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Comparative Efficacy and Safety of Ketamine Versus Electroconvulsive Therapy in Major Depressive Disorder: A Meta-Analysis of Randomized Controlled Trials

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Zhijian Ma
Zhijian Ma
Zhijian Ma
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Fengle Wu
Fengle Wu
Fengle Wu
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Wen Zheng
Wen Zheng
Wen Zheng
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This meta-analysis aimed to compare the efficacy and safety of ketamine versus electroconvulsive therapy (ECT) in patients with major depressive disorder(MDD). A comprehensive literature search was conducted across PubMed, Embase, and Web of Science databases up to November 2024. The randomized controlled trials evaluating the efficacy and safety of ketamine and ECT in MDD patients were included. Pooled standardized mean differences (SMD) and risk ratios (RR) were calculated with 95% confidence intervals. The Cochrane’s Risk of Bias Tool was employed to assess study quality. Six studies encompassing 643 patients were analyzed. No significant difference was observed in depression symptom severity scores between ketamine and ECT groups (SMD: -0.02, 95% CI: -0.53 to 0.48, P = 0.92). Response rates also showed no significant difference between the two interventions (RR: 1.08, 95% CI: 0.67 to 1.72, P = 0.76). Notably, ketamine demonstrated superior memory function improvement compared to ECT (SMD: 2.02, 95% CI: 1.64 to 2.48, P < 0.001). In terms of adverse events, ketamine was associated with significantly higher rates of dissociative symptoms, blurred vision, and dizziness(all P < 0.001), while demonstrating a lower incidence of muscle pain(P < 0.001). The meta-analysis revealed ketamine as a non-inferior therapeutic option for patients with major depressive disorder, with potential advantages in memory function. While promising, the limited number of included studies necessitates further large-scale randomized controlled trials using standardized assessment scales to validate these findings.
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REVIEW ARTICLE
Accepted: 11 February 2025
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2025
Zhijian Ma
15168672718@163.com
1 Department of Anesthesiology, XianJu People’s Hospital, Zhejiang Southeast Campus of
Zhejiang Provincial People’s Hospital, Aliated Xianju’s Hospital, Hangzhou Medical
College, Xianju Zhejiang, China
2 Department of Operating Room, XianJu People’s Hospital, Zhejiang Southeast Campus
of Zhejiang Provincial People’s Hospital, Aliated Xianju’s Hospital, Hangzhou Medical
College, Xianju Zhejiang, China
Comparative Ecacy and Safety of Ketamine Versus
Electroconvulsive Therapy in Major Depressive Disorder: A
Meta-Analysis of Randomized Controlled Trials
ZhijianMa1· FengleWu1· WenZheng2
Psychiatric Quarterly
https://doi.org/10.1007/s11126-025-10121-1
Abstract
This meta-analysis aimed to compare the ecacy and safety of ketamine versus
electroconvulsive therapy (ECT) in patients with major depressive disorder(MDD). A
comprehensive literature search was conducted across PubMed, Embase, and Web of
Science databases up to November 2024. The randomized controlled trials evaluating
the ecacy and safety of ketamine and ECT in MDD patients were included. Pooled
standardized mean dierences (SMD) and risk ratios (RR) were calculated with 95%
condence intervals. The Cochrane’s Risk of Bias Tool was employed to assess study
quality. Six studies encompassing 643 patients were analyzed. No signicant dierence
was observed in depression symptom severity scores between ketamine and ECT groups
(SMD: -0.02, 95% CI: -0.53 to 0.48, P = 0.92). Response rates also showed no signicant
dierence between the two interventions (RR: 1.08, 95% CI: 0.67 to 1.72, P = 0.76). Notably,
ketamine demonstrated superior memory function improvement compared to ECT (SMD:
2.02, 95% CI: 1.64 to 2.48, P < 0.001). In terms of adverse events, ketamine was associated
with signicantly higher rates of dissociative symptoms, blurred vision, and dizziness(all
P < 0.001), while demonstrating a lower incidence of muscle pain(P < 0.001). The meta-
analysis revealed ketamine as a non-inferior therapeutic option for patients with major
depressive disorder, with potential advantages in memory function. While promising, the
limited number of included studies necessitates further large-scale randomized controlled
trials using standardized assessment scales to validate these ndings.
