Skip to main content

Third-Generation Antidepressants

Do They Offer Advantages Over the SSRIs?

Abstract

Third-generation antidepressants are a group of antidepressant agents of variable action, not confined to serotonin reuptake inhibition. These agents include venlafaxine, reboxetine, nefazodone and mirtazapine. Claims have been made for these agents in terms of improved efficacy, faster speed of onset of effect and greater safety in the treatment of depression compared with previous medications, such as the selective serotonin reuptake inhibitors (SSRIs). This article reviews the evidence for these improvements.

Thirty active comparator studies were reviewed involving the third-generation antidepressant agents. While there were isolated reports of improvements over comparator agents for venlafaxine, reboxetine and mirtazepine, there were no convincing differences between third-generation agents and comparators in terms of overall efficacy, relapse prevention and speed of onset. The third-generation antidepressants were, however, of equivalent safety to SSRIs and maintained improvements in safety over first-generation agents

This is a preview of subscription content, access via your institution.

Table I
Table II
Table III
Table IV
Table V

References

  1. Bolden-Watson C, Richelson E. Blockade by newly developed antidepressants of biogenic uptake in the rat brain synaptosomes. Life Sci 1993; 52: 1023–9

    PubMed  Article  CAS  Google Scholar 

  2. Riva M, Brunello N, Rovescalli AC, et al. Effect of reboxetine, a new antidepressant drug, on the central noradrenergic system: behavioural and biochemical studies. J Drug Develop 1989; 1: 243–54

    Google Scholar 

  3. Cusack B, Nelson A, Richelson E. Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl) 1994 May; 114(4): 559–65

    Article  CAS  Google Scholar 

  4. de Boer TH, Maura G, Raiteri M, et al. Neurochemical and autonomic pharmacological profiles of the 6-aza-analogue of mianserin, Org 3770 and its enantiomers. Neuropharmacology 1988 Apr; 27(4): 399–408

    PubMed  Article  Google Scholar 

  5. Davis R, Wilde MI. Mirtazapine: a review of its pharmacology and therapeutic potential in the management of major depression. Drugs 1996; 5: 389–402

    CAS  Google Scholar 

  6. Rudolph R, Feiger A. A double blind, randomized, placebo-controlled trial of once-daily venlafaxine extended release (XR) and fluoxetine for the treatment of depression. J Affect Disord 1999; 56: 171–81

    PubMed  Article  CAS  Google Scholar 

  7. Cunningham L, Borison R, Carman J, et al. A comparison of venlafaxine, trazodone, and placebo in major depression. J Clin Psychopharmacol 1994; 14: 99–106

    PubMed  Article  CAS  Google Scholar 

  8. Gentil V, Kerr-Correa F, Moreno R, et al. Double-blind comparison of venlafaxine and amitriptyline in outpatients with major depression with or without melancholia. J Psychopharmacol 2000; 14: 61–6

    PubMed  Article  CAS  Google Scholar 

  9. Samuelian J, Hackett D. A randomized, double-blind, parallel-group comparison of venlafaxine and clomipramine in outpatients with major depression. J Psychopharmacol 1998; 12: 273–8

    PubMed  Article  CAS  Google Scholar 

  10. Mahaputra S, Hackett d. Arandomized, double-blind, parallel-group comparison of venlafaxine and dothiepin in geriatric patients with major depression. Int J Clin Pract 1997; 51: 209–13

    Google Scholar 

  11. Costa e Silva J. Randomised, double-blind comparison of venlafaxine and fluoxetine in outpatients with major depression. J Clin Psychiatry 1998; 59(7): 352–7

    Article  Google Scholar 

  12. Silverstone P, Ravindram A. Once-daily venlafaxine extended release (XR) compared with fluoxetine in outpatients with depression and anxiety. J Clin Psychiatry 1999; 60: 22–8

    PubMed  Article  CAS  Google Scholar 

  13. Mehtonen O-P, Søgaard J, Roponen P, et al. Randomised, double-blind comparison of venlafaxine and sertraline in outpatients with major depressive disorder. J Clin Psychiatry 2000; 61: 95–100

    PubMed  Article  CAS  Google Scholar 

  14. Ballus C, Quiros G, de la Torre J, et al. The efficacy and tolerability of venlafaxine and paroxetine in outpatients with depressive disorder or dysthymia. Int Clin Psychopharmacol 2000; 15: 43–8

