Inhibition of norepinephrine uptake in patients with major depression treated with paroxetine.
OBJECTIVE
The study examined whether paroxetine inhibits the human norepinephrine transporter in addition to the human serotonin (5-HT) transporter in patients with major depressive disorder.


METHODS
In an open-label, parallel-group, forced-titration study, 52 outpatients with DSM-IV major depressive disorder and a baseline Montgomery Asberg Depression Rating Scale score > or =20 were randomly assigned to treatment with paroxetine (to 60 mg/day) or desipramine (to 30 mg/day) in a 3-to-1 ratio, respectively. Norepinephrine and 5-HT transporter function were assayed by using human transporter transfected cells in the presence of serum collected at baseline and the end of each treatment week. Data from 36 patients were analyzed.


RESULTS
Paroxetine decreased norepinephrine uptake to 73% of control (27% inhibition) at an average serum concentration of 100 ng/ml and 57% of control (43% inhibition) at 200 ng/ml. Uptake of 5-HT was decreased to less than 15% (greater than 85% inhibition) of control at these paroxetine concentrations. Desipramine decreased norepinephrine uptake to near maximal 15% of control (85% inhibition) at 100 ng/ml. Uptake of 5-HT was decreased to 82% of control (18% inhibition) at 100 ng/ml and 49% of control (51% inhibition) at 500 ng/ml.


CONCLUSIONS
Paroxetine, currently classified as a selective 5-HT reuptake inhibitor, can act as a 5-HT/norepinephrine uptake inhibitor in vivo. The clinical significance of this action on norepinephrine uptake is currently unknown, but this action may contribute to the broad therapeutic efficacy of paroxetine in the treatment of depression, panic disorder, social anxiety disorder, posttraumatic stress disorder, and generalized anxiety disorder.
D000328:Adult; D000553:Ambulatory Care; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000097:blood; D003866:Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism; D003891:Desipramine / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000097:blood; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009419:Nerve Tissue Proteins; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D009638:Norepinephrine / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins; D017374:Paroxetine / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D011569:Psychiatric Status Rating Scales; D012701:Serotonin / Q000097:blood / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D027981:Symporters / Q000037:antagonists & inhibitors / Q000097:blood; D016896:Treatment Outcome
D002352:Carrier Proteins; D003891:Desipramine; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D014179:Neurotransmitter Uptake Inhibitors; D009638:Norepinephrine; D050484:Norepinephrine Plasma Membrane Transport Proteins; D017374:Paroxetine; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D027981:Symporters; C493227:SLC6A2 protein, human; C493230:SLC6A4 protein, human