Psychiatry - Research Publications

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    Heterogeneity and Classification of Recent Onset Psychosis and Depression: A Multimodal Machine Learning Approach
    Lalousis, PA ; Wood, SJ ; Schmaal, L ; Chisholm, K ; Griffiths, S ; Reniers, R ; Bertolino, A ; Borgwardt, S ; Brambilla, P ; Kambeitz, J ; Lencer, R ; Pantelis, C ; Ruhrmann, S ; Salokangas, RKR ; Schultze-Lutter, F ; Bonivento, C ; Dwyer, DB ; Ferro, A ; Haidl, T ; Rosen, M ; Schmidt, A ; Meisenzahl, E ; Koutsouleris, N ; Upthegrove, R (Elsevier BV, 2021-05)
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    Heterogeneity and Classification of Recent Onset Psychosis and Depression: A Multimodal Machine Learning Approach
    Lalousis, PA ; Wood, SJ ; Schmaal, L ; Chisholm, K ; Griffiths, SL ; Reniers, RLEP ; Bertolino, A ; Borgwardt, S ; Brambilla, P ; Kambeitz, J ; Lencer, R ; Pantelis, C ; Ruhrmann, S ; Salokangas, RKR ; Schultze-Lutter, F ; Bonivento, C ; Dwyer, D ; Ferro, A ; Haidl, T ; Rosen, M ; Schmidt, A ; Meisenzahl, E ; Koutsouleris, N ; Upthegrove, R (OXFORD UNIV PRESS, 2021-02-05)
    Diagnostic heterogeneity within and across psychotic and affective disorders challenges accurate treatment selection, particularly in the early stages. Delineation of shared and distinct illness features at the phenotypic and brain levels may inform the development of more precise differential diagnostic tools. We aimed to identify prototypes of depression and psychosis to investigate their heterogeneity, with common, comorbid transdiagnostic symptoms. Analyzing clinical/neurocognitive and grey matter volume (GMV) data from the PRONIA database, we generated prototypic models of recent-onset depression (ROD) vs. recent-onset psychosis (ROP) by training support-vector machines to separate patients with ROD from patients with ROP, who were selected for absent comorbid features (pure groups). Then, models were applied to patients with comorbidity, ie, ROP with depressive symptoms (ROP+D) and ROD participants with sub-threshold psychosis-like features (ROD+P), to measure their positions within the affective-psychotic continuum. All models were independently validated in a replication sample. Comorbid patients were positioned between pure groups, with ROP+D patients being more frequently classified as ROD compared to pure ROP patients (clinical/neurocognitive model: χ2 = 14.874; P < .001; GMV model: χ2 = 4.933; P = .026). ROD+P patient classification did not differ from ROD (clinical/neurocognitive model: χ2 = 1.956; P = 0.162; GMV model: χ2 = 0.005; P = .943). Clinical/neurocognitive and neuroanatomical models demonstrated separability of prototypic depression from psychosis. The shift of comorbid patients toward the depression prototype, observed at the clinical and biological levels, suggests that psychosis with affective comorbidity aligns more strongly to depressive rather than psychotic disease processes. Future studies should assess how these quantitative measures of comorbidity predict outcomes and individual responses to stratified therapeutic interventions.
