Internal medicine

Receptor

Serotonin

Serotonin reuptake inhibitor

Mood

Urea cycle

Reuptake

Endocrinology

Psychiatry

Psychology

Chemistry

Citalopram

Arginine

Glycine

Hippocampus

Antidepressant

Escitalopram

Sarcosine

Major depressive disorder

Amino acid

Biochemistry

Medicine

Pharmacology

Translational Psychiatry

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 (HRSD 17 ). Differences in metabolic profiles at baseline and post-treatment were noted between participants who remitted (HRSD 17 ≤ 7) and those who gained no meaningful benefits (&lt;30% reduction in HRSD 17 ). 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.

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