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Agomelatine in the treatment of major depressive disorder

Potential for clinical effectiveness

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Abstract

To demonstrate the clinical effectiveness of an antidepressant drug requires evidence beyond short- and long-term efficacy, including a favourable adverse-effect profile and sustained treatment adherence. Under these conditions, patients should experience enhanced social and functional outcomes. The novel antidepressant agomelatine, a melatonergic MT1/MT2 receptor agonist with serotonin 5-HT2C receptor antagonist activity, displays antidepressant efficacy with a favourable adverse-effect profile that is associated with good patient adherence. Specifically, agomelatine has demonstrated significant short-term (6–8 weeks) and sustained (6 months) antidepressant efficacy relative to placebo, as well as evidence of relapse prevention (up to 10 months). In head-to-head comparative studies with venlafaxine and sertraline, there was evidence of early (at 1–2 weeks) and sustained (at 6 months) advantages for agomelatine. In addition to evidence of early efficacy, agomelatine also restored disturbed sleep-wake patterns early in treatment. There was no evidence of antidepressant-induced sexual dysfunction, weight gain or discontinuation-emergent symptoms. Agomelatine has demonstrated a range of properties that suggest it could offer advantages over current treatments for major depressive disorder, although further comparative trials are still required, as is evidence from real-world clinical practice.

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References

  1. Mann JJ. The medical management of depression. N Engl J Med 2005; 353: 1819–34

    Article  PubMed  CAS  Google Scholar 

  2. Judd LL, Akiskal HS, Paulus MP. The role and clinical significance of subsyndromal depressive symptoms (SSD) in unipolar major depressive disorder. J Affect Disord 1997; 45: 5–17

    Article  PubMed  CAS  Google Scholar 

  3. Judd LL, Akiskal HS, Maser JD, et al. A prospective 12-year study of subsyndromal and syndromal depressive symptoms in unipolar major depressive disorders. Arch Gen Psychiatry 1998; 55: 694–700

    Article  PubMed  CAS  Google Scholar 

  4. Judd LL, Schettler PJ, Akiskal HS. The prevalence, clinical relevance, and public health significance of subthreshold depressions. Psychiatr Clin North Am 2002; 25: 685–98

    Article  PubMed  Google Scholar 

  5. Oquendo MA, Barrera A, Ellis SP, et al. Instability of symptoms in recurrent major depression: a prospective study. Am J Psychiatry 2004; 161: 255–61

    Article  PubMed  Google Scholar 

  6. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry 2000; 157: 1–45

    Google Scholar 

  7. Lam RW, Kennedy SH, Grigoriadis S, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults: III. Pharmacotherapy. J Affect Disord 2009; 117Suppl. 1: S26–43

    Article  PubMed  Google Scholar 

  8. Blier P, Keller MB, Pollack MH, et al. Preventing recurrent depression: long-term treatment for major depressive disorder. J Clin Psychiatry 2007; 68: e06

    Article  PubMed  Google Scholar 

  9. Katon W, Rutter C, Ludman EJ, et al. A randomized trial of relapse prevention of depression in primary care. Arch Gen Psychiatry 2001; 58: 241–7

    Article  PubMed  CAS  Google Scholar 

  10. Kennedy S, McIntyre R, Fallu A, et al. Pharmacotherapy to sustain the fully remitted state. J Psychiatry Neurosci 2002; 27: 269–80

    PubMed  Google Scholar 

  11. Kornstein SG, Bose A, Li D, et al. Escitalopram maintenance treatment for prevention of recurrent depression: a randomized, placebo-controlled trial. J Clin Psychiatry 2006; 67: 1767–75

    Article  PubMed  CAS  Google Scholar 

  12. Lepine JP, Caillard V, Bisserbe JC, et al. A randomized, placebo-controlled trial of sertraline for prophylactic treatment of highly recurrent major depressive disorder. Am J Psychiatry 2004; 161: 836–42

