Skip to main content
SpringerLink
Log in

Characterisation of Agomelatine-Induced Increase in Liver Enzymes: Frequency and Risk Factors Determined from a Pooled Analysis of 7605 Treated Patients

  • Original Research Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

Background

Antidepressant-induced liver injury is a major concern and a liver monitoring scheme has been recommended by the European Medicines Agency for agomelatine.

Objective

The objective of this study was to assess the liver safety and identify the characteristics of patients who developed a significant increase in transaminases whilst taking agomelatine.

Method

A retrospective pooled analysis of changes in transaminase levels in 9234 patients treated with agomelatine (25 or 50 mg/day; n = 7605) or placebo (n = 1629) from 49 phase II and III studies was undertaken. A significant increase in transaminase levels was defined as an increase to >3 times the upper limit of normal (ULN) (>3 × ULN). Final causality was determined in a case-by-case review by five academic experts.

Results

Serum transaminases increased to >3 × ULN in 1.3 and 2.5 % of patients treated with 25 and 50 mg of agomelatine, respectively, compared with 0.5 % for placebo. The onset of increased transaminases occurred before 12 weeks in 64 % of patients. The median time to recovery (to ≤2 × ULN) was 14 days following treatment withdrawal. Liver function tests recovered in 36.1 % of patients despite continuation of agomelatine, suggesting the presence of a liver adaptive mechanism. No cases of acute liver failure or fatal outcome occurred. Patients with elevated transaminases at baseline, secondary to obesity/fatty liver disease, had an equally increased risk of developing further elevations of transaminases with agomelatine and placebo.

Conclusion

Incidence of abnormal transaminases was low and dose dependent. No specific population was identified regarding potential risk factors. Withdrawal of agomelatine led to rapid recovery, and some patients exhibited an adaptive phenomenon. Overall, in clinical trials, the liver profile of agomelatine seems safe when serum transaminases are monitored.

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. European Medicines Agency. Agomelatine. Summary of product characteristics. 2016. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000915/WC500046227.pdf. Accessed 2 June 2016.

  2. Montgomery SA, Kennedy SH, Burrows GD, Lejoyeux M, Hindmarch I. 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  CAS  PubMed  Google Scholar 

  3. Bissell DM. Assessing fibrosis without a liver biopsy: are we there yet? Gastroenterology. 2004;127(6):1847–9.

    Article  PubMed  Google Scholar 

  4. Calabrese JR, Guelfi JD, Perdrizet-Chevallier C, Agomelatine Bipolar Study Group. Agomelatine adjunctive therapy for acute bipolar depression: preliminary open data. Bipolar Disord. 2007;9(6):628–35. doi:10.1111/j.1399-5618.2007.00507.x.

    Article  CAS  PubMed  Google Scholar 

  5. Corruble E, de Bodinat C, Belaidi C, Goodwin GM, Agomelatine study group. Efficacy of agomelatine and escitalopram on depression, subjective sleep and emotional experiences in patients with major depressive disorder: a 24-wk randomized, controlled, double-blind trial. Int J Neuropsychopharmacol. 2013;16(10):2219–34. doi:10.1017/S1461145713000679.

    Article  CAS  PubMed  Google Scholar 

  6. Demyttenaere K, Corruble E, Hale A, Quera-Salva MA, Picarel-Blanchot F, Kasper S. A pooled analysis of six month comparative efficacy and tolerability in four randomized clinical trials: agomelatine versus escitalopram, fluoxetine, and sertraline. CNS Spectr. 2013;18(3):163–70. doi:10.1017/S1092852913000060.

    Article  PubMed  Google Scholar 

  7. Goodwin GM, Boyer P, Emsley R, Rouillon F, de Bodinat C. Is it time to shift to better characterization of patients in trials assessing novel antidepressants? An example of two relapse prevention studies with agomelatine. Int Clin Psychopharmacol. 2013;28(1):20–8. doi:10.1097/YIC.0b013e32835b0814.

    Article  PubMed  Google Scholar 

  8. Goodwin GM, Emsley R, Rembry S, Rouillon F, Agomelatine Study Group. 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. doi:10.4088/JCP.08m04548.

    Article  PubMed  Google Scholar 

  9. Hale A, Corral RM, Mencacci C, Ruiz JS, Severo CA, Gentil V. Superior antidepressant efficacy results of agomelatine versus fluoxetine in severe MDD patients: a randomized, double-blind study. Int Clin Psychopharmacol. 2010;25(6):305–14. doi:10.1097/YIC.0b013e32833a86aa.

    Article  PubMed  Google Scholar 

  10. Heun R, Ahokas A, Boyer P, Gimenez-Montesinos N, Pontes-Soares F, Olivier V, et al. The efficacy of agomelatine in elderly patients with recurrent major depressive disorder: a placebo-controlled study. J Clin Psychiatry. 2013;74(6):587–94. doi:10.4088/JCP.12m08250.

