Evidence-Based Reviews

Management of treatment-resistant depression: A review of 3 studies

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An estimated 7.1% of the adults in United States had a major depressive episode in 2017, and this prevalence has been trending upward over the past few years.1 The prevalence is even higher in adults between age 18 and 25 (13.1%).1 Like other psychiatric diagnoses, major depressive disorder (MDD) has a significant impact on productivity as well as daily functioning. Only one-third of patients with MDD achieve remission on the first antidepressant medication.2 This leaves an estimated 11.47 million people in the United States in need of an alternate regimen for management of their depressive episode.

The data on evidence-based biologic treatments for treatment-resistant depression are limited (other than for electroconvulsive therapy). Pharmacologic options include switching to a different medication, combining medications, and augmentation strategies or novel approaches such as ketamine and related agents. Here we summarize the findings from 3 recent studies that investigate alternate management options for MDD.

Ketamine: Randomized controlled trial

Traditional antidepressants may reduce suicidal ideation by improving depressive symptoms, but this effect may take weeks. Ketamine, an N-methyl-D-aspartate antagonist, has become a target of research for its antidepressant effects at subanesthetic doses.


1. Grunebaum MF, Galfalvy HC, Choo TH, et al. Ketamine for rapid reduction of suicidal thoughts in major depression: a midazolam-controlled randomized clinical trial. Am J Psychiatry. 2018;175(4):327-335.

Grunebaum et al3 evaluated the acute effect of adjunctive subanesthetic IV keta­mine on clinically significant suicidal ideation in patients with MDD, with a comparison arm that received an infusion of midazolam.

Study design

  • 80 inpatients (age 18 to 65 years) with MDD who had a score ≥16 on the Hamilton Depression Rating Scale (HAM-D) and a score ≥4 on the Scale for Suicidal Ideation (SSI). Approximately one-half (54%) were taking an antidepressant
  • Patients were randomly assigned to IV racemic ketamine hydrochloride, .5 mg/kg, or IV midazolam, .02 mg/kg, both administered in 100 mL normal saline over 40 minutes.


  • Scale for Suicidal Ideation scores were assessed at screening, before infusion, 230 minutes after infusion, 24 hours after infusion, and after 1 to 6 weeks of follow-up. The average SSI score on Day 1 was 4.96 points lower in the ketamine group compared with the midazolam group. The proportion of responders (defined as patients who experienced a 50% reduction in SSI score) on Day 1 was 55% for patients in the ketamine group compared with 30% in the midazolam group.


  • Compared with midazolam, ketamine produced a greater clinically meaningful reduction in suicidal ideation 24 hours after infusion.

Apart from the primary outcome of reduction in suicidal ideation, greater reductions were also found in overall mood disturbance, depression subscale, and fatigue subscale scores as assessed on the Profile of Mood States (POMS). Although the study noted improvement in depression scores, the proportion of responders on Day 1 in depression scales, including HAM-D and the self-rated Beck Depression Inventory, fell short of statistical significance. Overall, compared with the midazolam infusion, a single adjunctive subanesthetic ketamine infusion was associated with a greater clinically significant reduction in suicidal ideation on Day 1.

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