Keywords Ketamine · Electroconvulsive therapy · Major depressive disorder · Meta-
analysis
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Ketamine and Esketamine in Clinical Trials: FDA-Approved and Emerging Indications, Trial Trends With Putative Mechanistic Explanations
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Full-text available
  • Oct 2024
  • CLIN PHARMACOL THER
Ketamine has a long and very eventful pharmacological history. Its enantiomer, esketamine ((S)‐ketamine), was approved by the US Food and Drug Administration (FDA) and EMA for patients with treatment‐resistant depression (TRD) in 2019. The number of approved indications for ketamine and esketamine continues to increase, as well as the number of clinical trials. This analysis provides a quantitative overview of the use of ketamine and its enantiomers in clinical trials during 2014–2024. A total of 363 trials were manually assessed from clinicaltrial.gov with the search term “Ketamine.” The highest number of trials were found for the FDA‐approved indications: anesthesia (~22%) and pain management (~28%) for ketamine and TRD for esketamine (~29%). Clinical trials on TRD for both ketamine and esketamine also comprised a large proportion of these trials, and interestingly, have reached phase III and phase IV status. Combinatorial treatment of psychiatric disorders and non‐psychiatric conditions with pharmacological and non‐pharmacological combinations (electroconvulsive therapy, psychotherapeutic techniques, virtual reality, and transcranial magnetic stimulation) is prevalent. Sub‐anesthetic doses of ketamine may represent novel therapeutic avenues in neuropsychiatric conditions, that is, major depression, schizophrenia, and bipolar disorder, where glutamate excitotoxicity and oxidative stress are likely to be involved. The study suggests that the number of ketamine studies will continue to grow and possible ketamine variants can be approved for treatment of additional indications.
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Efficacy and safety of ketamine-assisted electroconvulsive therapy in major depressive episode: a systematic review and network meta-analysis
Article
Full-text available
  • Dec 2023
Objective To meta-analyze clinical efficacy and safety of ketamine compared with other anesthetic agents in the course of electroconvulsive therapy (ECT) in major depressive episode (MDE). Methods PubMed/MEDLINE, Cochrane Library, Embase, GoogleScholar, and US and European trial registries were searched from inception through May 23, 2023, with no language limits. We included RCTs with (1) a diagnosis of MDE; (2) ECT intervention with ketamine and/or other anesthetic agents; and (3) measures included: depressive symptoms, cognitive performance, remission or response rates, and serious adverse events. Network meta-analysis (NMA) was performed to compare ketamine and 7 other anesthetic agents. Hedges’ g standardized mean differences (SMDs) were used for continuous measures, and relative risks (RRs) were used for other binary outcomes using random-effects models. Results Twenty-two studies were included in the systematic review. A total of 2322 patients from 17 RCTs were included in the NMA. The overall pooled SMD of ketamine, as compared with propofol as a reference group, was –2.21 (95% confidence interval [CI], –3.79 to –0.64) in depressive symptoms, indicating that ketamine had better antidepressant efficacy than propofol. In a sensitivity analysis, however, ketamine-treated patients had a worse outcome in cognitive performance than propofol-treated patients (SMD, –0.18; 95% CI, –0.28 to –0.09). No other statistically significant differences were found. Conclusions Ketamine-assisted ECT is tolerable and may be efficacious in improving depressive symptoms, but a relative adverse impact on cognition may be an important clinical consideration. Anesthetic agents should be considered based on patient profiles and/or preferences to improve effectiveness and safety of ECT use.
View
Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms
Article
Full-text available
  • Jul 2023
Ketamine is an open channel blocker of ionotropic glutamatergic N -Methyl- D -Aspartate (NMDA) receptors. The discovery of its rapid antidepressant effects in patients with depression and treatment-resistant depression fostered novel effective treatments for mood disorders. This discovery not only provided new insight into the neurobiology of mood disorders but also uncovered fundamental synaptic plasticity mechanisms that underlie its treatment. In this review, we discuss key clinical aspects of ketamine’s effect as a rapidly acting antidepressant, synaptic and circuit mechanisms underlying its action, as well as how these novel perspectives in clinical practice and synapse biology form a road map for future studies aimed at more effective treatments for neuropsychiatric disorders.
