Skip to main content
Log in

A Benefit-Risk Assessment of Agomelatine in the Treatment of Major Depression

  • Review Article
  • Published:
Drug Safety Aims and scope Submit manuscript

Abstract

Agomelatine is an antidepressant drug that is a synthetic analogue of the hormone melatonin. It stimulates the activity of melatonin MT1 and MT2 receptors and inhibits the activity of serotonin 5HT2C receptor subtypes.

The objective of this article is to critically review and evaluate the benefits and risks of agomelatine for the treatment of major depression. The published literature through April 2011 for articles relating to agomelatine, together with unpublished data on agomelatine available from the European Medicines Agency, the US FDA, US ClinicalTrials.gov and the Novartis Clinical Trial Results Database are reviewed.

The antidepressant efficacy of agomelatine has been systematically assessed in ten short-term, placebo-controlled studies and three longer-term, placebo-controlled, relapse prevention studies. Five short-term trials demonstrated clinically modest, but statistically significant, benefits over placebo, although two of these studies reported opposite effects for 25 mg versus 50 mg doses. The other five short-term trials did not find agomelatine more effective than placebo, but in two of these studies the active control drug was more effective than placebo.

A meta-analysis of six European trials demonstrated a small, statistically significant, marginally clinically relevant difference in efficacy favouring agomelatine over placebo. The only placebo-controlled study in elderly patients did not demonstrate a significant benefit for agomelatine. Agomelatine was shown to be more effective than placebo in one of three relapse prevention studies.

Agomelatine was generally well tolerated compared with placebo. Its adverse effect profile is different to that of other antidepressant drugs, but its overall tolerability in studies with other antidepressants as active control drugs did not appear to be substantially better than the controls. Agomelatine is contraindicated in patients with impaired liver function and in patients taking drugs that potently inhibit cytochrome P450 1A2 metabolic enzymes. Because elevated liver enzymes are common, and there is a rare risk of more serious liver reactions, routine laboratory monitoring of liver function is recommended periodically throughout treatment. Based on this comprehensive review, agomelatine does not have clinically significant advantages compared with other antidepressant drugs, and it has certain limitations and disadvantages. Because of the unique pharmacology of agomelatine and its reported tolerability profile, it should only be considered as an alternative drug for patients who do not respond to or cannot tolerate other antidepressant drugs.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Table I

Similar content being viewed by others

References

  1. Hirschfeld RMA, Weissman MM. Risk factors for major depression and bipolar disorder. In: Davis KL, Charney D, Coyle JT, et al., editors. Neuropsychopharmacology: the fifth generation of progress. Philadelphia (PA): Lippincott Williams s Wilkins, 2002: 1017–25

    Google Scholar 

  2. Browne G, Steiner M, Roberts J, et al. Prevalence of dysthymic disorder in primary care. J Affect Disord 1999; 54: 303–8

    Article  PubMed  Google Scholar 

  3. Kessler RC, Zhao S, Blazer DG, et al. Prevalence, correlates, and course of minor depression and major depression in the National Comorbidity Survey. J Affect Disord 1997; 45: 19–30

    Article  PubMed  CAS  Google Scholar 

  4. Howland RH. Health status, health care utilization, and medical comorbidity in dysthymia. Int J Psychiatry Med 1993; 23(3): 211–38

    Article  PubMed  CAS  Google Scholar 

  5. Howland RH, Schettler PJ, Rapaport MH, et al. Clinical features and functioning of patients with minor depression. Psychother Psychosom 2008; 77: 384–9

    Article  PubMed  Google Scholar 

  6. Rush AJ, Kraemer HC, Sackeim HA, et al. Report by the ACNP task force on response and remission in major depression. Neuropsychopharmacol 2006; 31: 1841–53

    Article  Google Scholar 

  7. Koplan C, Charuvastra A, Compton MT, et al. Prevention psychiatry. Psychiatr Ann 2007; 37: 319–28

    Google Scholar 

  8. Baune BT, Adrian I, Jacobi F. Medical disorders affect health outcome and general functioning depending on comorbid major depression in the general population. J Psychosomatic Res 2007; 62: 109–18

    Article  Google Scholar 

  9. Howland RH. Therapeutic armamentarium for treating depression. Postgrad Med 2010; 122(4): 66–93

    Article  PubMed  Google Scholar 

  10. de Bodinat C, Guardiola-Lemaitre B, Mocaer E, et al. Agomelatine, the first melatonergic antidepressant: discovery, characterization, and development. Nat Rev Drug Discov 2010; 9(8): 628–42

