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.

Essential Questions and References

What is a good first line strategy for managing MDD?

  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]

If my patient fails an SSRI, what should I try next?

STAR*D (Sequenced Treatment Alternatives to Relieve Depression)

  1. Trivedi MH, Rush AJ, Wisniewski SR, 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. [PubMed]
  2. Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354(12):1231-42.[PubMed]
  3. 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].
  4. McGrath PJ, Stewart JW, Fava M, 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. [PubMed]
  5. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354(12):1243-52. [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]

What is the role of augmentation in managing MDD symptoms?

STAR*D (Sequenced Treatment Alternatives to Relieve Depression)

  1. McGrath PJ, Stewart JW, Fava M, 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. [PubMed]
  2. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354(12):1243-52. [PubMed]
  3. 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]

CO-MED (Combining Medications to Enhance Depression Outcomes)

  1. 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]

How does augmentation compare to switching agents?

VAST-D (VA Augmentation and Switching Treatments for Improving Depression Outcomes

  1. Mohamed S, Johnson GR, Chen P, 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):132-45. [PubMed]

What is the role of ketamine in treatment-resistant depression?

VAST-D (VA Augmentation and Switching Treatments for Improving Depression Outcomes

  1. Popova V, Daly EJ, Trivdei M, 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]