Neurobiologically based stratification of recent-onset depression and psychosis: identification of two distinct transdiagnostic phenotypes

PRONIA Consortium; Paris Alexandros Lalousis; Lianne Schmaal; Stephen Wood; Renate Reniers; Nicholas Barnes; Katharine Chisholm; Lowri Griffiths; Alexandra Stainton; Junhao Wen; Gyujoon  Hwang; Christos Davatzikos; Julian Wenzel; Lana Kambeitz-Ilankovic; Christina Andreou; Carolina Bonivento; Udo Dannlowski; Adele Ferro; Theresa Liechtenstein; Anita Riecher-Rössler; Georg Romer; Marlene Rosen; Alessandro  Bertolino; Stefan Borgwardt; Paolo Brambilla; Joseph  Kambeitz; Rebekka Lencer; Christos Pantelis; Stephan Ruhrmann; Raimo K.r. Salokangas; Frauke Schultze-Lutter; André Schmidt; Eva M Meisenzahl; Nikolaos Koutsouleris; Dominic Dwyer; Rachel Upthegrove

doi:10.1016/j.biopsych.2022.03.021

Neurobiologically based stratification of recent-onset depression and psychosis: identification of two distinct transdiagnostic phenotypes

PRONIA Consortium, Paris Alexandros Lalousis^*, Lianne Schmaal, Stephen Wood, Renate Reniers, Nicholas Barnes, Katharine Chisholm, Lowri Griffiths, Alexandra Stainton, Junhao Wen, Gyujoon Hwang, Christos Davatzikos, Julian Wenzel, Lana Kambeitz-Ilankovic, Christina Andreou, Carolina Bonivento, Udo Dannlowski, Adele Ferro, Theresa Liechtenstein, Anita Riecher-RösslerGeorg Romer, Marlene Rosen, Alessandro Bertolino, Stefan Borgwardt, Paolo Brambilla, Joseph Kambeitz, Rebekka Lencer, Christos Pantelis, Stephan Ruhrmann, Raimo K.r. Salokangas, Frauke Schultze-Lutter, André Schmidt, Eva M Meisenzahl, Nikolaos Koutsouleris, Dominic Dwyer, Rachel Upthegrove

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Background: Identifying neurobiologically based transdiagnostic categories of depression and psychosis may elucidate heterogeneity and provide better candidates for predictive modeling. We aimed to identify clusters across patients with recent-onset depression (ROD) and recent-onset psychosis (ROP) based on structural neuroimaging data. We hypothesized that these transdiagnostic clusters would identify patients with poor outcome and allow more accurate prediction of symptomatic remission than traditional diagnostic structures.

Methods: HYDRA (Heterogeneity through Discriminant Analysis) was trained on whole-brain volumetric measures from 577 participants from the discovery sample of the multisite PRONIA study to identify neurobiologically driven clusters, which were then externally validated in the PRONIA replication sample (n = 404) and three datasets of chronic samples (Centre for Biomedical Research Excellence, n = 146; Mind Clinical Imaging Consortium, n = 202; Munich, n = 470).

Results: The optimal clustering solution was two transdiagnostic clusters (cluster 1: n = 153, 67 ROP, 86 ROD; cluster 2: n = 149, 88 ROP, 61 ROD; adjusted Rand index = 0.618). The two clusters contained both patients with ROP and patients with ROD. One cluster had widespread gray matter volume deficits and more positive, negative, and functional deficits (impaired cluster), and one cluster revealed a more preserved neuroanatomical signature and more core depressive symptomatology (preserved cluster). The clustering solution was internally and externally validated and assessed for clinical utility in predicting 9-month symptomatic remission, outperforming traditional diagnostic structures.

Conclusions: We identified two transdiagnostic neuroanatomically informed clusters that are clinically and biologically distinct, challenging current diagnostic boundaries in recent-onset mental health disorders. These results may aid understanding of the etiology of poor outcome patients transdiagnostically and improve development of stratified treatments.

