Mood Disorders and Antidepressants: Stahl's Essential Psychopharmacology by Stephen M. Stahl

Author:Stephen M. Stahl
Language: eng
Format: mobi
Publisher: Cambridge University Press
Published: 2013-10-27T22:00:00+00:00

Figure 7-35. Icon of a norepinephrine–dopamine reuptake inhibitor (NDRI). Another class of antidepressant consists of norepinephrine–dopamine reuptake inhibitors (NDRIs), for which the prototypical agent is bupropion. Bupropion has weak reuptake blocking properties for dopamine (DRI) and norepinephrine (NRI) but is an efficacious antidepressant, which may be explained in part by the more potent inhibitory properties of its metabolites.

Figure 7-36. NDRI actions. In this figure the norepinephrine reuptake inhibitor (NRI) portion of the NDRI molecule (left panel) and the dopamine reuptake inhibitor (DRI) portion of the NDRI molecule (right panel) are inserted into their respective reuptake pumps. Consequently both pumps are blocked, and the drug mediates an antidepressant effect.

Bupropion is metabolized to a number of active metabolites, some of which are not only more potent NET inhibitors than bupropion itself and equally potent DAT inhibitors, but are also concentrated in the brain. In some ways, therefore, bupropion is both an active drug and a precursor for other active drugs (i.e., a prodrug for multiple active metabolites). The most potent of these is the + enantiomer of the 6-hydroxy metabolite of bupropion, also known as radafaxine.

Can the net effects of bupropion on NET (Figure 7-37A and B) and DAT (Figure 7-37C) account for its clinical actions in depressed patients at therapeutic doses? If one believes that 90% transporter occupancy of DAT and NET are required for antidepressant actions, the answer would be “no.” Human PET scans suggest that no more than 20–30% and perhaps as little as 10–15% of striatal DATs may be occupied at therapeutic doses of bupropion. NET occupancy would be expected to be in this same range. Is this enough to explain bupropion’s antidepressant actions?

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