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Duloxetine

A Review of its Use in the Treatment of Major Depressive Disorder

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Summary

Abstract

Duloxetine (Cymbalta®) is an orally administered, selective serotonin and noradrenaline reuptake inhibitor (SNRI) that has been approved for the treatment of major depressive disorder (MDD).

Based on a considerable body of evidence, duloxetine at dosages ranging from 40 to 120 mg/day was effective in the short- and long-term treatment of MDD. Significant improvements versus placebo in core emotional symptoms as well as painful physical symptoms associated with depression, were seen in most, but not all, appropriately designed studies; results of meta-analyses suggested that improvements in these efficacy measures were apparent after 1–2 weeks’ treatment with the highest recommended dosage of 60mg once daily. Short-term (≤15 weeks) administration of duloxetine at fixed or flexible dosages between 60 and 120 mg/day was noninferior to paroxetine 20mg once daily, noninferior or inferior to escitalopram 10–20mg once daily, and had a similar global benefit-risk (GBR) profile to that of venlafaxine extended-release (XR) 150–225 mg/day in the treatment of MDD. Longer-term (6–8 months) treatment with duloxetine was similar in efficacy to paroxetine and escitalopram. Duloxetine is generally well tolerated, although it may be appropriate to avoid initiating treatment with the 60 mg/day dosage, as this has been associated with a higher discontinuation rate due to adverse events in some (but not all) comparative studies with escitalopram and venlafaxine XR.

Definitive comparisons are awaited, although duloxetine seemingly provides a useful alternative to SSRIs and other SNRIs for the treatment of MDD. It also appears to be an attractive option for MDD patients presenting with painful physical symptoms.

Pharmacological Properties

Duloxetine has a high affinity for serotonin and noradrenaline, but not dopamine, reuptake transporters. It binds to human serotonin and noradrenaline transporters with greater affinity than venlafaxine and milnacipran; the resulting inhibition of serotonin and noradrenaline reuptakein vitro is more ‘balanced’ than that of venlafaxine (i.e. ratio of human noradrenaline: serotonin binding affinities 9.4 vs 30.2), but less balanced than that of milnacipran (1.6).

Duloxetine has a low binding affinity for dopamine transporters, no significant binding affinity for dopamine D2, serotonin, α1- and α2-adrenergic, muscarinic, histamine H1 and opioid receptors, and does not appreciably inhibit choline and GABA transporters or monoamine oxidase activity.

Duloxetine 40–80 mg/day (20–40mg twice daily) exhibited linear pharmacokinetics; steady-state plasma concentrations were achieved within 3 days. Duloxetine can be administered without regard to meals. Once absorbed, duloxetine undergoes extensive hepatic metabolism via cytochrome P450 (CYP) 2D6 and 1A2 to form multiple metabolites, which are inactive and excreted primarily in the urine. The mean elimination half-life of duloxetine is ≈12 hours.

Duloxetine is not expected to decrease the metabolic clearance of drugs metabolised by CYP3A, 1A2, 2C9 or 2C19 to a clinically significant extent. However, it is a moderately potent inhibitor of CYP2D6; caution is necessary when coadministering duloxetine with other drugs that are predominantly metabolised by this isoenzyme, particularly those that have a narrow therapeutic index.

Therapeutic Efficacy

Duloxetine was effective in the short- and long-term treatment of MDD. Duloxetine 40–120 mg/day demonstrated superiority over placebo on the 17-item Hamilton Rating Scale for Depression total score (primary efficacy measure) in six of eight acute-phase registrational studies of 8–9 weeks’ duration. Moreover, the highest recommended dosage of 60mg once daily significantly improved painful physical symptoms and (in elderly patients) cognitive impairment in relation to placebo in acute-phase studies specifically designed to evaluate these symptoms in patients with MDD. Meta-analyses suggested that improvements in core emotional symptoms, global functioning and painful physical symptoms were apparent after 1–2 weeks’ treatment with duloxetine 60mg once daily, which was more consistently effective than the lowest recommended dosage of 40 mg/day (administered as 20mg twice daily). In a relapse prevention study of 26 weeks’ duration, duloxetine 60mg once daily significantly reduced the time from randomisation to relapse (primary efficacy measure) compared with placebo.