Original language	English
Pages (from-to)	552-562
Number of pages	11
Journal	Biological Psychiatry
Volume	92
Issue number	7
Early online date	11 Apr 2022
DOIs	https://doi.org/10.1016/j.biopsych.2022.03.021
Publication status	Published - 1 Oct 2022

Bibliographical note

Funding Information:
The PRONIA study is a Collaboration Project funded by the European Union under the Seventh Framework Programme under Grant Agreement No. 602152. The PRONIA Consortium: The collaborators listed here performed the screening, recruitment, rating, examination, and follow-up of the study participants. They were involved in implementing the examination protocols of the study, setting up its IT infrastructure, and organizing the flow and quality control of the data analyzed in this manuscript between the local study sites and the central study database. Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University, Munich, Germany: Linda Betz, Anne Erkens, Eva Gussmann, Shalaila Haas, Alkomiet Hasan, Claudius Hoff, Ifrah Khanyaree, Aylin Melo, Susanna Muckenhuber-Sternbauer, Janis Köhler, Ömer Öztürk, Nora Penzel, David Popovic, Adrian Rangnick, Sebastian von Saldern, Rachele Sanfelici, Moritz Spangemacher, Ana Tupac, Maria Fernanda Urquijo, Johanna Weiske, and Antonia Wosgien. Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany: Karsten Blume, Dominika Gebhardt, Nathalie Kaiser, Ruth Milz, Alexandra Nikolaides, Mauro Seves, Silke Vent, and Martina Wassen. Department of Psychiatry (Psychiatric University Hospital, UPK), University of Basel, Switzerland: Christina Andreou, Laura Egloff, Fabienne Harrisberger, Claudia Lenz, Letizia Leanza, Amatya Mackintosh, Renata Smieskova, Erich Studerus, Anna Walter, and Sonja Widmayer. Institute for Mental Health & School of Psychology, University of Birmingham, United Kingdom: Chris Day, Mariam Iqbal, Mirabel Pelton, Pavan Mallikarjun, Alexandra Stainton, and Ashleigh Lin. Department of Psychiatry, University of Turku, Finland: Alexander Denissoff, Anu Ellilä, Tiina From, Markus Heinimaa, Tuula Ilonen, Päivi Jalo, Heikki Laurikainen, Antti Luutonen, Akseli Mäkela, Janina Paju, Henri Pesonen, Reetta-Liina Säilä, Anna Toivonen, and Otto Turtonen. General Electric Global Research Inc.: Ana Beatriz Solana, Manuela Abraham, Nicolas Hehn, and Timo Schirmer, Workgroup of Paolo Brambilla, University of Milan, Milan, Italy:, Department of Neuroscience and Mental Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan: Carlo Altamura, Marika Belleri, Francesca Bottinelli, Adele Ferro, and Marta Re. Programma2000, Niguarda Hospital: Emiliano Monzani and Maurizio Sberna. San Paolo Hospital: Armando D'Agostino and Lorenzo Del Fabro. Villa San Benedetto Menni, Albese con Cassano: Giampaolo Perna, Maria Nobile, and Alessandra Alciati. Workgroup of Paolo Brambilla at the University of Udine, Italy:, Department of Medical Area, University of Udine, Udine, Italy: Matteo Balestrieri, Carolina Bonivento, Giuseppe Cabras, and Franco Fabbro. IRCCS Scientific Institute “E. Medea”, Polo FVG, Udine: Marco Garzitto and Sara Piccin. PAL, NK, RU, and DD had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors reviewed, revised, and approved the final version of the manuscript. Acquisition and analysis of data: PAL, SJW, KC, SLG, ASt, SB, PB, CP, CA, UD, AR-R, GR, CB, DD, AF, TL, MR, ASc, NK, and RU; drafting of the manuscript: PAL, LS, RLEPR, NK, RU, and DD; critical revision of the manuscript for important intellectual content: PAL, LS, SJW, NMB, SLG, ASt, JWen, GH, CD, AB, SB, PB, LK-I, RL, CP, SR, RKRS, FS-L, DD, ASc, EM, NK, and RU; statistical analysis and interpretation of data: PAL, LS, RU, and DD; obtained funding and designed the study: SJW, AB, SB, PB, LK-I, RL, CP, SR, RKRS, EM, NK, and RU; administrative, technical, or material support: KC, SB, PB, TL, MR, ASc, EM, NK, and RU; supervision: SJW, LS, RLEPR, SB, PB, FS-L, NK, RU, and DD. CP has participated on Advisory Boards for Janssen-Cilag, AstraZeneca, Lundbeck, and Servier. He has received honoraria for talks presented at educational meetings organized by AstraZeneca, Janssen-Cilag, Eli Lilly, Pfizer, Lundbeck, and Shire. NK received honoraria for talks presented at education meetings organized by Otsuka/Lundbeck. RU reports grants from the Medical Research Council, grants from National Institute for Health Research: Health Technology Assessment, grants from European Commission - Research: The Seventh Framework Programme, and personal speaker fees from Sunovion, outside the submitted work. TL was supported by the Koeln Fortune Program/Faculty of Medicine, University of Cologne (Grant No. 370/2020). All other authors report no biomedical financial interests or potential conflicts of interest.

