Alterations in acylcarnitines, amines, and lipids inform about the mechanism of action of citalopram/escitalopram in major depression

• Type of Material: Article
• Authors: Siamak MahmoudianDehkordi, Duke University; Ahmed T. Ahmed, Mayo Clinic; Sudeepa Bhattacharyya, Arkansas State University; Xianlin Han, University of Texas San Antonio; Rebecca A. Baillie, Rosa & Co LLC; Matthias Arnold, Duke University; Michelle K. Skime, Mayo Clinic; Lisa St. John-Williams, Duke University; M. Arthur Moseley, Duke University; J. Will Thompson, Duke University; Gregory Louie, Duke University; Patricio Riva Posse, Emory University; W Edward Craighead, Emory University; William McDonald, Emory University; Ranga Krishnan, Rush Medical College; A. John Rush, Duke University; Mark A. Frye, Mayo Clinic; Boadie Dunlop, Emory University; Richard M. Weinshilboum, Mayo Clinic; Rima Kaddurah-Daouk, Duke University
• Language: English
• Date: 2021-03-02
• Publisher: Nature Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1038%2Fs41398-020-01097-6
• Title of Journal or Parent Work: Translational Psychiatry
• Grant/Funding Information: M.A. was supported by the National Institute on Aging [R01AG057452, RF1AG051550, and R01AG046171], National Institute of Mental Health [R01MH108348], and Qatar National Research Fund [NPRP8–061–3–011].; The research and the authors are supported by funding from the NIH. This work was funded by grant support to Rima Kaddurah-Daouk through NIH grants R01MH108348, R01AG046171 & U01AG061359, RF1AG051550. R.M.W. was supported by NIH grants RO1 GM28157, U19 GM61388, U54 GM114838, and NSF1624615. S.B. was supported by the NIH grant R01MH108348.
• Keywords: Scientific community; Depression
• Research Categories: Biology, Neuroscience; Psychology, Clinical

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depressive disorder (MDD), yet their mechanisms of action are not fully understood and their therapeutic benefit varies among individuals. We used a targeted metabolomics approach utilizing a panel of 180 metabolites to gain insights into mechanisms of action and response to citalopram/escitalopram. Plasma samples from 136 participants with MDD enrolled into the Mayo Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) were profiled at baseline and after 8 weeks of treatment. After treatment, we saw increased levels of short-chain acylcarnitines and decreased levels of medium-chain and long-chain acylcarnitines, suggesting an SSRI effect on β-oxidation and mitochondrial function. Amines—including arginine, proline, and methionine sulfoxide—were upregulated while serotonin and sarcosine were downregulated, suggesting an SSRI effect on urea cycle, one-carbon metabolism, and serotonin uptake. Eighteen lipids within the phosphatidylcholine (PC aa and ae) classes were upregulated. Changes in several lipid and amine levels correlated with changes in 17-item Hamilton Rating Scale for Depression scores (HRSD17). Differences in metabolic profiles at baseline and post-treatment were noted between participants who remitted (HRSD17 ≤ 7) and those who gained no meaningful benefits (<30% reduction in HRSD17). Remitters exhibited (a) higher baseline levels of C3, C5, alpha-aminoadipic acid, sarcosine, and serotonin; and (b) higher week-8 levels of PC aa C34:1, PC aa C34:2, PC aa C36:2, and PC aa C36:4. These findings suggest that mitochondrial energetics—including acylcarnitine metabolism, transport, and its link to β-oxidation—and lipid membrane remodeling may play roles in SSRI treatment response.