CNS Drugs

, Volume 24, Issue 1, pp 35–53 | Cite as

Safety Reporting and Adverse-Event Profile of Mirtazapine Described in Randomized Controlled Trials in Comparison with Other Classes of Antidepressants in the Acute-Phase Treatment of Adults with Depression

Systematic Review and Meta-Analysis
  • Norio Watanabe
  • Ichiro M. Omori
  • Atsuo Nakagawa
  • Andrea Cipriani
  • Corrado Barbui
  • Hugh McGuire
  • Rachel Churchill
  • Toshi A. Furukawa
Original Research Article


Background: Mirtazapine has a unique mechanism of antidepressant action, and thus is thought to have a different profile of adverse events from that of other antidepressants.

Objective: To present a methodologically rigorous systematic review of the adverse event profile of mirtazapine and point to possible problems with safety reporting in randomized controlled trials (RCTs) of the acute-phase treatment of major depression in adults with mirtazapine in comparison with other types of antidepressant.

Methods: The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register was electronically searched using the following search terms: ‘depress*rs’, ‘dysthymi*’, ‘adjustment disorder*’, ‘mood disorder*’, ‘affective disorder’, ‘affective symptoms’ and ‘mirtazapine’. Pharmaceutical companies and experts in this field were contacted, and the reference lists of the relevant RCTs were checked, for additional data. No language restriction was imposed. Two authors independently assessed the quality of trials for inclusion in the review. Disagreements were resolved by consensus. Two authors independently extracted data on adverse events. Disagreements were resolved by consensus. The adequacy of safety reporting was assessed by one author.

Regarding the adequacy of safety reporting, the qualitative and quantitative parameters of safety reporting were determined. Regression analyses were conducted to assess characteristics of trials influencing safety reporting.

The primary and secondary outcomes in the systematic review of the adverse events associated with mirtazapine were defined as the proportion of patients having each of 43 adverse events listed in the modified version of the WHO Adverse Reaction Terminology, and the proportion of patients experiencing at least one adverse event, respectively. Meta-analyses were conducted for these outcomes.

Results: Twenty-five RCTs involving 4842 patients were identified as meeting our inclusion criteria. With regard to safety reporting, only two trials and no trials were rated as ‘adequate’ in terms of the reporting of clinical adverse events and laboratory-determined toxicity, respectively. The proportion of text in the results sections of the study reports devoted to safety reporting was a mean of 22%. No associations were observed between the adequacy of safety reporting and any characteristics of the trials; however, sample size over 100 participants in total and over 50 subjects in a study arm, double blindness and sponsorship by the company marketing mirtazapine were significantly associated with a greater number of reported adverse events in mirtazapine recipients.

In terms of individual adverse events, mirtazapine was significantly less likely to cause hypertension or tachycardia (risk ratio [RR] 0.51) and tremor (RR 0.43) than tricyclic antidepressants (TCAs). In comparison with selective serotonin uptake inhibitors (SSRIs), mirtazapine was significantly more likely to cause weight gain or increased appetite (RR 3.68), increased salivation (RR 3.66), somnolence (RR 1.62) and fatigue (RR 1.45), but less likely to cause flatulence (RR 0.26), sweating (RR 0.28), sexual dysfunction (RR 0.34), tremor (RR 0.37), nausea or vomiting (RR 0.40), sleep disturbance (RR 0.55) and diarrhoea (RR 0.61). In comparison with the serotonin-noradrenaline (norepinephrine) reuptake inhibitor (SNRI) venlafaxine, mirtazapine was significantly more likely to cause fatigue (RR 2.02), but less likely to cause sleep disturbance (RR 0.03), sweating (RR 0.03) and constipation (RR 0.25). Relative to trazodone, mirtazapine was significantly more likely to cause weight gain or increased appetite (RR 4.00). Approximately 70% of patients treated with mirtazapine experienced at least one adverse event, with no significant difference in comparison with other antidepressants.

Conclusions: The study confirmed the paucity of adequate safety reporting in trials comparing mirtazapine with other types of antidepressant in the acute-phase treatment of depression in adults. Based on the available evidence, mirtazapine appears to have a unique adverse-event profile. Using these findings, clinicians can inform their patients, not only of the simple frequency of adverse events with mirtazapine, but also of the relative difference in the frequency of adverse events in comparison with that of other antidepressants, to aid pragmatic clinical decisions.