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    Multimodal prognosis of negative symptom severity in individuals at increased risk of developing psychosis
    Hauke, DJ ; Schmidt, A ; Studerus, E ; Andreou, C ; Riecher-Roessler, A ; Radua, J ; Kambeitz, J ; Ruef, A ; Dwyer, DB ; Kambeitz-Ilankovic, L ; Lichtenstein, T ; Sanfelici, R ; Penzel, N ; Haas, SS ; Antonucci, LA ; Lalousis, PA ; Chisholm, K ; Schultze-Lutter, F ; Ruhrmann, S ; Hietala, J ; Brambilla, P ; Koutsouleris, N ; Meisenzahl, E ; Pantelis, C ; Rosen, M ; Salokangas, RKR ; Upthegrove, R ; Wood, SJ ; Borgwardt, S (SPRINGERNATURE, 2021-05-24)
    Negative symptoms occur frequently in individuals at clinical high risk (CHR) for psychosis and contribute to functional impairments. The aim of this study was to predict negative symptom severity in CHR after 9 months. Predictive models either included baseline negative symptoms measured with the Structured Interview for Psychosis-Risk Syndromes (SIPS-N), whole-brain gyrification, or both to forecast negative symptoms of at least moderate severity in 94 CHR. We also conducted sequential risk stratification to stratify CHR into different risk groups based on the SIPS-N and gyrification model. Additionally, we assessed the models' ability to predict functional outcomes in CHR and their transdiagnostic generalizability to predict negative symptoms in 96 patients with recent-onset psychosis (ROP) and 97 patients with recent-onset depression (ROD). Baseline SIPS-N and gyrification predicted moderate/severe negative symptoms with significant balanced accuracies of 68 and 62%, while the combined model achieved 73% accuracy. Sequential risk stratification stratified CHR into a high (83%), medium (40-64%), and low (19%) risk group regarding their risk of having moderate/severe negative symptoms at 9 months follow-up. The baseline SIPS-N model was also able to predict social (61%), but not role functioning (59%) at above-chance accuracies, whereas the gyrification model achieved significant accuracies in predicting both social (76%) and role (74%) functioning in CHR. Finally, only the baseline SIPS-N model showed transdiagnostic generalization to ROP (63%). This study delivers a multimodal prognostic model to identify those CHR with a clinically relevant negative symptom severity and functional impairments, potentially requiring further therapeutic consideration.
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    Impaired 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.
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    The clinical relevance of formal thought disorder in the early stages of psychosis: results from the PRONIA study
    Oeztuerk, OF ; Pigoni, A ; Wenzel, J ; Haas, SS ; Popovic, D ; Ruef, A ; Dwyer, DB ; Kambeitz-Ilankovic, L ; Ruhrmann, S ; Chisholm, K ; Lalousis, P ; Griffiths, SL ; Lichtenstein, T ; Rosen, M ; Kambeitz, J ; Schultze-Lutter, F ; Liddle, P ; Upthegrove, R ; Salokangas, RKR ; Pantelis, C ; Meisenzahl, E ; Wood, SJ ; Brambilla, P ; Borgwardt, S ; Falkai, P ; Antonucci, LA ; Koutsouleris, N (SPRINGER HEIDELBERG, 2021-09-17)
    BACKGROUND: Formal thought disorder (FTD) has been associated with more severe illness courses and functional deficits in patients with psychotic disorders. However, it remains unclear whether the presence of FTD characterises a specific subgroup of patients showing more prominent illness severity, neurocognitive and functional impairments. This study aimed to identify stable and generalizable FTD-subgroups of patients with recent-onset psychosis (ROP) by applying a comprehensive data-driven clustering approach and to test the validity of these subgroups by assessing associations between this FTD-related stratification, social and occupational functioning, and neurocognition. METHODS: 279 patients with ROP were recruited as part of the multi-site European PRONIA study (Personalised Prognostic Tools for Early Psychosis Management; www.pronia.eu). Five FTD-related symptoms (conceptual disorganization, poverty of content of speech, difficulty in abstract thinking, increased latency of response and poverty of speech) were assessed with Positive and Negative Symptom Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS). RESULTS: The results with two patient subgroups showing different levels of FTD were the most stable and generalizable clustering solution (predicted clustering strength value = 0.86). FTD-High subgroup had lower scores in social (pfdr < 0.001) and role (pfdr < 0.001) functioning, as well as worse neurocognitive performance in semantic (pfdr < 0.001) and phonological verbal fluency (pfdr < 0.001), short-term verbal memory (pfdr = 0.002) and abstract thinking (pfdr = 0.010), in comparison to FTD-Low group. CONCLUSIONS: Clustering techniques allowed us to identify patients with more pronounced FTD showing more severe deficits in functioning and neurocognition, thus suggesting that FTD may be a relevant marker of illness severity in the early psychosis pathway.