    PubMed  Article  CAS  Google Scholar 

  15. Tzanakaki M, Guazelli M, Nimatoudis I, et al. Increased remission rates with venlafaxine compared with fluoxetine in hospitalized patients with major depression and melancholia. Int Clin Psychopharmacol 2000; 15: 29–34

    PubMed  Article  CAS  Google Scholar 

  16. Clerc G, Ruimy P, Verdeau-Pailles J, et al. A double-blind comparison of venlafaxine and fluoxetine in patients hospitalized for major depression and melancholia. Int Clin Psychopharmacol 1994; 9: 139–43

    PubMed  Article  CAS  Google Scholar 

  17. Poirier MF, Boyer P. Venlafaxine and paroxetine in treatment-resistant depression. Double-blind, randomized comparison. Br J Psychiatry 1999; 175: 12–6

    CAS  Google Scholar 

  18. Dierick M, Ravizza L, Realini R, et al. A double-blind comparison of venlafaxine and fluoxetine for treatment of major depression in outpatients. Prog Neuropsychopharmacol Biol Psychiatry 1996; 20: 7–71

    Google Scholar 

  19. Thase ET, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry 2001 Mar; 178: 234–41

    PubMed  Article  CAS  Google Scholar 

  20. Berzewski H, van Moffaert M, Gagiano C. Efficacy and tolerability of reboxetine compared with imipramine in a double-blind study in patients suffering from major depression. Eur Neuropsychopharmacol 1997; 7 Suppl. 1: 37–47

    Article  Google Scholar 

  21. Katona C, Bercoff E, Chiu E, et al. Reboxetine versus imipramine in the treatment of elderly patients with major depressive disorders: a double-blind randomized trial. J Affect Disord 1999; 55: 203–13

    PubMed  Article  CAS  Google Scholar 

  22. Ban T, Gaszner P, Aguglia E, et al. Clinical efficacy of reboxetine: a comparative study with desipramine, with methodological considerations. Hum Psychopharmacology 1998; 13 Suppl.: 2: 9–39

    Google Scholar 

  23. Massana J. Reboxetine versus fluoxetine: an overview of efficacy and tolerability. J Clin Psychiatry 1998; 59 Suppl. 14: 8–10

    Google Scholar 

  24. Massana J, Moller HJ, Burrows G, et al. Reboxetine: a double-blind comparison with fluoxetine in major depressive disorder. Int Clin Psychopharmacol 1999 Mar; 14(2): 73–80

    PubMed  Article  CAS  Google Scholar 

  25. Bosc M, Dubini A, Polin V. Development and validation of a social functioning scale, the Social Adaptation Self-Evaluation Scale. Eur Neuropsychopharmacol 1997; 7 Suppl. 1: S57–70

    PubMed  Article  CAS  Google Scholar 

  26. Keller M. Role of serotonin and noradrenaline in social dysfunction: a review of data on reboxetine and the Social Adaptation Self-Evaluation Scale. Gen Hosp Psychiatry 2001; 23: 15–9

    PubMed  Article  CAS  Google Scholar 

  27. Venditti LN, Arcelus A, Birnbaum H, et al. The impact of anti-depressant use on social functioning: reboxetine versus fluoxetine. Int Clin Psychopharmacol 2000; 15: 279–89

    PubMed  Article  CAS  Google Scholar 

  28. Healy D. Reboxetine: its effects as measured by the Social Adaptation Self-Evaluation Scale. Acta Psychiatr Scand Suppl 2000; 402: 45–51

    Article  CAS  Google Scholar 

  29. Dubini A, Bosc M, Polin V. Noradrenaline-selective versus serotonin-selective antidepressant therapy: differential effects on social functioning. J Psychopharmacol 1997; 11 (4 Suppl.): S17–23

    PubMed  CAS  Google Scholar 

  30. Feighner J, Pambakian R, Fowler R, et al. A comparison of nefazodone, imipramine, and placebo in patients with moderate to severe depression. Psychopharmacol Bull 1989; 25: 219–21

