Clinical evidence for serotonin and norepinephrine reuptake inhibition of duloxetine

Abstract

Most antidepressants in clinical use are believed to function by enhancing neurotransmission of serotonin [5-hydroxytryptamine (5-HT)] and/or norepinephrine (NE) via inhibition of neurotransmitter reuptake. Agents that affect reuptake of both 5-HT and NE (serotonin-norepinephrine reuptake inhibitors) have been postulated to offer greater efficacy for the treatment of major depressive disorder (MDD). These dual-acting agents also display a broader spectrum of action, including efficacy for MDD and associated painful physical symptoms, diabetic peripheral neuropathic pain, generalized anxiety disorder, and fibromyalgia syndrome. Substantial preclinical evidence shows that duloxetine, an approved drug for the treatment of MDD, generalized anxiety disorder, and the management of diabetic peripheral neuropathic pain, inhibits reuptake of both 5-HT and NE. This paper reviews clinical and neurochemical evidence of duloxetine's effects on 5-HT and NE reuptake inhibition. The clinical evidence supporting duloxetine's effects on NE reuptake inhibition includes indirect measures such as altered excretion of NE metabolites, cardiovascular effects, and treatment-emergent adverse event profiles similar to those for other drugs believed to act through the inhibition of NE reuptake. In summary, the data presented in this report provide clinical evidence of a mechanism for duloxetine involving both 5-HT and NE reuptake inhibition in humans and are consistent with preclinical evidence for 5-HT/NE reuptake inhibition.

BDNF plasma levels variations in major depressed patients receiving duloxetine

“…In particular, duloxetine blocks the same extent the reuptake of NE and 5-HT at standard dose (e.g. 60 mg/day or lower), resulting in NE and 5-HT activity enhance [13]. However, such modulations may also depend on the effect of different components of the same drug on different neurobiological backgrounds on which act, resulting in differential trend over time in clinical and laboratory behaviors.…”

“…To our knowledge there are no clinical studies including depressed patients on the effects of duloxetine, a relatively newer SNRI which blocks the same extent the reuptake of norepinephrine (NE) and serotonin (5-HT) at standard dose (e.g., 60 mg/day or lower) [13], on BDNF levels. The objective of this study was to investigate the effect of 60 mg/day duloxetine on plasma concentration of BDNF in 30 depressed outpatients and 32 healthy controls within a period of 12 weeks.…”

Prediction of Human Serotonin and Norepinephrine Transporter Occupancy of Duloxetine by Pharmacokinetic/Pharmacodynamic Modeling in the Rat

“…Previous studies exploring NET target engagement by duloxetine via indirect assessments of changes in NE metabolite levels demonstrated changes consistent with moderate NET inhibition over average plasma concentrations of 40 to 70 ng/ml (Chalon et al, 2003). Moreover, the clinical efficacy and tolerability profile of duloxetine provides evidence for an effect on NE uptake (Trivedi et al, 2008). It should be noted that in the current study the observed NET occupancy in rats was underpredicted at low dose levels (Յ 5 mg/kg) and plasma concentrations of duloxetine, and this may limit the utility of the developed model to predict human CNS NET occupancy accurately.…”

Pharmacotherapy of Fibromyalgia: Focus on Duloxetine

“…17 Clinical evidence also largely substantiates this dual neurotransmitter reuptake in humans. 18 Clinical assessment of serotonin reuptake inhibition has been provided indirectly by measuring whole blood serotonin levels which are decreased after duloxetine treatment proportionally to the dose used in depressed patients 19 and in healthy subjects. 20 A direct evidence of serotonin transporter occupancy has been reported in healthy subjects by means of positron emission tomography (TEP) showing more than 80% occupancy of the transporter with doses of 40 and 60 mg of duloxetine.…”