Psychiatric Pharmacy Essentials: Major Clinical Trials in Major Depressive Disorder (MDD)

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, atypical antipsychotics, and NMDA-targeting agents, 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
  • Is augmentation or switching antidepressants preferred in managing MDD symptoms after an SSRI failure?11
  • What is the role of esketamine and ketamine in treatment-resistant depression?12-17
  • What is the role of newer glutamatergic-modulating medications in the treatment of MDD?18
  • What is the role of psychedelics in the treatment of MDD?19-20

Reviewer 1: Breanna Moody, PharmD, BCPP
Reviewer 2: Roisin Sabol, PharmD, BCPP
2026-2027 AAPP Resident and New Practitioner Committee

  1. Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, 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 Apr;391(10128):1357-1366. Elsevier BV. DOI: 10.1016/s0140-6736(17)32802-7.
  2. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and Longer-Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report. AJP. 2006 Nov;163(11):1905-1917. American Psychiatric Association Publishing. DOI: 10.1176/ajp.2006.163.11.1905.
  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. AJP. 2006 Jan 1;163(1):28-40. American Psychiatric Association Publishing. DOI: 10.1176/appi.ajp.163.1.28.
  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 Mar 23;354(12):1231-1242. Massachusetts Medical Society. DOI: 10.1056/nejmoa052963.
  5. Fava M. A Comparison of Mirtazapine and Nortriptyline Following Two Consecutive Failed Medication Treatments for Depressed Outpatients: A STAR*D Report. Am J Psychiatry. 2006 Jul 1;163(7):1161. American Psychiatric Association Publishing. DOI: 10.1176/appi.ajp.163.7.1161.
  6. Nierenberg AA, Fava M, Trivedi MH, Wisniewski SR, Thase ME, McGrath PJ, et al. A Comparison of Lithium and T 3 Augmentation Following Two Failed Medication Treatments for Depression: A STAR*D Report. AJP. 2006 Sep;163(9):1519-1530. American Psychiatric Association Publishing. DOI: 10.1176/ajp.2006.163.9.1519.
  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 Sep;163(9):1531-1541. American Psychiatric Association Publishing. DOI: 10.1176/ajp.2006.163.9.1531.
  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 Mar 23;354(12):1243-1252. Massachusetts Medical Society. DOI: 10.1056/nejmoa052964.
  9. 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. AJP. 2011 Jul;168(7):689-701. American Psychiatric Association Publishing. DOI: 10.1176/appi.ajp.2011.10111645.
  10. Gill H, Chen-Li DCJ, Haikazian S, Seyedin S, McIntyre RS, Mansur RB, et al. Adjunctive cariprazine for major depressive disorder: a systematic review and meta-analysis. CNS Spectr. 2024 Aug;29(4):233-242. Cambridge University Press (CUP). DOI: 10.1017/s1092852924000178.
  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. JAMA. 2017 Jul 11;318(2):132. American Medical Association (AMA). DOI: 10.1001/jama.2017.8036.
  12. Fedgchin M, Trivedi M, Daly EJ, Melkote R, Lane R, Lim P, 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). International Journal of Neuropsychopharmacology. 2019 Oct 1;22(10):616-630. Oxford University Press (OUP). DOI: 10.1093/ijnp/pyz039.
  13. Popova V, Daly EJ, Trivedi M, Cooper K, Lane R, Lim P, 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. AJP. 2019 Jun 1;176(6):428-438. American Psychiatric Association Publishing. DOI: 10.1176/appi.ajp.2019.19020172.
  14. Daly EJ, Trivedi MH, Janik A, Li H, Zhang Y, Li X, et al. Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression. JAMA Psychiatry. 2019 Sep 1;76(9):893. American Medical Association (AMA). DOI: 10.1001/jamapsychiatry.2019.1189.
  15. Wajs E, Leah A, Morrison R, Daly E, Lane R, Lim P, et al. Long-term safety of esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: SUSTAIN-2 phase 3 study. European Neuropsychopharmacol. 2019;29:S44-S45. Elsevier BV. DOI: 10.1016/j.euroneuro.2018.11.1016.
  16. Janik A, Qiu X, Lane R, Popova V, Drevets WC, Canuso CM, et al. Esketamine Monotherapy in Adults With Treatment-Resistant Depression. JAMA Psychiatry. 2025 Sep 1;82(9):877. American Medical Association (AMA). DOI: 10.1001/jamapsychiatry.2025.1317.
  17. McIntyre RS, Rosenblat JD, Nemeroff CB, Sanacora G, Murrough JW, Berk M, et al. Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation. AJP. 2021 May 1;178(5):383-399. American Psychiatric Association Publishing. DOI: 10.1176/appi.ajp.2020.20081251.
  18. Akbar D, Rhee TG, Ceban F, Ho R, Teopiz KM, Cao B, et al. Dextromethorphan-Bupropion for the Treatment of Depression: A Systematic Review of Efficacy and Safety in Clinical Trials. CNS Drugs. 2023 Oct;37(10):867-881. Springer Science and Business Media LLC. DOI: 10.1007/s40263-023-01032-5.
  19. Raison CL, Sanacora G, Woolley J, Heinzerling K, Dunlop BW, Brown RT, et al. Single-Dose Psilocybin Treatment for Major Depressive Disorder. JAMA. 2023 Sep 5;330(9):843. American Medical Association (AMA). DOI: 10.1001/jama.2023.14530.
  20. Davis AK, Barrett FS, May DG, Cosimano MP, Sepeda ND, Johnson MW, et al. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder. JAMA Psychiatry. 2021 May 1;78(5):481. American Medical Association (AMA). DOI: 10.1001/jamapsychiatry.2020.3285.