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    Multimodal Machine Learning Workflows for Prediction of Psychosis in Patients With Clinical High-Risk Syndromes and Recent-Onset Depression
    Koutsouleris, N ; Dwyer, DB ; Degenhardt, F ; Maj, C ; Urquijo-Castro, MF ; Sanfelici, R ; Popovic, D ; Oeztuerk, O ; Haas, SS ; Weiske, J ; Ruef, A ; Kambeitz-Ilankovic, L ; Antonucci, LA ; Neufang, S ; Schmidt-Kraepelin, C ; Ruhrmann, S ; Penzel, N ; Kambeitz, J ; Haidl, TK ; Rosen, M ; Chisholm, K ; Riecher-Rossler, A ; Egloff, L ; Schmidt, A ; Andreou, C ; Hietala, J ; Schirmer, T ; Romer, G ; Walger, P ; Franscini, M ; Traber-Walker, N ; Schimmelmann, BG ; Fluckiger, R ; Michel, C ; Rossler, W ; Borisov, O ; Krawitz, PM ; Heekeren, K ; Buechler, R ; Pantelis, C ; Falkai, P ; Salokangas, RKR ; Lencer, R ; Bertolino, A ; Borgwardt, S ; Noethen, M ; Brambilla, P ; Wood, SJ ; Upthegrove, R ; Schultze-Lutter, F ; Theodoridou, A ; Meisenzahl, E (AMER MEDICAL ASSOC, 2020-12-02)
    IMPORTANCE: Diverse models have been developed to predict psychosis in patients with clinical high-risk (CHR) states. Whether prediction can be improved by efficiently combining clinical and biological models and by broadening the risk spectrum to young patients with depressive syndromes remains unclear. OBJECTIVES: To evaluate whether psychosis transition can be predicted in patients with CHR or recent-onset depression (ROD) using multimodal machine learning that optimally integrates clinical and neurocognitive data, structural magnetic resonance imaging (sMRI), and polygenic risk scores (PRS) for schizophrenia; to assess models' geographic generalizability; to test and integrate clinicians' predictions; and to maximize clinical utility by building a sequential prognostic system. DESIGN, SETTING, AND PARTICIPANTS: This multisite, longitudinal prognostic study performed in 7 academic early recognition services in 5 European countries followed up patients with CHR syndromes or ROD and healthy volunteers. The referred sample of 167 patients with CHR syndromes and 167 with ROD was recruited from February 1, 2014, to May 31, 2017, of whom 26 (23 with CHR syndromes and 3 with ROD) developed psychosis. Patients with 18-month follow-up (n = 246) were used for model training and leave-one-site-out cross-validation. The remaining 88 patients with nontransition served as the validation of model specificity. Three hundred thirty-four healthy volunteers provided a normative sample for prognostic signature evaluation. Three independent Swiss projects contributed a further 45 cases with psychosis transition and 600 with nontransition for the external validation of clinical-neurocognitive, sMRI-based, and combined models. Data were analyzed from January 1, 2019, to March 31, 2020. MAIN OUTCOMES AND MEASURES: Accuracy and generalizability of prognostic systems. RESULTS: A total of 668 individuals (334 patients and 334 controls) were included in the analysis (mean [SD] age, 25.1 [5.8] years; 354 [53.0%] female and 314 [47.0%] male). Clinicians attained a balanced accuracy of 73.2% by effectively ruling out (specificity, 84.9%) but ineffectively ruling in (sensitivity, 61.5%) psychosis transition. In contrast, algorithms showed high sensitivity (76.0%-88.0%) but low specificity (53.5%-66.8%). A cybernetic risk calculator combining all algorithmic and human components predicted psychosis with a balanced accuracy of 85.5% (sensitivity, 84.6%; specificity, 86.4%). In comparison, an optimal prognostic workflow produced a balanced accuracy of 85.9% (sensitivity, 84.6%; specificity, 87.3%) at a much lower diagnostic burden by sequentially integrating clinical-neurocognitive, expert-based, PRS-based, and sMRI-based risk estimates as needed for the given patient. Findings were supported by good external validation results. CONCLUSIONS AND RELEVANCE: These findings suggest that psychosis transition can be predicted in a broader risk spectrum by sequentially integrating algorithms' and clinicians' risk estimates. For clinical translation, the proposed workflow should undergo large-scale international validation.