    Article  CAS  PubMed  Google Scholar 

  11. Kasper S, Hajak G, Wulff K, Hoogendijk WJ, Montejo AL, Smeraldi E, 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. doi:10.4088/JCP.09m05347blu.

    Article  CAS  PubMed  Google Scholar 

  12. Kennedy SH, Avedisova A, Gimenez-Montesinos N, Belaidi C, de Bodinat C, Agomelatine Study Group. A placebo-controlled study of three agomelatine dose regimens (10 mg, 25 mg, 25-50 mg) in patients with major depressive disorder. Eur Neuropsychopharmacol. 2014;24(4):553–63. doi:10.1016/j.euroneuro.2014.01.006.

    Article  CAS  PubMed  Google Scholar 

  13. Kennedy SH, Emsley R. Placebo-controlled trial of agomelatine in the treatment of major depressive disorder. Eur Neuropsychopharmacol. 2006;16(2):93–100. doi:10.1016/j.euroneuro.2005.09.002.

    Article  CAS  PubMed  Google Scholar 

  14. Kennedy SH, Rizvi S, Fulton K, Rasmussen J. A double-blind comparison of sexual functioning, antidepressant efficacy, and tolerability between agomelatine and venlafaxine XR. J Clin Psychopharmacol. 2008;28(3):329–33. doi:10.1097/JCP.0b013e318172b48c.

    Article  CAS  PubMed  Google Scholar 

  15. Kennedy SH, Rizvi SJ. Agomelatine in the treatment of major depressive disorder: potential for clinical effectiveness. CNS Drugs. 2010;24(6):479–99. doi:10.2165/11534420-000000000-00000.

    Article  CAS  PubMed  Google Scholar 

  16. 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(11):1723–32.

    Article  CAS  PubMed  Google Scholar 

  17. Loo H, Hale A, D’Haenen H. Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT(2C) antagonist, in the treatment of major depressive disorder: a placebo-controlled dose range study. Int Clin Psychopharmacol. 2002;17(5):239–47.

    Article  CAS  PubMed  Google Scholar 

  18. 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(5):661–73. doi:10.1017/S1461145707007766.

    CAS  PubMed  Google Scholar 

  19. Pjrek E, Winkler D, Konstantinidis A, Willeit M, Praschak-Rieder N, Kasper S. Agomelatine in the treatment of seasonal affective disorder. Psychopharmacology. 2007;190(4):575–9. doi:10.1007/s00213-006-0645-3.

    Article  CAS  PubMed  Google Scholar 

  20. Quera Salva MA, Vanier B, Laredo J, Hartley S, Chapotot F, Moulin C, et al. Major depressive disorder, sleep EEG and agomelatine: an open-label study. Int J Neuropsychopharmacol. 2007;10(5):691–6. doi:10.1017/S1461145707007754.

    CAS  PubMed  Google Scholar 

  21. Quera-Salva MA, Hajak G, Philip P, Montplaisir J, Keufer-Le Gall S, Laredo J, et al. Comparison of agomelatine and escitalopram on nighttime sleep and daytime condition and efficacy in major depressive disorder patients. Int Clin Psychopharmacol. 2011;26(5):252–62. doi:10.1097/YIC.0b013e328349b117.

    Article  PubMed  Google Scholar 

  22. Shu L, Sulaiman AH, Huang YS, Fones Soon Leng C, Crutel VS, Kim YS. Comparable efficacy and safety of 8 weeks treatment with agomelatine 25–50 mg or fluoxetine 20–40 mg in Asian out-patients with major depressive disorder. Asian J Psychiatry. 2014;8:26–32. doi:10.1016/j.ajp.2013.09.009.

  23. Stahl SM, Fava M, Trivedi MH, Caputo A, Shah A, Post A. Agomelatine in the treatment of major depressive disorder: an 8-week, multicenter, randomized, placebo-controlled trial. J Clin Psychiatry. 2010;71(5):616–26. doi:10.4088/JCP.09m05471blu.

    Article  CAS  PubMed  Google Scholar 

  24. Stein DJ, Ahokas A, Albarran C, Olivier V, Allgulander C. Agomelatine prevents relapse in generalized anxiety disorder: a 6-month randomized, double-blind, placebo-controlled discontinuation study. J Clin Psychiatry. 2012;73(7):1002–8. doi:10.4088/JCP.11m07493.

    Article  CAS  PubMed  Google Scholar 

  25. Stein DJ, Ahokas A, Marquez MS, Hoschl C, Oh KS, Jarema M, et al. Agomelatine in generalized anxiety disorder: an active comparator and placebo-controlled study. J Clin Psychiatry. 2014;75(4):362–8. doi:10.4088/JCP.13m08433.

