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https://www.ncbi.nlm...les/PMC9017767/
In the case of the NE system, there are some inconsistencies between different approaches to assess NE reuptake. In particular, venlafaxine exhibits low in vitro affinity for NET (i.e., in the micromolar range) that stands in contrast with its relatively high in vivo potency to inhibit NE reuptake compared with the high-affinity NET inhibitor desipramine (Owens et al., 1997; Béïque et al., 1998, 1999). Indeed, NE reuptake has been shown to be dose dependently inhibited in patients undergoing desipramine or venlafaxine treatment when their serum was used in a cell line expressing the human NET (Gilmor et al., 2002; Owens et al., 2008). The latter study showed that NE reuptake was inhibited by venlafaxine ex vivo to approximately 25% with 75 mg/d, 45% with 150 mg/d, 50% with 225 mg/d, 55% with 300 mg/d, and 60% with 375 mg/d. These results, however, do not indicate what degree of inhibition is necessary to inhibit NET to obtain a physiological effect in vivo, even more so as there is a high degree of inter-individual variability in the resultant steady-state serum concentrations produced by identical dosages. In contrast to the brain imaging data for the 5-HT system, the threshold of NET occupancy to obtain a therapeutic action in MDD through this mechanism is not as clear. For instance, repeated administration of the NET inhibitor nortriptyline to MDD patients leads to constant NET occupancy of approximately 60% with regimens of 75 to 200 mg/d without evidence of a concentration-dependent relationship in that range (Takano et al., 2014). Furthermore, single doses of the NET inhibitor atomoxetine of 25, 50, and 100 mg in the same healthy participants occupied the NET to approximately 40% with no significant differences between doses for any brain region (Logan et al., 2007).
https://www.nature.c...icles/npp200847
https://www.ncbi.nlm...les/PMC6441126/
In this study, we demonstrated that the NET occupancy in MDD patients who had responded to clinically relevant doses (37.5–300 mg/d) of venlafaxine ER was 8% to 61%, increasing in a dose- and plasma concentration-dependent manner.