Sertraline Sexual Dysfunction Venlafaxine Mirtazapine Trazodone 



No sources of funding were used to assist in the preparation of this manuscript. This study received no external funding. NW has received research funds from the Japanese Ministry of Health Labour and Welfare. IMO, AN, AC, CB, HM and RC have nothing to declare. TAF has received research funds and speaking fees from Asahi Kasei, Astellas, Dai-Nippon Sumitomo, Eisai, Eli Lilly, GlaxoSmithKline, Janssen, Kyowa Hakko, Meiji, Nikken Kagaku, Organon, Otsuka, Pfizer, Yoshitomi, the Japanese Ministry of Education, Science, and Technology and the Japanese Ministry of Health Labour and Welfare.

Supplementary material

40263_2012_24010035_MOESM1_ESM.pdf (23 kb)
Supplementary material, approximately 24 KB.


  1. 1.
    Trindade E, Menon D, Topfer LA, et al. Adverse effects associated with selective serotonin reuptake inhibitors and tricyclic antidepressants: a meta-analysis. CMAJ 1998 Nov 17; 159(10): 1245–52PubMedGoogle Scholar
  2. 2.
    Gregorian RS, Golden KA, Bahce A, et al. Antidepressant-induced sexual dysfunction. Ann Pharmacother 2002 Oct; 36(10): 1577–89PubMedCrossRefGoogle Scholar
  3. 3.
    De Boer T, Nefkens F, Van Helvoirt A. The alpha 2-adrenoceptor antagonist Org 3770 enhances serotonin transmission in vivo. Eur J Pharmacol 1994 Feb 21; 253(1–2): R5–6PubMedCrossRefGoogle Scholar
  4. 4.
    Watanabe N, Omori IM, Nakagawa A, et al. Mirtazapine versus other antidepressants in the acute-phase treatment of adults with major depression: systematic review and meta-analysis. J Clin Psychiatry 2008; 69(9): 1404–15PubMedCrossRefGoogle Scholar
  5. 5.
    Gartlehner G, Hansen RA, Carey TS, et al. Discontinuation rates for selective serotonin reuptake inhibitors and other second-generation antidepressants in outpatients with major depressive disorder: a systematic review and meta-analysis. Int Clin Psychopharmacol 2005 Mar; 20(2): 59–69PubMedCrossRefGoogle Scholar
  6. 6.
    Bremner JD. A double-blind comparison of Org 3770, amitriptyline, and placebo in major depression. J Clin Psychiatry 1995 Nov; 56(11): 519–25PubMedGoogle Scholar
  7. 7.
    Wade A, Crawford GM, Angus M, et al. A randomized, double-blind, 24-week study comparing the efficacy and tolerability of mirtazapine and paroxetine in depressed patients in primary care. Int Clin Psychopharmacol 2003 May; 18(3): 133–41PubMedGoogle Scholar
  8. 8.
    Hong CJ, Hu WH, Chen CC, et al. A double-blind, randomized, group-comparative study of the tolerability and efficacy of 6 weeks’ treatment with mirtazapine or fluoxetine in depressed Chinese patients. J Clin Psychiatry 2003 Aug; 64(8): 921–6PubMedCrossRefGoogle Scholar
  9. 9.
    Benkert O, Szegedi A, Kohnen R. Mirtazapine compared with paroxetine in major depression. J Clin Psychiatry 2000 Sep; 61(9): 656–63PubMedCrossRefGoogle Scholar
  10. 10.
    Leinonen E, Skarstein J, Behnke K, et al. Efficacy and tolerability of mirtazapine versus citalopram: a double-blind, randomized study in patients with major depressive disorder: Nordic Antidepressant Study Group. Int Clin Psychopharmacol 1999 Nov; 14(6): 329–37PubMedCrossRefGoogle Scholar
  11. 11.
    Versiani M, Moreno R, Ramakers-van Moorsel CJ, et al. Comparison of the effects of mirtazapine and fluoxetine in severely depressed patients. CNS Drugs 2005; 19(2): 137–46PubMedCrossRefGoogle Scholar
  12. 12.
    Papakostas GI, Homberger CH, Fava M. A meta-analysis of clinical trials comparing mirtazapine with selective serotonin reuptake inhibitors for the treatment of major depressive disorder. J Psychopharmacol 2008; 22(8): 843–8PubMedCrossRefGoogle Scholar
