raghava, JM ; Reyes-Madrigal, F ; Rossberg, JI ; Roessler, W ; Salisbury, DF ; Sasabayashi, D ; Schall, U ; Smigielski, L ; Sugranyes, G ; Suzuki, M ; Takahashi, T ; Tamnes, CK ; Theodoridou, A ; Thomopoulos, SI ; Thompson, PM ; Tomyshev, AS ; Uhlhaas, PJ ; Vaernes, TG ; van Amelsvoort, TAMJ ; van Erp, TGM ; Waltz, JA ; Wenneberg, C ; Westlye, LT ; Wood, SJ ; Zhou, JH ; Hernaus, D ; Jalbrzikowski, M ; Kahn, RS ; Corcoran, CM ; Frangou, S (AMER MEDICAL ASSOC, 2024-01)
    IMPORTANCE: The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in individuals at psychosis risk may be nested within the range observed in healthy individuals. OBJECTIVE: To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder. DESIGN, SETTING, AND PARTICIPANTS: This case-control study used clinical-, IQ-, and neuroimaging software (FreeSurfer)-derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1340 individuals with CHR-P and 1237 healthy individuals pooled from 29 international sites participating in the Enhancing Neuroimaging Genetics Through Meta-analysis (ENIGMA) Clinical High Risk for Psychosis Working Group. Healthy individuals and individuals with CHR-P were matched on age and sex within each recruitment site. Data were analyzed between September 1, 2021, and November 30, 2022. MAIN OUTCOMES AND MEASURES: For each regional morphometric measure, deviation scores were computed as z scores indexing the degree of deviation from their normative means from a healthy reference population. Average deviation scores (ADS) were also calculated for regional CT, SA, and SV measures and globally across all measures. Regression analyses quantified the association of deviation scores with clinical severity and cognition, and 2-proportion z tests identified case-control differences in the proportion of individuals with infranormal (z < -1.96) or supranormal (z > 1.96) scores. RESULTS: Among 1340 individuals with CHR-P, 709 (52.91%) were male, and the mean (SD) age was 20.75 (4.74) years. Among 1237 healthy individuals, 684 (55.30%) were male, and the mean (SD) age was 22.32 (4.95) years. Individuals with CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z scores, and all ADS values. For any given region, the proportion of individuals with CHR-P who had infranormal or supranormal values was low (up to 153 individuals [<11.42%]) and similar to that of healthy individuals (<115 individuals [<9.30%]). Individuals with CHR-P who converted to a psychotic disorder had a higher percentage of infranormal values in temporal regions compared with those who did not convert (7.01% vs 1.38%) and healthy individuals (5.10% vs 0.89%). In the CHR-P group, only the ADS SA was associated with positive symptoms (β = -0.08; 95% CI, -0.13 to -0.02; P = .02 for false discovery rate) and IQ (β = 0.09; 95% CI, 0.02-0.15; P = .02 for false discovery rate). CONCLUSIONS AND RELEVANCE: In this case-control study, findings suggest that macroscale neuromorphometric measures may not provide an adequate explanation of psychosis risk.
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    Intelligence trajectories in individuals at ultra-high risk for psychosis: An 8-year longitudinal analysis
    Cheng, N ; Lin, A ; Bowden, S ; Gao, C ; Yung, AR ; Nelson, B ; Thompson, A ; Yuen, HP ; Brewer, WJ ; Cagliarini, D ; Bruxner, A ; Simmons, M ; Broussard, C ; Pantelis, C ; McGorry, PD ; Allott, K ; Wood, SJ (ELSEVIER, 2022-10)
    Cognitive impairment is a well-documented predictor of transition to a full-threshold psychotic disorder amongst individuals at ultra-high risk (UHR) for psychosis. However, less is known about whether change in cognitive functioning differs between those who do and do not transition. Studies to date have not examined trajectories in intelligence constructs (e.g., acquired knowledge and fluid intelligence), which have demonstrated marked impairments in individuals with schizophrenia. This study aimed to examine intelligence trajectories using longitudinal data spanning an average of eight years, where some participants completed assessments over three time-points. Participants (N = 139) at UHR for psychosis completed the Wechsler Abbreviated Scale of Intelligence (WASI) at each follow-up. Linear mixed-effects models mapped changes in WASI Full-Scale IQ (FSIQ) and T-scores on Vocabulary, Similarities, Block Design, and Matrix Reasoning subtests. The sample showed stable and improving trajectories for FSIQ and all subtests. There were no significant differences in trajectories between those who did and did not transition to psychosis and between individuals with good and poor functional outcomes. However, although not significant, the trajectories of the acquired knowledge subtests diverged between transitioned and non-transitioned individuals (β = -0.12, 95 % CI [-0.29, 0.05] for Vocabulary and β = -0.14, 95 % CI [-0.33, 0.05] for Similarities). Overall, there was no evidence for long-term deterioration in intelligence trajectories in this UHR sample. Future studies with a larger sample of transitioned participants may be needed to explore potential differences in intelligence trajectories between UHR transition groups and other non-psychosis outcomes.
