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1. A longitudinal approach to biological psychiatric research: The PsyCourse study

Author

Monika Budde, Janos Kalman, Harald Scherk, Martin von Hagen, Fabian U. Lang, Markus Jäger, Jens Wiltfang, Georg Juckel, Udo Dannlowski, Manfred Koller, Fanny Senner, Katrin Gade, Kristina Adorjan, Eva Z. Reininghaus, Eva C. Schulte, Ida Sybille Haußleiter, Anna Gryaznova, Andreas J. Fallgatter, Till F. M. Andlauer, Ion-George Anghelescu, Markus Reitt, Here Folkerts, Sybille Schulz, Urs Heilbronner, Jens Reimer, Marcella Rietschel, Max Schmauß, Christian Figge, Maria Hake, Sebastian Stierl, Andreas Thiel, Laura Flatau, Markus M. Nöthen, Stephanie H. Witt, Moritz E. Wigand, Detlef E. Dietrich, Heike Anderson-Schmidt, Ashley L. Comes, Carsten Spitzer, Thomas Becker, Volker Arolt, Daniela Reich-Erkelenz, Bernhard T. Baune, Kim Bartholdi, Milena Meyers, Thomas G. Schulze, Vanessa Nieratschker, Barbara Emons, Franziska Degenhardt, Peter Falkai, Carsten Konrad, Silke Quast, Sabrina K. Schaupp, Jörg Zimmermann, Sophia Stegmaier, Andreas J. Forstner, Sergi Papiol, and Farah Klöhn-Saghatolislam

Subjects
Male, Research design, Bipolar Disorder, diagnosis, psychology [Psychotic Disorders], diagnosis [Schizophrenia], 0302 clinical medicine, psychosis, Longitudinal Studies, Research Articles, psychology [Bipolar Disorder], Genetics (clinical), Psychopathology, Mental Disorders, Middle Aged, 3. Good health, Diagnostic and Statistical Manual of Mental Disorders, Psychiatry and Mental health, Phenotype, Research Design, Schizophrenia, diagnosis [Psychotic Disorders], Female, Schizophrenic Psychology, Research Article, Clinical psychology, Adult, Psychosis, medicine.medical_specialty, diagnosis [Mental Disorders], methods [Psychopathology], 03 medical and health sciences, Cellular and Molecular Neuroscience, RDoC, medicine, Humans, ddc:610, Bipolar disorder, diagnosis [Bipolar Disorder], Psychiatry, Kraepelinian dichotomy, Aged, affective disorder, medicine.disease, Mental health, 030227 psychiatry, Psychotic Disorders, psychology [Mental Disorders], polygenic risk score, 030217 neurology & neurosurgery
Abstract

In current diagnostic systems, schizophrenia and bipolar disorder are still conceptualized as distinct categorical entities. Recently, both clinical and genomic evidence have challenged this Kraepelinian dichotomy. There are only few longitudinal studies addressing potential overlaps between these conditions. Here, we present design and first results of the PsyCourse study (N = 891 individuals at baseline), an ongoing transdiagnostic study of the affective-to-psychotic continuum that combines longitudinal deep phenotyping and dimensional assessment of psychopathology with an extensive collection of biomaterial. To provide an initial characterization of the PsyCourse study sample, we compare two broad diagnostic groups defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) classification system, that is, predominantly affective (n = 367 individuals) versus predominantly psychotic disorders (n = 524 individuals). Depressive, manic, and psychotic symptoms as well as global functioning over time were contrasted using linear mixed models. Furthermore, we explored the effects of polygenic risk scores for schizophrenia on diagnostic group membership and addressed their effects on nonparticipation in follow-up visits. While phenotypic results confirmed expected differences in current psychotic symptoms and global functioning, both manic and depressive symptoms did not vary between both groups after correction for multiple testing. Polygenic risk scores for schizophrenia significantly explained part of the variability of diagnostic group. The PsyCourse study presents a unique resource to research the complex relationships of psychopathology and biology in severe mental disorders not confined to traditional diagnostic boundaries and is open for collaborations.

Published
2018
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2. Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study

