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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 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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