Funding Information:
The PRONIA study is a Collaboration Project funded by the European Union under the Seventh Framework Programme under Grant Agreement No. 602152 .

Funding Information:
CP has participated on Advisory Boards for Janssen-Cilag, AstraZeneca, Lundbeck, and Servier. He has received honoraria for talks presented at educational meetings organized by AstraZeneca, Janssen-Cilag, Eli Lilly, Pfizer, Lundbeck, and Shire. NK received honoraria for talks presented at education meetings organized by Otsuka/Lundbeck. RU reports grants from the Medical Research Council, grants from National Institute for Health Research: Health Technology Assessment, grants from European Commission - Research: The Seventh Framework Programme, and personal speaker fees from Sunovion, outside the submitted work. TL was supported by the Koeln Fortune Program/Faculty of Medicine, University of Cologne (Grant No. 370/2020). All other authors report no biomedical financial interests or potential conflicts of interest.

Publisher Copyright:
© 2022 Society of Biological Psychiatry

Keywords

transdiagnostic
psychosis
depression
clustering
nosology
machine learning
Psychosis
Machine learning
Depression
Nosology
Transdiagnostic
Clustering

ASJC Scopus subject areas

Biological Psychiatry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.biopsych.2022.03.021Licence: Creative Commons: Attribution (CC BY)

LalousisP2022NerobiologicallyFinal published version, 969 KBLicence: Creative Commons: Attribution (CC BY)

FP7_COLLAB - PRONIA
Upthegrove, R.
European Commission - Management Costs, European Commission
1/10/13 → 31/03/19
Project: Research

Cite this

PRONIA Consortium, Lalousis, P. A., Schmaal, L., Wood, S., Reniers, R., Barnes, N., Chisholm, K., Griffiths, L., Stainton, A., Wen, J., Hwang, G., Davatzikos, C., Wenzel, J., Kambeitz-Ilankovic, L., Andreou, C., Bonivento, C., Dannlowski, U., Ferro, A., Liechtenstein, T., ... Upthegrove, R. (2022). Neurobiologically based stratification of recent-onset depression and psychosis: identification of two distinct transdiagnostic phenotypes. Biological Psychiatry, 92(7), 552-562. https://doi.org/10.1016/j.biopsych.2022.03.021

@article{7ff658a945284648839d50a2a6cc3cb5,

title = "Neurobiologically based stratification of recent-onset depression and psychosis: identification of two distinct transdiagnostic phenotypes",