Author

Francis M. Mondimore, Farah Klohn-Sagatholislam, Jana Strohmaier, Jens Wiltfang, Jay Raymond DePaulo, Udo Dannlowski, Markus Jäger, Moritz E. Wigand, Ion Anghelescu, Michael Bauer, Louise Frisén, Ashley L. Comes, Carsten Spitzer, Claire Slaney, Janice M. Fullerton, Giovanni Severino, Janusz K. Rybakowski, Andreas J. Fallgatter, Maria Hake, Martin Alda, Peter R. Schofield, Susanne Bengesser, Nirmala Akula, Stefan Herms, Paul D. Shilling, Franziska Degenhardt, Mazda Adli, Armin Birner, Alexandre Dayer, Cristiana Cruceanu, Fanny Senner, Peter Falkai, Maria Del Zompo, Mark A. Frye, Christian Simhandl, Stéphane Jamain, Andrea Pfennig, Layla Kassem, Sébastien Gard, Heike Anderson-Schmidt, Marion Leboyer, Peter P. Zandi, Susan L. McElroy, Martin Schalling, Sebastian Stierl, Detlef E. Dietrich, Frank Bellivier, Palmiero Monteleone, Sybille Schulz, Caterina Chillotti, Volker Arolt, Michael McCarthy, Alfonso Tortorella, Andreas Thiel, Marcella Rietschel, Kristina Adorjan, Tatyana Shekhtman, Maria Grigoroiu-Serbanescu, Jean-Michel Aubry, Daniela Reich-Erkelenz, Laura Flatau, Markus Reitt, Harald Scherk, Here Folkerts, Julia Veeh, Joanna Hauser, Fernando S. Goes, Philip B. Mitchell, Gustavo Turecki, John R. Kelsoe, Thomas Stamm, Sophia Stegmaier, Georg Juckel, Markus M. Nöthen, Lina Martinsson, Bárbara Arias, Vanessa Nieratschker, Clara Brichant-Petitjean, Antonio Benabarre, Bernhard T. Baune, James B. Potash, Urs Heilbronner, Caroline M. Nievergelt, Raffaella Ardau, Mikael Landén, Pablo Cervantes, Pavla Stopkova, Adam Wright, Tomas Novak, Scott R. Clark, Manfred Koller, Gonzalo Laje, Katrin Gade, Andreas J. Forstner, Sarah Kittel-Schneider, Susan G. Leckband, Sebastian Kliwicki, Guy A. Rouleau, Kim Bartholdi, Martin von Hagen, Per Hoffmann, Eva C. Schulte, Alessio Squassina, Monika Budde, Thomas G. Schulze, Eduard Vieta, Liping Hou, Jörg Zimmermann, Barbara König, Stephan Ripke, Sarah K. Tighe, Jean-Pierre Kahn, Julie Garnham, Piotr M. Czerski, Janos Kalman, Anna Gryaznova, Francis J. McMahon, Mario Maj, Thomas Becker, Thomas Ethofer, Andreas Reif, Carsten Konrad, Mirko Manchia, Lena Backlund, Jens Reimer, Urban Ösby, Esther Jiménez, Abesh Kumar Bhattacharjee, Marina Mitjans, Sergi Papiol, Stephanie H. Witt, Sven Cichon, Bruno Etain, Till F. M. Andlauer, Joanna M. Biernacka, Max Schmauß, Christian Figge, Fabian U. Lang, N. Lackner, Eva Z. Reininghaus, Francesc Colom, Catharina Lavebratt, K Oliver Schubert, Kalman, Janos L, Papiol, Sergi, Forstner, Andreas J, Heilbronner, Ur, Degenhardt, Franziska, Strohmaier, Jana, Adli, Mazda, Adorjan, Kristina, Akula, Nirmala, Alda, Martin, Anderson-Schmidt, Heike, Andlauer, Till Fm, Anghelescu, Ion-George, Ardau, Raffaella, Arias, Bárbara, Arolt, Volker, Aubry, Jean-Michel, Backlund, Lena, Bartholdi, Kim, Bauer, Michael, Baune, Bernhard T, Becker, Thoma, Bellivier, Frank, Benabarre, Antonio, Bengesser, Susanne, Bhattacharjee, Abesh Kumar, Biernacka, Joanna M, Birner, Armin, Brichant-Petitjean, Clara, Budde, Monika, Cervantes, Pablo, Chillotti, Caterina, Cichon, Sven, Clark, Scott R, Colom, Francesc, Comes, Ashley L, Cruceanu, Cristiana, Czerski, Piotr M, Dannlowski, Udo, Dayer, Alexandre, Del Zompo, Maria, Depaulo, Jay Raymond, Dietrich, Detlef E, Étain, Bruno, Ethofer, Thoma, Falkai, Peter, Fallgatter, Andrea, Figge, Christian, Flatau, Laura, Folkerts, Here, Frisen, Louise, Frye, Mark A, Fullerton, Janice M, Gade, Katrin, Gard, Sébastien, Garnham, Julie S, Goes, Fernando S, Grigoroiu-Serbanescu, Maria, Gryaznova, Anna, Hake, Maria, Hauser, Joanna, Herms, Stefan, Hoffmann, Per, Hou, Liping, Jäger, Marku, Jamain, Stephane, Jiménez, Esther, Juckel, Georg, Kahn, Jean-Pierre, Kassem, Layla, Kelsoe, John, Kittel-Schneider, Sarah, Kliwicki, Sebastian, Klohn-Sagatholislam, Farah, Koller, Manfred, König, Barbara, Konrad, Carsten, Lackner, Nina, Laje, Gonzalo, Landén, Mikael, Lang, Fabian U, Lavebratt, Catharina, Leboyer, Marion, Leckband, Susan G, Maj, Mario, Manchia, Mirko, Martinsson, Lina, Mccarthy, Michael J, Mcelroy, Susan L, Mcmahon, Francis J, Mitchell, Philip B, Mitjans, Marina, Mondimore, Francis M, Monteleone, Palmiero, Nieratschker, Vanessa, Nievergelt, Caroline M, Novák, Toma, Ösby, Urban, Pfennig, Andrea, Potash, James B, Reich-Erkelenz, Daniela, Reif, Andrea, Reimer, Jen, Reininghaus, Eva, Reitt, Marku, Ripke, Stephan, Rouleau, Guy A, Rybakowski, Janusz K, Schalling, Martin, Scherk, Harald, Schmauß, Max, Schofield, Peter R, Schubert, K Oliver, Schulte, Eva C, Schulz, Sybille, Senner, Fanny, Severino, Giovanni, Shekhtman, Tatyana, Shilling, Paul D, Simhandl, Christian, Slaney, Claire M, Spitzer, Carsten, Squassina, Alessio, Stamm, Thoma, Stegmaier, Sophia, Stierl, Sebastian, Stopkova, Pavla, Thiel, Andrea, Tighe, Sarah K, Tortorella, Alfonso, Turecki, Gustavo, Vieta, Eduard, Veeh, Julia, von Hagen, Martin, Wigand, Moritz E, Wiltfang, Jen, Witt, Stephanie, Wright, Adam, Zandi, Peter P, Zimmermann, Jörg, Nöthen, Marku, Rietschel, Marcella, and Schulze, Thomas G