    Article  PubMed  Google Scholar 

  13. Paykel ES. Continuation and maintenance therapy in depression. Br Med Bull 2001; 57: 145–59

    Article  PubMed  CAS  Google Scholar 

  14. Rost K, Nutting P, Smith JL, et al. Managing depression as a chronic disease: a randomised trial of ongoing treatment in primary care. BMJ 2002; 325: 934

    Article  PubMed  Google Scholar 

  15. Viguera AC, Baldessarini RJ, Friedberg J. Discontinuing antidepressant treatment in major depression. Harv Rev Psychiatry 1998; 5: 293–306

    Article  PubMed  CAS  Google Scholar 

  16. Geddes JR, Carney SM, Davies C, et al. Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. Lancet 2003; 361: 653–61

    Article  PubMed  CAS  Google Scholar 

  17. Akincigil A, Bowblis JR, Levin C, et al. Adherence to antidepressant treatment among privately insured patients diagnosed with depression. Med Care 2007; 45: 363–9

    Article  PubMed  Google Scholar 

  18. Bambauer KZ, Soumerai SB, Adams AS, et al. Provider and patient characteristics associated with antidepressant non-adherence: the impact of provider specialty. J Clin Psychiatry 2007; 68: 867–73

    Article  PubMed  Google Scholar 

  19. Demyttenaere K, Enzlin P, Dewe W, et al. Compliance with antidepressants in a primary care setting: I. Beyond lack of efficacy and adverse events. J Clin Psychiatry 2001; 62Suppl. 22: 30–3

    CAS  Google Scholar 

  20. Katon W, Cantrell CR, Sokol MC, et al. Impact of antidepressant drug adherence on comorbid medication use and resource utilization. Arch Intern Med 2005; 165: 2497–503

    Article  PubMed  Google Scholar 

  21. Lawrenson RA, Tyrer F, Newson RB, et al. The treatment of depression in UK general practice: selective serotonin reuptake inhibitors and tricyclic antidepressants compared. J Affect Disord 2000; 59: 149–57

    Article  PubMed  CAS  Google Scholar 

  22. Lewis E, Marcus SC, Olfson M, et al. Patients’ early discontinuation of antidepressant prescriptions. Psychiatr Serv 2004; 55: 494

    Article  PubMed  Google Scholar 

  23. Olfson M, Marcus SC, Tedeschi M, et al. Continuity of antidepressant treatment for adults with depression in the United States. Am J Psychiatry 2006; 163: 101–8

    Article  PubMed  Google Scholar 

  24. Eaddy MT, Druss BG, Sarnes MW, et al. Relationship of total health care charges to selective serotonin reuptake inhibitor utilization patterns including the length of antidepressant therapy: results from a managed care administrative claims database. J Manag Care Pharm 2005; 11: 145–50

    PubMed  Google Scholar 

  25. Melfi CA, Chawla AJ, Croghan TW, et al. The effects of adherence to antidepressant treatment guidelines on relapse and recurrence of depression. Arch Gen Psychiatry 1998; 55: 1128–32

    Article  PubMed  CAS  Google Scholar 

  26. Sheehan DV, Eaddy M, Sarnes M, et al. Evaluating the economic consequences of early antidepressant treatment discontinuation: a comparison between controlled-release and immediate-release paroxetine. J Clin Psychopharmacol 2004; 24: 544–8

    Article  PubMed  CAS  Google Scholar 

  27. Sood N, Treglia M, Obenchain RL, et al. Determinants of antidepressant treatment outcome. Am J Manag Care 2000; 6: 1327–36

    PubMed  CAS  Google Scholar 

  28. Aikens JE, Kroenke K, Swindle RW, et al. Nine-month predictors and outcomes of SSRI antidepressant continuation in primary care. Gen Hosp Psychiatry 2005; 27: 229–36

    Article  PubMed  Google Scholar 

  29. Aikens JE, Nease Jr DE, Klinkman MS. Explaining patients’ beliefs about the necessity and harmfulness of antidepressants. Ann Fam Med 2008; 6: 23–9

