Psychiatry - Research Publications
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ItemNeuroanatomical heterogeneity and homogeneity in individuals at clinical high risk for psychosisBaldwin, 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.
ItemThe 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.
ItemNo Preview AvailableAssociation of Structural Magnetic Resonance Imaging Measures With Psychosis Onset in Individuals at Clinical High Risk for Developing Psychosis An ENIGMA Working Group Mega-analysisJalbrzikowski, M ; Hayes, RA ; Wood, SJ ; Nordholm, D ; Zhou, JH ; Fusar-Poli, P ; Uhlhaas, PJ ; Takahashi, T ; Sugranyes, G ; Kwak, YB ; Mathalon, DH ; Katagiri, N ; Hooker, CI ; Smigielski, L ; Colibazzi, T ; Via, E ; Tang, J ; Koike, S ; Rasser, PE ; Michel, C ; Lebedeva, I ; Hegelstad, WTV ; de la Fuente-Sandoval, C ; Waltz, JA ; Mizrahi, R ; Corcoran, CM ; Resch, F ; Tamnes, CK ; Haas, SS ; Lemmers-Jansen, ILJ ; Agartz, I ; Allen, P ; Amminger, GP ; Andreassen, OA ; Atkinson, K ; Bachman, P ; Baeza, I ; Baldwin, H ; Bartholomeusz, CF ; Borgwardt, S ; Catalano, S ; Chee, MWL ; Chen, X ; Cho, KIK ; Cooper, RE ; Cropley, VL ; Dolz, M ; Ebdrup, BH ; Fortea, A ; Glenthoj, LB ; Glenthoj, BY ; de Haan, L ; Hamilton, HK ; Harris, MA ; Haut, KM ; He, Y ; Heekeren, K ; Heinz, A ; Hubl, D ; Hwang, WJ ; Kaess, M ; Kasai, K ; Kim, M ; Kindler, J ; Klaunig, MJ ; Koppel, A ; Kristensen, TD ; Kwon, JS ; Lawrie, SM ; Lee, J ; Leon-Ortiz, P ; Lin, A ; Loewy, RL ; Ma, X ; McGorry, P ; McGuire, P ; Mizuno, M ; Moller, P ; Moncada-Habib, T ; Munoz-Samons, D ; Nelson, B ; Nemoto, T ; Nordentoft, M ; Omelchenko, MA ; Oppedal, K ; Ouyang, L ; Pantelis, C ; Pariente, JC ; Raghava, JM ; Reyes-Madrigal, F ; Roach, BJ ; Rossberg, JI ; Rossler, W ; Salisbury, DF ; Sasabayashi, D ; Schall, U ; Schiffman, J ; Schlagenhauf, F ; Schmidt, A ; Sorensen, ME ; Suzuki, M ; Theodoridou, A ; Tomyshev, AS ; Tor, J ; Vaernes, TG ; Velakoulis, D ; Venegoni, GD ; Vinogradov, S ; Wenneberg, C ; Westlye, LT ; Yamasue, H ; Yuan, L ; Yung, AR ; van Amelsvoort, TAMJ ; Turner, JA ; van Erp, TGM ; Thompson, PM ; Hernaus, D (AMER MEDICAL ASSOC, 2021-05-05)IMPORTANCE: The ENIGMA clinical high risk (CHR) for psychosis initiative, the largest pooled neuroimaging sample of individuals at CHR to date, aims to discover robust neurobiological markers of psychosis risk. OBJECTIVE: To investigate baseline structural neuroimaging differences between individuals at CHR and healthy controls as well as between participants at CHR who later developed a psychotic disorder (CHR-PS+) and those who did not (CHR-PS-). DESIGN, SETTING, AND PARTICIPANTS: In this case-control study, baseline T1-weighted magnetic resonance imaging (MRI) data were pooled from 31 international sites participating in the ENIGMA Clinical High Risk for Psychosis Working Group. CHR status was assessed using the Comprehensive Assessment of At-Risk Mental States or Structured Interview for Prodromal Syndromes. MRI scans were processed using harmonized protocols and analyzed within a mega-analysis and meta-analysis framework from January to October 2020. MAIN OUTCOMES AND MEASURES: Measures of regional cortical thickness (CT), surface area, and subcortical volumes were extracted from T1-weighted MRI scans. Independent variables were group (CHR group vs control group) and conversion status (CHR-PS+ group vs CHR-PS- group vs control group). RESULTS: Of the 3169 included participants, 1428 (45.1%) were female, and the mean (SD; range) age was 21.1 (4.9; 9.5-39.9) years. This study included 1792 individuals at CHR and 1377 healthy controls. Using longitudinal clinical information, 253 in the CHR-PS+ group, 1234 in the CHR-PS- group, and 305 at CHR without follow-up data were identified. Compared with healthy controls, individuals at CHR exhibited widespread lower CT measures (mean [range] Cohen d = -0.13 [-0.17 to -0.09]), but not surface area or subcortical volume. Lower CT measures in the fusiform, superior temporal, and paracentral regions were associated with psychosis conversion (mean Cohen d = -0.22; 95% CI, -0.35 to 0.10). Among healthy controls, compared with those in the CHR-PS+ group, age showed a stronger negative association with left fusiform CT measures (F = 9.8; P < .001; q < .001) and left paracentral CT measures (F = 5.9; P = .005; q = .02). Effect sizes representing lower CT associated with psychosis conversion resembled patterns of CT differences observed in ENIGMA studies of schizophrenia (ρ = 0.35; 95% CI, 0.12 to 0.55; P = .004) and individuals with 22q11.2 microdeletion syndrome and a psychotic disorder diagnosis (ρ = 0.43; 95% CI, 0.20 to 0.61; P = .001). CONCLUSIONS AND RELEVANCE: This study provides evidence for widespread subtle, lower CT measures in individuals at CHR. The pattern of CT measure differences in those in the CHR-PS+ group was similar to those reported in other large-scale investigations of psychosis. Additionally, a subset of these regions displayed abnormal age associations. Widespread disruptions in CT coupled with abnormal age associations in those at CHR may point to disruptions in postnatal brain developmental processes.
ItemNo Preview AvailableCognitive functioning throughout adulthood and illness stages in individuals with psychotic disorders and their unaffected siblingsVelthorst, E ; Mollon, J ; Murray, RM ; de Haan, L ; Germeys, IM ; Glahn, DC ; Arango, C ; van der Ven, E ; Di Forti, M ; Bernardo, M ; Guloksuz, S ; Delespaul, P ; Mezquida, G ; Amoretti, S ; Bobes, J ; Saiz, PA ; Garcia-Portilla, MP ; Santos, JL ; Jimenez-Lopez, E ; Sanjuan, J ; Aguilar, EJ ; Arrojo, M ; Carracedo, A ; Lopez, G ; Gonzalez-Penas, J ; Parellada, M ; Atbasoglu, C ; Saka, MC ; Ucok, A ; Alptekin, K ; Akdede, B ; Binbay, T ; Altinyazar, V ; Ulas, H ; Yalincetin, B ; Gumus-Akay, G ; Beyaz, BC ; Soygur, H ; Cankurtaran, ES ; Kaymak, SU ; Maric, NP ; Mihaljevic, MM ; Petrovic, SA ; Mirjanic, T ; Del-Ben, CM ; Ferraro, L ; Gayer-Anderson, C ; Jones, PB ; Jongsma, HE ; Kirkbride, JB ; La Cascia, C ; Lasalvia, A ; Tosato, S ; Llorca, P-M ; Menezes, PR ; Morgan, C ; Quattrone, D ; Menchetti, M ; Selten, J-P ; Szoke, A ; Tarricone, I ; Tortelli, A ; McGuire, P ; Valmaggia, L ; Kempton, MJ ; van der Gaag, M ; Riecher-Rossler, A ; Bressan, RA ; Barrantes-Vidal, N ; Nelson, B ; McGorry, P ; Pantelis, C ; Krebs, M-O ; Ruhrmann, S ; Sachs, G ; Rutten, BPF ; van Os, J ; Alizadeh, BZ ; van Amelsvoort, T ; Bartels-Velthuis, AA ; Bruggeman, R ; van Beveren, NJ ; Luykx, JJ ; Cahn, W ; Simons, CJP ; Kahn, RS ; Schirmbeck, F ; van Winkel, R ; Reichenberg, A (SPRINGERNATURE, 2021-01-07)Important questions remain about the profile of cognitive impairment in psychotic disorders across adulthood and illness stages. The age-associated profile of familial impairments also remains unclear, as well as the effect of factors, such as symptoms, functioning, and medication. Using cross-sectional data from the EU-GEI and GROUP studies, comprising 8455 participants aged 18 to 65, we examined cognitive functioning