    Article  CAS  PubMed  Google Scholar 

  26. 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(5):561–6. doi:10.1097/JCP.0b013e318184ff5b.

    Article  CAS  PubMed  Google Scholar 

  27. Stein DJ, Picarel-Blanchot F, Kennedy SH. Efficacy of the novel antidepressant agomelatine for anxiety symptoms in major depression. Hum Psychopharmacol. 2013;28(2):151–9. doi:10.1002/hup.2294.

    Article  CAS  PubMed  Google Scholar 

  28. Yatham LN, Vieta E, Goodwin GM, Bourin M, de Bodinat C, Laredo J, et al. Agomelatine or placebo as adjunctive therapy to a mood stabiliser in bipolar I depression: randomised double-blind placebo-controlled trial. Br J Psychiatry. 2016;208(1):78–86. doi:10.1192/bjp.bp.114.147587.

    Article  PubMed  Google Scholar 

  29. Zajecka J, Schatzberg A, Stahl S, Shah A, Caputo A, Post A. Efficacy and safety of agomelatine in the treatment of major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled trial. J Clin Psychopharmacol. 2010;30(2):135–44. doi:10.1097/JCP.0b013e3181d420a7.

    Article  CAS  PubMed  Google Scholar 

  30. Delaveau P, Jabourian M, Lemogne C, Allaili N, Choucha W, Girault N, et al. Antidepressant short-term and long-term brain effects during self-referential processing in major depression. Psychiatry Res. 2016;247:17–24. doi:10.1016/j.pscychresns.2015.11.007.

    Article  PubMed  Google Scholar 

  31. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Guidance for industry. Drug-induced liver injury: premarketing clinical evaluation. 2009. http://www.fda.gov/downloads/Drugs/…/Guidances/UCM174090.pdf. Accessed 23 May 2016.

  32. Voican CS, Corruble E, Naveau S, Perlemuter G. Antidepressant-induced liver injury: a review for clinicians. Am J Psychiatry. 2014;171(4):404–15.

    Article  PubMed  Google Scholar 

  33. Gahimer J, Wernicke J, Yalcin I, Ossanna MJ, Wulster-Radcliffe M, Viktrup L. A retrospective pooled analysis of duloxetine safety in 23,983 subjects. Curr Med Res Opin. 2007;23(1):175–84.

    Article  CAS  PubMed  Google Scholar 

  34. Rudolph RL, Derivan AT. The safety and tolerability of venlafaxine hydrochloride: analysis of the clinical trials database. J Clin Psychopharmacol. 1996;16(3 Suppl 2):54S–9S (discussion 9S–61S).

  35. De Valle MB, Av Klinteberg V, Alem N, Olsson R, Bjornsson E. Drug-induced liver injury in a Swedish University hospital out-patient hepatology clinic. Aliment Pharmacol Ther. 2006;24(8):1187–95.

    Article  PubMed  Google Scholar 

  36. Lucena MI, Andrade RJ, Kaplowitz N, Garcia-Cortes M, Fernandez MC, Romero-Gomez M, et al. Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex. Hepatology. 2009;49(6):2001–9.

    Article  PubMed  Google Scholar 

  37. Bell LN, Chalasani N. Epidemiology of idiosyncratic drug-induced liver injury. Semin Liver Dis. 2009;29(4):337–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rosenzweig P, Miget N, Brohier S. Transaminase elevation on placebo during phase I trials: prevalence and significance. Br J Clin Pharmacol. 1999;48(1):19–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Perlemuter G, Bigorgne A, Cassard-Doulcier AM, Naveau S. Nonalcoholic fatty liver disease: from pathogenesis to patient care. Nat Clin Pract Endocrinol Metab. 2007;3(6):458–69.

    Article  CAS  PubMed  Google Scholar 

  40. Russmann S, Kullak-Ublick GA, Grattagliano I. Current concepts of mechanisms in drug-induced hepatotoxicity. Curr Med Chem. 2009;16(23):3041–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lammert C, Einarsson S, Saha C, Niklasson A, Bjornsson E, Chalasani N. Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals. Hepatology. 2008;47(6):2003–9.

    Article  CAS  PubMed  Google Scholar 

  42. Reuben A. Hy’s law. Hepatology. 2004;39(2):574–8.

    Article  PubMed  Google Scholar 

  43. Bjornsson E. Review article: drug-induced liver injury in clinical practice. Aliment Pharmacol Ther. 2010;32(1):3–13.

    Article  CAS  PubMed  Google Scholar 

  44. Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, et al. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med. 2006;174(8):935–52.

    Article  CAS  PubMed  Google Scholar 

  45. Watkins PB. Idiosyncratic liver injury: challenges and approaches. Toxicol Pathol. 2005;33(1):1–5.

    Article  CAS  PubMed  Google Scholar 

  46. Gruz F, Raffa S, Santucci C, Papale RM, Videla MG, Fernandez MG, et al. Agomelatine: fulminant liver failure in a patient with fatty liver [in Spanish]. Gastroenterol Hepatol. 2014;37(2):92–4. doi:10.1016/j.gastrohep.2013.04.008.