    Article  PubMed  Google Scholar 

  30. Bull SA, Hu XH, Hunkeler EM, et al. Discontinuation of use and switching of antidepressants: influence of patient-physician communication. JAMA 2002; 288: 1403–9

    Article  PubMed  Google Scholar 

  31. Zivin K, Kales HC. Adherence to depression treatment in older adults: a narrative review. Drugs Aging 2008; 25: 559–71

    Article  PubMed  Google Scholar 

  32. Brown C, Battista DR, Bruehlman R, et al. Beliefs about antidepressant medications in primary care patients: relationship to self-reported adherence. Med Care 2005; 43: 1203–7

    Article  PubMed  Google Scholar 

  33. Maidment R, Livingston G, Katona C. Just keep taking the tablets: adherence to antidepressant treatment in older people in primary care. Int J Geriatr Psychiatry 2002; 17: 752–7

    Article  PubMed  Google Scholar 

  34. Masand PS. Tolerability and adherence issues in antidepressant therapy. Clin Ther 2003; 25: 2289–304

    Article  PubMed  CAS  Google Scholar 

  35. van Geffen EC, van Hulten R, Bouvy ML, et al. Characteristics and reasons associated with nonacceptance of selective serotonin-reuptake inhibitor treatment. Ann Pharmacother 2008; 42: 218–25

    Article  PubMed  Google Scholar 

  36. Nasrallah HA, Targum SD, Tandon R, et al. Defining and measuring clinical effectiveness in the treatment of schizophrenia. Psychiatr Serv 2005; 56: 273–82

    Article  PubMed  Google Scholar 

  37. Fuchs E, Simon M, Schmelting B. Pharmacology of a new antidepressant: benefit of the implication of the melatonergic system. Int Clin Psychopharmacol 2006; 21Suppl. 1: S17–20

    Article  PubMed  Google Scholar 

  38. Millan MJ, Brocco M, Gobert A, et al. Anxiolytic properties of agomelatine, an antidepressant with melatoninergic and serotonergic properties: role of 5-HT2C receptor blockade. Psychopharmacology (Berl) 2005; 177: 448–58

    Article  CAS  Google Scholar 

  39. Millan MJ, Gobert A, Lejeune F, et al. The novel melatonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways. J Pharmacol Exp Ther 2003; 306: 954–64

    Article  PubMed  CAS  Google Scholar 

  40. Loô 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: 239–47

    Article  PubMed  Google Scholar 

  41. Olié 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  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  43. European Medicines Agency. CMHP assessment report for valdoxan [online]. Available from URL: http://www.emea.europa.eu/humandocs/PDFs/EPAR/valdoxan/H-915-en6.pdf [Accessed 2009 Nov 20]

  44. Goodwin G, Emsley R, Rembry S, et al. Agomelatine prevents relapse in patients with major depressive disorder, without evidence of a discontinuation syndrome. J Clin Psychiatry 2009; 70: 1128–37

    Article  PubMed  Google Scholar 

  45. Lemoine P, Guilleminault CAE. 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 

  46. Kasper S, Hajak G, Wulff C, et al. Efficacy of the novel antidepressant agomelatine on the circadian rest-activity cycle, 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 

  47. 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 

  48. 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: 271–80

    Article  PubMed  CAS  Google Scholar 

  49. Montejo A, 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 

  50. 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 

  51. Hamilton M. A rating scale for depression. J Neurol Neuro-surg Psychiatry 1960; 23: 56–62

    Article  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  53. Guy W. ECDEU assessment manual for psychopharmacology: publication ADM 76-338. Rockville (MD): US Department of Health, Education and Welfare, National Institute of Mental Health, 1976: 217–22

    Google Scholar 

  54. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol 1959; 32: 50–5

    Article  PubMed  CAS  Google Scholar 

  55. Parrott AC, Hindmarch I. Factor analysis of a sleep evaluation questionnaire. Psychol Med 1978; 8: 325–9

    Article  PubMed  CAS  Google Scholar 

  56. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983; 67: 361–70

    Article  PubMed  CAS  Google Scholar 

  57. Montgomery SA, Kasper S. Severe depression and antidepressants: focus on a pooled analysis of placebo-controlled studies on agomelatine. Int Clin Psychopharmacol 2007; 22: 283–91

