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      Treatment discontinuation and tolerability as a function of dose and titration of duloxetine in the treatment of major depressive disorder

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          We sought to better understand how dose and titration with duloxetine treatment may impact tolerability and treatment discontinuation in patients with major depressive disorder.

          Patients and methods

          We investigated Phase III duloxetine trials. Group 1 was a single placebo-controlled study with a 20 mg initial dose and a slow titration to 40 and 60 mg. Group 2 was a single study with a 40 mg initial dose and final “active” doses of 40 and 60 mg (5 mg control group), with 1-week titration. Group 3 consisted of eight placebo-controlled studies with starting doses of 40, 60, and 80 mg/day with minimal titration (final dose 40–120 mg/day). Tolerability was measured by rate of discontinuation due to adverse events (DCAE).


          The DCAE in Group 1 were 3.6% in the 60 mg group, 3.3% in the 40 mg group, and 3.2% in the placebo group. In Group 2, the DCAE were 15.0% in the 60 mg group, 8.1% in the 40 mg group, and 4.9% in the 5 mg group. In Group 3, the DCAE were 9.7% and 4.2% in the duloxetine and placebo groups, respectively.


          This study suggests that starting dose and titration may have impacted tolerability and treatment discontinuation. A lower starting dose of duloxetine and slower titration may contribute to improving treatment tolerability for patients with major depressive disorder.

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          Most cited references 37

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          Diagnostic and statistical manual of mental disorders.

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            A rating scale for depression.

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              Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis.

              Conventional meta-analyses have shown inconsistent results for efficacy of second-generation antidepressants. We therefore did a multiple-treatments meta-analysis, which accounts for both direct and indirect comparisons, to assess the effects of 12 new-generation antidepressants on major depression. We systematically reviewed 117 randomised controlled trials (25 928 participants) from 1991 up to Nov 30, 2007, which compared any of the following antidepressants at therapeutic dose range for the acute treatment of unipolar major depression in adults: bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, mirtazapine, paroxetine, reboxetine, sertraline, and venlafaxine. The main outcomes were the proportion of patients who responded to or dropped out of the allocated treatment. Analysis was done on an intention-to-treat basis. Mirtazapine, escitalopram, venlafaxine, and sertraline were significantly more efficacious than duloxetine (odds ratios [OR] 1.39, 1.33, 1.30 and 1.27, respectively), fluoxetine (1.37, 1.32, 1.28, and 1.25, respectively), fluvoxamine (1.41, 1.35, 1.30, and 1.27, respectively), paroxetine (1.35, 1.30, 1.27, and 1.22, respectively), and reboxetine (2.03, 1.95, 1.89, and 1.85, respectively). Reboxetine was significantly less efficacious than all the other antidepressants tested. Escitalopram and sertraline showed the best profile of acceptability, leading to significantly fewer discontinuations than did duloxetine, fluvoxamine, paroxetine, reboxetine, and venlafaxine. Clinically important differences exist between commonly prescribed antidepressants for both efficacy and acceptability in favour of escitalopram and sertraline. Sertraline might be the best choice when starting treatment for moderate to severe major depression in adults because it has the most favourable balance between benefits, acceptability, and acquisition cost.

                Author and article information

                Neuropsychiatr Dis Treat
                Neuropsychiatr Dis Treat
                Neuropsychiatric Disease and Treatment
                Neuropsychiatric Disease and Treatment
                Dove Medical Press
                11 January 2016
                : 12
                : 89-97
                [1 ]Eli Lilly Japan K.K., Medicines Development Unit Japan, Medical Science, Kobe, Japan
                [2 ]Department of Neuropsychiatry, Kinki University Faculty of Medicine, Osakasayama, Japan
                [3 ]Eli Lilly Japan K.K., Medicines Development Unit Japan, Statistical Science, Kobe, Japan
                [4 ]The University of Texas Health Science Center School of Medicine, Houston, TX, USA
                [5 ]Eli Lilly and Company, Neuroscience, Indianapolis, IN, USA
                Author notes
                Correspondence: Yoichi Satoi, Eli Lilly Japan K.K., Lilly Research Laboratories Japan, 6510086, Kobe, Japan, Tel +81 78 242 9185, Fax +81 78 242 9526, Email satoi_yoichi@
                © 2016 Harada et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research


                major depressive disorder, titration, duloxetine, antidepressant, dose


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