abstract = "Background: Identifying neurobiologically based transdiagnostic categories of depression and psychosis may elucidate heterogeneity and provide better candidates for predictive modeling. We aimed to identify clusters across patients with recent-onset depression (ROD) and recent-onset psychosis (ROP) based on structural neuroimaging data. We hypothesized that these transdiagnostic clusters would identify patients with poor outcome and allow more accurate prediction of symptomatic remission than traditional diagnostic structures.Methods: HYDRA (Heterogeneity through Discriminant Analysis) was trained on whole-brain volumetric measures from 577 participants from the discovery sample of the multisite PRONIA study to identify neurobiologically driven clusters, which were then externally validated in the PRONIA replication sample (n = 404) and three datasets of chronic samples (Centre for Biomedical Research Excellence, n = 146; Mind Clinical Imaging Consortium, n = 202; Munich, n = 470). Results: The optimal clustering solution was two transdiagnostic clusters (cluster 1: n = 153, 67 ROP, 86 ROD; cluster 2: n = 149, 88 ROP, 61 ROD; adjusted Rand index = 0.618). The two clusters contained both patients with ROP and patients with ROD. One cluster had widespread gray matter volume deficits and more positive, negative, and functional deficits (impaired cluster), and one cluster revealed a more preserved neuroanatomical signature and more core depressive symptomatology (preserved cluster). The clustering solution was internally and externally validated and assessed for clinical utility in predicting 9-month symptomatic remission, outperforming traditional diagnostic structures. Conclusions: We identified two transdiagnostic neuroanatomically informed clusters that are clinically and biologically distinct, challenging current diagnostic boundaries in recent-onset mental health disorders. These results may aid understanding of the etiology of poor outcome patients transdiagnostically and improve development of stratified treatments.",

keywords = "transdiagnostic, psychosis, depression, clustering, nosology, machine learning, Psychosis, Machine learning, Depression, Nosology, Transdiagnostic, Clustering",

author = "{PRONIA Consortium} and Lalousis, {Paris Alexandros} and Lianne Schmaal and Stephen Wood and Renate Reniers and Nicholas Barnes and Katharine Chisholm and Lowri Griffiths and Alexandra Stainton and Junhao Wen and Gyujoon Hwang and Christos Davatzikos and Julian Wenzel and Lana Kambeitz-Ilankovic and Christina Andreou and Carolina Bonivento and Udo Dannlowski and Adele Ferro and Theresa Liechtenstein and Anita Riecher-R{\"o}ssler and Georg Romer and Marlene Rosen and Alessandro Bertolino and Stefan Borgwardt and Paolo Brambilla and Joseph Kambeitz and Rebekka Lencer and Christos Pantelis and Stephan Ruhrmann and Salokangas, {Raimo K.r.} and Frauke Schultze-Lutter and Andr{\'e} Schmidt and Meisenzahl, {Eva M} and Nikolaos Koutsouleris and Dominic Dwyer and Rachel Upthegrove",

