Oral esketamine for treatment-resistant depression: rationale and design of a randomized controlled trial

BMC Psychiatry. 2019 Nov 29;19(1):375. doi: 10.1186/s12888-019-2359-1.


Background: There is an urgent need to develop additional treatment strategies for patients with treatment-resistant depression (TRD). The rapid but short-lived antidepressant effects of intravenous (IV) ketamine as a racemic mixture have been shown repeatedly in this population, but there is still a paucity of data on the efficacy and safety of (a) different routes of administration, and (b) ketamine's enantiomers esketamine and arketamine. Given practical advantages of oral over IV administration and pharmacodynamic arguments for better antidepressant efficacy of esketamine over arketamine, we designed a study to investigate repeated administration of oral esketamine in patients with TRD.

Methods: This study features a triple-blind randomized placebo-controlled trial (RCT) comparing daily oral esketamine versus placebo as add-on to regular antidepressant medications for a period of 6 weeks, succeeded by a follow-up of 4 weeks. The methods support examination of the efficacy, safety, tolerability, mechanisms of action, and economic impact of oral esketamine in patients with TRD.

Discussion: This is the first RCT investigating repeated oral esketamine administration in patients with TRD. If shown to be effective and tolerated, oral esketamine administration poses important advantages over IV administration.

Trial registration: Dutch Trial Register, NTR6161. Registered 21 October 2016.

Keywords: Clinical trial; Esketamine; Oral administration; Treatment-resistant depression.

Publication types

  • Clinical Trial Protocol
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Antidepressive Agents / therapeutic use*
  • Cost-Benefit Analysis
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Treatment-Resistant / drug therapy*
  • Drug Therapy, Combination
  • Female
  • Humans
  • Ketamine / therapeutic use*
  • Male
  • Treatment Outcome


  • Antidepressive Agents
  • Esketamine
  • Ketamine

Associated data

  • NTR/NTR6161