Skip to main content
SpringerLink
Log in

Levomilnacipran Extended-Release: A Review of Its Use in Adult Patients with Major Depressive Disorder

  • Adis Drug Evaluation
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

Oral levomilnacipran extended-release (ER) [Fetzima™], the more active enantiomer of milnacipran, is the most recent serotonin norepinephrine reuptake inhibitor to be approved in the USA for the treatment of adults with major depressive disorder (MDD). MDD is characterized by depression and impairment of cognitive, social and work functioning. Once-daily levomilnacipran ER 40–120 mg was an effective and generally well-tolerated treatment in adults with MDD participating in 8-week phase III trials and a 1-year extension study. After 8 weeks, levomilnacipran ER treatment was associated with significantly greater and clinically meaningful improvements in depressive symptoms than placebo treatment and, in general, higher Montgomery-Asberg Depression Rating Scale responder rates and greater improvements in functional outcomes than placebo. The efficacy of levomilnacipran ER was maintained during the extension study, with no new safety signals detected; ongoing postmarketing evidence should more fully define the long-term safety of levomilnacipran ER. In the absence of head-to-head clinical trials, the relative position of levomilnacipran ER to that of other antidepressants remains to be determined. In the meantime, it is a useful addition to pharmacological options for the treatment of adult patients with MDD. This article summarizes the clinical use of oral levomilnacipran ER in adults with MDD, and briefly reviews the pharmacological properties of levomilnacipran.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Shim RS, Baltrus P, Ye J, et al. Prevalence, treatment, and control of depressive symptoms in the United States: results from the National Health and Nutrition Examination Survey (NHANES), 2005–2008. J Am Board Fam Med. 2011;24(1):33–8.

    Article  PubMed Central  PubMed  Google Scholar 

  2. Lepine J-P, Briley M. The increasing burden of depression. Neuropsychiatr Dis Treat. 2011;7(Suppl 1):3–7.

    PubMed Central  PubMed  Google Scholar 

  3. Kessler RC. The costs of depression. Psychiatr Clin North Am. 2012;35(1):1–14.

    Article  PubMed Central  PubMed  Google Scholar 

  4. Ferrari AJ, Charlson FJ, Norman RE, et al. The epidemiological modelling of major depressive disorder: application for the Global Burden of Disease study 2010. PLoS One. 2013;8(7):e69637.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Kessler RC, Petukhova M, Sampson NA, et al. Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. Int J Methods Psychiatr Res. 2012;21(3):169–84.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Holtzheimer PE, Mayberg HS. Stuck in a rut: rethinking depression and its treatment. Trends Neurosci. 2011;34(1):1–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Ferrari AJ, Charlson FJ, Norman RE, et al. Burden of depressive disorders by country, sex, age, and year: findings from the Global Burden of Disease study 2010. PLoS Med. 2013;10(11):e1001547.

    Article  PubMed Central  PubMed  Google Scholar 

  8. American Psychiatric Association. Practice guidelines for the treatment of patients with major depressive disorder, 3rd edn. 2010. http://psychiatryonline.org/content.aspx?bookid=28&sectionid=1667485. Accessed 29 Jul 2014.

  9. Davidson JRT. Major depressive disorder treatment guidelines in America and Europe. J Clin Psychiatry. 2010;71(Suppl E1):e04.

  10. Nutt DJ, Davidson JRT, Gelenberg AJ, et al. International consensus statement on major depressive disorder. J Clin Psychiatry. 2010;71(Suppl E1):e08.

  11. Forest Pharamceuticals Inc. Fetzima™ (levomilnacipran) extended-release capsules, for oral use: US prescribing information. 2013. http://www.frx.com/pi/fetzima_pi.pdf. Accessed 18 Jul 2014.

  12. Auclair AL, Martel JC, Assie MB, et al. Levomilnacipran (F2695), a norepinephrine-preferring SNRI: profile in vitro and in models of depression and anxiety. Neuropharmacology. 2013;70:338–47.

    Article  CAS  PubMed  Google Scholar 

  13. Belmaker RH, Agam G. Major depressive disorder. N Engl J Med. 2008;358(1):55–68.

    Article  CAS  PubMed  Google Scholar 

  14. O’Connor J, Chen L, Gommoll C, et al. Levomilnacipran inhibits both norepinephrine and serotonin reuptake across the clinical dose range [abstract no. W191]. Neuropsychopharmacology. 2013;38(Suppl):S563–4.