note = "Funding Information: The PRONIA study is a Collaboration Project funded by the European Union under the Seventh Framework Programme under Grant Agreement No. 602152. The PRONIA Consortium: The collaborators listed here performed the screening, recruitment, rating, examination, and follow-up of the study participants. They were involved in implementing the examination protocols of the study, setting up its IT infrastructure, and organizing the flow and quality control of the data analyzed in this manuscript between the local study sites and the central study database. Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University, Munich, Germany: Linda Betz, Anne Erkens, Eva Gussmann, Shalaila Haas, Alkomiet Hasan, Claudius Hoff, Ifrah Khanyaree, Aylin Melo, Susanna Muckenhuber-Sternbauer, Janis K{\"o}hler, {\"O}mer {\"O}zt{\"u}rk, Nora Penzel, David Popovic, Adrian Rangnick, Sebastian von Saldern, Rachele Sanfelici, Moritz Spangemacher, Ana Tupac, Maria Fernanda Urquijo, Johanna Weiske, and Antonia Wosgien. Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany: Karsten Blume, Dominika Gebhardt, Nathalie Kaiser, Ruth Milz, Alexandra Nikolaides, Mauro Seves, Silke Vent, and Martina Wassen. Department of Psychiatry (Psychiatric University Hospital, UPK), University of Basel, Switzerland: Christina Andreou, Laura Egloff, Fabienne Harrisberger, Claudia Lenz, Letizia Leanza, Amatya Mackintosh, Renata Smieskova, Erich Studerus, Anna Walter, and Sonja Widmayer. Institute for Mental Health & School of Psychology, University of Birmingham, United Kingdom: Chris Day, Mariam Iqbal, Mirabel Pelton, Pavan Mallikarjun, Alexandra Stainton, and Ashleigh Lin. Department of Psychiatry, University of Turku, Finland: Alexander Denissoff, Anu Ellil{\"a}, Tiina From, Markus Heinimaa, Tuula Ilonen, P{\"a}ivi Jalo, Heikki Laurikainen, Antti Luutonen, Akseli M{\"a}kela, Janina Paju, Henri Pesonen, Reetta-Liina S{\"a}il{\"a}, Anna Toivonen, and Otto Turtonen. General Electric Global Research Inc.: Ana Beatriz Solana, Manuela Abraham, Nicolas Hehn, and Timo Schirmer, Workgroup of Paolo Brambilla, University of Milan, Milan, Italy:, Department of Neuroscience and Mental Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan: Carlo Altamura, Marika Belleri, Francesca Bottinelli, Adele Ferro, and Marta Re. Programma2000, Niguarda Hospital: Emiliano Monzani and Maurizio Sberna. San Paolo Hospital: Armando D'Agostino and Lorenzo Del Fabro. Villa San Benedetto Menni, Albese con Cassano: Giampaolo Perna, Maria Nobile, and Alessandra Alciati. Workgroup of Paolo Brambilla at the University of Udine, Italy:, Department of Medical Area, University of Udine, Udine, Italy: Matteo Balestrieri, Carolina Bonivento, Giuseppe Cabras, and Franco Fabbro. IRCCS Scientific Institute “E. Medea”, Polo FVG, Udine: Marco Garzitto and Sara Piccin. PAL, NK, RU, and DD had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors reviewed, revised, and approved the final version of the manuscript. Acquisition and analysis of data: PAL, SJW, KC, SLG, ASt, SB, PB, CP, CA, UD, AR-R, GR, CB, DD, AF, TL, MR, ASc, NK, and RU; drafting of the manuscript: PAL, LS, RLEPR, NK, RU, and DD; critical revision of the manuscript for important intellectual content: PAL, LS, SJW, NMB, SLG, ASt, JWen, GH, CD, AB, SB, PB, LK-I, RL, CP, SR, RKRS, FS-L, DD, ASc, EM, NK, and RU; statistical analysis and interpretation of data: PAL, LS, RU, and DD; obtained funding and designed the study: SJW, AB, SB, PB, LK-I, RL, CP, SR, RKRS, EM, NK, and RU; administrative, technical, or material support: KC, SB, PB, TL, MR, ASc, EM, NK, and RU; supervision: SJW, LS, RLEPR, SB, PB, FS-L, NK, RU, and DD. CP has participated on Advisory Boards for Janssen-Cilag, AstraZeneca, Lundbeck, and Servier. He has received honoraria for talks presented at educational meetings organized by AstraZeneca, Janssen-Cilag, Eli Lilly, Pfizer, Lundbeck, and Shire. NK received honoraria for talks presented at education meetings organized by Otsuka/Lundbeck. RU reports grants from the Medical Research Council, grants from National Institute for Health Research: Health Technology Assessment, grants from European Commission - Research: The Seventh Framework Programme, and personal speaker fees from Sunovion, outside the submitted work. TL was supported by the Koeln Fortune Program/Faculty of Medicine, University of Cologne (Grant No. 370/2020). All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: The PRONIA study is a Collaboration Project funded by the European Union under the Seventh Framework Programme under Grant Agreement No. 602152 . Funding Information: CP has participated on Advisory Boards for Janssen-Cilag, AstraZeneca, Lundbeck, and Servier. He has received honoraria for talks presented at educational meetings organized by AstraZeneca, Janssen-Cilag, Eli Lilly, Pfizer, Lundbeck, and Shire. NK received honoraria for talks presented at education meetings organized by Otsuka/Lundbeck. RU reports grants from the Medical Research Council, grants from National Institute for Health Research: Health Technology Assessment, grants from European Commission - Research: The Seventh Framework Programme, and personal speaker fees from Sunovion, outside the submitted work. TL was supported by the Koeln Fortune Program/Faculty of Medicine, University of Cologne (Grant No. 370/2020). All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: {\textcopyright} 2022 Society of Biological Psychiatry",