across adulthood in patients with psychotic disorders (n = 2883), and their unaffected siblings (n = 2271), compared to controls (n = 3301). An abbreviated WAIS-III measured verbal knowledge, working memory, visuospatial processing, processing speed, and IQ. Patients showed medium to large deficits across all functions (ES range = -0.45 to -0.73, p < 0.001), while siblings showed small deficits on IQ, verbal knowledge, and working memory (ES = -0.14 to -0.33, p < 0.001). Magnitude of impairment was not associated with participant age, such that the size of impairment in older and younger patients did not significantly differ. However, first-episode patients performed worse than prodromal patients (ES range = -0.88 to -0.60, p < 0.001). Adjusting for cannabis use, symptom severity, and global functioning attenuated impairments in siblings, while deficits in patients remained statistically significant, albeit reduced by half (ES range = -0.13 to -0.38, p < 0.01). Antipsychotic medication also accounted for around half of the impairment in patients (ES range = -0.21 to -0.43, p < 0.01). Deficits in verbal knowledge, and working memory may specifically index familial, i.e., shared genetic and/or shared environmental, liability for psychotic disorders. Nevertheless, potentially modifiable illness-related factors account for a significant portion of the cognitive impairment in psychotic disorders.
ItemVerbal memory performance predicts remission and functional outcome in people at clinical high-risk for psychosisHedges, EP ; Dickson, H ; Tognin, S ; Modinos, G ; Antoniades, M ; van der Gaag, M ; de Haan, L ; McGorry, P ; Pantelis, C ; Riecher-Rossler, A ; Bressan, R ; Barrantes-Vidal, N ; Krebs, M-O ; Nordentoft, M ; Ruhrmann, S ; Sachs, G ; Rutten, BP ; van Os, J ; Valmaggia, LR ; McGuire, P ; Kempton, MJ (ELSEVIER, 2022-02-17)Robust deficits in cognitive functioning are present in people with psychosis and are evident in the early stages of the disorder. Impairments in verbal memory and verbal fluency are reliably seen in individuals at clinical high-risk for psychosis (CHR) compared to healthy populations. As previous studies have shown a relationship between cognition and longer-term outcomes in schizophrenia, the aim of this paper was to explore whether verbal memory and verbal fluency performance predicted outcomes in a large CHR sample recruited as part of the EU-GEI High Risk Study. Participants included 316 CHR individuals, 90.8% of whom were not currently on antipsychotic medication, and 60 healthy controls. Verbal memory and verbal fluency performance were measured at baseline. At two-year follow-up, CHR individuals were assessed by three different outcome measures, those who did and did not (1) transition to psychosis, (2) experience burdening impairment or disabilities, or (3) remit clinically from CHR status. Individuals with CHR displayed significant verbal memory and verbal fluency deficits at baseline compared to healthy controls (Hedges' g effect size = 0.24 to 0.66). There were no significant differences in cognitive performance of those who did and did not transition to psychosis. However, impaired immediate verbal recall predicted both functional disability and non-remission from the CHR state. Results remained significant when analyses were restricted to only include antipsychotic-free CHR participants. These findings may inform the development of early interventions designed to improve cognitive deficits in the early stages of psychosis.