  13. 13.
    Papanikolaou PN, Churchill R, Wahlbeck K, et al. Safety reporting in randomized trials of mental health interventions. Am J Psychiatry 2004 Sep; 161(9): 1692–7PubMedCrossRefGoogle Scholar
  14. 14.
    Ioannidis JP, Lau J. Completeness of safety reporting in randomized trials: an evaluation of 7 medical areas. JAMA 2001 Jan 24–31; 285(4): 437–43PubMedCrossRefGoogle Scholar
  15. 15.
    Moher D, Schulz KF, Altman D. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. JAMA 2001 Apr 18; 285(15): 1987–91PubMedCrossRefGoogle Scholar
  16. 16.
    The Nordic Cochrane Centre. Review manager (RevMan) [computer program]. 5.0 ed. Copenhagen: The Cochrane Collaboration, 2008Google Scholar
  17. 17.
    Furukawa TA, Guyatt GH, Griffith LE. Can we individualize the ‘number needed to treat’? An empirical study of summary effect measures in meta-analyses. Int J Epidemiol 2002; 31(1): 72–6PubMedCrossRefGoogle Scholar
  18. 18.
    Oxman AD, Guyatt GH. A consumer’s guide to subgroup analyses. Ann Intern Med 1992; 116(1): 78–84PubMedGoogle Scholar
  19. 19.
    Altman DG. Confidence intervals for the number needed to treat. BMJ 1998 Nov 7; 317(7168): 1309–12PubMedCrossRefGoogle Scholar
  20. 20.
    Smeeth L, Haines A, Ebrahim S. Numbers needed to treat derived from meta-analyses: sometimes informative, usually misleading. BMJ 1999 Jun 5; 318(7197): 1548–51PubMedCrossRefGoogle Scholar
  21. 21.
    Schoemaker J, Gailledreau J, Hoyberg OJ. First, randomized, double-blind comparison of mirtazapine (15–45mg) and fluvoxamine (50–150mg) in the treatment of depression [abstract]. Int J Neuropsychopharmacol 2002; 5Suppl. 1: 140Google Scholar
  22. 22.
    Thase ME, Kremer C, Rodrigues H. Mirtazapine versus sertraline after SSRI nonresponse. 52nd Institute on Psychiatric Services; 2000 Oct 25–29; Philadelphia (PA)Google Scholar
  23. 23.
    Debonnel G, Gobbi G, Turcotte J, et al. Effects of mirtazapine, paroxetine and their combination: a double-blind study in major depression [abstract]. Eur Neuropsychopharmacol 2000; 10Suppl. 3: S252CrossRefGoogle Scholar
  24. 24.
    Turan M, Askin R, Telcioglu M, et al. Mirtazapine versus amitriptyline in treatment of major depressive disorder. Eur Neuropsychopharmacol 2000; 10Suppl. 3: S228CrossRefGoogle Scholar
  25. 25.
    Marttila M, Jaaskelainen J, Jarvi R, et al. A double-blind study comparing the efficacy and tolerability of mirtazapine and doxepin in patients with major depression. Eur Neuropsychopharmacol 1995 Dec; 5(4): 441–6PubMedGoogle Scholar
  26. 26.
    Richou H, Ruimy P, Charbaut J, et al. A multicentre, double-blind, clomipramine-controlled efficacy and safety study of Org 3770. Hum Psychopharmacol 1995; 10(4): 263–71CrossRefGoogle Scholar
  27. 27.
    Fava M, Rush AJ, Wisniewski SR, et al. A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report. Am J Psychiatry 2006 Jul; 163(7): 1161–72PubMedCrossRefGoogle Scholar
  28. 28.
    van Moffaert M, de Wilde J, Vereecken A, et al. Mirtazapine is more effective than trazodone: a double-blind controlled study in hospitalized patients with major depression. Int Clin Psychopharmacol 1995 Mar; 10(1): 3–9PubMedCrossRefGoogle Scholar
  29. 29.
    Gardner DM, MacKinnon N, Langille DB, et al. A comparison of factors used by physicians and patients in the selection of antidepressant agents. Psychiatr Serv 2007 Jan; 58(1): 34–40PubMedCrossRefGoogle Scholar
  30. 30.
    Fawcett J, Barkin RL. A meta-analysis of eight randomized, double-blind, controlled clinical trials of mirtazapine for the treatment of patients with major depression and symptoms of anxiety. J Clin Psychiatry 1998; 59(3): 123–7PubMedCrossRefGoogle Scholar
