, Volume 190, Issue 4, pp 575–579 | Cite as

Agomelatine in the treatment of seasonal affective disorder

  • Edda Pjrek
  • Dietmar Winkler
  • Anastasios Konstantinidis
  • Matthäus Willeit
  • Nicole Praschak-Rieder
  • Siegfried Kasper
Original Investigation



The novel antidepressant agomelatine acts as a melatonergic (MT1 and MT2) receptor agonist and as a serotonin-2C receptor antagonist. Previous studies showed that agomelatine is able to restore disrupted circadian rhythms, which were implicated in the pathophysiology of seasonal affective disorder (SAD).


The aim of this study was to investigate the efficacy and tolerability of agomelatine in the treatment of SAD.

Materials and methods

Thirty-seven acutely depressed SAD patients were included in an open study with agomelatine (25 mg/day in the evening) over 14 weeks. Efficacy assessments included the Structured Interview Guide for the Hamilton Depression Rating Scale (SAD version; SIGH-SAD), the Clinical Global Impression of Severity (CGI-S) and Improvement (CGI-I), the Circscreen, a self-rating scale for the assessment of sleep and circadian rhythm disorders, and the Hypomania Scale.


Agomelatine led to a progressive and statistically significant decrease of SIGH-SAD, CGI-S, and CGI-I scores from week 2 onward (p < 0.001). Furthermore, scores on the Circscreen improved significantly during the study (p < 0.001). Treatment with agomelatine over 14 weeks yielded a response rate of 75.7% (SIGH-SAD <50% of baseline value) and a remission rate (SIGH-SAD <8) of 70.3% in the intention to treat sample. Scores on the Hypomania Scale were consistently low during the study. Agomelatine showed good overall tolerability: throughout the study only one adverse event (mild fatigue) was related to the study drug.


The results of this study suggest that seasonal depression may be effectively and safely treated with agomelatine.


Depression Seasonal affective disorder SAD Agomelatine Antidepressant Pharmacotherapy 



This study was supported by a grant from Servier. The authors thank Mrs. Brigitta Kusternig (Department of General Psychiatry, Medical University of Vienna) for her dedicated support during the course of this study.

Statement of interest

Prof. Kasper has received research grants, consultancy fees, and lecture fees from a number of pharmaceutical companies in the area of CNS development. The authors of this study were supported by various travel grants.


