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The Journal of Clinical Psychiatry The Journal of Clinical Psychiatry

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Original Research August 25, 2025

Levomilnacipran, but Not Duloxetine, Inhibits Serotonin and Norepinephrine Reuptake Throughout Its Therapeutic Range

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J Clin Psychiatry 2025;86(3):25m15867

Abstract

Objective: The primary aim of this study was to establish that levomilnacipran potently inhibits norepinephrine (NE) reuptake in human participants starting at a minimally efficacious regimen in major depressive disorder (MDD) and to determine the dose needed to significantly inhibit serotonin (5-HT) reuptake. The secondary aim was to confirm that duloxetine is a selective 5-HT reuptake inhibitor at its minimally effective regimen in MDD and that it significantly inhibits NE reuptake only with dose escalation.

Methods: Inhibition of the NE reuptake process was estimated by assessing the attenuation of the systolic blood pressure produced by intravenous injections of small doses of tyramine. Inhibition of the 5-HT reuptake process was estimated using depletion of whole blood 5-HT. Healthy male participants took ascending daily doses of levomilnacipran (40, 80, and 120 mg), duloxetine (60, 90, and 120 mg) each for 7 days, or a placebo pill (n=10, 9, and 10, respectively), and all assays were carried out 2–6 hours after the last dose. The study took place between February 2018 and October 2022.

Results: Plasma levels of both medications increased in dose-dependent levels. Neither the tyramine pressor responses nor 5-HT levels were significantly altered in the placebo group. For the attenuation of the tyramine pressor response, levomilnacipran separated from baseline starting at 40 mg and duloxetine separated from baseline only at 120 mg. Both drugs robustly decreased 5-HT levels to the same extent at all 3 doses.

Conclusions: Levomilnacipran is a potent dual reuptake inhibitor from its minimally effective dose in MDD, whereas the dose of duloxetine needs to reach 120 mg/day to consistently inhibit NE reuptake.

Trial Registration: ClinicalTrials.gov identifier: NCT03249311.

J Clin Psychiatry 2025;86(3):25m15867

Author affiliations are listed at the end of this article.

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