In short-term (≤15 weeks) active comparator-controlled studies, duloxetine at fixed or flexible dosages between 60 and 120 mg/day was noninferior to paroxetine 20mg once daily (pre-planned pooled analysis of four trials), noninferior or inferior to escitalopram 10–20mg once daily, and had a similar GBR profile to that of venlafaxine XR 150–225 mg/day in the treatment of MDD. Longer-term (6–8 months) treatment with duloxetine had similar efficacy to that of paroxetine and escitalopram.

Tolerability

Short- and long-term treatment with duloxetine 40–120 mg/day was generally well tolerated. Nausea, dry mouth, constipation, insomnia and dizziness were among the most common acute treatment-emergent adverse events in acute-phase studies; the discontinuation rate due to adverse events was ≈10% (vs placebo, 4%). The adverse event profile for approved dosages (40–60 mg/day) was not substantially different.

The overall effect on bodyweight of long-term treatment with duloxetine at dosages ranging from 40 to 120 mg/day was minimal. Changes in heart rate and blood pressure were similarly modest; changes in ECG parameters were not clinically significant. Short-term treatment with duloxetine was associated with an increased incidence of treatment-emergent sexual dysfunction and a 3-fold increase in the risk of elevation of serum transaminase levels relative to placebo.

In terms of the discontinuation rate due to adverse events and/or the incidence of individual adverse events, duloxetine dosages between 40 and 120 mg/day appeared to be as well tolerated as paroxetine 20 mg/day, whereas fixed or flexible dosages between 60 and 120 mg/day were less well tolerated than fixed or flexible dosages of escitalopram between 10 and 20 mg/day and fixed or flexible dosages of venlafaxine XR between 150 and 225 mg/day. Duloxetine nonetheless showed tolerability advantages over paroxetine and (in one of two studies) over escitalopram with respect to sexual functioning during short- to medium-term administration, and over venlafaxine XR with respect to discontinuation-emergent adverse events following cessation of short-term administration.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Authors and Affiliations

  1. Wolters Kluwer Health | Adis, 41 Centorian Drive, Private Bag 65901 Mairangi Bay, North Shore 0754, Auckland, New Zealand

    James E. Frampton & Greg L. Plosker

  2. Wolters Kluwer Health, Conshohocken, Pennsylvania, USA

    James E. Frampton & Greg L. Plosker

Authors
  1. James E. Frampton

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  2. Greg L. Plosker

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Correspondence toJames E. Frampton.

Additional information

Data Selection

Sources: Medical literature published in any language since 1980 on ‘duloxetine’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health ∣ Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘duloxetine’ and (‘depression’ or ‘depressive disorders’). Searches were last updated 14 June 2007.

Selection: Studies in patients with major depressive disorder who received duloxetine. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Duloxetine, major depressive disorder, antidepressant, serotonin-noradrenaline reuptake inhibitor, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

Various sections of the manuscript reviewed by:P. Bech, Psychiatric Research Unit, Frederiksborg General Hospital, Hillerod, Denmark;M. Briley, NeuroBiz Consulting and Communications, Castres, France;J.I. Hudson, Biological Psychiatry Laboratory, McLean Hospital, Belmont, Massachusetts, USA;J. Ishigooka, Department of Psychiatry, Tokyo Women’s Medical University, Tokyo, Japan;S.A. Montgomery, Department of Psychiatry, University of Melbourne, Heidelberg, Victoria, Australia;T.R. Norman, Department of Psychiatry, University of Melbourne, Heidelberg, Victoria, Australia;O. Spigset, Department of Clinical Pharmacology, St Olav’s University Hospital, Trondheim, Norway;M.E. Thase, Department of Psychiatry, Western Psychiatric Institute Clinic, Pittsburgh, Pennsylvania, USA.

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