Age-related brain structural alterations as an intermediate phenotype of psychosis

Age-related brain structural alterations as an intermediate phenotype of psychosis


J Psychiatry Neurosci 2017;42(5):307-319

Juergen Dukart, PhD; Renata Smieskova, PhD; Fabienne Harrisberger, PhD; Claudia Lenz, PhD; André Schmidt, PhD; Anna Walter, MD; Christian Huber, MD; Anita Riecher-Rössler, MD, PhD; Andor Simon, MD; Undine E. Lang, MD, PhD; Paolo Fusar-Poli, MD, PhD; Stefan Borgwardt, MD, PhD

See the commentary by Palaniyappan and colleagues


Background: There is only limited agreement with respect to location, directionality and functional implications of brain structural alterations observed in patients with schizophrenia. Additionally, their link to occurrence of psychotic symptoms remains unclear. A viable way of addressing these questions is to examine populations in an at-risk mental state (ARMS) before the transition to psychosis.

Methods: We tested for structural brain alterations in individuals in an ARMS compared with healthy controls and patients with first-episode psychosis (FEP) using voxel-based morphometry and measures of cortical thickness. Furthermore, we evaluated if these alterations were modified by age and whether they were linked to the observed clinical symptoms.

Results: Our sample included 59 individuals with ARMS, 26 healthy controls and 59 patients with FEP. We found increased grey matter volume and cortical thickness in individuals with ARMS and a similar pattern of structural alterations in patients with FEP. We further found stronger age-related reductions in grey matter volume and cortical thickness in both patients with FEP and individuals with ARMS, linking these alterations to observed clinical symptoms.

Limitations: The ARMS group comprised subgroups with heterogeneous levels of psychosis risk and medication status. Furthermore, the cross-sectional nature of our study and the reduced number of older patients limit conclusions with respect to observed interactions with age.

Conclusion: Our findings on consistent structural alterations in individuals with ARMS and patients with FEP and their link to clinical symptoms have major implications for understanding their time of occurrence and relevance to psychotic symptoms. Interactions with age found for these alterations may explain the heterogeneity of findings reported in the literature.

Submitted Sept. 6, 2016; Revised Jan. 11, 2017; Accepted Mar. 17, 2017; Early-released May 2, 2017

Affiliations: From the F. Hoffmann-La Roche, Pharma Research Early Development, Roche Innovation Centre Basel, Basel, Switzerland (Dukart); the Department of Psychiatry (UPK), University of Basel, Basel, Switzerland (Dukart, Smieskova, Lenz, Schmidt, Walter, Huber, Riecher-Rössler, Lang, Borgwardt); the University Hospital of Psychiatry, University Hospital of Bern, Bern, Switzerland, and Specialized Early Psychosis Outpatient Service for Adolescents and Young Adults, Department of Psychiatry, Bruderholz, Switzerland (Simon); and the Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience IoPPN), King’s College London, London, UK (Schmidt, Borgwardt).

Competing interests: J. Dukart is a full-time employee of F. Hoffmann-La Roche, but received no specific funding for this work. F. Hoffmann-La Roche provided support in the form of salary, but did not have any additional role in the study design, data collection, statistical analysis, decision to publish, or preparation of the manuscript.

Contributors: J. Dukart and S. Borgwardt designed the study. R. Smieskova, F. Harrisberger, C. Lenz, A. Schmidt, A. Walter and A. Simon acquired the data, which J. Dukart, C. Huber, A. Riecher-Rössler, U. Lang, P. Fusar-Poli and S. Borgwardt analyzed. J. Dukart wrote the article, which all authors reviewed and approved for publication.

DOI: 10.1503/jpn.160179

Correspondence to: J. Dukart, Biomarkers & Clinical Imaging, NORD DTA, F. Hoffmann-La Roche, Grenzacherstrasse 170, 4070 Basel, Switzerland;