Differential Potency of Venlafaxine, Paroxetine, and Atomoxetine to Inhibit Serotonin and Norepinephrine Reuptake in Patients With Major Depressive Disorder

• Type of Material: Article
• Authors: Fahad Aldosary, University of Ottawa; Sandhaya Norris, University of Ottawa; Philippe Tremblay, Centre Hospitalier Universitaire de Québec; Jonathan S James, University of Ottawa; James Ritchie, Emory University; Pierre Blier, University of Ottawa
• Language: English
• Date: 2022-01-29
• Publisher: OXFORD UNIV PRESS
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021. Published by Oxford University Press on behalf of CINP.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1093/ijnp/pyab086
• Title of Journal or Parent Work: INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY
• Volume: 25
• Issue: 4
• Start Page: 283
• End Page: 292
• Keywords: serotonin levels; Neurosciences & Neurology; PROFILE; ANTIDEPRESSANT RESPONSE; EXTRACELLULAR LEVELS; Psychiatry; Life Sciences & Biomedicine; Antidepressant doses; Science & Technology; blood pressure; Neurosciences; Clinical Neurology; DOUBLE-BLIND; tyramine; plasma levels; Pharmacology & Pharmacy; POLYMORPHISMS; BLOCKADE; OCCUPANCY; TRANSPORTER BINDING; PET; PROMOTER REGION
• Research Categories: Health Sciences, Mental Health

Abstract

Background: Venlafaxine is a dual serotonin (5-HT) and norepinephrine reuptake inhibitor. The specific dose at which it begins to efficiently engage the norepinephrine transporter (NET) remained to be determined. Paroxetine is generally considered as a selective 5-HT reuptake inhibitor but exhibits some affinity for NET. Atomoxetine is a NET inhibitor but also has some affinity for the 5-HT reuptake transporter (SERT). Methods: This study examined the effects of forced titration of venlafaxine from 75 to 300 mg/d, paroxetine from 20 to 50 mg/d, or atomoxetine from 25 to 80 mg/d in 32 patients with major depressive disorder. Inhibition of SERT was estimated using the depletion of whole-blood 5-HT. Inhibition of NET was assessed using the attenuation of the systolic blood pressure produced by i.v. injections of tyramine. Results: All 3 medications significantly reduced 5-HT levels at the initiating regimens: Venlafaxine and paroxetine by approximately 60% and atomoxetine by 16%. The 3 subsequent regimens of venlafaxine and paroxetine reduced 5-HT levels by over 90%, but the highest dose of atomoxetine only reached a 40% inhibition. Atomoxetine dose dependently inhibited the tyramine pressor response from the lowest dose, venlafaxine from 225 mg/d, and paroxetine left it unaltered throughout. Conclusion: These results confirm that venlafaxine and paroxetine are potent SERT inhibitors over their usual therapeutic range but that venlafaxine starts inhibiting NET only at 225 mg/d, whereas paroxetine remains selective for SERT up to 50 mg/d. Atomoxetine dose dependently inhibits NET from a low dose but does not inhibit SERT to a clinically relevant degree.