Over the years, numerous classes of medications have been studied for the management of major depressive disorder, from MAOIs and TCAs to SSRIs, SNRIs, mirtazapine, bupropion, and atypical antipsychotics, among many others. The following questions aim to guide in how to manage MDD when considering the many available agents for treatment.

Essential Questions and References

  • What are evidence-based strategies for managing MDD?1,2
  • If my patient fails an SSRI, what should I try to next?2-8
  • What is the role of augmentation in managing MDD symptoms?7-10
  • How does augmentation in managing MDD symptoms?11
  • What is the role of esketamine and ketamine in treatment-resistant depression?12-16

Reviewer 1: Lindsey Anderson, PharmD, BCPS, BCPP
Reviewer 2:  Mackenzie Pierce PharmD, BCPS, BCPP
Reviewer 3: Austin Smith, PharmD, BCPP
2023-2024 AAPP Resident and New Practitioner Committee


  1. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391(10128):1357-1366. [PubMed]
  2. Rush AJ., Trivedi MH., Wisniewski SR., et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D Report. Am J Psychiatry 2006;163:1905-1917. [PubMed]
  3. Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, 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(1):28-40. DOI: 10.1176/appi.ajp.163.1.28. PubMed PMID: 16390886.
  4. Rush AJ, Trivedi MH, Wisniewski SR, Stewart JW, Nierenberg AA, Thase ME, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354(12):1231-42. DOI: 10.1056/NEJMoa052963. PubMed PMID: 16554525.
  5. 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;163(7):1161-72. [PubMed]
  6. Nierenberg AA, Fava M, Trivedi MH, et al.  A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1519-30. [Pubmed]
  7. 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. AJP. 2006;163(9):1531-41; quiz 1666. DOI: 10.1176/ajp.2006.163.9.1531. PubMed PMID: 16946177.
  8. 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. DOI: 10.1056/NEJMoa052964. PubMed PMID: 16554526.
  9. Nierenberg AA, Fava M, Trivedi MH, et al.  A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1519-30. [Pubmed]
  10. Rush AJ, Trivedi MH, Stewart JW, 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. [Pubmed]
  11. Mohamed S, Johnson GR, Chen P, Hicks PB, Davis LL, Yoon J, et al. Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial. JAMA. 2017;318(2):132-145. DOI: 10.1001/jama.2017.8036. PubMed PMID: 28697253; PubMed Central PMCID: PMC5817471.
  12. Fedgchin M, Trivedi M, Daly EJ, et al. Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1). Int J Neuropsychopharmacol. 2019;22(10):616-630. [PubMed]
  13. Popova V, Daly EJ, Trivdei MH, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176(6):428-438. [PubMed]
  14. Daly EJ, Trivedi MH, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2019;76(9):893-903. [PubMed]
  15. Wajs E, Aluisio L, Holder R, et al. Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2). J Clin Psychiatry. 2020;81(3):19m12891. [PubMed]
  16. Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-864. [PubMed]
  17. Smith-Apeldoorn SY, Veraart JKE, Kamphuis J, et al. Oral esketamine for treatment-resistant depression: Rationale and design of a randomized controlled trial. BMC Psychiatry 2019;19:375. [PubMed]