    PubMed  Google Scholar 

  11. European Medicines Agency. CMHP assessment report for valdoxan. 20 November 2008 [online]. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000915/WC500046226.pdf [Accessed 2011 Jul 13]

  12. European Medicines Agency, Committee for Medicinal Products for Human Use. Summary of positive opinion for valdoxan. 20 November 2008. Doc. Ref. EMEA/ CHMP/575411/2008 [online]. Available from URL: http://www.emea.europa.eu/pdfs/human/opinion/Valdoxan_57541108en.pdf [Accessed 2011 Jul 13]

  13. European Medicines Agency. Valdoxan product information: summary of product characteristics [online]. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000915/WC500046227.pdf [Accessed 2011 Jul 13]

  14. United States Food and Drug Administration [online]. Available from URL: http://www.fda.gov/ [Accessed 2011 Jul 13]

  15. ClinicalTrials.gov, a service of the US National Institutes of Health [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jul 13]

  16. Zlotos DP. Recent advances in melatonin receptor ligands. Arch Pharm Chem Life Sci 2005; 338: 229–47

    Article  CAS  Google Scholar 

  17. Rajaratnam SMW, Cohen DA, Rogers NL. Melatonin and melatonin analogues. Sleep Med Clin 2009; 4: 179–93

    Article  Google Scholar 

  18. Landolt HP, Wehrle R. Antagonism of serotonergic 5-HT2A/2C receptors: mutual improvement of sleep, cognition, and mood? Eur J Neurosci 2009; 29: 1795–809

    Article  PubMed  Google Scholar 

  19. Millan MJ, Gobert A, Lejeune F, et al. The novel melatonin agonist agomelatine is an antagonist at 5-hydoxy-tryptamine-2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways. J Pharmacol Exp Ther 2003; 306(3): 954–64

    Article  PubMed  CAS  Google Scholar 

  20. Quera-Salva MA, Vanier B, Laredo J, et al. Major depressive disorder, sleep EEG and agomelatine: an open-label study. Int J Neuropsychopharmacol 2007; 10: 691–6

    PubMed  CAS  Google Scholar 

  21. Kupfer DJ. Depression and associated sleep disturbances: patient benefits with agomelatine. Eur Neuropsychopharmacol 2006; 16 Suppl. 5: S639–43

    Article  CAS  Google Scholar 

  22. Leproult R, Van Onderbergen A, L’Hermite-Baleriaux M, et al. Phase-shifts of 24-h rhythms of hormonal release and body termperature following early evening administration of the melatonin agonist agomelatine in healthy older men. Clin Endocrinol 2005; 63: 298–304

    Article  CAS  Google Scholar 

  23. Descamps A, Rousset C, Millan M, et al. Influence of the novel antidepressant and melatonin agonist/serotonin2C receptor antagonist, agomelatine, on the rat sleep-wake cycle architecture. Psychopharmaology 2009; 2005: 93–106

    Article  Google Scholar 

  24. Racagni G, Riva MA, Popoli M. The interaction between the internal clock and antidepressant efficacy. Int Clin Psychopharmacol 2007; 22 Suppl. 2: S9–14

    Article  PubMed  Google Scholar 

  25. Sharpley AL, Rawlings NB, Brain S, et al. Does agomelatine block 5-HT2c receptors in humans? Psychopharmacology 2011; 213(2-3): 653–5

    Article  PubMed  CAS  Google Scholar 

  26. Hale A, Corral RM, Mencacci C, et al. Superior antidepressant efficacy results of agomelatine versus fluoxetine in severe MDD patients: a randomized double-blind study. Int Clin Psychopharmacol 2010; 25: 305–14

    Article  PubMed  Google Scholar 

  27. Loo H, Hale A, D’Haenen H. Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT2C antagonist, in the treatment of major depressive disorder: a placebo-controlled dose range study. Int Clin Psychopharmacol 2002; 17(5): 239–47

    Article  PubMed  CAS  Google Scholar 

  28. Kennedy SH, Emsley R. Placebo-controlled trial of agomelatine in the treatment of major depressive disorder. Eur Neuropsychopharmacol 2006; 16(2): 93–100

    Article  PubMed  CAS  Google Scholar 

  29. Olie JP, Kasper S. Efficacy of agomelatine, a MT1/MT2 receptor agonist with 5-HT2C antagonistic properties, in major depressive disorder. Int J Neuropsychopharmacol 2007; 10: 661–73

    PubMed  CAS  Google Scholar 

  30. Zajecka J, Schatzberg A, Stahl S, et al. Efficacy and safety of agomelatine in the treatment of major depressive disorder. J Clin Psychopharmacol 2010; 30: 135–44