    Google Scholar 

  15. Chen L, Chen C, Carrothers TJ et al. Evaluation of effects of sequential multiple-dose regimens of levomilnacipran ER on cardiac repolarization in healthy subjects [poster]. Presented at the American Society for Clinical Pharmacology and Therapeutics Meeting; March 18–22 2014, Atlanta.

  16. Carrothers TJ, Khariton T, Chen C, et al. Population pharmacokinetic model for levomilnacipran in healthy subjects and patients with major depressive disorder [abstract no. T-008]. J Pharmacokinet Pharmacodyn. 2013;40(Suppl):S61–3.

    Google Scholar 

  17. Chen L, Periclou A, Ghahramani P et al. Pharmacokinetic characteristics of levomilnacipran sustained released capsule following single- and multiple-dose administration [poster]. Presented at the 166th Annual American Psychiatric Association Meeting; May 18–22 2013, San Francisco.

  18. Chen L, Boinpally R, Gad N et al. Drug-drug interactions of levomilnacipran sustained release capsule with ketoconazole, carbamazepine, or alprazolam in healthy subjects [poster]. Presented at the 166th Annual American Psychiatric Association Meeting; May 18–22 2013, San Francisco.

  19. Chen L, Carrothers TJ, Periclou A et al. A single-dose pharmacokinetic study of levomilnacipran SR in subjects with normal or impaired renal function [poster]. Presented at the 53rd Annual New Clinical Drug Evaluation Unit Meeting; May 28–31 2013, Hollywood.

  20. Chen L, Boinpally R, Greenberg WM, et al. Effect of hepatic impairment on the pharmacokinetics of levomilnacipran following a single oral dose of a levomilnacipran extended-release capsule in human participants. Clin Drug Investig. 2014;34(5):351–9.

    Article  CAS  PubMed  Google Scholar 

  21. Asnis GM, Bose A, Gommoll CP. Efficacy and safety of levomilnacipran sustained release 40 mg, 80 mg, or 120 mg in major depressive disorder: a phase 3, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2013;74(3):242–8.

    Article  CAS  PubMed  Google Scholar 

  22. Bakish D, Bose A, Gommoll C, et al. Levomilnacipran ER 40 mg and 80 mg in patients with major depressive disorder: a phase III, randomized, double-blind, fixed-dose, placebo-controlled study. J Psychiatry Neurosci. 2014;39(1):40–9.

    Article  PubMed Central  PubMed  Google Scholar 

  23. Sambunaris A, Bose A, Gommoll CP, et al. A phase III, double-blind, placebo-controlled, flexible-dose study of levomilnacipran extended-release in patients with major depressive disorder. J Clin Psychopharmacol. 2013;29(10):47–56.

    Google Scholar 

  24. Gommoll CP, Greenberg WM, Chen C. A randomized, double-blind, placebo-controlled study of flexible doses of levomilnacipran ER (40–120 mg/day) in patients with major depressive disorder. J Drug Assess. 2014;3:10–9.

    Google Scholar 

  25. Montgomery SA, Mansuy L, Ruth A, et al. Efficacy and safety of levomilnacipran sustained release in moderate to severe major depressive disorder: a randomized, double-blind, placebo- controlled, proof-of-concept study. J Clin Psychiatry. 2013;74(4):363–9.

    Article  CAS  PubMed  Google Scholar 

  26. Montgomery SA, Mansuy L, Ruth AC, et al. The efficacy of extended-release levomilnacipran in moderate to severe major depressive disorder: secondary and post-hoc analyses from a randomized, double-blind, placebo-controlled study. Int Clin Psychopharmacol. 2014;29(1):26–35.

    Article  PubMed  Google Scholar 

  27. Gommoll C, Greenberg WM, Chen C, et al. Post hoc analyses of levomilnacipran SR 40, 80, and 120 mg on functional outcomes in major depressive disorder [abstract no. P.2.b.018]. Eur Neuropsychopharmacol. 2013;23(Suppl 2):S329.

    Article  Google Scholar 

  28. Montgomery S, Gommoll C, Chen C. Levomilnacipran SR efficacy in major depressive disorder (MDD) across patient subgroups: pooled analysis of 5 double-blind, placebo-controlled trials [abstract no. P.2.b.029]. Eur Neuropsychopharmacol. 2013;23(Suppl 2):S336.

    Article  Google Scholar 

  29. Greenberg W, Gommoll C, Bose A, et al. Levomilnacipran in the treatment of major depressive disorder: an analysis of efficacy and safety data from two phase III studies [abstract no. P.2.c.021]. Eur Neuropsychopharmacol. 2012;22(Suppl 2):S262.