ItemFrontostriatothalamic effective connectivity and dopaminergic function in the psychosis continuumSabaroedin, K ; Razi, A ; Chopra, S ; Tran, N ; Pozaruk, A ; Chen, Z ; Finlay, A ; Nelson, B ; Allott, K ; Alvarez-Jimenez, M ; Graham, J ; Yuen, HP ; Harrigan, S ; Cropley, V ; Sharma, S ; Saluja, B ; Williams, R ; Pantelis, C ; Wood, SJ ; O'Donoghue, B ; Francey, S ; McGorry, P ; Aquino, K ; Fornito, A (OXFORD UNIV PRESS, 2022-01-30)Dysfunction of fronto-striato-thalamic (FST) circuits is thought to contribute to dopaminergic dysfunction and symptom onset in psychosis, but it remains unclear whether this dysfunction is driven by aberrant bottom-up subcortical signalling or impaired top-down cortical regulation. We used spectral dynamic causal modelling of resting-state functional MRI to characterize the effective connectivity of dorsal and ventral FST circuits in a sample of 46 antipsychotic-naïve first-episode psychosis patients and 23 controls and an independent sample of 36 patients with established schizophrenia and 100 controls. We also investigated the association between FST effective connectivity and striatal 18F-DOPA uptake in an independent healthy cohort of 33 individuals who underwent concurrent functional MRI and PET. Using a posterior probability threshold of 0.95, we found that midbrain and thalamic connectivity were implicated as dysfunctional across both patient groups. Dysconnectivity in first-episode psychosis patients was mainly restricted to the subcortex, with positive symptom severity being associated with midbrain connectivity. Dysconnectivity between the cortex and subcortical systems was only apparent in established schizophrenia patients. In the healthy 18F-DOPA cohort, we found that striatal dopamine synthesis capacity was associated with the effective connectivity of nigrostriatal and striatothalamic pathways, implicating similar circuits to those associated with psychotic symptom severity in patients. Overall, our findings indicate that subcortical dysconnectivity is evident in the early stages of psychosis, that cortical dysfunction may emerge later in the illness, and that nigrostriatal and striatothalamic signalling are closely related to striatal dopamine synthesis capacity, which is a robust marker for psychosis.
ItemNo Preview AvailableImpaired olfactory ability associated with larger left hippocampus and rectus volumes at earliest stages of schizophrenia: A sign of neuroinflammation?Masaoka, Y ; Velakoulis, D ; Brewer, WJ ; Cropley, VL ; Bartholomeusz, CF ; Yung, AR ; Nelson, B ; Dwyer, D ; Wannan, CMJ ; Izumizaki, M ; McGorry, PD ; Wood, SJ ; Pantelis, C (ELSEVIER IRELAND LTD, 2020-07-01)Impaired olfactory identification has been reported as a first sign of schizophrenia during the earliest stages of illness, including before illness onset. The aim of this study was to examine the relationship between volumes of these regions (amygdala, hippocampus, gyrus rectus and orbitofrontal cortex) and olfactory ability in three groups of participants: healthy control participants (Ctls), patients with first-episode schizophrenia (FE-Scz) and chronic schizophrenia patients (Scz). Exploratory analyses were performed in a sample of individuals at ultra-high risk (UHR) for psychosis in a co-submission paper (Masaoka et al., 2020). The relationship to brain structural measures was not apparent prior to psychosis onset, but was only evident following illness onset, with a different pattern of relationships apparent across illness stages (FE-Scz vs Scz). Path analysis found that lower olfactory ability was related to larger volumes of the left hippocampus and gyrus rectus in the FE-Scz group. We speculate that larger hippocampus and rectus in early schizophrenia are indicative of swelling, potentially caused by an active neurochemical or immunological process, such as inflammation or neurotoxicity, which is associated with impaired olfactory ability. The volumetric decreases in the chronic stage of Scz may be due to degeneration resulting from an active immune process and its resolution.