  31. 31.
    Montgomery SA. Safety of mirtazapine: a review. Int Clin Psychopharmacol 1995 Dec; 10Suppl. 4: 37–45PubMedCrossRefGoogle Scholar
  32. 32.
    Anttila SA, Leinonen EV. A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev 2001 Fall; 7(3): 249–64PubMedCrossRefGoogle Scholar
  33. 33.
    Storosum JG, Elferink AJ, van Zwieten BJ, et al. Natural course and placebo response in short-term, placebo-controlled studies in major depression: a meta-analysis of published and non-published studies. Pharmacopsychiatry 2004 Jan; 37(1): 32–6PubMedCrossRefGoogle Scholar
  34. 34.
    Brambilla P, Cipriani A, Hotopf M, et al. Side-effect profile of fluoxetine in comparison with other SSRIs, tricyclic and newer antidepressants: a meta-analysis of clinical trial data. Pharmacopsychiatry 2005 Mar; 38(2): 69–77PubMedCrossRefGoogle Scholar
  35. 35.
    Greist J, McNamara RK, Mallinckrodt CH, et al. Incidence and duration of antidepressant-induced nausea: duloxetine compared with paroxetine and fluoxetine. Clin Ther 2004 Sep; 26(9): 1446–5PubMedCrossRefGoogle Scholar
  36. 36.
    Als-Nielsen B, Chen W, Gluud C, et al. Association of funding and conclusions in randomized drug trials: a reflection of treatment effect or adverse events? JAMA 2003; 290(7): 921–8PubMedCrossRefGoogle Scholar
  37. 37.
    Lexchin J, Bero LA, Djulbegovic B, et al. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ 2003; 1167–70Google Scholar
  38. 38.
    Perlis RH, Perlis CS, Wu Y, et al. Industry sponsorship and financial conflict of interest in the reporting of clinical trials in psychiatry. Am J Psychiatry 2005; 162(10): 1957–60PubMedCrossRefGoogle Scholar
  39. 39.
    Chan AW, Hrobjartsson A, Haahr MT, et al. Empirical evidence for selective reporting of outcomes in randomized trials: comparison of protocols to published articles. JAMA 2004 May 26; 291(20): 2457–65PubMedCrossRefGoogle Scholar
  40. 40.
    Furukawa TA, Watanabe N, Omori IM, et al. Association between unreported outcomes and effect size estimates in Cochrane meta-analyses. JAMA 2007 Feb 7; 297(5): 468–70PubMedGoogle Scholar
  41. 41.
    Thompson SG, Higgins JPT. How should meta-regression analyses be undertaken and interpreted? Stat Med 2002; 21: 1559–74PubMedCrossRefGoogle Scholar
  42. 42.
    Alwan S, Reefhuis J, Rasmussen SA, et al. Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med 2007 Jun 28; 356(26): 2684–92PubMedCrossRefGoogle Scholar
  43. 43.
    Louik C, Lin AE, Werler MM, et al. First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med 2007 Jun 28; 356(26): 2675–83PubMedCrossRefGoogle Scholar
  44. 44.
    US FDA. FDA proposes new warnings about suicidal thinking, behavior in young adults who take antidepressant medications, 2007 May 2 [online]. Available from URL: [Accessed 2008 Jan 4]

Copyright information

© Adis Data Information BV 2010

Authors and Affiliations

  • Norio Watanabe
    • 1
  • Ichiro M. Omori
    • 1
  • Atsuo Nakagawa
    • 2
  • Andrea Cipriani
    • 3
  • Corrado Barbui
    • 3
  • Hugh McGuire
    • 4
  • Rachel Churchill
    • 4
  • Toshi A. Furukawa
    • 1
  1. 1.Department of Psychiatry and Cognitive-Behavioral MedicineNagoya City University Graduate School of Medical SciencesMizuho-ku, NagoyaJapan
  2. 2.Department of Neuropsychiatry School of MedicineKeio UniversityTokyoJapan
  3. 3.Department of Medicine and Public Health, Section of Psychiatry and Clinical PsychologyUniversity of VeronaVeronaItaly
  4. 4.Academic Unit of Psychiatry, Department of Community Based MedicineUniversity of BristolBristolUK

Personalised recommendations