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Associations of depression status with plasma levels of candidate lipid and amino acid metabolites: a meta-analysis of individual data from three independent samples of US postmenopausal women

Molecular Psychiatry volume 26, pages 3315–3327 (2021)Cite this article

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Abstract

Recent animal and small clinical studies have suggested depression is related to altered lipid and amino acid profiles. However, this has not been examined in a population-based sample, particularly in women. We identified multiple metabolites associated with depression as potential candidates from prior studies. Cross-sectional data from three independent samples of postmenopausal women were analyzed, including women from the Women’s Health Initiative-Observational Study (WHI-OS, n = 926), the WHI-Hormone Trials (WHI-HT; n = 1,325), and the Nurses’ Health Study II Mind-Body Study (NHSII-MBS; n = 218). Positive depression status was defined as having any of the following: elevated depressive symptoms, antidepressant use, or depression history. Plasma metabolites were measured using liquid chromatography-tandem mass spectrometry (21 phosphatidylcholines (PCs), 7 lysophosphatidylethanolamines, 5 ceramides, 3 branched chain amino acids, and 9 neurotransmitters). Associations between depression status and metabolites were evaluated using multivariable linear regression; results were pooled by random-effects meta-analysis with multiple testing adjustment using the false discovery rate (FDR). Prevalence rates of positive depression status were 24.4% (WHI-OS), 25.7% (WHI-HT), and 44.7% (NHSII-MBS). After multivariable adjustment, positive depression status was associated with higher levels of glutamate and PC 36 : 1/38 : 3, and lower levels of tryptophan and GABA-to-glutamate and GABA-to-glutamine ratio (FDR-p < 0.05). Positive associations with LPE 18 : 0/18 : 1 and inverse associations with valine and serotonin were also observed, although these associations did not survive FDR adjustment. Associations of positive depression status with several candidate metabolites including PC 36 : 1/38 : 3 and amino acids involved in neurotransmission suggest potential depression-related metabolic alterations in postmenopausal women, with possible implications for later chronic disease.

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Fig. 1: Associations of depression status with plasma lipids, including phosphatidylcholines (PC), lysophosphatidylethanolamines (LPEs), and ceramides (CERs).
Fig. 2: Associations of depression status with branched-chain amino acids and amino acid neurotransmitters in the plasma.
Fig. 3: Pooled associations of depression characteristics with plasma lipid and amino acid metabolites identified in the primary analyses, adjusted for age, race/ethnicity, BMI, hypertension, diabetes, aspirin use, statin use, other lipid-lowering medications, and hormone therapy.

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Acknowledgements

Metabolomic analysis in the Women’s Health Initiative (WHI) was funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contract HHSN268201300008C. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. We thank the participants and the staff of the Nurses’ Health Study II for their valuable contributions. The Nurses’ Health Study II is supported by the National Institutes of Health (UM1 CA176726, R01 CA67262). This work was supported by the National Institutes of Health (R01 AG051600, R01 CA163451). T.H. is supported by K01 HL143034. The authors assume full responsibility for analyses and interpretation of these data.

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  1. These authors contributed equally: Tianyi Huang, Raji Balasubramanian, Laura D. Kubzansky, Susan E. Hankinson

Authors and Affiliations

  1. Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA

    Tianyi Huang, JoAnn E. Manson & Susan E. Hankinson

  2. Department of Biostatistics and Epidemiology, University of Massachusetts Amherst, Amherst, MA, USA

    Raji Balasubramanian, Yubing Yao & Susan E. Hankinson

  3. Broad Institute of MIT and Harvard, Boston, MA, USA

    Clary B. Clish

  4. Department of Family Medicine and Public Health, University of California San Diego School of Medicine, La Jolla, CA, USA

    Aladdin H. Shadyab

  5. Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, IA, USA

    Buyun Liu

  6. Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    Shelley S. Tworoger

  7. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Shelley S. Tworoger & JoAnn E. Manson

  8. Division of Women’s Health, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    Kathryn M. Rexrode

  9. Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Kathryn M. Rexrode & JoAnn E. Manson

  10. Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Laura D. Kubzansky

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Huang, T., Balasubramanian, R., Yao, Y. et al. Associations of depression status with plasma levels of candidate lipid and amino acid metabolites: a meta-analysis of individual data from three independent samples of US postmenopausal women. Mol Psychiatry 26, 3315–3327 (2021). https://doi.org/10.1038/s41380-020-00870-9

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