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

Abstract

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 ¼ 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 À16.7 (SE 8.59) and À17.3 (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 À3.42, 4.54, p ¼ 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.

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“…However, the neurobiological significance of our results is limited by serotonergic-noradrenergic interactions and neurotransmitter nonspecificity of both drugs (Baldessarini, 2006;Owens et al, 2008). Paroxetine is predominantly serotonergic, but in a novel assay of human serum samples, it showed potential norepinephrine transporter inhibition (hypothetically 10-20% at the doses used in our study) (Owens et al, 2008).…”

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“…However, inhibition of NA uptake or ligand binding at NET has been demonstrated in vitro for a range of antidepressants and their metabolites (Pristupa et al, 1994;Owens et al, 1997;Tatsumi et al, 1997;Bymaster et al, 2001;Millan et al, 2001;Bymaster et al, 2002;Koch et al, 2003;Kuo et al, 2004;Vaishnavi et al, 2004), and maprotiline, desipramine, reboxetine, and to a lesser extent nortriptyline are highly selective for NET (above SERT and DAT). Paroxetine and venlafaxine act as NET antagonists in vivo at clinical doses (Gilmor et al, 2002;Davidson et al, 2005;Owens et al, 2008). In addition, it has been known for some time that the tricyclic antidepressant clomipramine occupies 80% of SERT at doses (and plasma concentrations) much lower than those used clinically (Suhara et al, 2003), suggesting a role for NET inhibition (via its active metabolite desmethylclomipramine (Thomas and Jones, 1977;Maj et al, 1982).…”

Authors' reply

“…Unfortunately, there are no established PET ligands for the NET to address this issue. Using the discrepancy noted between SERT occupancy rates ex vivo and in PET studies (Owens 2008), Blier (2008) indirectly estimated NET occupancy rates for 225 mg venlafaxine to be around 70%. If venlafaxine, considered by Dr Gillman to be an 'extremely weak NRI' that cannot produce a clinically meaningful NRI effect, is able to produce 70% NET occupancy at 225 mg, then a 'true SNRI' must be producing very high occupancy levels defying logic.…”