    Article  PubMed  Google Scholar 

  58. Bonierbale M, Lancon C, Tignol J. The ELIXIR study: evaluation of sexual dysfunction in 4557 depressed patients in France. Curr Med Res Opin 2003; 19: 114–24

    PubMed  Google Scholar 

  59. Kennedy SH, Fulton KA, Bagby RM, et al. Sexual function during bupropion or paroxetine treatment of major depressive disorder. Can J Psychiatry 2006; 51: 42

    Google Scholar 

  60. Montejo AL, Garcia M, Espada M, et al., on behalf of the Spanish work group for the study of psychotropic-related sexual dysfunctions. Psychometric characteristics of the psychotropic-related sexual dysfunction questionnaire. Actas Esp Psiquiatr 2000; 28: 141–50

    PubMed  CAS  Google Scholar 

  61. Rosenbaum JF, Fava M, Hoog SL, et al. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry 1998; 44: 77–87

    Article  PubMed  CAS  Google Scholar 

  62. Hansen RA, Gartlehner G, Lohr KN, et al. Efficacy and safety of second-generation antidepressants in the treatment of major depressive disorder. Ann Intern Med 2005; 143: 415–26

    PubMed  CAS  Google Scholar 

  63. Kirsch I, Moore TJ, Scoboria A, et al. The emperor’s new drugs: an analysis of antidepressant medication data submitted to the U.S. Food and Drug Administration. Prev Treat 2002; 5: 1–14

    Google Scholar 

  64. Melander H, Salmonson T, Abadie E, et al. A regulatory apologia: a review of placebo-controlled studies in regulatory submissions of new-generation antidepressants. Eur Neuropsychopharmacol 2008; 18: 623–7

    Article  PubMed  CAS  Google Scholar 

  65. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet 2009; 373: 746–58

    Article  PubMed  CAS  Google Scholar 

  66. Nemeroff CB, Entsuah R, Benattia I, et al. Comprehensive analysis of remission (COMPARE) with venlafaxine versus SSRIs. Biol Psychiatry 2008; 63: 424–34

    Article  PubMed  CAS  Google Scholar 

  67. Papakostas GI, Thase ME, Fava M, et al. Are antidepressant drugs that combine serotonergic and noradrenergic mechanisms of action more effective than the selective serotonin reuptake inhibitors in treating major depressive disorder? A meta-analysis of studies of newer agents. Biol Psychiatry 2007; 62: 1217–27

    Article  PubMed  CAS  Google Scholar 

  68. Kennedy SH, Andersen HF, Lam RW. Escitalopram in the treatment of major depressive disorder: a meta-analysis. Curr Med Res Opin 2009; 25: 161–75

    Article  PubMed  CAS  Google Scholar 

  69. Gartlehner G, Gaynes BN, Hansen RA, et al. Comparative benefits and harms of second-generation antidepressants: background paper for the American College of Physicians. Ann Intern Med 2008; 149: 734–50

    PubMed  Google Scholar 

  70. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006; 163: 28–40

    Article  PubMed  Google Scholar 

  71. Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 2006; 354: 1231–42

    Article  PubMed  CAS  Google Scholar 

  72. Thase ME, Friedman ES, Biggs MM, et al. Cognitive therapy versus medication in augmentation and switch strategies as second-step treatments: a STAR*D report. Am J Psychiatry 2007; 164: 739–52

    Article  PubMed  Google Scholar 

  73. Staedt J, Hunerjager H, Ruther E, et al. Sleep cluster arousal analysis and treatment response to heterocyclic antidepressants in patients with major depression. J Affect Disord 1998; 49: 221–7