Subjects
Adult, Male, Oncology, Multifactorial Inheritance, medicine.medical_specialty, Schizophrenia/genetics, Disease onset, Adolescent, early onset, Late onset, ddc:616.89, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Bipolar disorder, Child, Research Articles, Biological Psychiatry, bipolar disorder, Trastorn bipolar, business.industry, Bipolar Disorder/genetics, age at onset, polygenic risk score, schizophrenia, Age Factors, Bipolar Disorder, Female, Middle Aged, Phenotype, Schizophrenia, Original Articles, medicine.disease, Genetic architecture, 030227 psychiatry, Psychiatry and Mental health, Institutional repository, Clinical research, Esquizofrènia, Original Article, business, 030217 neurology & neurosurgery
Abstract

OBJECTIVES: Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients. METHODS: A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models. RESULTS: BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment. CONCLUSIONS: The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype. peerReviewed

Published
2018
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3. An investigation of psychosis subgroups with prognostic validation and exploration of genetic underpinnings: the PsyCourse Study

Author

Ida Sybille Haußleiter, Sabrina K. Schaupp, Nikola S. Mueller, Eva Z. Reininghaus, Joseph Kambeitz, Sophia Stegmaier, Anne Ruef, Andreas J. Forstner, Markus Jäger, Georg Juckel, Jörg Zimmermann, Jens Reimer, Here Folkerts, Stephanie H. Witt, Katrin Gade, Laura Flatau-Nagel, Alkomiet Hasan, Fabian U. Lang, Harald Scherk, Lana Kambeitz-Ilankovic, Dominic B. Dwyer, Kristina Adorjan, Carsten Konrad, Thomas Becker, Till F. M. Andlauer, Ivan Kondofersky, Volker Arolt, Sergi Papiol, Monika Budde, Farah Klöhn-Saghatolislam, Anna Gryaznova, Daniela Reich-Erkelenz, Markus Reitt, Martin von Hagen, Maria Hake, Janos Kalman, Vanessa Nieratschker, Bernhard T. Baune, Max Schmauß, Christian Figge, Tomoya Yoshida, Ashley L. Comes, Carsten Spitzer, Urs Heilbronner, Linda A. Antonucci, Fanny Senner, Moritz E. Wigand, Jens Wiltfang, Ion-George Anghelescu, Udo Dannlowski, Nikolaos Koutsouleris, Detlef E. Dietrich, Kim Bartholdi, Milena Meyers, Thomas G. Schulze, Barbara Emons, Markus M. Nöthen, Marcella Rietschel, Manfred Koller, Eva C. Schulte, Andreas Thiel, Andreas J. Fallgatter, Peter Falkai, Silke Quast, Heike Anderson-Schmidt, and Franziska Degenhardt

Subjects
Adult, Male, Multifactorial Inheritance, Psychosis, Bipolar Disorder, Schizoaffective disorder, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Genetic Predisposition to Disease, Longitudinal Studies, Bipolar disorder, Schizophreniform disorder, Original Investigation, Depressive Disorder, Major, business.industry, Reproducibility of Results, Brief psychotic disorder, Middle Aged, Prognosis, medicine.disease, 3. Good health, 030227 psychiatry, Psychiatry and Mental health, Psychotic Disorders, Schizophrenia, Educational Status, Major depressive disorder, Female, business, 030217 neurology & neurosurgery, Clinical psychology, Cohort study
Abstract

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 (R(2) = 0.41; 95% CI, 0.38-0.44), depression symptoms (R(2) = 0.28; 95% CI, 0.25-0.32), global functioning (R(2) = 0.16; 95% CI, 0.14-0.20), and quality of life (R(2) = 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 η(2) = 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.

Published
2020

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