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Original Investigation
February 12, 2020

An Investigation of Psychosis Subgroups With Prognostic Validation and Exploration of Genetic Underpinnings: The PsyCourse Study

Dominic B. Dwyer, PhD1; Janos L. Kalman, MD1,2,3; Monika Budde, Dipl-Psych2; et al Joseph Kambeitz, MD4; Anne Ruef, PhD1; Linda A. Antonucci, PhD1,5; Lana Kambeitz-Ilankovic, PhD4; Alkomiet Hasan, MD1; Ivan Kondofersky, PhD6,7; Heike Anderson-Schmidt, PhD2,8; Katrin Gade, MD2,8; Daniela Reich-Erkelenz, MA2; Kristina Adorjan, MD1,2; Fanny Senner, MD1,2; Sabrina Schaupp, MSc2,9; Till F. M. Andlauer, PhD10; Ashley L. Comes, MSc2,3; Eva C. Schulte, MD1,2; Farah Klöhn-Saghatolislam, MD1,2; Anna Gryaznova, BSc2; Maria Hake, DiplPsych2; Kim Bartholdi, PhD2; Laura Flatau-Nagel, MSc2; Markus Reitt, PhD8; Silke Quast, BSc8; Sophia Stegmaier, MSc11; Milena Meyers, MSc12; Barbara Emons, MD12; Ida Sybille Haußleiter, MD12; Georg Juckel, MD12; Vanessa Nieratschker, PhD11; Udo Dannlowski, PhD13; Tomoya Yoshida, MD14; Max Schmauß, MD9; Jörg Zimmermann, MD15; Jens Reimer, MD16,17; Jens Wiltfang, MD8,18,19; Eva Reininghaus, MD20; Ion-George Anghelescu, MD21; Volker Arolt, MD13; Bernhard T. Baune, PhD13,22,23; Carsten Konrad, MD24; Andreas Thiel, MD24; Andreas J. Fallgatter, MD11; Christian Figge, MD25; Martin von Hagen, MD26; Manfred Koller, MD27; Fabian U. Lang, MD28; Moritz E. Wigand, MD28; Thomas Becker, MD28; Markus Jäger, MD28; Detlef E. Dietrich, MD29,30,31; Harald Scherk, MD32; Carsten Spitzer, MD33; Here Folkerts, MD34; Stephanie H. Witt, PhD35; Franziska Degenhardt, MD36,37; Andreas J. Forstner, MD36,37,38,39; Marcella Rietschel, MD35; Markus M. Nöthen, MD36,37; Nikola Mueller, PhD6; Sergi Papiol, PhD1,2; Urs Heilbronner, PhD2; Peter Falkai, MD1; Thomas G. Schulze, MD2; Nikolaos Koutsouleris, MD1,40
Author Affiliations
  • 1Department of Psychiatry and Psychotherapy, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany
  • 2Institute of Psychiatric Phenomics and Genomics, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany
  • 3International Max Planck Research School (IMPRS-TP), Munich, Germany
  • 4Faculty of Medicine and University Hospital, University of Cologne, Cologne, Germany
  • 5Department of Education, Psychology and Communication, University of Bari Aldo Moro, Bari, Italy
  • 6Institute of Computational Biology, Helmholtz Zentrum Munich, Oberschleißheim, Germany
  • 7Department of Mathematics, Technical University of Munich Garching, Garching, Germany
  • 8Department of Psychiatry and Psychotherapy, University Medical Center Gottingen, Gottingen, Germany
  • 9Department of Psychiatry and Psychotherapy, Bezirkskrankenhaus Augsburg, Augsburg, Germany
  • 10Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
  • 11Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
  • 12Department of Psychiatry, Ruhr University Bochum, LWL University Hospital, Bochum, Germany
  • 13Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany
  • 14Department of Physiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  • 15Psychiatrieverbund Oldenburger Land gGmbH, Karl-Jaspers-Klinik, Bad Zwischenahn, Germany
  • 16Department of Psychiatry, Klinikum Bremen-Ost, Bremen, Germany
  • 17Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • 18German Center for Neurodegenerative Diseases (DZNE), Gottingen, Germany
  • 19Institute of BioMedicine (iBiMED), Medical Sciences Department, University of Aveiro, Aveiro, Portugal
  • 20Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for Bipolar Affective Disorder, Medical University of Graz, Graz, Austria
  • 21Department of Psychiatry, Dr Fontheim–Mental Health, Liebenburg, Germany
  • 22Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Melbourne, Victoria, Australia
  • 23The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia
  • 24Department of Psychiatry and Psychotherapy, Agaplesion Diakonieklinikum, Rotenburg, Germany
  • 25Karl-Jaspers Clinic, European Medical School Oldenburg-Groningen, Oldenburg, Germany
  • 26Clinic for Psychiatry and Psychotherapy, Clinical Center Werra-Meißner, Eschwege, Germany
  • 27Asklepios Specialized Hospital, Göttingen, Germany
  • 28Department of Psychiatry II, Ulm University, Bezirkskrankenhaus Günzburg, Günzburg, Germany
  • 29AMEOS Clinical Center Hildesheim, Hildesheim, Germany
  • 30Center for Systems Neuroscience, Hannover, Germany
  • 31Burghof-Klinik Rinteln, Rinteln, Germany
  • 32AMEOS Clinical Center Osnabrück, Osnabrück, Germany
  • 33Department of Psychosomatics and Psychotherapeutic Medicine, University Medical Center Rostock, Rostock, Germany
  • 34Department of Psychiatry, Psychotherapy and Psychosomatics, Clinical Center Wilhelmshaven, Wilhelmshaven, Germany
  • 35Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
  • 36Institute of Human Genetics, University Hospital Bonn, Bonn, Germany
  • 37Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany
  • 38Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland
  • 39Centre for Human Genetics, University of Marburg, Marburg, Germany
  • 40International Max-Planck Research School for Translational Psychiatry, Max-Planck Institute of Psychiatry, Munich, Germany
JAMA Psychiatry. Published online February 12, 2020. doi:10.1001/jamapsychiatry.2019.4910
Key Points

