Trait dissociation as a predictor of induced dissociation by ketamine or esketamine in treatment-resistant depression: Secondary analysis from a randomized controlled trial

J Psychiatr Res. 2021 Jun:138:576-583. doi: 10.1016/j.jpsychires.2021.05.014. Epub 2021 May 8.


Dissociative symptoms are common, possibly severe, side effects associated with the use of ketamine and esketamine in depression. We investigated the relationship between trait dissociation and dissociation induced by ketamine and esketamine used as augmentation therapy in treatment-resistant depression (TRD). Adults with TRD were randomly assigned to receive a single intravenous infusion, with a duration of 40 min, of either esketamine 0.25 mg/kg or ketamine 0.5 mg/kg. We assessed trait dissociation with the Dissociative Experience Scale (DES) and, to evaluate induced dissociation, the Clinician-Administered Dissociative States Scale (CADSS) was used. Thirty-two subjects received esketamine and 29 received ketamine. The groups had similar median DES scores (p = 0.26). More than 30% of the patients in both groups had DES scores ≥30 points. The median CADSS score in the esketamine group was equivalent to that in the ketamine group (p = 0.40). Every 5 points increment in the DES was associated with a 10.9% (95% CI 4.5-17.8%) increase in the CADSS, in an exponential fashion when the two groups were pooled together. Subjects with high trait dissociation had a higher risk of induced dissociation state (relative risk [RR] 1.41, 95% CI 1.11-1.78) and very high induced dissociation (RR 3.05, 95% CI 1.14-8.15). Induced dissociation was not a serious adverse effect. The findings suggest that trait dissociation is a predictor of induced dissociation by Ketamine or Esketamine in TRD subjects. Screening for trait dissociation and counseling patients with high trait dissociation on the risks of dissociation by these drugs are recommended.

Keywords: Adverse effects; Dissociation; Esketamine; Ketamine; Treatment-resistant depression.

Publication types

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

MeSH terms

  • Adult
  • Antidepressive Agents / adverse effects
  • Depression
  • Depressive Disorder, Treatment-Resistant* / drug therapy
  • Humans
  • Ketamine* / adverse effects


  • Antidepressive Agents
  • Esketamine
  • Ketamine