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

• Main Authors: Aldosary, F. (Author), Blier, P. (Author), James, J.S (Author), Norris, S. (Author), Ritchie, J.C (Author), Tremblay, P. (Author)
• Format: Article
• Language: English
• Published: NLM (Medline) 2022
• Subjects: antidepressant agent; Antidepressant doses; Antidepressive Agents, Second-Generation; atomoxetine; Atomoxetine Hydrochloride; blood pressure; cyclohexanol derivative; Cyclohexanols; Depressive Disorder, Major; human; Humans; major depression; noradrenalin; noradrenalin transporter; Norepinephrine; Norepinephrine Plasma Membrane Transport Proteins; paroxetine; Paroxetine; plasma levels; serotonin; Serotonin; serotonin levels; serotonin uptake inhibitor; Serotonin Uptake Inhibitors; tyramine; Tyramine; venlafaxine; Venlafaxine Hydrochloride
• Online Access: View Fulltext in Publisher

 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. © The Author(s) 2021. Published by Oxford University Press on behalf of CINP.