TY - JOUR
T1 - Alterations in acylcarnitines, amines, and lipids inform about the mechanism of action of citalopram/escitalopram in major depression
AU - The Mood Disorders Precision Medicine Consortium (MDPMC)
AU - MahmoudianDehkordi, Siamak
AU - Ahmed, Ahmed T.
AU - Bhattacharyya, Sudeepa
AU - Han, Xianlin
AU - Baillie, Rebecca A.
AU - Arnold, Matthias
AU - Skime, Michelle K.
AU - John-Williams, Lisa St
AU - Moseley, M. Arthur
AU - Thompson, J. Will
AU - Louie, Gregory
AU - Riva-Posse, Patricio
AU - Craighead, W. Edward
AU - McDonald, William
AU - Krishnan, Ranga
AU - Rush, A. John
AU - Frye, Mark A.
AU - Dunlop, Boadie W.
AU - Weinshilboum, Richard M.
AU - Kaddurah-Daouk, Rima
AU - Kaddurah-Daouk, Rima
AU - Rush, John
AU - Tenenbaum, Jessica
AU - Moseley, Arthur
AU - Thompson, Will
AU - Louie, Gregory
AU - Blach, Colette
AU - Mahmoudiandehkhordi, Siamak
AU - Baillie, Rebecca
AU - Han, Xianlin
AU - Bhattacharyya, Sudeepa
AU - Frye, Mark
AU - Ahmed, Ahmed
AU - Neavin, Drew
AU - Liu, Duan
AU - Skime, Michelle
AU - Rinaldo, Piero
AU - Fiehn, Oliver
AU - Brydges, Christopher
AU - Mayberg, Helen
AU - Choi, Ki Sueng
AU - Cha, Jungho
AU - Kastenmüller, Gabi
AU - Binder, Elisabeth
AU - Knauer-Arloth, Janine
AU - Nevado-Holgado, Alejo
AU - Shi, Liu
AU - Dunlop, Boadie
AU - Craighead, Ed
AU - McDonald, William
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/6/1
Y1 - 2021/6/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85102077774&partnerID=8YFLogxK
U2 - 10.1038/s41398-020-01097-6
DO - 10.1038/s41398-020-01097-6
M3 - Article
C2 - 33654056
AN - SCOPUS:85102077774
SN - 2158-3188
VL - 11
JO - Translational psychiatry
JF - Translational psychiatry
IS - 1
M1 - 153
ER -