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    T223. MULTIVARIATE PREDICTION OF FOLLOW UP SOCIAL AND OCCUPATIONAL OUTCOME IN CLINICAL HIGH-RISK INDIVIDUALS BASED ON GRAY MATTER VOLUMES AND HISTORY OF ENVIRONMENTAL ADVERSE EVENTS
    Antonucci, L ; Pigoni, A ; Sanfelici, R ; Kambeitz-Ilankovic, L ; Dwyer, D ; Ruef, A ; Chisholm, K ; Haidl, T ; Rosen, M ; Kambeitz, J ; Ruhrmann, S ; Schultze-Lutter, F ; Falkai, P ; Lencer, R ; Dannlowski, U ; Upthegrove, R ; Salokangas, R ; Pantelis, C ; Meisenzahl, E ; Wood, S ; Brambilla, P ; Borgwardt, S ; Bertolino, A ; Koutsouleris, N (Oxford University Press (OUP), 2020-05-18)
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    O8.5. SIGNS OF ADVERSITY - A NOVEL MACHINE LEARNING APPROACH TO CHILDHOOD TRAUMA, BRAIN STRUCTURE AND CLINICAL PROFILES
    Popovic, D ; Ruef, A ; Dwyer, DB ; Hedderich, D ; Antonucci, LA ; Kambeitz-Ilankovic, L ; Öztürk, ÖF ; Dong, MS ; Paul, R ; Kambeitz, J ; Ruhrmann, S ; Chisholm, K ; Schultze-Lutter, F ; Falkai, P ; Bertolino, A ; Lencer, R ; Dannlowski, U ; Upthegrove, R ; Salokangas, RKR ; Pantelis, C ; Meisenzahl, E ; Wood, S ; Brambilla, P ; Borgwardt, S ; Koutsouleris, N (Oxford University Press (OUP), 2020-05-18)
    Abstract Background Childhood maltreatment (CM) is a major psychiatric risk factor and leads to long-lasting physical and mental health implications throughout the affected individual’s lifespan. Nonetheless, the neuroanatomical correlates of CM and their specific clinical impact remain elusive. This might be attributed to the complex, multidimensional nature of CM as well as to the restrictions of traditional analysis pipelines using nosological grouping, univariate analysis and region-of-interest approaches. To overcome these issues, we present a novel transdiagnostic and naturalistic machine learning approach towards a better and more comprehensive understanding of the clinical and neuroanatomical complexity of CM. Methods We acquired our dataset from the multi-center European PRONIA cohort (www.pronia.eu). Specifically, we selected 649 male and female individuals, comprising young, minimally medicated patients with clinical high-risk states for psychosis as well as recent-onset of depression or psychosis and healthy volunteers. As part of our analysis approach, we created a new Matlab Toolbox, which performs multivariate Sparse Partial Least Squares Analysis in a robust machine learning framework. We employed this algorithm to detect multi-layered associations between combinations of items from the Childhood Trauma Questionnaire (CTQ) and grey matter volume (GMV) and assessed their generalizability via nested cross-validation. The clinical relevance of these CM signatures was assessed by correlating them to a wide range of clinical measurements, including current functioning (GAF, GF), depressivity (BDI), quality of life (WHOQOL-BREF) and personality traits (NEO-FFI). Results Overall, we detected three distinct signatures of sexual, physical and emotional maltreatment. The first signature consisted of an age-dependent sexual abuse pattern and a corresponding GMV pattern along the prefronto-thalamo-cerebellar axis. The second signature yielded a sex-dependent physical and sexual abuse pattern with a corresponding GMV pattern in parietal, occipital and subcortical regions. The third signature was a global emotional trauma signature, independent of age or sex, and projected to a brain structural pattern in sensory and limbic brain regions. Regarding the clinical impact of these signatures, the emotional trauma signature was most strongly associated with massively impaired state- and trait-level characteristics. Both on a phenomenological and on a brain structural level, the emotional trauma pattern was significantly correlated with lower levels of functioning, higher depression scores, decreased quality of life and maladaptive personality traits. Discussion Our findings deliver multimodal, data-driven evidence for a differential impact of sexual, physical and emotional trauma on brain structure and clinical state- and trait-level phenotypes. They also highlight the multidimensional nature of CM, which consists of multiple layers of highly complex trauma-brain patterns. In broader terms, our study emphasizes the potential of machine learning approaches in generating novel insights into long-standing psychiatric topics.