ItemImpact of Comorbid Affective Disorders on Longitudinal Clinical Outcomes in Individuals at Ultra-high Risk for PsychosisSchirmbeck, F ; van der Burg, NC ; Blankers, M ; Vermeulen, JM ; McGuire, P ; Valmaggia, LR ; Kempton, MJ ; van der Gaag, M ; Riecher-Rossler, A ; Bressan, RA ; Barrantes-Vidal, N ; Nelson, B ; Amminger, GP ; McGorry, P ; Pantelis, C ; Krebs, M-O ; Ruhrmann, S ; Sachs, G ; Rutten, BPF ; van Os, J ; Nordentoft, M ; Glenthoj, B ; Fusar-Poli, P ; de Haan, L (OXFORD UNIV PRESS, 2021-08-21)INTRODUCTION: Diagnoses of anxiety and/or depression are common in subjects at Ultra-High Risk for Psychosis (UHR) and associated with extensive functional impairment. Less is known about the impact of affective comorbidities on the prospective course of attenuated psychotic symptoms (APS). METHOD: Latent class mixed modelling identified APS trajectories in 331 UHR subjects assessed at baseline, 6, 12, and 24 months follow-up. The prognostic value of past, baseline, and one-year DSM-IV depressive or anxiety disorders on trajectories was investigated using logistic regression, controlling for confounders. Cox proportional hazard analyses investigated associations with transition risk. RESULTS: 46.8% of participants fulfilled the criteria for a past depressive disorder, 33.2% at baseline, and 15.1% at one-year follow-up. Any past, baseline, or one-year anxiety disorder was diagnosed in 42.9%, 37.2%, and 27.0%, respectively. Participants were classified into one of three latent APS trajectory groups: (1) persistently low, (2) increasing, and (3) decreasing. Past depression was associated with a higher risk of belonging to the increasing trajectory group, compared to the persistently low (OR = 3.149, [95%CI: 1.298-7.642]) or decreasing group (OR = 3.137, [1.165-8.450]). In contrast, past (OR = .443, [.179-1.094]) or current (OR = .414, [.156-1.094]) anxiety disorders showed a trend-level association with a lower risk of belonging to the increasing group compared to the persistently low group. Past depression was significantly associated with a higher risk of transitioning to psychosis (HR = 2.123, [1.178-3.828]). CONCLUSION: A past depressive episode might be a particularly relevant risk factor for an unfavorable course of APS in UHR individuals. Early affective disturbances may be used to advance detection, prognostic, and clinical strategies.
ItemFunctional Connectivity in Antipsychotic-Treated and Antipsychotic-Naive Patients With First-Episode Psychosis and Low Risk of Self-harm or Aggression A Secondary Analysis of a Randomized Clinical TrialChopra, S ; Francey, SM ; O'Donoghue, B ; Sabaroedin, K ; Arnatkeviciute, A ; Cropley, V ; Nelson, B ; Graham, J ; Baldwin, L ; Tahtalian, S ; Yuen, HP ; Allott, K ; Alvarez-Jimenez, M ; Harrigan, S ; Pantelis, C ; Wood, SJ ; McGorry, P ; Fornito, A (AMER MEDICAL ASSOC, 2021-06-23)IMPORTANCE: Altered functional connectivity (FC) is a common finding in resting-state functional magnetic resonance imaging (rs-fMRI) studies of people with psychosis, yet how FC disturbances evolve in the early stages of illness, and how antipsychotic treatment influences these disturbances, remains unknown. OBJECTIVE: To investigate longitudinal FC changes in antipsychotic-naive and antipsychotic-treated patients with first-episode psychosis (FEP). DESIGN, SETTING, AND PARTICIPANTS: This secondary analysis of a triple-blind, randomized clinical trial was conducted over a 5-year recruitment period between April 2008 and December 2016 with 59 antipsychotic-naive patients with FEP receiving either a second-generation antipsychotic or a placebo pill over a treatment period of 6 months. Participants were required to have low suicidality and aggression, to have a duration of untreated psychosis of less than 6 months, and to be living in stable accommodations with social support. Both FEP groups received intensive psychosocial therapy. A healthy control group was also recruited. Participants completed rs-fMRI scans at baseline, 3 months, and 12 months. Data were analyzed from May 2019 to August 2020. INTERVENTIONS: Resting-state functional MRI was used to probe brain FC. Patients received either a