Brain morphometric biomarkers distinguishing unipolar and bipolar depression. A voxel-based morphometry-pattern classification approach

JAMA Psychiatry. 2014 Nov;71(11):1222-30. doi: 10.1001/jamapsychiatry.2014.1100.


Importance: The structural abnormalities in the brain that accurately differentiate unipolar depression (UD) and bipolar depression (BD) remain unidentified.

Objectives: First, to investigate and compare morphometric changes in UD and BD, and to replicate the findings at 2 independent neuroimaging sites; second, to differentiate UD and BD using multivariate pattern classification techniques.

Design, setting, and participants: In a 2-center cross-sectional study, structural gray matter data were obtained at 2 independent sites (Pittsburgh, Pennsylvania, and Münster, Germany) using 3-T magnetic resonance imaging. Voxel-based morphometry was used to compare local gray and white matter volumes, and a novel pattern classification approach was used to discriminate between UD and BD, while training the classifier at one imaging site and testing in an independent sample at the other site. The Pittsburgh sample of participants was recruited from the Western Psychiatric Institute and Clinic at the University of Pittsburgh from 2008 to 2012. The Münster sample was recruited from the Department of Psychiatry at the University of Münster from 2010 to 2012. Equally divided between the 2 sites were 58 currently depressed patients with bipolar I disorder, 58 age- and sex-matched unipolar depressed patients, and 58 matched healthy controls.

Main outcomes and measures: Magnetic resonance imaging was used to detect structural differences between groups. Morphometric analyses were applied using voxel-based morphometry. Pattern classification techniques were used for a multivariate approach.

Results: At both sites, individuals with BD showed reduced gray matter volumes in the hippocampal formation and the amygdala relative to individuals with UD (Montreal Neurological Institute coordinates x = -22, y = -1, z = 20; k = 1938 voxels; t = 4.75), whereas individuals with UD showed reduced gray matter volumes in the anterior cingulate gyrus compared with individuals with BD (Montreal Neurological Institute coordinates x = -8, y = 32, z = 3; k = 979 voxels; t = 6.37; all corrected P < .05). Reductions in white matter volume within the cerebellum and hippocampus were found in individuals with BD. Pattern classification yielded up to 79.3% accuracy (P < .001) by differentiating the 2 depressed groups, training and testing the classifier at one site, and up to 69.0% accuracy (P < .001), training the classifier at one imaging site (Pittsburgh) and testing it at the other independent sample (Münster). Medication load did not alter the pattern of results.

Conclusions and relevance: Individuals with UD and those with BD are differentiated by structural abnormalities in neural regions supporting emotion processing. Neuroimaging and multivariate pattern classification techniques are promising tools to differentiate UD from BD and show promise as future diagnostic aids.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Atrophy / pathology
  • Biomarkers
  • Bipolar Disorder / diagnosis*
  • Bipolar Disorder / pathology*
  • Case-Control Studies
  • Cross-Sectional Studies
  • Depressive Disorder / diagnosis*
  • Depressive Disorder / pathology*
  • Diagnosis, Differential
  • Female
  • Gray Matter / pathology*
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Neuroimaging
  • White Matter / pathology*
  • Young Adult


  • Biomarkers