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    O6.6. MULTIMODAL PROGNOSIS OF NEGATIVE SYMPTOM SEVERITY IN INDIVIDUALS WITH INCREASED RISK OF DEVELOPING PSYCHOSIS
    Hauke, D ; Schmidt, A ; Studerus, E ; Andreou, C ; Riecher-Rössler, A ; Radua, J ; Kambeitz, J ; Ruef, A ; Dwyer, D ; Sanfelici, R ; Penzel, N ; Haas, S ; Antonucci, L ; Schultze-Lutter, F ; Ruhrmann, S ; Hietala, J ; Brambilla, P ; Koutsouleris, N ; Meisenzahl, E ; Pantelis, C ; Rosen, M ; Salokangas, RKR ; Upthegrove, R ; Wood, S ; Borgwardt, S (Oxford University Press (OUP), 2020-05-18)
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    O6.4. ASSOCIATION BETWEEN CLUSTERS OF FORMAL THOUGHT DISORDERS SEVERITY AND NEUROCOGNITIVE AND FUNCTIONAL OUTCOME INDICES IN THE EARLY STAGES OF PSYCHOSIS – RESULTS FROM THE PRONIA COHORT
    Öztürk, ÖF ; Pigoni, A ; Wenzel, J ; Haas, S ; Popovic, D ; Ruef, A ; Dwyer, DB ; Kambeitz-Ilankovic, L ; Haidl, T ; Rosen, M ; Kambeitz, J ; Ruhrmann, S ; Chisholm, K ; Schultze-Lutter, F ; Liddle, PF ; Upthegrove, R ; Salokangas, RKR ; Pantelis, C ; Meisenzahl, E ; Wood, SJ ; Brambilla, P ; Borgwardt, S ; Falkai, P ; Antonucci, LA ; Koutsouleris, N (Oxford University Press (OUP), 2020-05-18)
    Abstract Background Formal thought disorder (FThD) has been associated with more severe illness courses and functional deficits in psychosis patients. Given these associations, it remains unclear whether the presence of FThD accounts for the heterogeneous presentation of psychoses, and whether it characterises a specific subgroup of patients showing prominent differential illness severity, neurocognitive and functional impairments already in the early stages of psychosis. Thus, our aim is 1) to evaluate whether there are stable subtypes of patients with Recent-Onset Psychosis (ROP) that are characterized by distinct FThD patterns, 2) to investigate whether this FThD-related stratification is associated with clinical, and neurocognitive phenotypes at an early stage of the disease, and 3) to explore correlation patterns among the FThD-related symptoms, functioning and neurocognition through network analysis. Methods 279 individuals experiencing ROP were recruited for this project as part of multi-site European PRONIA study. In the present study, FThD was assessed with conceptual disorganization, difficulty in abstract thinking, poverty of content of speech, increased latency of response and poverty of speech items from the Positive and Negative Symptom Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS). We first applied a multi-step clustering protocol comparing three clustering algorithms: (i) k-means, (ii) hierarchical clustering, and (iii) partitioning around medoids with the number of clusters ranging from 2 to 10. Our protocol runs following four checkpoints; (i) validity [ClValid package], (ii) re-evaluation of validity results and unbiased determination of the winning algorithm [NbClust package], (iii) stability test [ClusterStability package] and (iv) generalizability [predict.strength package] testing for the most optimal clustering solution. Thereafter, we investigated whether the identified FThD subgrouping solution was associated with neurocognitive performance, social and occupational functioning by using Welch’s two-sample t-test or Mann-Whitney-U test based on the distribution of data, and explored the interrelation of these domains with network analysis by using qgraph package with the spearman correlation matrix among variables. All analyses and univariate statistical comparisons were conducted with R version 3.5.2. We used the False Discovery Rate (FDR)37 to correct all P-values for the multiple comparisons. Results The k-means algorithm-based on two-cluster solution (FThD high vs. low) surviving these validity, stability and generalizability tests was chosen for further association tests and network analysis with core disease phenotypes. Patients in FThD high subgroup had lower scores in global (pfdr = 0.0001), social (pfdr &lt; 0.0001) and role (pfdr &lt; 0.0001) functioning, in semantic (pfdr &lt; 0.0001) and phonological verbal fluency (pfdr = 0.0004), verbal short-term memory (pfdr = 0.0018) and abstract thinking (pfdr = 0.0099). Cluster assignment was not informed by the global disease severity (pfdr = 0.7786) but was associated with more pronounced negative symptoms (pfdr = 0.0001) in the FThD high subgroup. Discussion Our findings highlight how the combination of unsupervised machine learning algorithms with network analysis techniques may provide novel insight about the mappings between psychopathology, neurocognition and functioning. Furthermore, they point how FThD may represent a target variable for individualized psycho-, socio-, logotherapeutic interventions aimed at improving neurocognition abilities and functioning. Prospective studies should further test this promising perspective.