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    Pineal morphology of the clinical high-risk state for psychosis and different psychotic disorders
    Takahashi, T ; Wood, SJ ; Yung, AR ; Nelson, B ; Lin, A ; Yuen, HP ; Phillips, LJ ; Suzuki, M ; McGorry, PD ; Velakoulis, D ; Pantelis, C (ELSEVIER, 2022-06)
    BACKGROUND: Pineal volume reductions have been reported in schizophrenia and clinical high-risk states for the development of psychosis, supporting the role of melatonin dysregulation in the pathophysiology of psychosis. However, it remains unclear whether pineal volume is associated with the later onset of psychosis in individuals at clinical high-risk (CHR) of psychosis or if pineal atrophy is specific to schizophrenia among different psychotic disorders. METHODS: This magnetic resonance imaging study examined the volume of and cyst prevalence in the pineal gland in 135 individuals at CHR of psychosis [52 (38.5%) subsequently developed psychosis], 162 with first-episode psychosis (FEP), 89 with chronic schizophrenia, and 87 healthy controls. The potential contribution of the pineal morphology to clinical characteristics was also examined in the CHR and FEP groups. RESULTS: Pineal volumes did not differ significantly between the CHR, FEP, and chronic schizophrenia groups, but were significantly smaller than that in healthy controls. However, pineal volumes were not associated with the later onset of psychosis in the CHR group or FEP sub-diagnosis (i.e., schizophrenia, schizophreniform disorder, affective psychosis, and other psychoses). No significant differences were observed in the prevalence of pineal cysts between the groups, and it also did not correlate with clinical characteristics in the CHR and FEP groups. CONCLUSION: These results suggest that pineal atrophy is a general vulnerability marker of psychosis, while pineal cysts do not appear to contribute to the pathophysiology of psychosis.
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    Gradients of striatal function in antipsychotic-free first-episode psychosis and schizotypy
    Oldehinkel, M ; Tiego, J ; Sabaroedin, K ; Chopra, S ; Francey, SM ; O'Donoghue, B ; Cropley, V ; Nelson, B ; Graham, J ; Baldwin, L ; Yuen, HP ; Allott, K ; Alvarez-Jimenez, M ; Harrigan, S ; Pantelis, C ; Wood, SJ ; McGorry, P ; Bellgrove, MA ; Fornito, A (SPRINGERNATURE, 2023-04-18)
    Both psychotic illness and subclinical psychosis-like experiences (PLEs) have been associated with cortico-striatal dysfunction. This work has largely relied on a discrete parcellation of the striatum into distinct functional areas, but recent evidence suggests that the striatum comprises multiple overlapping and smoothly varying gradients (i.e., modes) of functional organization. Here, we investigated two of these functional connectivity modes, previously associated with variations in the topographic patterning of cortico-striatal connectivity (first-order gradient), and dopaminergic innervation of the striatum (second-order gradient), and assessed continuities in striatal function from subclinical to clinical domains. We applied connectopic mapping to resting-state fMRI data to obtain the first-order and second-order striatal connectivity modes in two distinct samples: (1) 56 antipsychotic-free patients (26 females) with first-episode psychosis (FEP) and 27 healthy controls (17 females); and (2) a community-based cohort of 377 healthy individuals (213 females) comprehensively assessed for subclinical PLEs and schizotypy. The first-order "cortico-striatal" and second-order "dopaminergic" connectivity gradients were significantly different in FEP patients compared to controls bilaterally. In the independent sample of healthy individuals, variations in the left first-order "cortico-striatal" connectivity gradient were associated with inter-individual differences in a factor capturing general schizotypy and PLE severity. The presumed cortico-striatal connectivity gradient was implicated in both subclinical and clinical cohorts, suggesting that variations in its organization may represent a neurobiological trait marker across the psychosis continuum. Disruption of the presumed dopaminergic gradient was only noticeable in patients, suggesting that neurotransmitter dysfunction may be more apparent to clinical illness.
