Skip to main content

Advertisement

SpringerLink
Log in

Antidepressant Combinations: Cutting Edge Psychopharmacology or Passing Fad?

  • Mood Disorders (SM Strakowski, Section Editor)
  • Published:
Current Psychiatry Reports Aims and scope Submit manuscript

Abstract

This article reviews the rationale for and history of combining antidepressants, as well as the current state of the evidence, in the treatment of major depression. Although it has long been suggested that some individuals may benefit from regimens that combine two dissimilar antidepressants, enthusiasm for this practice has waxed and waned and there was never a strong empirical foundation to support this practice. The tangibly better safety profiles of the newer generation antidepressants, both singly and in combination, have permitted greater use of such combinations in contemporary practice than ever before. Combinations that pair a selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI) with a dissimilar antidepressant, such as bupropion or mirtazapine, are now widely used for patients who have not responded to trials of first- or second-line antidepressant monotherapies and have been tested as a potential way of speeding the benefits of treatment. However, there still is no strong evidence that even the most widely used combinations have particular merit and clinicians should be mindful that alternatives exist with more established efficacy. Moreover, aside from selected cases of drug-drug interactions, it may take full therapeutic doses of both drugs across a typically adequate duration of exposure to achieve the desired effects of combined treatment.

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

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. • Mojtabai R, Olfson M. National trends in psychotropic medication polypharmacy in office-based psychiatry. Arch Gen Psychiatry. 2010;67(1):26–36. This article provides evidence about temporal changes in treatment selection and documents the prevalence of combining antidepressants.

    Article  PubMed  Google Scholar 

  2. • Richelson E. Multi-modality: a new approach for the treatment of major depressive disorder. Int J Neuropsychopharmacol. 2013;30:1–10. A good summary of the rationale for combining antidepressants and the pros and cons of monotherapy versus combination therapy.

    Article  Google Scholar 

  3. Rush AJ. Combining antidepressant medications: a good idea? Am J Psychiatry. 2010;167(3):241–3.

    Article  PubMed  Google Scholar 

  4. Preskorn SH, Lacey RL. Polypharmacy: when is it rational? J Psychiatr Pract. 2007;13(2):97–105.

    Article  PubMed  Google Scholar 

  5. Thase ME. Antidepressant combinations: widely used, but far from empirically validated. Can J Psychiatry. 2011;56(6):317–23.

    PubMed  Google Scholar 

  6. Berlanga C, Ortega-Soto HA. A 3-year follow-up of a group of treatment-resistant depressed patients with a MAOI/tricyclic combination. J Affect Disord. 1995;34(3):187–92.

    Article  PubMed  CAS  Google Scholar 

  7. Thase ME, Trivedi MH, Rush AJ. MAOIs in the contemporary treatment of depression. Neuropsychopharmacology. 1995;12(3):185–219.

    Article  PubMed  CAS  Google Scholar 

  8. Anderson IM. SSRIS versus tricyclic antidepressants in depressed inpatients: a meta-analysis of efficacy and tolerability. Depress Anxiety. 1998;7 Suppl 1:11–7.

    Article  PubMed  Google Scholar 

  9. Lam RW, Wan DD, Cohen NL, Kennedy SH. Combining antidepressants for treatment-resistant depression: a review. J Clin Psychiatry. 2002;63(8):685–93.

    Article  PubMed  CAS  Google Scholar 

  10. Nelson JC, Mazure CM, Bowers Jr MB, Jatlow PI. A preliminary, open study of the combination of fluoxetine and desipramine for rapid treatment of major depression. Arch Gen Psychiatry. 1991;48(4):303–7.

    Article  PubMed  CAS  Google Scholar 

  11. Fava M, Rosenbaum JF, McGrath PJ, Stewart JW, Amsterdam JD, Quitkin FM. Lithium and tricyclic augmentation of fluoxetine treatment for resistant major depression: a double-blind, controlled study. Am J Psychiatry. 1994;151(9):1372–4.

    PubMed  CAS  Google Scholar 

  12. Fava M, Alpert J, Nierenberg A, Lagomasino I, Sonawalla S, Tedlow J, et al. Double-blind study of high-dose fluoxetine versus lithium or desipramine augmentation of fluoxetine in partial responders and nonresponders to fluoxetine. J Clin Psychopharmacol. 2002;22(4):379–87.

    Article  PubMed  CAS  Google Scholar 

  13. Nelson JC, Mazure CM, Jatlow PI, Bowers Jr MB, Price LH. Combining norepinephrine and serotonin reuptake inhibition mechanisms for treatment of depression: a double-blind, randomized study. Biol Psychiatry. 2004;55(3):296–300.

    Article  PubMed  CAS  Google Scholar 

  14. Meyer JH, Goulding VS, Wilson AA, Hussey D, Christensen BK, Houle S. Bupropion occupancy of the dopamine transporter is low during clinical treatment. Psychopharmacology (Berl). 2002;163(1):102–5.

