TY - JOUR
T1 - Metabolomic and inflammatory signatures of symptom dimensions in major depression
AU - Brydges, Christopher R.
AU - Bhattacharyya, Sudeepa
AU - Dehkordi, Siamak Mahmoudian
AU - Milaneschi, Yuri
AU - Penninx, Brenda
AU - Jansen, Rick
AU - Kristal, Bruce S.
AU - Han, Xianlin
AU - Arnold, Matthias
AU - Kastenmüller, Gabi
AU - Bekhbat, Mandakh
AU - Mayberg, Helen S.
AU - Craighead, W. Edward
AU - Rush, A. John
AU - Fiehn, Oliver
AU - Dunlop, Boadie W.
AU - Mood Disorders Precision Medicine Consortium
AU - Kaddurah-Daouk, Rima
N1 - Funding Information: Dr. Craighead receives research support from the NIH and private foundations, including the Fuqua family foundations, William I. H. and Lula E. Pitts Foundation, and the Mary and John Brock Foundation. He receives book royalties from John Wiley & Sons. He is on the Board of Directors of Hugarheill ehf, an Icelandic company dedicated to prevention of depression. He serves on the Scientific Advisory Boards of Anxiety and Depression Association of America, the George West Mental Health Foundation, and AIM for Mental Health. Funding Information: We acknowledge the assistance of Ms. Lisa Howerton (Duke). This work was funded by grant support to Dr. Rima Kaddurah-Daouk (PI) through NIH grants R01MH108348, R01AG046171 and U01AG061359. Dr. Boadie Dunlop has support from NIH grants P50-MH077083 (PI Mayberg), R01-MH080880 (PI Craighead), UL1-RR025008 (PI Stevens), M01-RR0039 (PI Stevens) and the Fuqua Family Foundations. The PReDICT study was supported by NIH Grants numbered: P50 MH077083 and RO1 MH080880. Dr. Penninx has received research funding (unrelated to the work reported here) from Jansen Research and Boehringer Ingelheim. Drs. Gabi Kastenm?ller and Matthias Arnold have support from NIH grants U01AG061359 (PI Kaddurah-Daouk), 1RF1AG059093 (PI Kaddurah-Daouk), 1RF1AG058942 (PI Kaddurah-Daouk), and 1U19AG063744 (PI Kaddurah-Daouk). Dr. Bhattacharyya had support for this work from the NIH grant R01MH108348 (PI Kaddurah-Daouk and Dunlop). Funding Information: We acknowledge the assistance of Ms. Lisa Howerton (Duke). This work was funded by grant support to Dr. Rima Kaddurah-Daouk (PI) through NIH grants R01MH108348, R01AG046171 and U01AG061359. Dr. Boadie Dunlop has support from NIH grants P50-MH077083 (PI Mayberg), R01-MH080880 (PI Craighead), UL1-RR025008 (PI Stevens), M01-RR0039 (PI Stevens) and the Fuqua Family Foundations. The PReDICT study was supported by NIH Grants numbered: P50 MH077083 and RO1 MH080880. Dr. Penninx has received research funding (unrelated to the work reported here) from Jansen Research and Boehringer Ingelheim. Drs. Gabi Kastenmüller and Matthias Arnold have support from NIH grants U01AG061359 (PI Kaddurah-Daouk), 1RF1AG059093 (PI Kaddurah-Daouk), 1RF1AG058942 (PI Kaddurah-Daouk), and 1U19AG063744 (PI Kaddurah-Daouk). Dr. Bhattacharyya had support for this work from the NIH grant R01MH108348 (PI Kaddurah-Daouk and Dunlop). Publisher Copyright: © 2022 Elsevier Inc.
