Urothelial toxicity of esketamine in the treatment of depression

Psychopharmacology (Berl). 2020 Nov;237(11):3295-3302. doi: 10.1007/s00213-020-05611-y. Epub 2020 Jul 26.


Rationale: Ketamine is the first widely used substance with rapid-onset antidepressant action. However, there are uncertainties regarding its potential urothelial toxicity, particularly after repeated application. In the context of rising recreational ketamine use, severe side effects affecting the human urinary tract have been reported. It is assumed that ketamine interacts with bladder urothelial cells and induces apoptosis.

Objectives: This study aimed to assess whether single or repeated doses of esketamine used in an antidepressant indication are associated with urinary toxicity.

Methods: We included male and female inpatients with a current episode of depression and a diagnosis of recurrent depressive disorder, bipolar disorder or schizoaffective disorder according to ICD-10 criteria (n = 25). The esketamine treatment schedule involved a maximum of 3× weekly dosing at 0.25-0.5 mg/kg i.v. or s.c. The primary outcome was the change in urine toxicity markers (leukocytes, erythrocytes, protein and free haemoglobin). Description of demographic, clinical and laboratory data was conducted using means, standard deviations, frequencies and percentages. Changes in urinary toxicity markers over time were evaluated using linear mixed models with gender as a covariate.

Results: The participants received an average of 11.4 (SD 8) esketamine treatments, and an average number of 11.2 (SD 8) urine samples were analysed over the course of treatment. Neither urinary leukocyte concentration (F(20; 3.0) = 3.1; p = 0.2) nor erythrocyte concentration (F(20;2.2) = 4.1; p = 0.2) showed a significant trend towards increase during the course of esketamine treatment. Similarly, free haemoglobin and protein concentrations, which were analysed descriptively, did not display a rise during treatment. There was a significant improvement in depression ratings after esketamine treatment (p < 0.001).

Conclusions: This study is, to the best of our knowledge, the first to focus on urothelial toxicity of esketamine used in antidepressant indication and dose. The results indicate that the use of single or repeated doses of esketamine is unlikely to cause urothelial toxicity. The results are in need of confirmation as sample size was small.

Keywords: Affective disorder; Depression; Esketamine; Side effects; Urothelial toxicity.

MeSH terms

  • Adult
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / adverse effects
  • Antidepressive Agents / urine*
  • Depressive Disorder / diagnosis
  • Depressive Disorder / drug therapy*
  • Depressive Disorder / urine*
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Injections, Intravenous
  • Injections, Subcutaneous
  • Ketamine / administration & dosage
  • Ketamine / adverse effects
  • Ketamine / urine*
  • Male
  • Middle Aged
  • Urothelium / drug effects*
  • Urothelium / metabolism*


  • Antidepressive Agents
  • Esketamine
  • Ketamine