    PubMed  CAS  Google Scholar 

  31. Cohn C, Robinson D, Roberts D, et al. Responders to antidepressant drug treatment: a study comparing nefazodone, imipramine, and placebo in patients with major depression. J Clin Psychiatry 1996; 57 Suppl. 2: 15–8

    Google Scholar 

  32. Marcus R, Mendels J. Nefazodone in the treatment of severe, melancholic, and recurrent depression. J Clin Psychiatry 1996; 57 Suppl. 2: 19–23

    Google Scholar 

  33. Rickels K, SchweizerE, Clary C, et al. Nefazodone and imipramine in major depression: a placebo-controlled trial. Br J Psychiatry 1994; 164(6): 802–5

    PubMed  Article  CAS  Google Scholar 

  34. Fontaine R, Ontiveros A, Elie R, et al. A double-blind comparison of nefazodone, imipramine, and placebo in major depression. J Clin Psychiatry 1994; 55(6): 234–41

    PubMed  CAS  Google Scholar 

  35. Baldwin D, Hawley C, Abed R, et al. A multicenter double-blind comparison of nefazodone and paroxetine in the treatment of outpatients with moderate-to-severe depression. J Clin Psychiatry 1996; 57 Suppl. 2: 46–52

    Google Scholar 

  36. Feiger A, Kiev A, Shrivastava R, et al. Nefazodone versus sertraline in outpatients with major depression: focus on efficacy, tolerability, and effects on sexual function and satisfaction. J Clin Psychiatry 1996; 57 Suppl. 2: 53–62

    Google Scholar 

  37. Halikas JA. Org 3770 (mirtazapine) versus trazodone: a placebo controlled trial in depressed elderly patients. Hum Psychopharmacol 1995; 10 Suppl. 2: S125–33

    Article  CAS  Google Scholar 

  38. Hoyberg OJ, Maragakis B, Mullin J, et al. A double-blind multi-centre comparison of mirtazapine and amitriptyline in elderly depressed patients. Acta Psychiatr Scand 1996; 93: 184–90

    PubMed  Article  CAS  Google Scholar 

  39. Smith WT, Glaudin V, Panagides J, et al. Mirtazapine vs amitriptyline vs placebo in the treatment of major depressive disorder. Psychopharmacol Bull 1990; 26(2): 192–6

    Google Scholar 

  40. Bremner JD. A double-blind comparison of ORG 3770, amitriptyline, and placebo in major depression. J Clin Psychiatry 1995; 56: 519–25

    PubMed  CAS  Google Scholar 

  41. Mullin J, Lodge A, Bennie E, et al. A multicentre, double-blind, amitriptyline-controlled study of mirtazapine in patients with major depression. J Psychopharmacol 1996; 10(3): 235–40

    PubMed  Article  CAS  Google Scholar 

  42. 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: 263–71

    Article  CAS  Google Scholar 

  43. Zivkov M, de Jongh GD. Org 3770 versus amitriptyline: a 6-week randomized double blind multicentre trial in hospitalized depressed patients. Hum Psychopharmacol 1995; 10: 173–80

    Article  Google Scholar 

  44. 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; 14: 329–37

    Article  CAS  Google Scholar 

  45. Wheatley DP, van Moffaert M, Timmerman L, et al. Mirtazapine: efficacy and tolerability in comparison with fluoxetine in patients with moderate to severe major depressive disorder. J Clin Psychiatry 1998; 59: 306–12

    PubMed  Article  CAS  Google Scholar 

  46. 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; 10: 3–9

    PubMed  Article  Google Scholar 

  47. Angst J. How recurrent and predictable is depressive illness? In: Montgomery S, Rouillon F, editors. Perspectives in psychiatry, Vol. 3. Long-term treatment of depression. New York: John Wiley, 1992: 1–13

    Google Scholar 

  48. Entsuah A, Rudolph R, Hackett D, et al. Efficacy of venlafaxine and placebo during long-term treatment of depression: a pooled analysis of relapse rates. Int Clin Psychopharmacol 1996; 11: 137–45

    PubMed  CAS  Google Scholar 

  49. Versiani M, Mehilane L, Gaszner P, et al. Reboxetine, a unique selective NRI, prevents relapse and recurrence in long-term treatment of major depressive disorder. J Clin Psychiatry 1999; 60: 400–6