PY - 2022/5
Y1 - 2022/5
N2 - Background: Major depressive disorder (MDD) is a highly heterogenous disease, both in terms of clinical profiles and pathobiological alterations. Recently, immunometabolic dysregulations were shown to be correlated with atypical, energy-related symptoms but less so with the Melancholic or Anxious distress symptom dimensions of depression in The Netherlands Study of Depression and Anxiety (NESDA) study. In this study, we aimed to replicate these immunometabolic associations and to characterize the metabolomic correlates of each of the three MDD dimensions. Methods: Using three clinical rating scales, Melancholic, and Anxious distress, and Immunometabolic (IMD) dimensions were characterized in 158 patients who participated in the Predictors of Remission to Individual and Combined Treatments (PReDICT) study and from whom plasma and serum samples were available. The NESDA-defined inflammatory index, a composite measure of interleukin-6 and C-reactive protein, was measured from pre-treatment plasma samples and a metabolomic profile was defined using serum samples analyzed on three metabolomics platforms targeting fatty acids and complex lipids, amino acids, acylcarnitines, and gut microbiome-derived metabolites among other metabolites of central metabolism. Results: The IMD clinical dimension and the inflammatory index were positively correlated (r = 0.19, p = 0.019) after controlling for age, sex, and body mass index, whereas the Melancholic and Anxious distress dimensions were not, replicating the previous NESDA findings. The three symptom dimensions had distinct metabolomic signatures using both univariate and set enrichment statistics. IMD severity correlated mainly with gut-derived metabolites and a few acylcarnitines and long chain saturated free fatty acids. Melancholia severity was significantly correlated with several phosphatidylcholines, primarily the ether-linked variety, lysophosphatidylcholines, as well as several amino acids. Anxious distress severity correlated with several medium and long chain free fatty acids, both saturated and polyunsaturated ones, sphingomyelins, as well as several amino acids and bile acids. Conclusion: The IMD dimension of depression appears reliably associated with markers of inflammation. Metabolomics provides powerful tools to inform about depression heterogeneity and molecular mechanisms related to clinical dimensions in MDD, which include a link to gut microbiome and lipids implicated in membrane structure and function.
AB - Background: Major depressive disorder (MDD) is a highly heterogenous disease, both in terms of clinical profiles and pathobiological alterations. Recently, immunometabolic dysregulations were shown to be correlated with atypical, energy-related symptoms but less so with the Melancholic or Anxious distress symptom dimensions of depression in The Netherlands Study of Depression and Anxiety (NESDA) study. In this study, we aimed to replicate these immunometabolic associations and to characterize the metabolomic correlates of each of the three MDD dimensions. Methods: Using three clinical rating scales, Melancholic, and Anxious distress, and Immunometabolic (IMD) dimensions were characterized in 158 patients who participated in the Predictors of Remission to Individual and Combined Treatments (PReDICT) study and from whom plasma and serum samples were available. The NESDA-defined inflammatory index, a composite measure of interleukin-6 and C-reactive protein, was measured from pre-treatment plasma samples and a metabolomic profile was defined using serum samples analyzed on three metabolomics platforms targeting fatty acids and complex lipids, amino acids, acylcarnitines, and gut microbiome-derived metabolites among other metabolites of central metabolism. Results: The IMD clinical dimension and the inflammatory index were positively correlated (r = 0.19, p = 0.019) after controlling for age, sex, and body mass index, whereas the Melancholic and Anxious distress dimensions were not, replicating the previous NESDA findings. The three symptom dimensions had distinct metabolomic signatures using both univariate and set enrichment statistics. IMD severity correlated mainly with gut-derived metabolites and a few acylcarnitines and long chain saturated free fatty acids. Melancholia severity was significantly correlated with several phosphatidylcholines, primarily the ether-linked variety, lysophosphatidylcholines, as well as several amino acids. Anxious distress severity correlated with several medium and long chain free fatty acids, both saturated and polyunsaturated ones, sphingomyelins, as well as several amino acids and bile acids. Conclusion: The IMD dimension of depression appears reliably associated with markers of inflammation. Metabolomics provides powerful tools to inform about depression heterogeneity and molecular mechanisms related to clinical dimensions in MDD, which include a link to gut microbiome and lipids implicated in membrane structure and function.
KW - Anxiety
KW - Depression
KW - Inflammation
KW - Metabolomics
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85124414500&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/35131442
U2 - https://doi.org/10.1016/j.bbi.2022.02.003
DO - https://doi.org/10.1016/j.bbi.2022.02.003
M3 - Article
C2 - 35131442
SN - 0889-1591
VL - 102
SP - 42
EP - 52
JO - Brain Behavior and Immunity
JF - Brain Behavior and Immunity
ER -