year = "2022",

month = oct,

day = "1",

doi = "10.1016/j.biopsych.2022.03.021",

language = "English",

volume = "92",

pages = "552--562",

journal = "Biological Psychiatry",

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PRONIA Consortium, Lalousis, PA, Schmaal, L, Wood, S , Reniers, R , Barnes, N, Chisholm, K, Griffiths, L, Stainton, A, Wen, J, Hwang, G, Davatzikos, C, Wenzel, J, Kambeitz-Ilankovic, L, Andreou, C, Bonivento, C, Dannlowski, U, Ferro, A, Liechtenstein, T, Riecher-Rössler, A, Romer, G, Rosen, M, Bertolino, A, Borgwardt, S, Brambilla, P, Kambeitz, J, Lencer, R, Pantelis, C, Ruhrmann, S, Salokangas, RKR, Schultze-Lutter, F, Schmidt, A, Meisenzahl, EM, Koutsouleris, N, Dwyer, D & Upthegrove, R 2022, 'Neurobiologically based stratification of recent-onset depression and psychosis: identification of two distinct transdiagnostic phenotypes', Biological Psychiatry, vol. 92, no. 7, pp. 552-562. https://doi.org/10.1016/j.biopsych.2022.03.021

TY - JOUR

T1 - Neurobiologically based stratification of recent-onset depression and psychosis

T2 - identification of two distinct transdiagnostic phenotypes

AU - PRONIA Consortium

AU - Lalousis, Paris Alexandros

AU - Schmaal, Lianne

AU - Wood, Stephen

AU - Reniers, Renate

AU - Barnes, Nicholas

AU - Chisholm, Katharine

AU - Griffiths, Lowri

AU - Stainton, Alexandra

AU - Wen, Junhao

AU - Hwang, Gyujoon

AU - Davatzikos, Christos

AU - Wenzel, Julian

AU - Kambeitz-Ilankovic, Lana

AU - Andreou, Christina

AU - Bonivento, Carolina

AU - Dannlowski, Udo

AU - Ferro, Adele

AU - Liechtenstein, Theresa

AU - Riecher-Rössler, Anita

AU - Romer, Georg

AU - Rosen, Marlene

AU - Bertolino, Alessandro

AU - Borgwardt, Stefan

AU - Brambilla, Paolo

AU - Kambeitz, Joseph

AU - Lencer, Rebekka

AU - Pantelis, Christos

AU - Ruhrmann, Stephan

AU - Salokangas, Raimo K.r.

