Atomoxetine, but not paroxetine, blocks norepinephrine reuptake in depressed patientss

Purpose: Paroxetine is a potent serotonin (5-HT) reuptake inhibitor. However, a purported norepinephrine (NE) reuptake blockade action remains to be established. Atomoxetine is a potent NE reuptake inhibitor with the indication of attention deficit hyperactivity disorder (ADHD). The present study was aimed at confirming a NE reuptake inhibitory action with ascending doses of atomoxetine and possibly with paroxetine in depressed patients. Methods: Patients were randomized to escalating doses of either paroxetine (20 to 50 mg/day), or atomoxetine (25-80 mg/day) in a four to six week period. Inhibition of NE reuptake was assessed using the attenuation of systolic blood pressure (SBP) elevations produced by intravenous injections of tyramine. Tyramine penetrates into peripheral NE terminals via the NE reuptake transporter and releases NE. Then, NE acts on the vascular adrenoceptors, which causes an elevation of SBP. Drugs that block NE reuptake attenuate the pressor effects of tyramine. Two-way ANOVA for repeated measures for doses of tyramine and treatments were used to assess the effects of the different drug regimens on the pressor response to loads of 3–6 mg of tyramine. Sixteen patients with unipolar major depressive disorder were assessed weekly after increasing the dose of paroxetine (9 patients) and atomoxetine (7 patients). Results: Atomoxetine exerted a robust inhibition of the tyramine response, starting at the dose of 25mg/day in a dose-dependent pattern. Neither the low nor the high doses of paroxetine altered the tyramine pressor response. Conclusions: These results provide evidence that atomoxetine started significantly inhibiting NE reuptake at subtherapeutic dose for ADHD, whereas paroxetine leaves the activity of the NE transporter unaltered, even at the highest recommended dose for depression.