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

Abstract and Introduction

Purpose: The pharmacology, pharmacokinetics, efficacy, safety, drug interactions, dosage and administration, cost, and place in therapy of duloxetine for major depression, pain from diabetic peripheral neuropathy, and stress urinary incontinence are reviewed.
Summary: Duloxetine is a balanced selective serotonin and norepinephrine-reuptake inhibitor available in the United States for the treatment of major depressive disorder (MDD) and diabetic peripheral neuropathic pain (DPNP). Duloxetine has also been used for the treatment of stress urinary incontinence (SUI). Absorption of duloxetine begins two hours after oral administration, reaching a maximum plasma concentration in six hours. Half-life and volume of distribution are 12 hours and 1640 L, respectively. The recommended dosage of duloxetine is 40–80 mg daily, depending on the indication, preferably split into two doses per day. For the treatment of major depression, duloxetine has achieved remission rates similar to that of existing selective serotonin-reuptake inhibitors (SSRIs). For SUI and pain associated with diabetic peripheral neuropathy, duloxetine has not demonstrated equivalence or superiority to existing therapies. The adverse effects of duloxetine are similar to those of traditional SSRIs. Nausea is common and has been cited as the primary reason for discontinuation of duloxetine in trials. Increases in blood pressure have been mild, but caution should be used in patients with hypertension. Patients with a creatinine clearance of < 30 mL/min and patients with hepatic impairment should avoid duloxetine. Duloxetine should not be recommended as first-line therapy for SUI or DPNP. For MDD, duloxetine may be a useful alternative for patients who do not benefit from or are unable to tolerate other antidepressant therapy.
Conclusion: Duloxetine has been approved for the treatment of MDD and pain associated with diabetic peripheral neuropathy in adults.

The years from 1990 through 1999 were termed the "Decade of the Brain" by the Library of Congress and the National Institute of Mental Health.[1] Since that decade, our understanding of depression has grown enormously. The various roles of individual monoamines in depression and how they interrelate have been investigated.[2] Despite this gain in knowledge, the incidence of depression continues to increase.[3] Major depressive disorder (MDD) currently affects 18 million people in the United States and is projected to be the second leading cause of disability worldwide by 2020.[3,4]

The treatment of depression has been an evolving process. Monoamine oxidase inhibitors (MAOIs) were first-line treatment options at one time, followed by tricyclic antidepressants and then selective serotoninreuptake inhibitors (SSRIs). While this evolution has provided more tolerable drug therapy for depression, the efficacy of our first-line drugs still needs improvement.[5] Currently only 30–40% of patients reach remission during an initial trial with an antidepressant.[6,7,8,9,10,11,12,13,14,15,16] With these low percentages of success, our need for more effective antidepressant therapy is apparent. Recently, FDA approved duloxetine hydrochloride for MDD. Duloxetine is a new antidepressant with dual norepinephrine- and serotonin-reuptake inhibitor properties.[17] There are some data showing increased remission rates with dual reuptake inhibition of both serotonin and norepinephrine over serotonin alone that raise our hopes for this mechanism of treatment.[8–16]

Duloxetine may also offer a new treatment option for patients with neuropathic pain or stress urinary incontinence. These indications, although seemingly dissimilar, have strong relationships to depression. The single highest predictor of urinary incontinence in women is depression (odds ratio, 2.48; p < 0.001).[18] Pain and depression have also been consistently linked.[19,20] The precise reason for the relationships have not been established, but they are thought to be bidirectional.[18,21]

This article reviews the pharmacology, pharmacokinetics, clinical efficacy, safety, drug interactions, dosage and administration, cost, and place in therapy of duloxetine for major depression, diabetic peripheral neuropathic pain, and stress urinary incontinence.