    Article  Google Scholar 

  30. Freeman M, Fava M, Gommoll C et al. The efficacy of levomilnacipran ER in the treatment of patients with depression-associated fatigue symptoms [poster no. NR6-100]. Presented at the 167th Annual American Psychiatric Association Meeting; May 3–7 2014, New York.

  31. Shiovitz T, Greenberg WM, Chen C, et al. A randomized, double-blind, placebo-controlled trial of the efficacy and safety of levomilnacipran ER 40–120 mg/day for prevention of relapse in patients with major depressive disorder. Innov Clin Neurosci. 2014;11(1–2):10–22.

    PubMed Central  PubMed  Google Scholar 

  32. Blum SI, Tourkodimitris S, Gommoll C et al. Sustained improvement in functional health and well-being in MDD patients following long-term treatment with levomilnacipran SR [poster]. Presented at the 53rd Annual New Clinical Drug Evaluation Unit Meeting; May 28–31 2013, Hollywood.

  33. Mago R, Forero G, Greenberg WM. Safety and tolerability of levomilnacipran ER in major depressive disorder: results from an open-label, 48-week extension study. Clin Drug Investig. 2013;33(10):761–71.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Rutherford BR, Roose SP. A model of placebo response in antidepressant trials. Am J Psychiatry. 2013;170(7):723–33.

    Article  PubMed Central  PubMed  Google Scholar 

  35. Citrome L. Levomilnacipran for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antidepressant. What is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract. 2013;67(11):1089–104.

    Article  CAS  PubMed  Google Scholar 

  36. Fava M, Freeman M, Gommoll C et al. Levomilnacipran ER for fatigue associated with major depressive disorder: a double-blind, randomized, placebo- and active-controlled study [poster]. Presented at the US Psychiatric and Mental Health Congress; Sep 30–Oct 3 2013, Las Vegas.

  37. Sambunaris A, Gommoll C, Chen C, et al. Efficacy of levomilnacipran extended-release in improving functional impairment associated with major depressive disorder: pooled analyses of five double-blind, placebo-controlled trials. Int Clin Psychopharmacol. 2014;29(4):197–205.

    Article  PubMed Central  PubMed  Google Scholar 

  38. Blum SI, Tourkodimitris S, Ruth A. Evaluation of functional health and well-being in patients receiving levomilnacipran ER for the treatment of major depressive disorder. J Affect Dis. 2014. doi:10.1016/j.jad.2014.09.005.

    PubMed  Google Scholar 

  39. Palmer R, Shrestha P, Greenberg WM et al. Cardiovascular safety profile of levomilnacipran SR in the treatment of major depressive disorder [poster]. Presented at the 166th Annual American Psychiatric Association Meeting; May 18–22 2013, San Francisco.

  40. Richelson E. Multi-modality: a new approach for the treatment of major depressive disorder. Int J Neuropsychopharmacol. 2013;16:1433–42.

    Article  CAS  PubMed Central  Google Scholar 

  41. Palmer EC, Binns LN, Carey H. Levomilnacipran: a new serotonin-norepinephrine reuptake inhibitor for the treatment of major depressive disorder. Ann Pharmacother. 2014. doi:10.1177/1060028014535074.

    Google Scholar 

Download references

Disclosure

The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the authors on the basis of scientific and editorial merit. Lesley Scott is a salaried employee of Adis/Springer.

Author information

Authors and Affiliations

  1. Springer, Private Bag 65901, Mairangi Bay 0754, Auckland, New Zealand

    Lesley J. Scott

Authors
  1. Lesley J. Scott
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lesley J. Scott.

Additional information

The manuscript was reviewed by: D. Bakish, Ottawa Psychopharmacology Clinic, Ottawa, ON, Canada; R.T. Joffe, New Jersey Medical School, Department of Psychiatry, Maplewood, NJ, USA; E.C. Palmer, Sullivan University College of Pharmacy, Louisville, KY, USA; J.W. Stewart, Columbia University College of Physicians and Surgeons, Department of Psychiatry, New York, NY, USA.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Scott, L.J. Levomilnacipran Extended-Release: A Review of Its Use in Adult Patients with Major Depressive Disorder. CNS Drugs 28, 1071–1082 (2014). https://doi.org/10.1007/s40263-014-0203-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40263-014-0203-1

Keywords

Search

Navigation