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Racemic Ketamine as an Alternative to Electroconvulsive Therapy for Unipolar Depression: A Randomized, Open-Label, Non-Inferiority Trial (KetECT)
Article
Full-text available
  • Dec 2021
BACKGROUND Ketamine has emerged as a fast-acting and powerful antidepressant, but no head to head trial has been performed, Here, ketamine is compared to electroconvulsive therapy (ECT), the most effective therapy for depression. METHODS Hospitalized patients with unipolar depression were randomized (1:1) to thrice-weekly racemic ketamine (0.5 mg/kg) infusions or ECT, in a parallel, open-label, non-inferiority study. The primary outcome was remission (Montgomery Åsberg Depression Rating Scale [MADRS] score ≤10). Secondary outcomes included adverse events (AEs), time to remission and relapse. Treatment sessions (maximum of twelve) were administered until remission or maximal effect was achieved. Remitters were followed for twelve months after the final treatment session. RESULTS 186 inpatients were included and received treatment. Among patients receiving ECT 63% remitted, compared to 46% receiving ketamine infusions (p=0.026; difference 95% CI 2%, 30%). Both ketamine and ECT required a median of six treatment sessions to induce remission. Distinct adverse events (2015) were associated with each treatment. Serious and long-lasting AE, including cases of persisting amnesia, were more common with ECT, while treatment emergent AE led to more dropouts in the ketamine group. Among remitters, 70% and 63%, with 57 and 61 median days in remission, relapsed within twelve months in the ketamine and ECT group respectively (p=0.52). CONCLUSION Remission and cumulative symptom reduction following multiple racemic ketamine infusions in severely ill patients (age 18-85) in an authentic clinical setting suggest that ketamine, despite being inferior to ECT, can be a safe and valuable tool in treating unipolar depression.
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Choosing Between Ketamine and Electroconvulsive Therapy for Outpatients With Treatment-Resistant Depression—Advantage Ketamine?
Article
  • Oct 2023
This Viewpoint examines key issues stemming from several recent reports of electroconvulsive therapy (ECT) vs ketamine for improving depressive symptoms in treatment-resistant depression (TRD).
View
View
Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression
Article
  • May 2023
  • NEW ENGL J MED
Background: Electroconvulsive therapy (ECT) and subanesthetic intravenous ketamine are both currently used for treatment-resistant major depression, but the comparative effectiveness of the two treatments remains uncertain. Methods: We conducted an open-label, randomized, noninferiority trial involving patients referred to ECT clinics for treatment-resistant major depression. Patients with treatment-resistant major depression without psychosis were recruited and assigned in a 1:1 ratio to receive ketamine or ECT. During an initial 3-week treatment phase, patients received either ECT three times per week or ketamine (0.5 mg per kilogram of body weight over 40 minutes) twice per week. The primary outcome was a response to treatment (i.e., a decrease of ≥50% from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report; scores range from 0 to 27, with higher scores indicating greater depression). The noninferiority margin was -10 percentage points. Secondary outcomes included scores on memory tests and patient-reported quality of life. After the initial treatment phase, the patients who had a response were followed over a 6-month period. Results: A total of 403 patients underwent randomization at five clinical sites; 200 patients were assigned to the ketamine group and 203 to the ECT group. After 38 patients had withdrawn before initiation of the assigned treatment, ketamine was administered to 195 patients and ECT to 170 patients. A total of 55.4% of the patients in the ketamine group and 41.2% of those in the ECT group had a response (difference, 14.2 percentage points; 95% confidence interval, 3.9 to 24.2; P<0.001 for the noninferiority of ketamine to ECT). ECT appeared to be associated with a decrease in memory recall after 3 weeks of treatment (mean [±SE] decrease in the T-score for delayed recall on the Hopkins Verbal Learning Test-Revised, -0.9±1.1 in the ketamine group vs. -9.7±1.2 in the ECT group; scores range from -300 to 200, with higher scores indicating better function) with gradual recovery during follow-up. Improvement in patient-reported quality-of-life was similar in the two trial groups. ECT was associated with musculoskeletal adverse effects, whereas ketamine was associated with dissociation. Conclusions: Ketamine was noninferior to ECT as therapy for treatment-resistant major depression without psychosis. (Funded by the Patient-Centered Outcomes Research Institute; ELEKT-D ClinicalTrials.gov number, NCT03113968.).