second-generation antipsychotic or a matched placebo tablet. Both patient groups received a manualized psychosocial intervention. MAIN OUTCOMES AND MEASURES: The primary outcomes of this analysis were to investigate (1) FC differences between patients and controls at baseline; (2) FC changes in medicated and unmedicated patients between baseline and 3 months; and (3) associations between longitudinal FC changes and clinical outcomes. An additional aim was to investigate long-term FC changes at 12 months after baseline. These outcomes were not preregistered. RESULTS: Data were analyzed for 59 patients (antipsychotic medication plus psychosocial treatment: 28 [47.5%]; mean [SD] age, 19.5 [3.0] years; 15 men [53.6%]; placebo plus psychosocial treatment: 31 [52.5%]; mean [SD] age, 18.8 [2.7]; 16 men [51.6%]) and 27 control individuals (mean [SD] age, 21.9 [1.9] years). At baseline, patients showed widespread functional dysconnectivity compared with controls, with reductions predominantly affecting interactions between the default mode network, limbic systems, and the rest of the brain. From baseline to 3 months, patients receiving placebo showed increased FC principally within the same systems; some of these changes correlated with improved clinical outcomes (canonical correlation analysis R = 0.901; familywise error-corrected P = .005). Antipsychotic exposure was associated with increased FC primarily between the thalamus and the rest of the brain. CONCLUSIONS AND RELEVANCE: In this secondary analysis of a clinical trial, antipsychotic-naive patients with FEP showed widespread functional dysconnectivity at baseline, followed by an early normalization of default mode network and cortical limbic dysfunction in patients receiving placebo and psychosocial intervention. Antipsychotic exposure was associated with FC changes concentrated on thalamocortical networks. TRIAL REGISTRATION: ACTRN12607000608460.
ItemStress reactivity as a putative mechanism linking childhood trauma with clinical outcomes in individuals at ultra-high-risk for psychosis: Findings from the EU-GEI High Risk StudyPaetzold, I ; Myin-Germeys, I ; Schick, A ; Nelson, B ; Velthorst, E ; Schirmbeck, F ; van Os, J ; Morgan, C ; Hartmann, J ; van der Gaag, M ; de Haan, L ; Valmaggia, L ; McGuire, P ; Kempton, M ; Reininghaus, U (CAMBRIDGE UNIV PRESS, 2021-05-28)AIMS: Childhood trauma is associated with an elevated risk for psychosis, but the psychological mechanisms involved remain largely unclear. This study aimed to investigate emotional and psychotic stress reactivity in daily life as a putative mechanism linking childhood trauma and clinical outcomes in individuals at ultra-high-risk (UHR) for psychosis. METHODS: Experience sampling methodology was used to measure momentary stress, affect and psychotic experiences in the daily life of N = 79 UHR individuals in the EU-GEI High Risk Study. The Childhood Trauma Questionnaire was used to assess self-reported childhood trauma. Clinical outcomes were assessed at baseline, 1- and 2-year follow-up. RESULTS: The association of stress with positive (β = -0.14, p = 0.010) and negative affect (β = 0.11, p = 0.020) was modified by transition status such that stress reactivity was greater in individuals who transitioned to psychosis. Moreover, the association of stress with negative affect (β = 0.06, p = 0.019) and psychotic experiences (β = 0.05, p = 0.037) was greater in individuals exposed to high v. low levels of childhood trauma. We also found evidence that decreased positive affect in response to stress was associated with reduced functioning at 1-year follow-up (B = 6.29, p = 0.034). In addition, there was evidence that the association of childhood trauma with poor functional outcomes was mediated by stress reactivity (e.g. indirect effect: B = -2.13, p = 0.026), but no evidence that stress reactivity mediated the association between childhood trauma and transition (e.g. indirect effect: B = 0.14, p = 0.506). CONCLUSIONS: Emotional and psychotic stress reactivity may be potential mechanisms linking childhood trauma with clinical outcomes in UHR individuals.
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