AU - Schultze-Lutter, Frauke

AU - Schmidt, André

AU - Meisenzahl, Eva M

AU - Koutsouleris, Nikolaos

AU - Dwyer, Dominic

AU - Upthegrove, Rachel

N1 - Funding Information: The PRONIA study is a Collaboration Project funded by the European Union under the Seventh Framework Programme under Grant Agreement No. 602152. The PRONIA Consortium: The collaborators listed here performed the screening, recruitment, rating, examination, and follow-up of the study participants. They were involved in implementing the examination protocols of the study, setting up its IT infrastructure, and organizing the flow and quality control of the data analyzed in this manuscript between the local study sites and the central study database. Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University, Munich, Germany: Linda Betz, Anne Erkens, Eva Gussmann, Shalaila Haas, Alkomiet Hasan, Claudius Hoff, Ifrah Khanyaree, Aylin Melo, Susanna Muckenhuber-Sternbauer, Janis Köhler, Ömer Öztürk, Nora Penzel, David Popovic, Adrian Rangnick, Sebastian von Saldern, Rachele Sanfelici, Moritz Spangemacher, Ana Tupac, Maria Fernanda Urquijo, Johanna Weiske, and Antonia Wosgien. Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany: Karsten Blume, Dominika Gebhardt, Nathalie Kaiser, Ruth Milz, Alexandra Nikolaides, Mauro Seves, Silke Vent, and Martina Wassen. Department of Psychiatry (Psychiatric University Hospital, UPK), University of Basel, Switzerland: Christina Andreou, Laura Egloff, Fabienne Harrisberger, Claudia Lenz, Letizia Leanza, Amatya Mackintosh, Renata Smieskova, Erich Studerus, Anna Walter, and Sonja Widmayer. Institute for Mental Health & School of Psychology, University of Birmingham, United Kingdom: Chris Day, Mariam Iqbal, Mirabel Pelton, Pavan Mallikarjun, Alexandra Stainton, and Ashleigh Lin. Department of Psychiatry, University of Turku, Finland: Alexander Denissoff, Anu Ellilä, Tiina From, Markus Heinimaa, Tuula Ilonen, Päivi Jalo, Heikki Laurikainen, Antti Luutonen, Akseli Mäkela, Janina Paju, Henri Pesonen, Reetta-Liina Säilä, Anna Toivonen, and Otto Turtonen. General Electric Global Research Inc.: Ana Beatriz Solana, Manuela Abraham, Nicolas Hehn, and Timo Schirmer, Workgroup of Paolo Brambilla, University of Milan, Milan, Italy:, Department of Neuroscience and Mental Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan: Carlo Altamura, Marika Belleri, Francesca Bottinelli, Adele Ferro, and Marta Re. Programma2000, Niguarda Hospital: Emiliano Monzani and Maurizio Sberna. San Paolo Hospital: Armando D'Agostino and Lorenzo Del Fabro. Villa San Benedetto Menni, Albese con Cassano: Giampaolo Perna, Maria Nobile, and Alessandra Alciati. Workgroup of Paolo Brambilla at the University of Udine, Italy:, Department of Medical Area, University of Udine, Udine, Italy: Matteo Balestrieri, Carolina Bonivento, Giuseppe Cabras, and Franco Fabbro. IRCCS Scientific Institute “E. Medea”, Polo FVG, Udine: Marco Garzitto and Sara Piccin. PAL, NK, RU, and DD had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors reviewed, revised, and approved the final version of the manuscript. Acquisition and analysis of data: PAL, SJW, KC, SLG, ASt, SB, PB, CP, CA, UD, AR-R, GR, CB, DD, AF, TL, MR, ASc, NK, and RU; drafting of the manuscript: PAL, LS, RLEPR, NK, RU, and DD; critical revision of the manuscript for important intellectual content: PAL, LS, SJW, NMB, SLG, ASt, JWen, GH, CD, AB, SB, PB, LK-I, RL, CP, SR, RKRS, FS-L, DD, ASc, EM, NK, and RU; statistical analysis and interpretation of data: PAL, LS, RU, and DD; obtained funding and designed the study: SJW, AB, SB, PB, LK-I, RL, CP, SR, RKRS, EM, NK, and RU; administrative, technical, or material support: KC, SB, PB, TL, MR, ASc, EM, NK, and RU; supervision: SJW, LS, RLEPR, SB, PB, FS-L, NK, RU, and DD. CP has participated on Advisory Boards for Janssen-Cilag, AstraZeneca, Lundbeck, and Servier. He has received honoraria for talks presented at educational meetings organized by AstraZeneca, Janssen-Cilag, Eli Lilly, Pfizer, Lundbeck, and Shire. NK received honoraria for talks presented at education meetings organized by Otsuka/Lundbeck. RU reports grants from the Medical Research Council, grants from National Institute for Health Research: Health Technology Assessment, grants from European Commission - Research: The Seventh Framework Programme, and personal speaker fees from Sunovion, outside the submitted work. TL was supported by the Koeln Fortune Program/Faculty of Medicine, University of Cologne (Grant No. 370/2020). All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: The PRONIA study is a Collaboration Project funded by the European Union under the Seventh Framework Programme under Grant Agreement No. 602152 . Funding Information: CP has participated on Advisory Boards for Janssen-Cilag, AstraZeneca, Lundbeck, and Servier. He has received honoraria for talks presented at educational meetings organized by AstraZeneca, Janssen-Cilag, Eli Lilly, Pfizer, Lundbeck, and Shire. NK received honoraria for talks presented at education meetings organized by Otsuka/Lundbeck. RU reports grants from the Medical Research Council, grants from National Institute for Health Research: Health Technology Assessment, grants from European Commission - Research: The Seventh Framework Programme, and personal speaker fees from Sunovion, outside the submitted work. TL was supported by the Koeln Fortune Program/Faculty of Medicine, University of Cologne (Grant No. 370/2020). All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: © 2022 Society of Biological Psychiatry