    Article  PubMed  CAS  Google Scholar 

  31. Stahl SM, Fava M, Trivedi MH, et al. Agomelatine in the treatment of major depressive disorder: an 8-week multicenter randomized placebo-controlled trial. J Clin Psychiatry 2010; 71(5): 616–26

    Article  PubMed  CAS  Google Scholar 

  32. Novartis. Clinical trial results database [online]. Available from URL: http://www.novctrd.com/ctrdWebApp/clinicaltrialrepository/public/login.jsp [Accessed 2011 Jul 13]

  33. Goodwin GM, Emsley R, Rembry S, et al. Agomelatine prevents relapse in patients with major depressive disorder without evidence of a discontinuation syndrome: a 24-week randomized double-blind placebo-controlled trial. J Clin Psychiatry 2009; 70(8): 1128–37

    Article  PubMed  Google Scholar 

  34. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23: 56–62

    Article  PubMed  CAS  Google Scholar 

  35. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134: 382–9

    Article  PubMed  CAS  Google Scholar 

  36. Novartis. A placebo- and paroxetine-controlled study of the efficacy, safety and tolerability of agomelatine (25 or 50 mg) in the treatment of major depressive disorder (MDD) [ClinicalTrials.gov identifier NCT00463242]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jul 13]

  37. Novartis. Efficacy, safety and tolerability of agomelatine in the treatment of major depressive disorder [ClinicalTrials.gov identifier NCT00411242]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jul 13]

  38. Novartis. Efficacy, safety and tolerability of agomelatine in the treatment of major depressive disorder [ClinicalTrials.gov identifier NCT00411099]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jul 13]

  39. Novartis. Efficacy, safety and tolerability of agomelatine in the prevention of relapse of major depressive disorder [ClinicalTrials.gov identifier NCT00467402]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jul 13]

  40. Novartis. Efficacy, safety and tolerability of agomelatine sublingual tablets in the treatment of major depressive disorder [ClinicalTrials.gov identifier NCT01110889]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jul 13]

  41. Novartis. Efficacy, safety and tolerability of agomelatine sublingual tablets in the treatment of major depressive disorder (MDD) [ClinicalTrials.gov identifier NCT01110902]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jul 13]

  42. Novartis. Open-label long term (52 weeks) safety and tolerability of agomelatine sublingual tablets in major depressive disorder (MDD) [ClinicalTrials.gov identifier NCT01156415]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jul 13]

  43. Guy W. Clinical Global Impression (CGI) ECDEU Assessment Manual for Psychopharmacology. US Department of Health Education and Welfare publication (ADM); 1976: 76–338

  44. Loo H, Dalery J, Macher JP. Pilot study comparing in blind the therapeutic effect of two doses of agomelatine, melatoninergic agonist and selective 5HTin2C receptors antagonist, in the treatment of major depressive disorders [in French]. Encephale 2002; 28(4): 356–62

    PubMed  CAS  Google Scholar 

  45. Kennedy SH, Rizvi S, Fulton K, et al. A double-blind comparison of sexual functioning, antidepressant efficacy, and tolerability between agomelatine and venlafaxine XR. J Clin Psychopharmacol 2008; 28: 329–33

    Article  PubMed  CAS  Google Scholar 

  46. Montejo AL, Prieto N, Terleira A, et al. Better sexual acceptability of agomelatine (25 and 50 mg) compared with paroxetine (20 mg) in healthy male volunteers: an 8-week placebo-controlled study using the PRSEXDQ-SALSEX scale. J Psychopharmacol 2010; 24(1): 111–20

    Article  PubMed  CAS  Google Scholar 

  47. Lemoine P, Guilleminault C, Alvarez E. Improvement in subjective sleep in major depressive disorder with a novel antidepressant agomelatine: randomized double-blind comparison with venlafaxine. J Clin Psychiatry 2007; 68: 1723–32

    Article  PubMed  CAS  Google Scholar 

  48. Kasper S, Hajak G, Wulff K, et al. Efficacy of the novel antidepressant agomelatine on the circadian rest-activity cycle and depressive and anxiety symptoms in patients with major depressive disorder: a randomized double-blind comparison with sertraline. J Clin Psychiatry 2010; 71(2): 109–20

    Article  PubMed  CAS  Google Scholar 

  49. Montgomery SA, Kennedy SH, Burrows GD, et al. Absence of discontinuation symptoms with agomelatine and occurrence of discontinuation symptoms with paroxetine: a randomized, double-blind, placebo-controlled discontinuation study. Int Clin Psychopharmacol 2004; 19(5): 271–80

