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Randomized Controlled Trial
. 2025 Apr 15:375:397-405.
doi: 10.1016/j.jad.2025.01.064. Epub 2025 Jan 14.

Metabolomics signatures of serotonin reuptake inhibitor (escitalopram), serotonin norepinephrine reuptake inhibitor (duloxetine) and cognitive-behavioral therapy on key neurotransmitter pathways in major depressive disorder

Sudeepa Bhattacharyya  1 , Siamak MahmoudianDehkordi  2 , Matthew J Sniatynski  3 , Marina Belenky  3 , Vasant R Marur  3 , A John Rush  4 , W Edward Craighead  5 , Helen S Mayberg  6 , Boadie W Dunlop  5 , Bruce S Kristal  3 , Rima Kaddurah-Daouk  7 ; Mood Disorder Precision Medicine Consortium
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Free article
Randomized Controlled Trial

Metabolomics signatures of serotonin reuptake inhibitor (escitalopram), serotonin norepinephrine reuptake inhibitor (duloxetine) and cognitive-behavioral therapy on key neurotransmitter pathways in major depressive disorder

Sudeepa Bhattacharyya et al. J Affect Disord. .
Free article

Abstract

Metabolomics provides powerful tools that can inform about heterogeneity in disease and response to treatments. In this exploratory study, we employed an electrochemistry-based targeted metabolomics platform to assess the metabolic effects of three randomly-assigned treatments: escitalopram, duloxetine, and Cognitive-Behavioral Therapy (CBT) in 163 treatment-naïve outpatients with major depressive disorder. Serum samples from baseline and 12 weeks post-treatment were analyzed using targeted liquid chromatography-electrochemistry for metabolites related to tryptophan, tyrosine metabolism and related pathways. Changes in metabolite concentrations related to each treatment arm were identified and compared to define metabolic signatures of exposure. In addition, association between metabolites and depressive symptom severity (assessed with the 17-item Hamilton Rating Scale for Depression [HRSD17]) and anxiety symptom severity (assessed with the 14-item Hamilton Rating Scale for Anxiety [HRSA14]) were evaluated, both at baseline and after 12 weeks of treatment. Significant reductions in serum serotonin level and increases in tryptophan-derived indoles that are gut bacterially derived were observed with escitalopram and duloxetine arms but not in CBT arm. These include indole-3-propionic acid (I3PA), indole-3-lactic acid (I3LA) and Indoxyl sulfate (IS), a uremic toxin. Purine-related metabolites were decreased across all arms. Different metabolites correlated with improved symptoms in the different treatment arms revealing potentially different mechanisms between response to antidepressant medications and to CBT.

Keywords: Cognitive-behavioral therapy; Gut microbial metabolites; Major depressive disorder; Metabolomics; Serotonin norepinephrine reuptake inhibitor; Serotonin reuptake inhibitor.

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Conflict of interest statement

Declaration of competing interest Dr. Dunlop has received research support from, Boehringer Ingelheim, Compass, NIMH, and Usona Institute, and has served as a consultant to Biohaven, Cerebral Therapeutics, Myriad Neuroscience, and Otsuka. Dr. Craighead receives research support from the NIH; is a board member of Hugarheill ehf, an Icelandic company dedicated to the prevention of depression; receives book royalties from John Wiley; and is supported by the Mary and John Brock Foundation, the Pitts Foundation, and the Fuqua family foundations. He is a consultant to the George West Mental Health Foundation and a member of the Scientific Advisory Boards of AIM for Mental Health, Galen Mental Health, and the ADAA. A. John Rush has received consulting fees from Compass Inc., Curbstone Consultant LLC, Emmes Corp., Evecxia Therapeutics, Inc., Holmusk Technologies, Inc., ICON, PLC, Johnson and Johnson (Janssen), Liva-Nova, MindStreet, Inc., Neurocrine Biosciences Inc., Otsuka-US; speaking fees from Liva-Nova, Johnson and Johnson (Janssen); and royalties from Wolters Kluwer Health, Guilford Press and the University of Texas Southwestern Medical Center, Dallas, TX (for the Inventory of Depressive Symptoms and its derivatives). He is also named co-inventor on two patents: U.S. Patent No. 7,795,033: Methods to Predict the Outcome of Treatment with Antidepressant Medication, Inventors: McMahon FJ, Laje G, Manji H, Rush AJ, Paddock S, Wilson AS; and U.S. Patent No. 7,906,283: Methods to Identify Patients at Risk of Developing Adverse Events During Treatment with Antidepressant Medication, Inventors: McMahon FJ, Laje G, Manji H, Rush AJ, Paddock S. Rima Kaddurah-Daouk is an inventor on key patents in the field of Metabolomics and hold equity in Metabolon, a biotech company in North Carolina. In addition, she holds patents licensed to Chymia LLC and PsyProtix with royalties and ownership. All other authors reported no biomedical financial interests or potential conflicts of interest.

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