Estimates of Serotonin and Norepinephrine Transporter Inhibition in Depressed Patients Treated with Paroxetine or Venlafaxine

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 33; no. 13; pp. 3201 - 3212
• Main Authors: OWENS, Michael J, KRULEWICZ, Stan, SIMON, Jeffrey S, SHEEHAN, David V, THASE, Michael E, CARPENTER, David J, PLOTT, Susan J, NEMEROFF, Charles B
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.12.2008
• Subjects: Adolescent; Adult; Adult and adolescent clinical studies; Aged; Antidepressants; Antidepressive Agents, Second-Generation - therapeutic use; Behavioral sciences; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Brain Chemistry - drug effects; Brain Chemistry - physiology; Cyclohexanols - therapeutic use; Depression; Depressive Disorder - blood; Depressive Disorder - drug therapy; Depressive Disorder - physiopathology; Dose-Response Relationship, Drug; Double-Blind Method; Drug dosages; Estimates; Female; Humans; Laboratory animals; Male; Medical sciences; Mental depression; Middle Aged; Mood disorders; Neuropharmacology; Nordefrin - metabolism; Norepinephrine Plasma Membrane Transport Proteins - antagonists & inhibitors; Norepinephrine Plasma Membrane Transport Proteins - blood; Paroxetine - therapeutic use; Pharmacology. Drug treatments; Psychiatry; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; Research centers; Serotonin; Serotonin - metabolism; Serotonin Plasma Membrane Transport Proteins - blood; Serotonin Uptake Inhibitors - therapeutic use; Time Factors; Venlafaxine Hydrochloride; Young Adult; Atlanta Georgia; United States > US; Mood disorder; Human; Paroxetine; Serotonin; transporters; Psychotropic; occupancy; antidepressant; Phénéthylamine derivatives; Depression; Catecholamine; Reuptake inhibitor; Selective serotonin reuptake inhibitor; SSRI; Serotonin transporter; Piperidine derivatives; reuptake; Neurotransmitter; Antidepressant agent; Venlafaxine; Norepinephrine; Inhibition; Carrier protein
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/npp.2008.47

Paroxetine and venlafaxine are potent serotonin transporter (SERT) antagonists and weaker norepinephrine transporter (NET) antagonists. However, the relative magnitude of effect at each of these sites during treatment is unknown. Using a novel blood assay that estimates CNS transporter occupancy we estimated the relative SERT and NET occupancy of paroxetine and venlafaxine in human subjects to assess the relative magnitude of SERT and NET inhibition. Outpatient subjects (N=86) meeting criteria for major depression were enrolled in a multicenter, 8 week, randomized, double-blind, parallel group, antidepressant treatment study. Subjects were treated by forced-titration of paroxetine CR (12.5-75 mg/day) or venlafaxine XR (75-375 mg/day) over 8 weeks. Blood samples were collected weekly to estimate transporter inhibition. Both medications produced dose-dependent inhibition of the SERT and NET. Maximal SERT inhibition at week 8 for paroxetine and venlafaxine was 90% (SD 7) and 85% (SD 10), respectively. Maximal NET inhibition for paroxetine and venlafaxine at week 8 was 36% (SD 19) and 60% (SD 13), respectively. The adjusted mean change from baseline (mean 28.6) at week 8 LOCF in MADRS total score was -16.7 (SE 8.59) and -17.3 (SE 8.99) for the paroxetine and venlafaxine-treated patients, respectively. The magnitudes of the antidepressant effects were not significantly different from each other (95%CI -3.42, 4.54, p=0.784). The results clearly demonstrate that paroxetine and venlafaxine are potent SERT antagonists and less potent NET antagonists in vivo. NET antagonism has been posited to contribute to the antidepressant effects of these compounds. The clinical significance of the magnitude of NET antagonism by both medications remains unclear at present.