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.
Highlights
Major depressive disorder (MDD) is a common, often disabling condition that affects more than 300 million individuals worldwide[1], but much about its pathobiology and the biology of treatment response remains unknown
We used a targeted metabolomics approach to interrogate possible functions for acylcarnitines, amino acids, biogenic amines, and lipids to addresses the following questions regarding mitochondrial function and neurotransmission in MDD: 1. What are the overall changes in the metabolic profile over 8 weeks of SSRI exposure, and which of these metabolic changes are related to each other?
Within the classes of amino acids and biogenic amines, we observed a statistically significant increase in two amino acids and one biogenic amine, and a significant decrease in two biogenic amines
Summary
Major depressive disorder (MDD) is a common, often disabling condition that affects more than 300 million individuals worldwide[1], but much about its pathobiology and the biology of treatment response remains unknown. Selective serotonin reuptake inhibitors (SSRIs) are common first-line agents used for the treatment of MDD2,3, yet ~40% of patients who receive SSRI treatment do not respond and more than two-thirds do not achieve. Clinical symptoms are insufficient to guide treatment selection for individual patients[5]. MDD patients who achieve remission after treatment with an antidepressant appear to have a metabolic state distinct from never-depressed individuals, with alterations in methylation, purine metabolism, and oxidative stress pathways[7]. Pilot studies have implicated metabolic dysregulation in the pathogenesis of MDD, with alterations in several pathways, including neurotransmission (GABA, glutamine, tryptophan, phenylalanine), nitrogen metabolism, methylation, and lipid metabolism[8,9,10,11,12]
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