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    Neuroanatomical heterogeneity and homogeneity in individuals at clinical high risk for psychosis
    Baldwin, H ; Radua, J ; Antoniades, M ; Haas, SS ; Frangou, S ; Agartz, I ; Allen, P ; Andreassen, OA ; Atkinson, K ; Bachman, P ; Baeza, I ; Bartholomeusz, CF ; Chee, MWL ; Colibazzi, T ; Cooper, RE ; Corcoran, CM ; Cropley, VL ; Ebdrup, BH ; Fortea, A ; Glenthoj, LB ; Hamilton, HK ; Haut, KM ; Hayes, RA ; He, Y ; Heekeren, K ; Kaess, M ; Kasai, K ; Katagiri, N ; Kim, M ; Kindler, J ; Klaunig, MJ ; Koike, S ; Koppel, A ; Kristensen, TD ; Bin Kwak, Y ; Kwon, JS ; Lawrie, SM ; Lebedeva, I ; Lee, J ; Lin, A ; Loewy, RL ; Mathalon, DH ; Michel, C ; Mizrahi, R ; Moller, P ; Nelson, B ; Nemoto, T ; Nordholm, D ; Omelchenko, MA ; Pantelis, C ; Raghava, JM ; Rossberg, J ; Roessler, W ; Salisbury, DF ; Sasabayashi, D ; Schall, U ; Smigielski, L ; Sugranyes, G ; Suzuki, M ; Takahashi, T ; Tamnes, CK ; Tang, J ; Theodoridou, A ; Thomopoulos, S ; Tomyshev, AS ; Uhlhaas, PJ ; Vaernes, TG ; van Amelsvoort, TAMJ ; Van Erp, TGM ; Waltz, JA ; Westlye, LT ; Wood, SJ ; Zhou, JH ; McGuire, P ; Thompson, PM ; Jalbrzikowski, M ; Hernaus, D ; Fusar-Poli, P (SPRINGERNATURE, 2022-07-26)
    Individuals at Clinical High Risk for Psychosis (CHR-P) demonstrate heterogeneity in clinical profiles and outcome features. However, the extent of neuroanatomical heterogeneity in the CHR-P state is largely undetermined. We aimed to quantify the neuroanatomical heterogeneity in structural magnetic resonance imaging measures of cortical surface area (SA), cortical thickness (CT), subcortical volume (SV), and intracranial volume (ICV) in CHR-P individuals compared with healthy controls (HC), and in relation to subsequent transition to a first episode of psychosis. The ENIGMA CHR-P consortium applied a harmonised analysis to neuroimaging data across 29 international sites, including 1579 CHR-P individuals and 1243 HC, offering the largest pooled CHR-P neuroimaging dataset to date. Regional heterogeneity was indexed with the Variability Ratio (VR) and Coefficient of Variation (CV) ratio applied at the group level. Personalised estimates of heterogeneity of SA, CT and SV brain profiles were indexed with the novel Person-Based Similarity Index (PBSI), with two complementary applications. First, to assess the extent of within-diagnosis similarity or divergence of neuroanatomical profiles between individuals. Second, using a normative modelling approach, to assess the 'normativeness' of neuroanatomical profiles in individuals at CHR-P. CHR-P individuals demonstrated no greater regional heterogeneity after applying FDR corrections. However, PBSI scores indicated significantly greater neuroanatomical divergence in global SA, CT and SV profiles in CHR-P individuals compared with HC. Normative PBSI analysis identified 11 CHR-P individuals (0.70%) with marked deviation (>1.5 SD) in SA, 118 (7.47%) in CT and 161 (10.20%) in SV. Psychosis transition was not significantly associated with any measure of heterogeneity. Overall, our examination of neuroanatomical heterogeneity within the CHR-P state indicated greater divergence in neuroanatomical profiles at an individual level, irrespective of psychosis conversion. Further large-scale investigations are required of those who demonstrate marked deviation.
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    The Relationship Between Grey Matter Volume and Clinical and Functional Outcomes in People at Clinical High Risk for Psychosis.
    Tognin, S ; Richter, A ; Kempton, MJ ; Modinos, G ; Antoniades, M ; Azis, M ; Allen, P ; Bossong, MG ; Perez, J ; Pantelis, C ; Nelson, B ; Amminger, P ; Riecher-Rössler, A ; Barrantes-Vidal, N ; Krebs, M-O ; Glenthøj, B ; Ruhrmann, S ; Sachs, G ; Rutten, BPF ; de Haan, L ; van der Gaag, M ; EU-GEI High Risk Study Group, ; Valmaggia, LR ; McGuire, P (Oxford University Press (OUP), 2022-01)
    OBJECTIVE: To examine the association between baseline alterations in grey matter volume (GMV) and clinical and functional outcomes in people at clinical high risk (CHR) for psychosis. METHODS: 265 CHR individuals and 92 healthy controls were recruited as part of a prospective multi-center study. After a baseline assessment using magnetic resonance imaging (MRI), participants were followed for at least two years to determine clinical and functional outcomes, including transition to psychosis (according to the Comprehensive Assessment of an At Risk Mental State, CAARMS), level of functioning (according to the Global Assessment of Functioning), and symptomatic remission (according to the CAARMS). GMV was measured in selected cortical and subcortical regions of interest (ROI) based on previous studies (ie orbitofrontal gyrus, cingulate gyrus, gyrus rectus, inferior temporal gyrus, parahippocampal gyrus, striatum, and hippocampus). Using voxel-based morphometry, we analysed the relationship between GMV and clinical and functional outcomes. RESULTS: Within the CHR sample, a poor functional outcome (GAF < 65) was associated with relatively lower GMV in the right striatum at baseline (P < .047 after Family Wise Error correction). There were no significant associations between baseline GMV and either subsequent remission or transition to psychosis. CONCLUSIONS: In CHR individuals, lower striatal GMV was associated with a poor level of overall functioning at follow-up. This finding was not related to effects of antipsychotic or antidepressant medication. The failure to replicate previous associations between GMV and later psychosis onset, despite studying a relatively large sample, is consistent with the findings of recent large-scale multi-center studies.