Article pubs.acs.org/jpr
Divergent Urinary Metabolic Phenotypes between Major Depressive Disorder and Bipolar Disorder Identified by a Combined GC−MS and NMR Spectroscopic Metabonomic Approach Jian-jun Chen,†,§,∥,# Chan-juan Zhou,†,§,∥,# Zhao Liu,‡,§,∥,# Yu-ying Fu,‡,§,∥,# Peng Zheng,‡,§,∥ De-yu Yang,†,§,∥ Qi Li,‡,§,∥ Jun Mu,‡,§,∥ You-dong Wei,‡,§,∥ Jing-jing Zhou,‡,§,∥ Hua Huang,‡,§,∥ and Peng Xie*,†,‡,§,∥ †
Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing 402460, China Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China § Institute of Neuroscience and the Collaborative Innovation Center for Brain Science and ∥Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing 400016, China ‡
S Supporting Information *
ABSTRACT: Bipolar disorder (BD) is a complex debilitating mental disorder that is often misdiagnosed as major depressive disorder (MDD). Therefore, a large percentage of BD subjects are incorrectly treated with antidepressants in clinical practice. To address this challenge, objective laboratory-based tests are needed to discriminate BD from MDD patients. Here, a combined gas chromatography−mass spectrometry (GC− MS)-based and nuclear magnetic resonance (NMR) spectroscopic-based metabonomic approach was performed to profile urine samples from 76 MDD and 43 BD subjects (training set) to identify the differential metabolites. Samples from 126 healthy controls were included as metabolic controls. A candidate biomarker panel was identified by further analyzing these differential metabolites. A testing set of, 50 MDD and 28 BD subjects was then used to independently validate the diagnostic efficacy of the identified panel using an area under the receiver operating characteristic curve (AUC). A total of 20 differential metabolites responsible for the discrimination between MDD and BD subjects were identified. A panel consisting of six candidate urinary metabolite biomarkers (propionate, formate, (R*,S*)2,3-dihydroxybutanoic acid, 2,4-dihydroxypyrimidine, phenylalanine, and βalanine) was identified. This panel could distinguish BD from MDD subjects with an AUC of 0.913 and 0.896 in the training and testing sets, respectively. These results reveal divergent urinary metabolic phenotypes between MDD and BD. The identified urinary biomarkers can aid in the future development of an objective laboratory-based diagnostic test for distinguishing BD from MDD patients. KEYWORDS: bipolar disorder, BD, major depressive disorder, MDD, metabonomic, biomarker, nuclear magnetic resonance, NMR, gas chromatography−mass spectrometry, GC−MS
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INTRODUCTION Major depressive disorder (MDD) is a common mental disorder and a significant cause of disability that affects up to 15% of the general population worldwide. 1 MDD is characterized by a loss of interest in activities that were once pleasurable, low self-esteem, and changes in appetite.2 Bipolar disorder (BD) is also a debilitating mental disorder that affects up to 1% of the general population and is characterized by a higher risk of suicide as well as cyclical episodes of depression and mania.3 There are extensive environmental and genetic correlations between these two psychiatric disorders. In clinical practice, an episode of depression is often the first mood syndrome at the onset of BD, and multiple depressive episodes usually occur prior to the first manic episode in many BD patients.4,5 These factors usually lead to a long time period between the onset of depression and a definitive diagnosis of © 2015 American Chemical Society
BD. Moreover, compared to BD’s hypomanic or manic phases, BD’s depressive phases occur more frequently.6 Moreover, in clinical practice, hypomania is notoriously difficult to detect. Therefore, the underdiagnosis and misdiagnosis of BD, especially bipolar II disorder (BD II), contributes to inadequate or inappropriate treatments for BD patients.7,8 The pathophysiological mechanisms underlying MDD and BD still remain unclear. Due to the lack of empirical laboratory tests, the subjective identification of symptomatic clusters based on standardized structured diagnostic interviews is still widely used by clinicians to diagnose MDD and BD. However, the considerably complex and diverse clinical presentations of the two diseases make this diagnostic modality highly unreliable. Received: May 19, 2015 Published: July 14, 2015 3382
DOI: 10.1021/acs.jproteome.5b00434 J. Proteome Res. 2015, 14, 3382−3389
Article
Journal of Proteome Research Table 1. Demographic and Clinical Characteristics of Recruited Subjectsa training set sample size sex (M/F) age in yearsc BMIc medication BD-I BD-II
test set
HC
MDD
BD
P valueb
HC
MDD
BD
P value
78 49/29 33.2 ± 11.2 21.1 ± 2.3 0 0 0
76 37/39 33.2 ± 9.6 21.9 ± 2.9 19 0 0
43 22/21 29.7 ± 11.8 21.6 ± 2.4 38 23 20
− 0.18 0.18 0.23
