Repeated subcutaneous esketamine for treatment-resistant depression: Impact of the degree of treatment resistance and anxiety comorbidity

J Psychopharmacol. 2021 Feb;35(2):142-149. doi: 10.1177/0269881120978398. Epub 2021 Jan 9.


Background: A large number of studies indicate that subanesthetic doses of ketamine induce a fast antidepressant effect. Limited studies have investigated the subcutaneous (SC) route, and it remains unclear for whom this treatment is most suitable.

Aims: The aim of this study was to examine the effect on depressive symptoms of repeated subanesthetic doses of SC esketamine in unipolar and bipolar treatment-resistant depression (TRD) and clinical predictors of response.

Methods: A retrospective analysis of 70 patients who received six SC esketamine doses weekly as an adjunctive treatment was carried out. Doses started at 0.5 mg/kg and it could be titrated up to 1 mg/kg, according to response. The primary outcome was reduction in depressive symptoms. Statistical analysis to investigate clinical predictors of effectiveness included logistic regression analysis using a dependent variable of a 50% reduction in rating scale scores at the end of treatment. Comparisons between groups were made through analysis of variance and treatment effects.

Results: At baseline, our sample presented with severe treatment resistance in 65.7%, as assessed by the Maudsley Staging Method (MSM), and 47.1% had anxiety disorder comorbidity. The response rate was 50%. A better outcome was predicted by mild and moderate MSM scores (OR = 3.162, p = 0.041) and anxiety disorder comorbidity (OR = 3.149, p = 0.028).

Conclusions: Our results suggest that higher levels of treatment resistance may be associated with a poor response to SC esketamine. Unlike traditional pharmacotherapies, it might benefit those with poor prognosis such as patients with depression and comorbid anxiety. Therefore, future research could investigate whether esketamine should receive a more prominent place in the treatment algorithm for TRD.

Keywords: Esketamine; mood disorders; predictors; subcutaneous; treatment-resistant depression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antidepressive Agents / administration & dosage*
  • Anxiety / drug therapy*
  • Anxiety Disorders / drug therapy*
  • Comorbidity
  • Depression / drug therapy
  • Depressive Disorder, Major / drug therapy
  • Depressive Disorder, Treatment-Resistant / drug therapy*
  • Drug Therapy, Combination / methods
  • Female
  • Humans
  • Ketamine / administration & dosage*
  • Male
  • Retrospective Studies


  • Antidepressive Agents
  • Esketamine
  • Ketamine