    Article  PubMed  CAS  Google Scholar 

  15. Learned-Coughlin SM, Bergström M, Savitcheva I, Ascher J, Schmith VD, Långstrom B. In vivo activity of bupropion at the human dopamine transporter as measured by positron emission tomography. Biol Psychiatry. 2003;54(8):800–5.

    Article  PubMed  CAS  Google Scholar 

  16. Lam RW, Hossie H, Solomons K, Yatham LN. Citalopram and bupropion-SR: combining versus switching in patients with treatment-resistant depression. J Clin Psychiatry. 2004;65(3):337–40.

    Article  PubMed  CAS  Google Scholar 

  17. Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, Warden D, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354(12):1243–52.

    Article  PubMed  CAS  Google Scholar 

  18. •• Rush AJ, Trivedi MH, Stewart JW, Nierenberg AA, Fava M, Kurian BT, et al. Combining medications to enhance depression outcomes (CO-MED): acute and long-term outcomes of a single-blind randomized study. Am J Psychiatry. 2011;168(7):689–701. A very important randomized trial evaluating whether antidepressant combinations might accelerate remission or improve outcomes if used from the outset of therapy. This large multicenter study found no evidence to support the use of combined therapy from the outset of treatment.

    Article  PubMed  Google Scholar 

  19. Bech P, Fava M, Trivedi MH, Wisniewski SR, Rush AJ. Outcomes on the pharmacopsychometric triangle in bupropion-SR vs. buspirone augmentation of citalopram in the STAR*D trial. Acta Psychiatr Scand. 2012;125(4):342–8.

    Article  PubMed  CAS  Google Scholar 

  20. Thase ME, Nierenberg AA, Vrijland P, van Oers HJ, Schutte AJ, Simmons JH. Remission with mirtazapine and selective serotonin reuptake inhibitors: a meta-analysis of individual patient data from 15 controlled trials of acute phase treatment of major depression. Int Clin Psychopharmacol. 2010;25(4):189–98.

    Article  PubMed  Google Scholar 

  21. Carpenter LL, Yasmin S, Price LH. A double-blind, placebo-controlled study of antidepressant augmentation with mirtazapine. Biol Psychiatry. 2002;51(2):183–8.

    Article  PubMed  CAS  Google Scholar 

  22. Blier P, Gobbi G, Turcotte JE, de Montigny C, Boucher N, Hébert C, et al. Mirtazapine and paroxetine in major depression: a comparison of monotherapy versus their combination from treatment initiation. Eur Neuropsychopharmacol. 2009;19:457–65.

    Article  PubMed  CAS  Google Scholar 

  23. •• Blier P, Ward HE, Tremblay P, Laberge L, Hébert C, Bergeron R. Combination of antidepressant medications from treatment initiation for major depressive disorder: a double-blind randomized study. Am J Psychiatry. 2010;167(3):281–8. In contrast to the findings of COMED, this single center study found that vigorously dosed combinations were more effective than monotherapy with fluoxetine.

    Article  PubMed  Google Scholar 

  24. McGrath PJ, Stewart JW, Fava M, Trivedi MH, Wisniewski SR, Nierenberg AA, et al. Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1531–41.

    Article  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Michael E. Thase has provided scientific consultation to Alkermes, AstraZeneca, Bristol-Myers Squibb, Dey Pharma, Eli Lilly & Company, Forest Pharmaceuticals, Gerson Lehman Group, GlaxoSmithKline, Guidepoint Global, H. Lundbeck A/S, MedAvante, Merck and Co., Neuronetics, Novartis, Otsuka, Ortho-McNeil Pharmaceuticals, PamLab, Pfizer (formerly Wyeth-Ayerst Laboratories), Schering-Plough (formerly Organon), Shire US, Sunovion Pharmaceuticals, Takeda (Lundbeck), and Transcept Pharmaceuticals. Dr. Thase receives grant funding from the Agency for Healthcare Research and Quality, Eli Lilly & Company, GlaxoSmithKline (ended 7/10/2013), National Institute of Mental Health, Otsuka, and Sepracor. He has equity holdings in MedAvante and receives royalties from American Psychiatric Foundation, Guilford Publications, Herald House, Oxford University Press, and W.W. Norton & Company. His wife is employed as the Group Scientific Director for Embryon (formerly Advogent; Embyron does business with Bristol-Myers Squibb and Pfizer/Wyeth).

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by the author.

Author information

Authors and Affiliations

  1. Perelman School of Medicine, University of Pennsylvania, 3535 Market St., Suite 670, Philadelphia, PA, 19104, USA

    Michael E. Thase

Authors
  1. Michael E. Thase
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael E. Thase.

Additional information

This article is part of the Topical Collection on Mood Disorders

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thase, M.E. Antidepressant Combinations: Cutting Edge Psychopharmacology or Passing Fad?. Curr Psychiatry Rep 15, 403 (2013). https://doi.org/10.1007/s11920-013-0403-2

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11920-013-0403-2

Keywords

Search

Navigation