    PubMed  Article  CAS  Google Scholar 

  50. Anton S, Robinson D, Roberts D, et al. Long-term treatment of depression with nefazodone. Psychopharmacol Bull 1994; 30: 165–9

    PubMed  CAS  Google Scholar 

  51. Feiger A, Bielski R, Bremner J, et al. Double-blind, placebo-substitution study of nefazodone in the prevention of relapse during continuation treatment of outpatients with major depression. Int Clin Psychopharmacol 1999; 14: 19–28

    PubMed  Article  CAS  Google Scholar 

  52. Montgomery S, Reimitz P-E, Zivkov M. Mirtazapine versus amitriptyline in the long-term treatment of depression: a double-blind placebo-controlled study. Int Clin Psychopharmacol 1998; 13: 63–73

    PubMed  Article  CAS  Google Scholar 

  53. Derivan A. Antidepressants: can we determine how quickly they work?. Issues for the literature. Psychopharmacol Bull 1995; 31: 23–8

    CAS  Google Scholar 

  54. Montgomery SA, Asberg M. The new depression scale designed to be sensitive to change. Br J Psychiatry 1997; 134: 382–9

    Article  Google Scholar 

  55. Prien EF, Blane JD, Leven J. Antidepressant drug therapy: the role of the new antidepressants. Hosp Community Psychiatry 1985; 36: 513–6

    PubMed  CAS  Google Scholar 

  56. Gelenberg AJ, Chesen CL. How fast are antidepressants? J Clin Psychiatry 2000; 61: 712–21

    PubMed  Article  CAS  Google Scholar 

  57. Entsuah R. Early onset of antidepressant action of venlafaxine: pattern analysis in intent-to-treat patients. Clin Ther 1998; 20: 517–26

    PubMed  Article  CAS  Google Scholar 

  58. Benkert O, Grander G, Wetzel H, et al. A randomized, double-blind comparison of a rapidly escalating dose of venlafaxine and imipramine in inpatients with major depression and melancholia. J Psychiatr Res 1996; 30: 441–51

    PubMed  Article  CAS  Google Scholar 

  59. Thompsom C. Mirtazapine versus selective serotonin reuptake inhibitors. J Clin Psychiatry 1999; 60 Suppl. 17: 18–22

    Google Scholar 

  60. Fava M, Mulroy R, Alpert J, et al. Emergence of adverse events following discontinuation of treatment with extended-release venlafaxine. Am J Psychiatry 1997; 154(12): 1760–2

    PubMed  CAS  Google Scholar 

  61. Feighner JP. Cardiovascular safety in depressed patients: focus on venlafaxine. J Clin Psychiatry 1995; 56: 574–9

    PubMed  CAS  Google Scholar 

  62. Holliday S, Benfield P. Venlafaxine: a review of its pharmacology and therapeutic potential in depression. Drugs 1995; 49(2): 280–94

    PubMed  Article  CAS  Google Scholar 

  63. Banham NDG. Fatal venlafaxine overdose. Med J Aust 1998; 169: 445–8

    PubMed  CAS  Google Scholar 

  64. Jaffe PD, Batziris HP, van der Hoeven P, et al. A study involving venlafaxine overdoses: comparison of fatal and therapeutic concentrations in postmortem specimens. J Forensic Sci 1999; 44(1): 193–6

    PubMed  CAS  Google Scholar 

  65. Daniels R. Serotonin syndrome due to venlafaxine overdose. J Accid Emerg Med 1998; 15: 333–4

    PubMed  Article  CAS  Google Scholar 

  66. Blythe D, Hackett L. Cardiovascular and neurological toxicity of venlafaxine. Hum Exp Toxicol 1999; 18: 309–13

    PubMed  Article  CAS  Google Scholar 

  67. Ereshefsky L. Drug-drug interactions involving antidepressants: focus on venlafaxine. J Clin Psychopharmacol 1996; 16(3 Suppl. 2): 37–50

    Article  Google Scholar 

  68. Mucci M. Reboxetine: a review of antidepressant tolerability. J Psychopharmacol 1997; 11 Suppl. 4: 33–7

    Google Scholar 

  69. Baldwin DS, Buis C, Carabal E. Tolerability and safety of reboxetine. Rev Contemp Pharmacother 2000; 11(5): 321–30

    CAS  Google Scholar 

  70. Jannuzzo MG, Bosc M, Renoux A, et al. Effect of reboxetine on the pharmacokinetics of lorazepam in healthy volunteers [abstract]. Eur Neuropsychopharmacol 1995; 5: 300–1

