Shared intermediate phenotypes for schizophrenia and bipolar disorder: neuroanatomical features of subtypes distinguished by executive dysfunction

Shared intermediate phenotypes for schizophrenia and bipolar disorder: neuroanatomical features of subtypes distinguished by executive dysfunction


J Psychiatry Neurosci 2015;40(1):58-68

Alana M. Shepherd, BSc (Hons), PhD; Yann Quidé, PhD; Kristin R. Laurens, BSc (Hons), PhD; Nicole O’Reilly, BSc-Psych (Hons); Jesseca E. Rowland, BA Psych (Hons); Philip B. Mitchell, AM, MBBS, MD; Vaughan J. Carr, MD; Melissa J. Green, PhD


Background: Shared genetic vulnerability for schizophrenia and bipolar disorder may be associated with common neuroanatomical features. In view of the evidence for working memory dysfunction as a candidate intermediate phenotype for both disorders, we explored neuroanatomical distinctions between subtypes defined according to working memory (n-back task) performance.

Methods: We analyzed T1-weighted MRI scans for patients with schizophrenia-spectrum disorder, bipolar-I disorder (BD-I) and healthy controls. The VBM8 toolbox was used to assess differences in grey and white matter volume across traditional diagnostic groups (schizophrenia v. BD-I). Subsequently, groups were defined as “executively spared” (ES) based on the achievement of greater than 50% accuracy in the 2-back task performance (comparable to performance in the control group) or “executively deficit” (ED) based on the achievement of less than 50% accuracy.

Results: Our study included 40 patients with schizophrenia-spectrum disorders, 30 patients with BD-I and 34 controls. Both the schizophrenia and BD-I groups showed grey matter volume reductions relative to the control group, but not relative to each other. The ED subtype (n = 32 [10 BD-I, 22 schizophrenia]) showed grey matter volume reductions in the bilateral superior and medial frontal gyri, right inferior opercular gyri and hippocampus relative to controls. The ES subtype (n = 38 [20 BD-I, 18 schizophrenia]) showed grey matter volume reductions in the right precuneus and left superior and medial orbital frontal gyri relative to controls. The ED subtype showed grey matter volume reduction in the right inferior frontal and precentral gyri relative to the ES subtype. There were no significant differences in white matter volume in any group comparisons.

Limitations: This analysis was limited by small sample sizes. Further, insufficient numbers were available to assess a control-deficit comparison group. We were unable to assess the effects of mood stabilizer dose on brain structure.

Conclusion: Neuroanatomical commonalities are evident among patients with schizophrenia-spectrum disorders and BD-I with working memory deficits. Reduced inferior frontal lobe volume may mediate cognitive deficits shared across the psychosis–mood spectrum.

Submitted Dec. 11, 2013; Revised Apr. 15, 2014; Accepted May 26, 2014; Early-released Sept. 30, 2014.

Acknowledgements: This study involved volunteers from the Australian Schizophrenia Research Bank (ASRB), funded by the National Health and Medical Research Council of Australia (NHMRC) Enabling Grant (No. 386500) held by V. Carr, U. Schall, R. Scott, A. Jablensky, B. Mowry, P. Michie, S. Catts, F. Henskens and C. Pantelis (Chief Investigators), also supported by the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation and the Schizophrenia Research Institute, utilizing infrastructure funding from the NSW Ministry of Health.

Affiliations: School of Psychiatry, University of New South Wales, Sydney NSW, Australia (Shepherd, Laurens, O’Reilly, Rowland, Mitchell, Carr, Green); Schizophrenia Research Institute, Sydney NSW, Australia (Shepherd, Quidé, Laurens, Carr, Green); Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom (Laurens); Black Dog Institute, Sydney NSW, Australia (Mitchell, Green); Neuroscience Research Australia, Sydney NSW, Australia (Green).

Funding: This study was supported by the NHMRC Project Grant (APP630471) awarded to M. Green. A. Shepherd was supported by a NHMRC Postgraduate Scholarship (APP1039941) and a scholarship from the Schizophrenia Research Institute. Y. Quidé is supported by the Schizophrenia Research Institute. K. Laurens is affiliated with the National Institute of Health Research Specialist Biomedical Research Centre for Mental Health at the South London and Maudsley National Health Service Foundation Trust and Institute of Psychiatry, King’s College London. M. Green was supported by an Australian Research Council Future Fellowship (FT0991511; 2009-13) and the NHMRC R.D. Wright Biomedical Career Development Award (APP1061875; 2014-17).

Competing interests: None declared.

Contributors: A. Shepherd, Y. Quidé and M. Green designed the study. N. O’Reilly, J. Rowland and P. Mitchell acquired the data, which A. Shepherd, Y. Quidé, K. Laurens, V. Carr and M. Green analyzed. A. Shepherd wrote the article, which all authors reviewed and approved for publication.

DOI: 10.1503/jpn.130283

Correspondence to: M.J. Green, Research Unit for Schizophrenia Epidemiology, Level 4, O’Brien Centre, St Vincent’s Hospital, 394-404 Victoria Rd., Darlinghurst, Sydney NSW 2010;