Abstract
The objective of this study was to determine whether proteomic profiling in serum samples can be utilized in identifying and differentiating mood disorders. A consecutive sample of patients with a confirmed diagnosis of unipolar (UP n=52) or bipolar depression (BP-I n=46, BP-II n=49) and controls (n=141) were recruited. A 7.5-ml blood sample was drawn for proteomic multiplex profiling of 320 proteins utilizing the Myriad RBM Discovery Multi-Analyte Profiling platform. After correcting for multiple testing and adjusting for covariates, growth differentiation factor 15 (GDF-15), hemopexin (HPX), hepsin (HPN), matrix metalloproteinase-7 (MMP-7), retinol-binding protein 4 (RBP-4) and transthyretin (TTR) all showed statistically significant differences among groups. In a series of three post hoc analyses correcting for multiple testing, MMP-7 was significantly different in mood disorder (BP-I+BP-II+UP) vs controls, MMP-7, GDF-15, HPN were significantly different in bipolar cases (BP-I+BP-II) vs controls, and GDF-15, HPX, HPN, RBP-4 and TTR proteins were all significantly different in BP-I vs controls. Good diagnostic accuracy (ROC-AUC⩾0.8) was obtained most notably for GDF-15, RBP-4 and TTR when comparing BP-I vs controls. While based on a small sample not adjusted for medication state, this discovery sample with a conservative method of correction suggests feasibility in using proteomic panels to assist in identifying and distinguishing mood disorders, in particular bipolar I disorder. Replication studies for confirmation, consideration of state vs trait serial assays to delineate proteomic expression of bipolar depression vs previous mania, and utility studies to assess proteomic expression profiling as an advanced decision making tool or companion diagnostic are encouraged.
Highlights
Psychiatric diagnoses are still based on criteria that focus on behavioral observation and symptom endorsement without corresponding biological validation
(141 controls, 52 Unipolar, 49 Bipolar II, 46 Bipolar I), 73 showed nominally significant difference among the 4 compared groups at an uncorrected significance level (P o 0.05. see bold font in Supplementary Table 1); 6 of those proteins showed statistically significant differences after Bonferroni correction (P o 0.05/ 272 = 1.84e − 04) (growth differentiation factor 15 (GDF-15), medication status was not considered in the primary analysis due to a hemopexin (HPX), hepsin (HPN), matrix metalloproteinase-7 high degree of confounding with diagnosis, a visual inspection of protein level differences was conducted by medication status for each protein that was significantly different by diagnostic group
Taking advantage of an established platform based initially on immune mediator and cytokine quantification, increasingly recognized in the underlying neurobiology of mood disorders,[4,5] we have identified six proteins, all expressed in brain,[25,26] that distinguish mood disorder patients, bipolar I patients from healthy controls
Summary
Psychiatric diagnoses are still based on criteria that focus on behavioral observation and symptom endorsement without corresponding biological validation. This contrasts with other fields of medicine, where diagnosis and treatment are often based on a sound clinical examination, and biological tests based on validated biomarkers. Bipolar disorder and major depressive disorder have highlighted the potential utility of multiplex biomarker development. These studies were primarily non-hypothesis driven, based on an established immune mediator and cytokine quantification platforms, and were predominantly compared with a healthy control population. While there has been initial validation, replication and development of classification decision rules in a series of studies in schizophrenia,[3,4,5,6] the majority of studies have not been comparative within mood disorders and have not corrected for multiple testing and adjusted for covariates, limiting their replication potential and overall generalizability.[7,8,9,10,11,12] This study was conducted with Myriad RBM Human Multi-Analyte Profiling (MAP) platform to assess the feasibility of MAP in distinguishing (vs healthy controls) and differentiating subgroups of mood disorder patients
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