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Efficacy and adverse effects of ketamine versus electroconvulsive therapy for major depressive disorder: A systematic review and meta-analysis
Article
  • Mar 2023
  • J AFFECT DISORDERS
Background: ECT is considered the fastest and most effective treatment for TRD. Ketamine seems to be an attractive alternative due to its rapid-onset antidepressant effects and impact on suicidal thoughts. This study aimed to compare efficacy and tolerability of ECT and ketamine for different depression outcomes (PROSPERO/CRD42022349220). Methods: We searched MEDLINE, Web of Science, Embase, PsycINFO, Google Scholar, Cochrane Library and trial registries, which were the ClinicalTrials.gov and the World Health Organization's International Clinical Trials Registry Platform, without restrictions on publication date. Selection criteria: randomized controlled trials or cohorts comparing ketamine versus ECT in patients with TRD. Results: Eight studies met the inclusion criteria (of 2875 retrieved). Random-effects models comparing ketamine and ECT regarding the following outcomes were conducted: a) reduction of depressive symptoms severity through scales, g = -0.12, p = 0.68; b) response to therapy, RR = 0.89, p = 0.51; c) reported side-effects: dissociative symptoms, RR = 5.41, p = 0.06; nausea, RR = 0.73, p = 0.47; muscle pain, RR = 0.25, p = 0.02; and headache, RR = 0.39, p = 0.08. Influential & subgroup analyses were performed. Limitations: Methodological issues with high risk of bias in some of the source material, reduced number of eligible studies with high in-between heterogeneity and small sample sizes. Conclusion: Our study showed no evidence to support the superiority of ketamine over ECT for severity of depressive symptoms and response to therapy. Regarding side effects, there was a statistically significant decreased risk of muscle pain in patients treated with ketamine compared to ECT.
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Maintenance ketamine treatment for depression: a systematic review of efficacy, safety, and tolerability
Article
  • Nov 2022
Ketamine has rapid yet often transient antidepressant effects in patients with treatment-resistant depression. Different strategies have been proposed to prolong these effects. Maintenance ketamine treatment appears promising, but little is known about its efficacy, safety, and tolerability in depression. We searched Pubmed, Embase, and the Cochrane Library and identified three randomised controlled trials, eight open-label trials, and 30 case series and reports on maintenance ketamine treatment. We found intravenous, intranasal, oral, and possibly intramuscular and subcutaneous maintenance ketamine treatment to be effective in sustaining antidepressant effect in treatment-resistant depression. Tachyphylaxis, cognitive impairment, addiction, and serious renal and urinary problems seem uncommon. Despite the methodological limitations, we conclude that from a clinical view, maintenance ketamine treatment seems to be of therapeutic potential. We recommend both controlled and naturalistic studies with long-term follow-up and sufficient power to determine the position of maintenance ketamine treatment within routine clinical practice.
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Efficacy and Safety of Ketamine vs Electroconvulsive Therapy Among Patients With Major Depressive Episode: A Systematic Review and Meta-analysis
Article
  • Oct 2022
Importance Whether ketamine is as effective as electroconvulsive therapy (ECT) among patients with major depressive episode remains unknown. Objective To systematically review and meta-analyze data about clinical efficacy and safety for ketamine and ECT in patients with major depressive episode. Data Sources PubMed, MEDLINE, Cochrane Library, and Embase were systematically searched using Medical Subject Headings (MeSH) terms and text keywords from database inception through April 19, 2022, with no language limits. Two authors also manually and independently searched all relevant studies in US and European clinical trial registries and Google Scholar. Study Selection Included were studies that involved (1) a diagnosis of depression using standardized diagnostic criteria, (2) intervention/comparator groups consisting of ECT and ketamine, and (3) depressive symptoms as an efficacy outcome using standardized measures. Data Extraction and Synthesis Data extraction was completed independently by 2 extractors and cross-checked for errors. Hedges g standardized mean differences (SMDs) were used for improvement in depressive symptoms. SMDs with corresponding 95% CIs were estimated using fixed- or random-effects models. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Main Outcomes and Measures Efficacy outcomes included depression severity, cognition, and memory performance. Safety outcomes included serious adverse events (eg, suicide attempts and deaths) and other adverse events. Results Six clinical trials comprising 340 patients (n = 162 for ECT and n = 178 for ketamine) were included in the review. Six of 6 studies enrolled patients who were eligible to receive ECT, 6 studies were conducted in inpatient settings, and 5 studies were randomized clinical trials. The overall pooled SMD for depression symptoms for ECT when compared with ketamine was −0.69 (95% CI, −0.89 to −0.48; Cochran Q , P = .15; I ² = 39%), suggesting an efficacy advantage for ECT compared with ketamine for depression severity. Significant differences were not observed between groups for studies that assessed cognition/memory or serious adverse events. Both ketamine and ECT had unique adverse effect profiles (ie, ketamine: lower risks for headache and muscle pain; ECT: lower risks for blurred vision, vertigo, diplopia/nystagmus, and transient dissociative/depersonalization symptoms). Limitations included low to moderate methodological quality and underpowered study designs. Conclusions and Relevance Findings from this systematic review and meta-analysis suggest that ECT may be superior to ketamine for improving depression severity in the acute phase, but treatment options should be individualized and patient-centered.
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