Exploratory Biomarker Study of the Triple Reuptake Inhibitor SEP‐432 Compared to the Dual Reuptake Inhibitor Duloxetine in Healthy Normal Subjects
Open accessAbstract
Summary: Introduction: SEP‐432 is a triple monoamine reuptake inhibitor of norepinephrine (NE), serotonin (5‐HT), and dopamine (DA), based on in vitro binding studies. We sought evidence that SEP‐432 engages these monoamine systems by measuring concentrations of monoamines and/or their main metabolites in cerebrospinal fluid (CSF) and plasma and comparing results to duloxetine, a dual reuptake inhibitor of NE and 5‐HT. Methods: Eighteen healthy normal subjects received either SEP‐432 (300 mg/day), duloxetine (60 mg/day), or placebo for 14 days in‐clinic (double blind) with CSF and plasma collections at baseline (single lumbar puncture) and Day 14 (24‐h CSF and plasma collection). Concentrations of monoamines and their metabolites, as well as pharmacokinetic concentrations of SEP‐432 and metabolite, were quantified by liquid chromatography–tandem mass spectrometry. Results: Compared to placebo in the Day 14 area under the curve 24‐h (AUC 0–24 h) analysis, SEP‐432 significantly (P < 0.05) decreased the NE metabolite dihydroxyphenylglycol (DHPG) in CSF and plasma, decreased 5‐HT in plasma, and did not affect DA metabolites, while duloxetine had significant effects on DHPG and 5‐HT. Time‐matched baseline to Day 14 biomarker comparisons confirmed these findings. Conclusion: CSF monoamine biomarkers confirmed central NET activity for SEP‐432 and duloxetine's dual reuptake inhibition.
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SNRIs inhibit the reuptake of both NE and 5-HT, and this dual inhibitory effect is believed to contribute to the broader therapeutic effects of SNRIs compared to SSRIs.
“Third, SNRIs inhibit the reuptake of both NE and 5-HT; thus, they have a dual mechanism of action. This dual inhibitory effect is believed to contribute to the broader therapeutic effects of SNRIs compared to SSRIs. 373”
From Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024) · cites this paper as [373]
The Introduction (page unavailable) identifies duloxetine as a norepinephrine and serotonin reuptake inhibitor, supporting the dual-mechanism part of the claim. The paper does not say that this mechanism gives SNRIs broader therapeutic effects than SSRIs; its study measured biomarkers in healthy subjects, not comparative therapeutic effects. (LLM, conf=0.88)
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Major depressive disorder: hypothesis, mechanism, prevention and treatment
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“373 Chronic treatment with fl uoxetine has been shown to increase the expression of Cx43 in the rat PFC, which further prevents the dysfunction of astrocytic gap junctions induced by CUS and reverses the depressive-like behaviors caused by gap junction blockade.”
Background
- Authors
- Sramek, J. J., Hardy, L. W., Bieck, P., Zamora, C., Versavel, M., Kharidia, J., Grinnell, T., Chen, Y., Sullivan, M., Ding, H., & Cutler, N. R.
- Affiliations
- Worldwide Clinical Trials (United States) (US)
- Sunovion (United States) (US)
- Corresponding author
- Cutler, Neal R.
- Venue
- CNS Neuroscience & Therapeutics
- Publisher
- Wiley
- Published
- 2016-02-05
- Volume
- 22
- Issue
- 5
- Pages
- 404-412
- ISSN
- 1755-5930 (ISSN-L)
- 1755-5949
- PMC
- PMC6492792
- OpenAlex
- W2278805889
- Cited by
- 5
- References
- 49
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2017: 1
- FWCI
- 0.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- CNS Neuroscience & Therapeutics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Sunovion
- 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
- duloxetine, norepinephrine transporter, serotonin transporter, dopamine transporter, monoamine metabolites, dihydroxyphenylglycol, cerebrospinal fluid, pharmacokinetics
- MeSH terms
- Duloxetine Hydrochloride, Adult, Chromatography, High Pressure Liquid, Cyclohexanols, Dimethylamines, Dose-Response Relationship, Drug, Double-Blind Method, Electrocardiography, Female, Humans, Male, Methoxyhydroxyphenylglycol, Middle Aged, Time Factors, Neurotransmitter Uptake Inhibitors, Biogenic Monoamines, Neurotransmitter Agents, Tandem Mass Spectrometry, Biomarkers, Pharmacological, Young Adult, Healthy Volunteers
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