Do the dissociative side effects of ketamine mediate its antidepressant effects?

J Affect Disord. 2014 Apr:159:56-61. doi: 10.1016/j.jad.2014.02.017. Epub 2014 Feb 18.


Background: The N-methyl-d-aspartate receptor antagonist ketamine has rapid antidepressant effects in major depression. Psychotomimetic symptoms, dissociation and hemodynamic changes are known side effects of ketamine, but it is unclear if these side effects relate to its antidepressant efficacy.

Methods: Data from 108 treatment-resistant inpatients meeting criteria for major depressive disorder and bipolar disorder who received a single subanesthetic ketamine infusion were analyzed. Pearson correlations were performed to examine potential associations between rapid changes in dissociation and psychotomimesis with the Clinician-Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale (BPRS), respectively, manic symptoms with Young Mania Rating Scale (YMRS), and vital sign changes, with percent change in the 17-item Hamilton Depression Rating scale (HDRS) at 40 and 230min and Days 1 and 7.

Results: Pearson correlations showed significant association between increased CADSS score at 40min and percent improvement with ketamine in HDRS at 230min (r=-0.35, p=0.007) and Day 7 (r=-0.41, p=0.01). Changes in YMRS or BPRS Positive Symptom score at 40min were not significantly correlated with percent HDRS improvement at any time point with ketamine. Changes in systolic blood pressure, diastolic blood pressure, and pulse were also not significantly related to HDRS change.

Limitations: Secondary data analysis, combined diagnostic groups, potential unblinding.

Conclusions: Among the examined mediators of ketamine׳s antidepressant response, only dissociative side effects predicted a more robust and sustained antidepressant. Prospective, mechanistic investigations are critically needed to understand why intra-infusion dissociation correlates with a more robust antidepressant efficacy of ketamine.

Keywords: Bipolar depression; Blood pressure; Ketamine; Major depressive disorder; Predictors; Psychotomimetic.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Antidepressive Agents / adverse effects*
  • Antidepressive Agents / therapeutic use
  • Bipolar Disorder / drug therapy*
  • Bipolar Disorder / psychology
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / psychology
  • Dissociative Disorders / chemically induced*
  • Female
  • Humans
  • Ketamine / adverse effects*
  • Ketamine / therapeutic use
  • Male
  • Middle Aged
  • Prospective Studies
  • Psychiatric Status Rating Scales
  • Treatment Outcome


  • Antidepressive Agents
  • Ketamine