Serotonin is a common thread linking different classes of antidepressants
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Abstract
Depression pathology remains elusive. The monoamine hypothesis has placed much focus on serotonin, but due to the variable clinical efficacy of monoamine reuptake inhibitors, the community is looking for alternative therapies such as ketamine (neurogenesis theory of antidepressant action). There is evidence that different classes of antidepressants may affect serotonin levels; a notion we test here. We measure hippocampal serotonin in mice with voltammetry and study the effects of acute challenges of escitalopram, fluoxetine, reboxetine, and ketamine. We find that pseudo-equivalent doses of these drugs similarly raise ambient serotonin levels, despite their differing pharmacodynamics because of differences in Uptake 1 and 2, rapid SERT trafficking, and modulation of serotonin by histamine. These antidepressants have different pharmacodynamics but have strikingly similar effects on extracellular serotonin. Our findings suggest that serotonin is a common thread that links clinically effective antidepressants, synergizing different theories of depression (synaptic plasticity, neurogenesis, and the monoamine hypothesis).
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Shu, Y. L., Tian, L., Wang, X., Meng, T., Yu, S., & Li, Y. (2025) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2025.1572462 · Cited by 23 · see citing works
Jager, J. E. D., Boesjes, R., Roelandt, G. H. J., Koliaki, I., Sommer, I. E., Schoevers, R. A., & Nuninga, J. O. (2024) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2024.105796 · Cited by 17 · see citing works
Huang, Y., You, Y., Wang, W., Chen, Y.-H., Zhang, H., Li, Q.-P., Liu, L., Tong, K., Sun, N., Hao, J., et al. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.110209 · Cited by 16 · see citing works
Modulation of serotonin transporter expression by escitalopram under inflammation
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Self-citationMeasurement of Real-Time Serotonin Dynamics from Human-Derived Gut Organoids
Bohl, B., Lei, Y., Bewick, G. A., & Hashemi, P. (2025) · Analytical Chemistry · doi:10.1021/acs.analchem.4c06033 · Cited by 6 · see citing works
Self-citationChan, A. C. Y. (2026) · Cureus · doi:10.7759/cureus.100719 · Cited by 5 · see citing works
Ayala-Rodríguez, J. D., & García‐Colunga, J. (2023) · PLoS ONE · doi:10.1371/journal.pone.0294151 · Cited by 4 · see citing works
Die Bedeutung von Antidepressiva bei COVID-19 und Long-COVID – Ein Scoping-Review Update
Bonnet, U., & Juckel, G. (2024) · Fortschritte der Neurologie · Psychiatrie · doi:10.1055/a-2374-2218 · Cited by 4 · see citing works
Antidepressants can help to prevent and manage long COVID depression, anxiety, brain fog and fatigue
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Clinical application of antidepressants: Advantages and opportunities for individual drugs
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Engineering localized injury: a 3D microfluidic platform approach for ex vivo tissue interrogation
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How Electrochemical Measurements in the Brain Have Shaped Our Understanding of Depression
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- Authors
- Witt, C. E., Mena, S., Holmes, J., Hersey, M., Buchanan, A. M., Parke, B., Saylor, R., Honan, L. E., Berger, S. N., Lumbreras, S., Nijhout, F. H., Reed, M. C., Best, J., Fadel, J., Schloss, P., Lau, T., & Hashemi, P.
- Affiliations
- University of South Carolina (US)
- Imperial College London (GB)
- Heidelberg University (DE)
- Duke University (US)
- The Ohio State University (US)
- Corresponding author
- Hashemi, Parastoo
- ORCID
- Venue
- Cell Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2023-12
- Volume
- 30
- Issue
- 12
- Pages
- 1557-1570.e6
- ISSN
- 2451-9448 (ISSN-L)
- 2451-9456
- PMC
- PMC10081366
- OpenAlex
- W4388871305
- Cited by
- 18
- References
- 106
- Citations by year
- 2026: 7 · 2025: 3 · 2024: 7 · 2023: 1
- FWCI
- 2.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 386 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell chemical biology (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- Funders
- Chinese Academy of Medical Sciences
- National Institutes of Health
- University of South Carolina (R01AG050518, R01MH106563)
- Chinese American Medical Society
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- serotonin, antidepressants, depression, hippocampus, extracellular serotonin, monoamine hypothesis, monoamine reuptake inhibitors, escitalopram, fluoxetine, reboxetine, ketamine, serotonin transporter, neurogenesis, synaptic plasticity, voltammetry
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