Early symptomatic improvements as a predictor of response to repeated-dose intravenous ketamine: Results from the Canadian Rapid Treatment Center of Excellence

Prog Neuropsychopharmacol Biol Psychiatry. 2021 Mar 8;105:110126. doi: 10.1016/j.pnpbp.2020.110126. Epub 2020 Oct 5.


Background: Early symptomatic improvement with monoamine-based antidepressants is predictive of treatment response. The objective of this study was to determine if early symptomatic improvements with intravenous (IV) ketamine predicted treatment response to an acute course of four infusions.

Method: 134 adults with treatment resistant depression (TRD) received four ketamine infusions over one to two weeks. Depressive symptoms were measured using the Quick Inventory for Depressive Symptomatology Self-Report16 (QIDS-SR16) at baseline and post-infusions 1, 2, 3, and 4. Early improvement was defined as ≥20% reduction in QIDS-SR16 scores after the first or second infusion. Linear models were used to determine whether early improvement was associated with post-infusion 4 QIDS-SR16 scores after controlling for baseline characteristics.

Results: Early improvement post-infusion 1 (β = -3.52, 95% BCa CI [-5.40, -1.78]) and 2 (β = -3.16, 95% BCa CI [-5.75, -1.59]) both significantly predicted QIDS-SR16 scores post-infusion 4. Early improvers had significantly lower QIDS-SR16 scores at post-infusion 4 (post-infusion 1 improvers: M = 9.8, SD = 4.5; post-infusion 2 improvers: M = 10.6, SD = 5.7) compared to non-early improvers (post-infusion 1 non-improvers: M = 13.7, SD = 5.8; post-infusion 2 non-improvers: M = 14.1, SD = 5.3) when controlling for baseline characteristics. The majority (58%) of individuals who did not improve post-infusions 1 or 2 still experienced an antidepressant response or partial response (≥20% reduction in QIDS-SR16) post-infusion 4.

Limitations: This is a post-hoc analysis of an open-label study.

Conclusion: Early improvement was associated with greater antidepressant effects following a course of four ketamine infusions. However, individuals who did not show early improvements still had a high likelihood of experiencing clinically significant symptom reduction after the fourth infusion, suggesting that completing four infusions, regardless of early symptom changes, is appropriate and merited.

Trial registration: ClinicalTrials.gov NCT04209296.

Keywords: Antidepressant; Bipolar disorder; Esketamine; Glutamate; Major depressive disorder; NMDA; Treatment-resistant depression.

MeSH terms

  • Adult
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / therapeutic use*
  • Depressive Disorder, Treatment-Resistant / drug therapy*
  • Female
  • Humans
  • Infusions, Intravenous
  • Ketamine / administration & dosage
  • Ketamine / therapeutic use*
  • Male
  • Middle Aged
  • Retreatment
  • Symptom Assessment
  • Treatment Outcome


  • Antidepressive Agents
  • Ketamine

Associated data

  • ClinicalTrials.gov/NCT04209296