Duloxetine: A Balanced and Selective Norepinephrine and Serotonin-Reuptake Inhibitor

Anders D. Westanmo; Jon Gayken; Robert Haight


Am J Health Syst Pharm. 2005;62(23):2481-2490. 

In This Article


Although the exact mechanism of duloxetine's antidepressant activity is unknown, preclinical studies have demonstrated that duloxetine is a potent inhibitor of both serotonin and norepinephrine reuptake. Duloxetine is in the class of selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs). Traditional SSRIs are generally selective for blocking the re-uptake of serotonin, with ratios of blockade of serotonin to blockade of norepinephrine of over 300.[22] In comparison, the SNRIs venlafaxine, milnacipran, and duloxetine have ratios of 30, 9, and 9, respectively.[22,23,24] Duloxetine's metabolites do not significantly contribute to its pharmacologic activity.[25]

Both serotonin and norepinephrine contribute to the pathology and treatment of depression.[2] Serotonin affects areas of the brain controlling impulsivity, aggression, appetite, and sexual function, while norepinephrine plays a role in areas controlling vigilance and motivation. Both serotonin and norepinephrine have shared roles in relation to anxiety, irritability, cognitive function, mood, and emotion.[26] The benefits of both serotonin and norepinephrine may overlap, but the risks of adverse effects seem to be distinct for each monoamine. After almost 20 years of experience with SSRIs, we have a good idea of what adverse effects are associated with them.[26] The most common include gastrointestinal effects (nausea, diarrhea, constipation), sleep disturbances, and sexual dysfunction. The nausea, although poorly understood, seems to be mediated by action on serotonin type 3 receptors.[27] More recently, we have gained insight into the adverse effects of increased norepinephrine levels because of the introduction of the selective norepinephrine-reuptake inhibitors atomoxetine and reboxetine. The primary risks associated with norepinephrine-reuptake inhibition are slight increases in blood pressure or pulse rate.[28,29]

Although the precise mechanism of antidepressant and central pain inhibition of duloxetine is not known, it is thought to be related to potentiation of adrenergic and serotoninergic activity in the central nervous system.[25] Tricyclic antidepressants have long been recognized for their pain-reducing properties.[30] SSRIs have not shown as much benefit, even though serotonin is a known mediator of pain.[30]

The female urethra contains a distinct layer of circularly arranged striated muscle (the rhabdosphincter) that is thickest in the middle third of the urethra.[31] During voiding, the rhab-dosphincter relaxes to allow free urine flow.[31] The cell bodies that innervate the rhabdosphincter lie in an area of the sacral spinal cord (S2–S4) called Onuf's nucleus.[31] In stress urinary incontinence, duloxetine blocks the reuptake of serotonin and norepinephrine in Onuf's nucleus to stimulate contraction of the rhab-dosphincter.[32] The increased muscle tone inhibits involuntary urine loss.[32]