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

Author:

MahmoudianDehkordi Siamak, ,Ahmed Ahmed T.,Bhattacharyya Sudeepa,Han Xianlin,Baillie Rebecca A.ORCID,Arnold MatthiasORCID,Skime Michelle K.,John-Williams Lisa St.,Moseley M. Arthur,Thompson J. Will,Louie GregoryORCID,Riva-Posse Patricio,Craighead W. EdwardORCID,McDonald William,Krishnan Ranga,Rush A. JohnORCID,Frye Mark A.,Dunlop Boadie W.ORCID,Weinshilboum Richard M.ORCID,Kaddurah-Daouk RimaORCID

Abstract

AbstractSelective 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.

Funder

U.S. Department of Health & Human Services | NIH | National Institute of Mental Health

U.S. Department of Health & Human Services | NIH | National Institute on Aging

Publisher

Springer Science and Business Media LLC

Subject

Biological Psychiatry,Cellular and Molecular Neuroscience,Psychiatry and Mental health

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