Question  Will data-driven clustering using high-dimensional clinical data reveal psychosis subgroups with relevance to prognoses and polygenic risk?

Findings  In this cohort study including 1223 individuals, in the discovery sample of 765 individuals with predominantly bipolar and schizophrenia diagnoses, 5 subgroups were detected with different clinical signatures, illness trajectories, and genetic scores for educational attainment. Results were validated in a sample of 458 individuals.

Meaning  New data-driven clustering paired with rigorous validation may offer a means to extend symptom-based psychosis taxonomies toward functional outcomes, genetic markers, and trajectory-based stratifications.


Importance  Identifying psychosis subgroups could improve clinical and research precision. Research has focused on symptom subgroups, but there is a need to consider a broader clinical spectrum, disentangle illness trajectories, and investigate genetic associations.

Objective  To detect psychosis subgroups using data-driven methods and examine their illness courses over 1.5 years and polygenic scores for schizophrenia, bipolar disorder, major depression disorder, and educational achievement.

Design, Setting, and Participants  This ongoing multisite, naturalistic, longitudinal (6-month intervals) cohort study began in January 2012 across 18 sites. Data from a referred sample of 1223 individuals (765 in the discovery sample and 458 in the validation sample) with DSM-IV diagnoses of schizophrenia, bipolar affective disorder (I/II), schizoaffective disorder, schizophreniform disorder, and brief psychotic disorder were collected from secondary and tertiary care sites. Discovery data were extracted in September 2016 and analyzed from November 2016 to January 2018, and prospective validation data were extracted in October 2018 and analyzed from January to May 2019.

Main Outcomes and Measures  A clinical battery of 188 variables measuring demographic characteristics, clinical history, symptoms, functioning, and cognition was decomposed using nonnegative matrix factorization clustering. Subtype-specific illness courses were compared with mixed models and polygenic scores with analysis of covariance. Supervised learning was used to replicate results in validation data with the most reliably discriminative 45 variables.

Results  Of the 765 individuals in the discovery sample, 341 (44.6%) were women, and the mean (SD) age was 42.7 (12.9) years. Five subgroups were found and labeled as affective psychosis (n = 252), suicidal psychosis (n = 44), depressive psychosis (n = 131), high-functioning psychosis (n = 252), and severe psychosis (n = 86). Illness courses with significant quadratic interaction terms were found for psychosis symptoms (R2 = 0.41; 95% CI, 0.38-0.44), depression symptoms (R2 = 0.28; 95% CI, 0.25-0.32), global functioning (R2 = 0.16; 95% CI, 0.14-0.20), and quality of life (R2 = 0.20; 95% CI, 0.17-0.23). The depressive and severe psychosis subgroups exhibited the lowest functioning and quadratic illness courses with partial recovery followed by reoccurrence of severe illness. Differences were found for educational attainment polygenic scores (mean [SD] partial η2 = 0.014 [0.003]) but not for diagnostic polygenic risk. Results were largely replicated in the validation cohort.

Conclusions and Relevance  Psychosis subgroups were detected with distinctive clinical signatures and illness courses and specificity for a nondiagnostic genetic marker. New data-driven clinical approaches are important for future psychosis taxonomies. The findings suggest a need to consider short-term to medium-term service provision to restore functioning in patients stratified into the depressive and severe psychosis subgroups.

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