Clinical evidence for serotonin and norepinephrine reuptake inhibition of duloxetine.
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.
Trivedi
Madhukar H
MH
Mood Disorders Program and Clinic, University of Texas Southwestern Medical School, Dallas, TX 75235-9119, USA. Madhukar.Trivedi@UTSouthwestern.edu
Desaiah
Durisala
D
Ossanna
Melissa J
MJ
Pritchett
Yili L
YL
Brannan
Stephen K
SK
Detke
Michael J
MJ
D018759:Adrenergic Uptake Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D000928:Antidepressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D003863:Depression / Q000188:drug therapy* / Q000378:metabolism; D000068736:Duloxetine Hydrochloride; D019317:Evidence-Based Medicine; D006801:Humans; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D013876:Thiophenes / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
D018759:Adrenergic Uptake Inhibitors; D000928:Antidepressive Agents; D000068736:Duloxetine Hydrochloride; D050484:Norepinephrine Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D013876:Thiophenes