    Article  PubMed  CAS  Google Scholar 

  74. Mayers AG, Baldwin DS. Antidepressants and their effect on sleep. Hum Psychopharmacol 2005; 20: 533–59

    Article  PubMed  CAS  Google Scholar 

  75. Wilson S, Argyropoulos S. Antidepressants and sleep: a qualitative review of the literature. Drugs 2005; 65: 927–47

    Article  PubMed  CAS  Google Scholar 

  76. Descamps A, Rousset C, Millan MJ, et al. Influence of the novel antidepressant and melatonin agonist/serotonin2C receptor antagonist, agomelatine, on the rat sleep-wake cycle architecture. Psychopharmacology (Berl) 2009; 205: 93–106

    Article  CAS  Google Scholar 

  77. Pandi-Perumal SR, Trakht I, Srinivasan V, et al. The effect of melatonergic and non-melatonergic antidepressants on sleep: weighing the alternatives. World J Biol Psychiatry 2008; 1-13

  78. Demyttenaere K, Albert A, Mesters P, et al. What happens with adverse events during 6 months of treatment with selective serotonin reuptake inhibitors? J Clin Psychiatry 2005; 66: 859–63

    Article  PubMed  Google Scholar 

  79. Gartlehner G, Thieda P, Hansen RA, et al. Comparative risk for harms of second-generation antidepressants: a systematic review and meta-analysis. Drug Saf 2008; 31: 851–65

    Article  PubMed  CAS  Google Scholar 

  80. Papakostas GI. Tolerability of modern antidepressants. J Clin Psychiatry 2008; 69 Suppl. E1: 8–13

    Google Scholar 

  81. Williams VS, Baldwin DS, Hogue SL. Estimating the prevalence and impact of antidepressant-induced sexual dysfunction in 2 European countries: a cross-sectional patient survey. J Clin Psychiatry 2006; 67: 204–10

    Article  PubMed  CAS  Google Scholar 

  82. Clayton AH, Pradko JK, Croft HA, et al. Prevalence of sexual dysfunction among newer antidepressants. J Clin Psychiatry 2002; 63: 357–66

    Article  PubMed  Google Scholar 

  83. Gregorian RS, Golden KA, Bahce A, et al. Antidepressant-induced sexual dysfunction. Ann Pharmacother 2002; 36: 1577–89

    Article  PubMed  CAS  Google Scholar 

  84. Werneke U, Northey S, Bhugra D. Antidepressants and sexual dysfunction. Acta Psychiatr Scand 2006; 114: 384–97

    Article  PubMed  CAS  Google Scholar 

  85. Turner EH, Matthews AM, Linardatos E, et al. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008; 358: 252–60

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors acknowledge technical support from Dr Francoise Picarel, who is an employee of Servier, and from Miss Niette Yeung at the University Health Network. Both assisted with the preparation of tables, figures and editorial support for an earlier draft of this manuscript. Dr Sidney H. Kennedy did not receive financial support for the preparation of this manuscript, but has received honoraria and research support from the Institute de Recherches Internationales Servier (IRIS). In the past 5 years, he has received honoraria or research support from Advanced Neuromodulation Systems Inc., AstraZeneca, Biovail, Boehringer Ingelheim, Brain Cells Inc., Eli Lilly, GlaxoSmithKline, Janssen-Ortho, Lundbeck, Merck Frosst, Organon, Pfizer, Servier and Wyeth. Sakina Rizvi has no conflicts of interest that are directly relevant to the content of this review.

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  1. Department of Psychiatry, University Health Network, 200 Elizabeth Street, 8EN-222, Toronto, Ontario, M5G 2C4, Canada

    Sidney H. Kennedy & Sakina J. Rizvi

  2. Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada

    Sidney H. Kennedy

  3. Departments of Pharmaceutical Sciences and Neuroscience, University of Toronto, Toronto, Ontario, Canada

    Sakina J. Rizvi

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Kennedy, S.H., Rizvi, S.J. Agomelatine in the treatment of major depressive disorder. CNS Drugs 24, 479–499 (2010). https://doi.org/10.2165/11534420-000000000-00000

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