PY - 2022/10/1

Y1 - 2022/10/1

N2 - Background: Identifying neurobiologically based transdiagnostic categories of depression and psychosis may elucidate heterogeneity and provide better candidates for predictive modeling. We aimed to identify clusters across patients with recent-onset depression (ROD) and recent-onset psychosis (ROP) based on structural neuroimaging data. We hypothesized that these transdiagnostic clusters would identify patients with poor outcome and allow more accurate prediction of symptomatic remission than traditional diagnostic structures.Methods: HYDRA (Heterogeneity through Discriminant Analysis) was trained on whole-brain volumetric measures from 577 participants from the discovery sample of the multisite PRONIA study to identify neurobiologically driven clusters, which were then externally validated in the PRONIA replication sample (n = 404) and three datasets of chronic samples (Centre for Biomedical Research Excellence, n = 146; Mind Clinical Imaging Consortium, n = 202; Munich, n = 470). Results: The optimal clustering solution was two transdiagnostic clusters (cluster 1: n = 153, 67 ROP, 86 ROD; cluster 2: n = 149, 88 ROP, 61 ROD; adjusted Rand index = 0.618). The two clusters contained both patients with ROP and patients with ROD. One cluster had widespread gray matter volume deficits and more positive, negative, and functional deficits (impaired cluster), and one cluster revealed a more preserved neuroanatomical signature and more core depressive symptomatology (preserved cluster). The clustering solution was internally and externally validated and assessed for clinical utility in predicting 9-month symptomatic remission, outperforming traditional diagnostic structures. Conclusions: We identified two transdiagnostic neuroanatomically informed clusters that are clinically and biologically distinct, challenging current diagnostic boundaries in recent-onset mental health disorders. These results may aid understanding of the etiology of poor outcome patients transdiagnostically and improve development of stratified treatments.

AB - Background: Identifying neurobiologically based transdiagnostic categories of depression and psychosis may elucidate heterogeneity and provide better candidates for predictive modeling. We aimed to identify clusters across patients with recent-onset depression (ROD) and recent-onset psychosis (ROP) based on structural neuroimaging data. We hypothesized that these transdiagnostic clusters would identify patients with poor outcome and allow more accurate prediction of symptomatic remission than traditional diagnostic structures.Methods: HYDRA (Heterogeneity through Discriminant Analysis) was trained on whole-brain volumetric measures from 577 participants from the discovery sample of the multisite PRONIA study to identify neurobiologically driven clusters, which were then externally validated in the PRONIA replication sample (n = 404) and three datasets of chronic samples (Centre for Biomedical Research Excellence, n = 146; Mind Clinical Imaging Consortium, n = 202; Munich, n = 470). Results: The optimal clustering solution was two transdiagnostic clusters (cluster 1: n = 153, 67 ROP, 86 ROD; cluster 2: n = 149, 88 ROP, 61 ROD; adjusted Rand index = 0.618). The two clusters contained both patients with ROP and patients with ROD. One cluster had widespread gray matter volume deficits and more positive, negative, and functional deficits (impaired cluster), and one cluster revealed a more preserved neuroanatomical signature and more core depressive symptomatology (preserved cluster). The clustering solution was internally and externally validated and assessed for clinical utility in predicting 9-month symptomatic remission, outperforming traditional diagnostic structures. Conclusions: We identified two transdiagnostic neuroanatomically informed clusters that are clinically and biologically distinct, challenging current diagnostic boundaries in recent-onset mental health disorders. These results may aid understanding of the etiology of poor outcome patients transdiagnostically and improve development of stratified treatments.

KW - transdiagnostic

KW - psychosis

KW - depression

KW - clustering

KW - nosology

KW - machine learning

KW - Psychosis

KW - Machine learning

KW - Depression

KW - Nosology

KW - Transdiagnostic

KW - Clustering

UR - http://www.scopus.com/inward/record.url?scp=85132873503&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2022.03.021

DO - 10.1016/j.biopsych.2022.03.021

M3 - Article

C2 - 35717212

SN - 0006-3223

VL - 92

SP - 552

EP - 562

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 7

ER -

Neurobiologically based stratification of recent-onset depression and psychosis: identification of two distinct transdiagnostic phenotypes

Abstract

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FP7_COLLAB - PRONIA

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