    Article  PubMed  CAS  Google Scholar 

  50. Calabrese JR, Guelfi JD, Perdrizet-Chevallier C. Agomelatine adjunctive therapy for acute bipolar depression: preliminary open data. Bipolar Disord 2007; 9(6): 628–35

    Article  PubMed  CAS  Google Scholar 

  51. Pjrek E, Winkler D, Konstantinidis A, et al. Agomelatine in the treatment of seasonal affective disorder. Psychopharmacology 2007; 190: 575–9

    Article  PubMed  CAS  Google Scholar 

  52. Williams JBW, Link MJ, Rosenthal NE, et al. Structured interview guide for the Hamilton Depression Rating Scale-Seasonal Affective Disorder. 2002 rev. New York (NY): New York State Psychiatric Institute, 2002

    Google Scholar 

  53. Stein DJ, Ahokas AA, de Bodinat C. Efficacy of agomelatine in generalized anxiety disorder: a randomized double-blind placebo-controlled study. J Clin Psychopharmacol 2008; 28: 561–6

    Article  PubMed  CAS  Google Scholar 

  54. Hamilton M. A rating scale for anxiety. J Neurol Neurosurg Psychiatr 1959; 23: 56–62

    Article  Google Scholar 

  55. Fabiano A, de Leersnyder H. Agomelatine efficacy on major sleep disturbances in Smith-Magenis syndrome: an exploratory open study in children [abstract]. Eur Neuro-psychopharmacol 2007; 17 Suppl. 4: S567

    Google Scholar 

  56. Kozian R, Syrbe G. QTc-Zeit-Verlangerung unter Therapie mit Agomelatin. Psychiat Prax 2010; 37: 405–7

    Article  Google Scholar 

  57. National Taiwan University Hospital. The effect of agomelatine or fluoxentine on heart rate variability in patients with major depressive disorder [ClinicalTrials.gov identifier NCT00451490]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jul 13]

  58. Dolder CR, Nelson M, Snider M. Agomelatine treatment of major depressive disorder. Ann Pharmacother 2008; 42: 1822–31

    Article  PubMed  CAS  Google Scholar 

  59. Harmer CJ, de Bodinat C, Dawson GR, et al. Agomelatine facilitates positive versus negative affective processing in healthy volunteer models. J Psychopharmacol. Epub 2010 Jul 21

  60. Wisniewski SR, Rush AJ, Nierenberg AA, et al. Can phase III trial results of antidepressant medications be generalized to clinical practice? A STAR*D report. Am J Psychiatry 2009; 166: 599–607

    Article  PubMed  Google Scholar 

  61. Howland RH. Evaluating the safety of medications during pregnancy and lactation. J Psychosoc Nurs Ment Health Serv 2009; 47(3): 19–22

    Article  Google Scholar 

  62. Howland RH. Prescribing psychotropic medications during pregnancy and lactation: principles and guidelines. J Psychosoc Nurs Ment Health Serv 2009; 47(5): 19–23

    Article  Google Scholar 

  63. Trivedi MH, Rush AJ, Gaynes BN, et al. Maximizing the adequacy of medication treatment in controlled trials and clinical practice: STAR*D measurement-based care. Neuropsychopharmacology 2007; 32: 2479–89

    Article  PubMed  CAS  Google Scholar 

  64. Servier. Efficacy of agomelatine in patients with obsessive-compulsive disorder [ClinicalTrials.gov identifier NCT01108393]. US National Institutes of Health, Clinical Trials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jul 13]

  65. Marqués Cabezas P, Cabus Piñol G, Coullaut-Valera García J, et al. Agomelatine in the treatment of obsessive-compulsive-disorder: potential for clinical effectiveness. A 4-week multicenter randomized placebo-controlled trial [abstract]. Eur Psychiatry 2011; 26 Suppl. 1: 974

    Article  Google Scholar 

  66. Howland RH. Medication adherence. Psychiatr Ann 2008; 38(5): 323–6

    Article  Google Scholar 

  67. Howland RH. Limitations of evidence in the practice of evidence-based medicine. Psychiatr Ann 2008; 38(5): 334–6

    Article  Google Scholar 

  68. Wisniewski SR, Fava M, Trivedi MH, et al. Acceptability of second-step treatments to depressed outpatients: a STAR*D report. Am J Psychiatry 2007; 164: 753–60

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

No sources of funding were used to prepare this manuscript. Dr Howland has received past grant support from Novartis.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Robert H. Howland MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Howland, R.H. A Benefit-Risk Assessment of Agomelatine in the Treatment of Major Depression. Drug-Safety 34, 709–731 (2011). https://doi.org/10.2165/11593960-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11593960-000000000-00000

Keywords

Navigation