Duloxetine (Cymbalta, Yentreve): a serotonin-norepinephrine reuptake inhibitor for major depression. Australian prescriber review

From Australian Prescriber:

Duloxetine

Cymbalta (Eli Lilly)
30 mg and 60 mg capsules
Approved indication: major depression
Australian Medicines Handbook section 18.1.2

Duloxetine is a new antidepressant which selectively inhibits serotonin and noradrenaline reuptake. It also weakly inhibits dopamine uptake. (See details of its mechanism of action)

After oral administration of duloxetine, maximum plasma concentrations are reached after six hours. Duloxetine is extensively metabolised in the liver and has an overall half-life of about 12 hours. Most of the metabolites are excreted in the urine.

The efficacy of duloxetine (60 mg/day) has been compared to that of escitalopram (10 mg/day) and placebo in a randomised study of 684 patients (randomised in a 2:2:1 ratio). The onset of efficacy was defined as a 20% sustained reduction in the patient’s score on the Hamilton Rating Scale for Depression Maier subscale, by the second week of treatment. The probability of meeting these criteria was 42.6% in patients given duloxetine, 35.2% in patients given escitalopram and 21.5% in patients given placebo. After eight weeks, the probability of responding to treatment (defined as a 50% improvement from baseline on the Hamilton Rating Scale for Depression) was not statistically different between patients given active drug or placebo. Response rates were 48.7% for duloxetine, 45.3% for escitalopram and 36.9% for placebo.1

In a review analysing efficacy data from nine duloxetine trials, the number needed to treat for a duloxetine dose of 60 mg/day or more was 6 for a response (based on the Hamilton Rating Scale for Depression), 7-9 for remission and 6-7 for a Clinical Global Impression-defined improvement by eight weeks. For fluoxetine or paroxetine (20 mg/day), the number needed to treat was 7 for a response, 11 for remission and 8 for a Clinical Global Impression-defined improvement.2

A safety analysis revealed significantly more nausea, dry mouth, vomiting and yawning reported by patients on duloxetine treatment compared to those on escitalopram or placebo. Nausea was the most common adverse event occurring in 23.8% of patients taking duloxetine, 12% of patients taking escitalopram and 8.8% of patients taking placebo. There were considerably more dropouts due to nausea in the duloxetine group than in the escitalopram group. Mean changes in blood pressure and heart rate after treatment were higher for duloxetine than escitalopram.1

Fatal cases of liver failure have been reported with duloxetine so it is contraindicated for patients with hepatic impairment and should not be given to patients who are drinking substantial amounts of alcohol. A lower dose of 30 mg/day should be used in patients with end-stage renal disease.

The concomitant use of monoamine oxidase inhibitors with duloxetine is contraindicated. Duloxetine should be started at least 14 days after finishing monoamine oxidase inhibitor treatment.

The metabolism of duloxetine involves cytochrome P450 1A2 and 2D6 therefore concomitant administration of P450 1A2 inhibitors such as ciprofloxacin should be avoided. Caution should be used when giving duloxetine with drugs that are metabolised by P450 2D6. Thioridazine should be avoided.

If tolerability is a concern, patients can be started on a dose of 30 mg/day before increasing to 60 mg/day. If patients do not respond to 60 mg/day, there is little evidence to suggest that they will respond to a higher dose. When discontinuing duloxetine after more than one week of treatment, tapering of the dose is recommended.

The short-term effectiveness of duloxetine is comparable to low-dose escitalopram but its tolerability is less. There appear to be no published studies comparing duloxetine to other drugs that inhibit the reuptake of noradrenaline and serotonin, such as venlafaxine and reboxetine. There are limited data about the long-term use of duloxetine.

manufacturer provided only the product information

References*†

1. Nierenberg AA, Greist JH, Mallinckrodt CH, Prakash A, Sambunaris A, Tollefson GD, et al. Duloxetine versus escitalopram and placebo in the treatment of patients with major depressive disorder: onset of antidepressant action, a non-inferiority study. Curr Med Res Opin 2007;23:401-16.
2. Cookson J, Gilaberte I, Desaiah D, Kajdasz DK. Treatment benefits of duloxetine in major depressive disorder as assessed by number needed to treat. Int Clin Psychopharmacol 2006;21:267-73.

Source: Australian Prescriber. New drugs:duloxetine. Volume 31 Number 3 – June 2008.

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