    Article  PubMed  Google Scholar 

  47. Gartlehner G, Gaynes BN, Hansen RA, Thieda P, DeVeaugh-Geiss A, Krebs EE, et al. Comparative benefits and harms of second-generation antidepressants: background paper for the American College of Physicians. Ann Intern Med. 2008;149(10):734–50.

    Article  PubMed  Google Scholar 

  48. Cooper GL. The safety of fluoxetine–an update. Br J Psychiatry Suppl. 1988;3:77–86.

    PubMed  Google Scholar 

  49. DeSanty KP, Amabile CM. Antidepressant-induced liver injury. Ann Pharmacother. 2007;41(7):1201–11. doi:10.1345/aph.1K114.

    Article  CAS  PubMed  Google Scholar 

  50. Taylor D, Sparshatt A, Varma S, Olofinjana O. Antidepressant efficacy of agomelatine: meta-analysis of published and unpublished studies. BMJ. 2014;348:g1888. doi:10.1136/bmj.g1888.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Authorship statement

GP, PC, DV, DG and KM analysed all of the suspected cases of liver injury. GP wrote the manuscript. PC, DV, DG, BS and KM corrected the manuscript. BS and CB performed the statistical analyses.

Author information

Authors and Affiliations

  1. Univ. Paris-Sud, Univ. Paris-Saclay, CHU Bicêtre, 94270, Kremlin-Bicêtre, France

    Gabriel Perlemuter

  2. AP-HP, Hôpital Antoine-Béclère, Service d’Hépato-Gastroentérologie et Nutrition, DHU Hepatinov, 157 rue de la Porte de Trivaux, 92140, Clamart, France

    Gabriel Perlemuter

  3. INSERM U996, IPSIT, Labex Lermit, Clamart, France

    Gabriel Perlemuter

  4. Sorbonne Universités, UPMC Université Paris 06, UMR 7211, Paris, France

    Patrice Cacoub

  5. Inflammation-Immunopathology-Biotherapy Department (DHU i2B), 75005, Paris, France

    Patrice Cacoub

  6. INSERM, UMR_S 959, 75013, Paris, France

    Patrice Cacoub

  7. CNRS, FRE3632, 75005, Paris, France

    Patrice Cacoub

  8. Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, 75013, Paris, France

    Patrice Cacoub

  9. DHU UNITY, Service d’Hépatologie, AP-HP, Hôpital Beaujon, Clichy, France

    Dominique Valla

  10. CRI, UMR1149, Université Paris Diderot, Paris, France

    Dominique Valla

  11. INSERM U1149, Paris, France

    Dominique Valla

  12. Liver Disease Unit and INSERM U991, CHU Pontchaillou, Rennes, France

    Dominique Guyader

  13. University of Rennes 1, CHU de Rennes, Rennes, France

    Dominique Guyader

  14. Institut de Recherches Internationales Servier, 92415, Suresnes, France

    Barbara Saba & Cécile Batailler

  15. UCL Institute of Liver and Digestive Health, University College London, Royal Free Campus, London, UK

    Kevin Moore

Authors
  1. Gabriel Perlemuter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Patrice Cacoub
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dominique Valla
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dominique Guyader
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Barbara Saba
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cécile Batailler
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kevin Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gabriel Perlemuter.

Ethics declarations

Funding

This work was supported by Servier Pharmaceuticals.

Conflict of interest

GP, PC, DV, DG and KM belong to the liver safety committee and received fees from Servier Pharmaceuticals. GP has also received travel funds from Janssen, Abbvie and Gilead, consulting fees from Bayer, Biocodex and Gilead, and royalties from Elsevier-Masson, John Libbey Eurotext and Solar. PC has also received fees from Abbvie, AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Janssen, Merck Sharp Dohme, Pfizer, Roche, Servier and Vifor. PC is an inventor of a patent application owned by his academic institution and licensed to ILTOO Pharma, a biotechnology company developing low-dose interleukin-2 in autoimmune diseases, in which he holds shares. DV has also received consulting fees from Sequana Medical. DG has also received consulting fees from Abbvie, Roche, MSD, Gilead, BMS, Janssen and Alios. BS and CB have received salaries from Servier.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Perlemuter, G., Cacoub, P., Valla, D. et al. Characterisation of Agomelatine-Induced Increase in Liver Enzymes: Frequency and Risk Factors Determined from a Pooled Analysis of 7605 Treated Patients. CNS Drugs 30, 877–888 (2016). https://doi.org/10.1007/s40263-016-0351-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40263-016-0351-6

Keywords

Search

Navigation