    Google Scholar 

  71. Holm K, Spencer C. Reboxetine: a review of its use in depression. CNS Drugs 1999; 12(1): 65–83

    Article  CAS  Google Scholar 

  72. Lader M. Tolerability and safety: essentials in antidepressant pharmacotherapy. J Clin Psychiatry 1996; 57 Suppl. 2: 39–44

    Google Scholar 

  73. Aranda-Michel J, Koehler A, Bejarano P, et al. Nefazodone-induced liver failure: report of three cases. Ann Intern Med 1999; 130: 285–8

    PubMed  CAS  Google Scholar 

  74. Benson B, Mathiason M, Dahl B, et al. Toxicities and outcomes associated with nefazodone poisoning: an analysis of 1,338 exposures. Am J Emerg Med 2000; 18(5): 587–92

    PubMed  Article  CAS  Google Scholar 

  75. Greenblatt D, von Moltke L, Harmatz J, et al. Drug interactions with newer antidepressants: role of human cytochromes P450. J Clin Psychiatry 1998; 59 Suppl. 15: 19–27

    PubMed  CAS  Google Scholar 

  76. Richelson E. Pharmacokinetic interactions of antidepressants. J Clin Psychiatry 1998; 59 Suppl. 10: 22–6

    PubMed  CAS  Google Scholar 

  77. Greene D, Slazar D, Pittman K, et al. Coadministration of nefazodone and benzodiazepines, III: a pharmacokinetic interaction study with alprazolam. J Clin Psychopharmacol 1995; 15: 399–408

    PubMed  Article  CAS  Google Scholar 

  78. Barbhaiya R, Shukla U, Kroboth P, et al. Coadministration of nefazodone and benzodiazepines, II: a pharmacokinetic interaction study with triazolam. J Clin Psychopharmacol 1995; 15: 320–6

    PubMed  Article  CAS  Google Scholar 

  79. Sussman N, Stahl S. Update in the pharmacotherapy of depression. Am J Med 1996; 101 Suppl. 6A: 26–36

    Article  Google Scholar 

  80. Settle EC. Antidepressant drugs: disturbing and potentially dangerous adverse effects. J Clin Psychiatry 1998; 59 Suppl. 16: 25–30

    PubMed  CAS  Google Scholar 

  81. Hoes MJ, Zeijpveld JH. First report of mirtazapine overdose. Int Clin Psychopharmacol 1996; 11(2): 147

    PubMed  CAS  Google Scholar 

  82. Bremner JD, Wingard P, Walshe TA. Safety of mirtazapine in overdose. J Clin Psychiatry 1998; 59(5): 233–5

    PubMed  Article  CAS  Google Scholar 

  83. Dahl M-L, Voortman G, Alm C, et al. In vitro and in vivo studies on the disposition of mirtazapine in humans. Clin Drug Invest 1997; 13: 37–46

    Article  CAS  Google Scholar 

  84. Stormer E, von Moltke LL, Shader RI, et al. Metabolism of the antidepressant mirtazapine in vitro: contribution of cytochromes P-450 1A2, 2D6 and 3A4. Drug Metab Dispos 2000; 28(10): 1168–75

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

No funding was received for the preparation of this article. Dr Graham Burrows has given advice to a number of pharmaceutical companies involved in the production of psychotropic drugs including Organon, Bristol-Myers Squibb, Wyeth-Ayerst and Pharmacia. Dr Trevor Norman has received funding from Bristol-Myers Squibb for research projects and has been a funded speaker for Organon, Bristol-Myers Squibb and Wyeth-Ayerst, and has advised Bristol-Myers Squibb.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Trevor R. Norman.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Olver, J.S., Burrows, G.D. & Norman, T.R. Third-Generation Antidepressants. CNS Drugs 15, 941–954 (2001). https://doi.org/10.2165/00023210-200115120-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00023210-200115120-00004

Keywords

  • Fluoxetine
  • Imipramine
  • Venlafaxine
  • Mirtazapine
  • Nefazodone