Real-world effectiveness of ketamine in treatment-resistant depression: A systematic review & meta-analysis

This meta-analysis (2022) assessed the effectiveness of ketamine for treatment-resistant depression (TRD) using real-world data. While the mean antidepressant effect of ketamine was found to be significant, there are high levels of variability between patients. Treatment effects were found to be similar following repeated treatments.


“Ketamine is a promising therapeutic option in treatment-resistant depression (TRD). The acute efficacy of ketamine in TRD has been demonstrated in replicated randomised-controlled trials (RCTs), but the generalizability of RCT data to real-world practice is limited. To this end, we conducted a systematic review (Search date: 25/12/2021; 1482 records identified) and meta-analysis of studies evaluating the real-world clinical effectiveness of ketamine in TRD patients. Four overlapping syntheses (Total n = 2665 patients; k = 79 studies) and 32 meta-regressions (Total n = 2050; k = 37) were conducted. All results suggest that the mean antidepressant effect is substantial (mean ± 95% CI, % responded = 45 ± 10%; p < 0.0001, % remitted = 30 ± 5.9%; p < 0.0001, Hedges g of symptomatological improvement = 1.44 ± 0.609; p < 0.0001), but the effect varies considerably among patients. The more treatment-resistant cases were found to remit less often (p < 0.01), but no such effect on response was evident (p > 0.05). Meta-regressions also confirmed that the therapeutic effect does not significantly decline with repeated treatments (p > 0.05). These results demonstrate that even the most treatment-resistant patients may benefit from ketamine, and that mid-to-long term treatment is effective in many patients.”

Abstract: Yazen Alnefeesi, David Chen-Li, Ella Krane, Muhammad Y. Jawad, Nelson B. Rodrigues, Felicia Ceban, Joshua D. Di Vincenzo, Shakila Meshkat, Roger C. M. Ho, Hartej Gill, Kayla M. Teopiz, Bing Cao, Yena Lee, Roger S. McIntyre & Joshua D. Rosenblat

Author Highlights

  • This work quantifies the real-world clinical effectiveness of ketamine in a naturalistic sample of patients with treatment-resistant depression (TRD).
  • The clinical effectiveness of ketamine in TRD is substantial on average, but varies considerably among patient populations.
  • The number of failed antidepressant trials is negatively associated with stable remission, but not stable response (i.e., ≥ 50% reduction in symptomatologic score).
  • Several quantitative analyses converge on the conclusion that repeated ketamine treatments retain their effectiveness in many TRD cases if not most.


Short communication

Herein we evaluated the impact of COVID-19 restrictions on antidepressant effectiveness of intravenous ketamine in adults with treatment-resistant depression. Ketamine treatment was comparable to treatment in the previous year.

  1. Introduction

Since March of 2020, many countries have adopted public health measures to prevent the spread of COVID-19. However, evidence shows that these measures increase the risk of negative mental health outcomes, especially among vulnerable groups such as individuals with pre-existing mood disorders. Despite the negative effects of social isolation measures on overall health outcomes, no study has yet investigated the impact of social isolation measures on individuals receiving antidepressant therapies.

Intravenous ketamine is a rapid-acting treatment option for adults with treatment-resistant depression who have not responded to multiple other treatment trials. It may be a lifesaving treatment for some individuals.

In Ontario, Canada, prolonged social isolation measures were adopted by patients receiving ketamine therapy. The effects of ketamine were similar in patients receiving treatment prior to the pandemic.

  1. Methods

We performed a retrospective case series analysis of adults who received IV ketamine for TRD in an outpatient clinic in Ontario, Canada to evaluate treatment response during COVID-19.

During COVID-19, the clinic followed provincial and regional public health guidelines to protect patients and staff members, and all patients were required to wear personal protective equipment (PPE). The clinic returned to pre-COVID-19 capacity in May 2020, and infusion booking times decreased from 60 minutes to 45 minutes.

Mixed models were performed to compare changes in depressive symptoms, suicidal ideation, anxiety symptoms, and functional disability from pre-treatment to post-infusion 4 and post-infusion 3. Bonferroni corrections were used to account for multiple post-hoc between-group comparisons.

  1. Results

We analyzed data from 267 subjects, including 107 patients who received ketamine treatment during the COVID-19 pandemic and 160 comparators who received ketamine treatment before the COVID-19 pandemic. We found that patients who received repeated infusions of ketamine experienced significant reductions in depressive symptoms, SI, anxiety, and function.

  1. Discussion

In this study, adults with TRD who received four IV ketamine infusions during the COVID-19 pandemic experienced commensurate symptomatic improvements compared to patients who received the same treatment prior to the pandemic.

Patients with serious mental illness, including treatment-resistant depression, may be at increased risk for contracting COVID-19 and may experience adverse health outcomes if hospitalized. Treatment for serious mental illness may reduce adverse outcomes related to COVID-19.


JDR is the medical director of the Braxia Health, a center that provides ketamine and esketamine treatment for depression. He has received research grant support from several organizations.

RSM, YL, KK, AA, EHC, WS, and LW have received grant support, speaker/consultation fees, and personal fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Novo Nordisk, and Braxia Scientific Corp.

CRediT authorship contribution statement

Joshua D. Rosenblat, Orly Lipsitz, Nelson B. Rodrigues, Kevin Kratiuk, Mehala Subramaniapillai, Anil K. Arekapudi, Amir Abrishami, Edmond H. Chau, Witold Szpejda, Leslie Wong, Rodrigo B. Mansur, Roger S. McIntyre contributed to this article.


Authors associated with this publication with profiles on Blossom

Joshua Rosenblat
Joshua Rosenblat is a psychiatrist and clinician-researcher at the Mood Disorders Psychopharmacology Unit at the University of Toronto. He is also the Medical Director of the Canadian Rapid Treatment Centre of Excellence (CRCTE), Chief Medical & Scientific Officer of Braxia Scientific and co-founder of 1907 Research.