  1. American Psychiatric Association (2000) Diagnostic and Statistical Manual of Mental Disorder, text revision (DSM-IV-TR), 4th edn. American Psychiatric Press, Washington, DCGoogle Scholar
  2. Bech P, Allerup P, Gram LF, Reisby N, Rosenberg R, Jacobsen O, Nagy A (1981) The Hamilton depression scale. Evaluation of objectivity using logistic models. Acta Psychiatr Scand 63:290–299PubMedGoogle Scholar
  3. Dahl K, Avery DH, Lewy AJ, Savage MV, Brengelmann GL, Larsen LH, Vitiello MV, Prinz PN (1993) Dim light melatonin onset and circadian temperature during a constant routine in hypersomnic winter depression. Acta Psychiatr Scand 88:60–66PubMedGoogle Scholar
  4. Danilenko KV, Putilov AA, Russkikh GS, Duffy LK, Ebbesson SO (1994) Diurnal and seasonal variations of melatonin and serotonin in women with seasonal affective disorder. Arctic Med Res 53:137–145PubMedGoogle Scholar
  5. Grassi-Zucconi G, Semprevivo M, Mocaer E, Kristensson K, Bentivoglio M (1996) Melatonin and its new agonist S-20098 restore synchronized sleep fragmented by experimental trypanosome infection in the rat. Brain Res Bull 39:63–68PubMedCrossRefGoogle Scholar
  6. Guy W (1976) ECDEU assessment manual for psychopharmacology. US Department of Health, Education and Welfare publication (ADM) 76–338. National Institute of Mental Health, Rockville, MDGoogle Scholar
  7. Karadottir R, Axelsson J (2001) Melatonin secretion in SAD patients and healthy subjects matched with respect to age and sex. Int J Circumpolar Health 60:548–551PubMedGoogle Scholar
  8. Kasper S, Rogers LBS, Yancey A, Schulz PM, Skwerer RG, Rosenthal NE (1989a) Phototherapy in individuals with and without subsyndromal seasonal affective disorder. Arch Gen Psychiatry 46:837–844PubMedGoogle Scholar
  9. Kasper S, Rogers S, Yancey A, Skwerer RG, Schulz PM, Rosenthal NE (1989b) Psychological effects of light therapy in normals. In: Rosenthal NE, Blehar M (eds) Seasonal affective disorders and phototherapy. Guilford Press, New York, NY, pp 260–270Google Scholar
  10. Kennedy SH, Emsley R (2006) Placebo-controlled trial of agomelatine in the treatment of major depressive disorder. Eur Neuropsychopharmacol 16:93–100PubMedCrossRefGoogle Scholar
  11. Koorengevel KM, Beersma DG, den Boer JA, van den Hoofdakker RH (2002) A forced desynchrony study of circadian pacemaker characteristics in seasonal affective disorder. J Biol Rhythms 17:463–475PubMedCrossRefGoogle Scholar
  12. Laredo J, Quera Salva MA, Falissard B, de Bodinat C (2002) Screening of sleep and circadian rhythms in major depression. J Sleep Res 11(Suppl 1):132–133Google Scholar
  13. Leppamaki S, Partonen T, Vakkuri O, Lonnqvist J, Partinen M, Laudon M (2003) Effect of controlled-release melatonin on sleep quality, mood, and quality of life in subjects with seasonal or weather-associated changes in mood and behaviour. Eur Neuropsychopharmacol 13:137–145PubMedCrossRefGoogle Scholar
  14. Leproult R, Van Onderbergen A, L’Hermite-Baleriaux M, Van Cauter E, Copinschi G (2005) Phase-shifts of 24-h rhythms of hormonal release and body temperature following early evening administration of the melatonin agonist agomelatine in healthy older men. Clin Endocrinol (Oxf) 63:298–304CrossRefGoogle Scholar
  15. Levine ME, Milliron AN, Duffy LK (1994) Diurnal and seasonal rhythms of melatonin, cortisol and testosterone in interior Alaska. Arctic Med Res 53:25–34PubMedGoogle Scholar
  16. Lewy AJ, Bauer VK, Cutler NL, Sack RL (1998) Melatonin treatment of winter depression: a pilot study. Psychiatry Res 77:57–61PubMedCrossRefGoogle Scholar
  17. Lewy AJ, Lefler BJ, Hasler BP, Bauer VK, Bernert RA, Emens JS (2003) Plasma DLMO10 zeitgeber time 14: the therapeutic window for phase-delayed winter depressives treated with melatonin. Chronobiol Int 20:1215–1217CrossRefGoogle Scholar
  18. Loo H, Hale A, D’Haenen H (2002) 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 17:239–247PubMedCrossRefGoogle Scholar
  19. Millan MJ, Gobert A, Lejeune F, Dekeyne A, Newman-Tancredi A, Pasteau V, Rivet JM, Cussac D (2003) 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 306:954–964PubMedCrossRefGoogle Scholar
  20. Nathan PJ, Burrows GD, Norman TR (1999) Melatonin sensitivity to dim white light in affective disorders. Neuropsychopharmacology 21:408–413PubMedCrossRefGoogle Scholar
  21. Pjrek E, Winkler D, Stastny J, Konstantinidis A, Heiden A, Kasper S (2004) Bright light therapy in seasonal affective disorder—does it suffice? Eur Neuropsychopharmacol 14:347–351PubMedCrossRefGoogle Scholar
  22. Pjrek E, Winkler D, Stastny J, Praschak-Rieder N, Willeit M, Kasper S (2006) Escitalopram in seasonal affective disorder: results of an open trial. Phamacopsychiatry (in press)Google Scholar
  23. Redman JR, Guardiola-Lemaitre B, Brown M, Delagrange P, Armstrong SM (1995) Dose dependent effects of S-20098, a melatonin agonist, on direction of re-entrainment of rat circadian activity rhythms. Psychopharmacology (Berl) 118:385–390CrossRefGoogle Scholar
  24. Rosenthal NE, Sack DA, Gillin JC, Lewy AJ, Goodwin FK, Davenport Y, Mueller PS, Newsome DA, Wehr TA (1984) Seasonal affective disorder: a description of the syndrome and preliminary findings with light therapy. Arch Gen Psychiatry 41:72–80PubMedGoogle Scholar
  25. Sack RL, Lewy AJ, White DM, Singer CM, Fireman MJ, Vandiver R (1990) Morning vs evening light treatment for winter depression. Evidence that the therapeutic effects of light are mediated by circadian phase shifts. Arch Gen Psychiatry 47:343–351PubMedGoogle Scholar
  26. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC (1998) The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59(Suppl 20):22–33; quiz 34–57PubMedGoogle Scholar
  27. SPSS (1989–2003) SPSS 12.0 for Windows. Release 12.0. SPSS, Chicago, IL, USAGoogle Scholar
  28. Van Reeth O, Weibel L, Olivares E, Maccari S, Mocaer E, Turek FW (2001) Melatonin or a melatonin agonist corrects age-related changes in circadian response to environmental stimulus. Am J Physiol Regul Integr Comp Physiol 280:R1582–R1591PubMedGoogle Scholar
  29. Weaver DR (1999) Melatonin and circadian rhythmicity in vertebrates. In: Turek FW, Zee P (eds) Neurobiology of sleep and circadian rhythms. Dekker, New York, NY, pp 197–262Google Scholar
  30. Williams JBW, Link MJ, Rosenthal NE, Amira L, Terman M (2002) Structured Interview Guide for the Hamilton Depression Rating Scale—Seasonal Affective Disorder version, 2002 rev. New York State Psychiatric Institute, New York, NYGoogle Scholar
  31. Winkler D, Pjrek E, Praschak-Rieder N, Willeit M, Pezawas L, Konstantinidis A, Stastny J, Kasper S (2005) Actigraphy in patients with seasonal affective disorder and healthy control subjects treated with light therapy. Biol Psychiatry 58:331–336PubMedCrossRefGoogle Scholar
  32. Winkler D, Pjrek E, Iwaki R, Kasper S (2006) The treatment of seasonal affective disorder. Expert Rev Neurother 6:1039–1048PubMedCrossRefGoogle Scholar
  33. World Medical Association General Assembly (2004) World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. J Int Bioethique 15:124–129CrossRefGoogle Scholar
  34. Yous S, Andrieux J, Howell HE, Morgan PJ, Renard P, Pfeiffer B, Lesieur D, Guardiola-Lemaitre B (1992) Novel naphthalenic ligands with high affinity for the melatonin receptor. J Med Chem 35:1484–1485PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Edda Pjrek
    • 1
  • Dietmar Winkler
    • 1
  • Anastasios Konstantinidis
    • 1
  • Matthäus Willeit
    • 1
  • Nicole Praschak-Rieder
    • 1
  • Siegfried Kasper
    • 1
  1. 1.Department of General PsychiatryMedical University of ViennaViennaAustria

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