Distinct trajectories of antidepressant response to intravenous ketamine

J Affect Disord. 2021 May 1:286:320-329. doi: 10.1016/j.jad.2021.03.006. Epub 2021 Mar 9.


Background: The N-methyl-D-aspartate receptor antagonist ketamine is potentially effective in treatment resistant depression. However, its antidepressant efficacy is highly variable, and there is little information about predictors of response.

Methods: We employed growth mixture modeling (GMM) analysis to examine specific response trajectories to intravenous (IV) ketamine (three infusions; mean dose 0.63 mg/kg, SD 0.28, range 0.30 - 2.98 mg/kg over 40 min) in 328 depressed adult outpatients referred to a community clinic. The Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) assessed depression severity at baseline and before each infusion, up to three infusions for four total observations.

Results: GMM revealed three QIDS-SR response trajectories. There were two groups of severely depressed patients, with contrasting responses to ketamine. One group (n=135, baseline QIDS-SR=18.8) had a robust antidepressant response (final QIDS-SR=7.3); the other group (n=97, QIDS-SR=19.8) was less responsive (final QIDS-SR=15.6). A third group (n=96) was less severely depressed at baseline (QIDS-SR=11.7), with intermediate antidepressant response (final QIDS-SR=6.6). Comparisons of demographic and clinical characteristics between groups with severe baseline depression revealed higher childhood physical abuse in the group with robust ketamine response (p=0.01).

Limitations: This was a retrospective analysis on a naturalistic sample. Patients were unblinded and more heterogenous than those included in most controlled clinical trial samples. Information pertaining to traumatic events occurring after childhood and pre-existing or concurrent medical conditions that may have affected outcomes was not available.

Conclusions: Overall, ketamine's effect in patients with severe baseline depression and history of childhood maltreatment may be consistent with ketamine-induced blockade of behavioral sensitization.

Keywords: Behavioral sensitization; Childhood trauma; Depression; Ketamine; Naturalistic; Response trajectory.

MeSH terms

  • Adult
  • Antidepressive Agents / therapeutic use
  • Child
  • Depressive Disorder, Major* / drug therapy
  • Depressive Disorder, Treatment-Resistant* / drug therapy
  • Humans
  • Infusions, Intravenous
  • Ketamine* / therapeutic use
  • Retrospective Studies
  • Treatment Outcome


  • Antidepressive Agents
  • Ketamine