Research

JAMA Psychiatry | Brief Report

Ketamine vs Electroconvulsive Therapy for Major Depressive Episode

A Systematic Review and Meta-analysis
Vikas Menon, MD; Natarajan Varadharajan, MD; Abdul Faheem, MD; Chittaranjan Andrade, MD

Supplemental content
IMPORTANCE The relative efficacy of ketamine and electroconvulsive therapy (ECT) in adults
with major depressive episode (MDE) needs clarification.

OBJECTIVE To compare depression rating outcomes with ketamine vs ECT in adults with MDE
and to compare response and remission rates, number of sessions to response and remission,
and adverse effects.

DATA SOURCES Two investigators independently systematically searched MEDLINE,

ScienceDirect, and Google Scholar databases using a combination of relevant Medical Subject
Headings terms and free-text keywords from database inception through May 15, 2022, to
identify relevant English-language trials.

STUDY SELECTION Parallel-group randomized clinical trials (RCTs).

DATA EXTRACTION AND SYNTHESIS Two investigators independently extracted data and
assessed risk of bias. One-week posttreatment outcomes were pooled as standardized mean
difference (SMD; Hedges g) for continuous outcomes and risk ratio (RR) for categorical
outcomes in random-effects meta-analyses.

MAIN OUTCOMES AND MEASURES Efficacy outcomes were 1-week (or nearest) posttreatment
depression ratings, 1-week (or nearest) study-defined response and remission rates, and
number of sessions to treatment response and remission. Safety outcomes were reported
adverse effects.

RESULTS Five trials (ketamine group: n = 141; ECT group: n = 137) were meta-analyzed. The
overall pooled SMD for posttreatment depression ratings was −0.39 (95% CI, −0.81 to 0.02;
I2 = 45%; 5 RCTs). For this efficacy outcome, in a sensitivity analysis of methodologically
stronger trials, ECT was superior to ketamine (SMD, −0.45; 95% CI, −0.75 to −0.14; I2 = 6%; 2
RCTs). ECT was also superior to ketamine for study-defined response (RR, 1.27; 95% CI,
1.06-1.53; I2 = 0%; 3 RCTs) and remission (RR, 1.43; 95% CI, 1.12-1.82; I2 = 0%; 2 RCTs) rates.
No significant differences were noted between groups for number of sessions to response
and remission and for cognitive outcomes. Key limitations were small number of studies,
limited sample size, and high risk of bias in all trials.

CONCLUSION AND RELEVANCE The findings of this systematic review and meta-analysis
suggest an efficacy advantage for ECT over ketamine in adults with MDE. These conclusions
are tempered by the small number and size of existing trials.

Author Affiliations: Department of

Psychiatry, JIPMER, Puducherry, India
(Menon, Faheem); Department of
Psychiatry, ESIC Medical College and
Hospital, KK Nagar, Chennai, India
(Varadharajan); Department of
Clinical Psychopharmacology and
Neurotoxicology, National Institute of
Mental health and Neurosciences,
Bangalore, Karnataka, India
(Andrade).
Corresponding Author: Vikas
Menon, MD, Department of
Psychiatry, JIPMER, Puducherry
JAMA Psychiatry. doi:10.1001/jamapsychiatry.2023.0562 605006, India (drvmenon@
Published online April 12, 2023. gmail.com).

(Reprinted) E1
© 2023 American Medical Association. All rights reserved.
 Research Brief Report
T
he use of electroconvulsive therapy (ECT), a criterion
standard antidepressant treatment, is limited by nega-
tive attitudes toward the treatment, by its cognitive ad-
verse effects, and by geographical variations in its availabil-
ity, among other factors. There is a need for alternate treatments
that are as effective as ECT and with better adverse effect pro-
files. In this context, ketamine, a noncompetitive N-methyl-
D-aspartate receptor antagonist, is gaining credibility as a rela-
tively safe, effective, and rapidly acting antidepressant. During
the past 10 years, several randomized clinical trials (RCTs) have
compared the efficacy of ketamine and ECT in patients with
major depressive episode (MDE). There is need for a quanti-
tative synthesis of the results of these studies that could guide
research and clinical practice.
Rhee et al1 meta-analyzed studies comparing ECT and ket-
amine in patients with MDE. They found that ECT was supe-
rior to ketamine in antidepressant action and that the treat-
ments did not differ significantly in cognitive adverse effects
and serious adverse events. We had ourselves earlier regis-
tered a protocol on this subject (CRD42022332645). In our
meta-analysis, we examined posttreatment depression ratings
as well as efficacy outcomes not examined by Rhee et al1: study-
defined response and remission rates and number of treatment
sessions to response and remission.
Methods
We followed the recommendations of the Cochrane handbook2
and 2020 Preferred Reporting Items for Systematic Reviews and
Meta-analyses (PRISMA) reporting guideline (eAppendix 1 in
Supplement 1).3 We limited our search to parallel-group RCTs,
published in English, that compared ketamine and ECT in
patients with MDE. We searched MEDLINE, ScienceDirect, and
Google Scholar databases from inception until May 31, 2022,
using a combination of the following Medical Subject Headings
(MeSH) terms and their morphological variations in sequential
MeSH and free-text terms search: depression (MeSH), bipolar
depression (MeSH), electroconvulsive therapy (MeSH), and
ketamine (MeSH). The complete search strategy is presented in
eAppendix 2 in Supplement 1.
Our primary outcome was the depression rating at 1 week
(or nearest) after treatment end point. Secondary outcomes
were response and remission rates, number of treatment ses-
sions taken to attain response and remission, and adverse ef-
fects. Effect sizes in random-effects meta-analyses were esti-
mated as standardized mean difference (SMD; Hedges g) with
95% CI for continuous outcomes and risk ratio (RR) with 95%
CI for categorical outcomes.
We performed random-effects meta-analyses because we be-
lieved that outcomes could differ at the population level in dif-
ferent parts of the world. For example, sociocultural variables
influencing onset, course, and outcome of depression could dif-
fer between Asia and Europe; patients may be diagnosed and
treated differently in different countries; and placebo effects re-
lated to ketamine and ECT may differ across cultures.
We sought additional relevant data, not presented in their
articles, from all authors but received the requested data only
E2 JAMA Psychiatry Published online April 12, 2023 (Reprinted)
© 2023 American Medical Association. All rights reserved.
Ketamine vs ECT for Depression
Key Points
Question How does ketamine compare with electroconvulsive
therapy (ECT) for efficacy and safety in adults with major
depressive episode?
Findings In the systematic review and meta-analysis of 5
randomized clinical trials that included 278 individuals, there was a
nonsignificant trend for superiority of ECT over ketamine for
1-week posttreatment depression ratings. In a sensitivity analysis
excluding 3 methodologically problematic trials, ECT was
significantly superior to ketamine for this outcome and was
associated with significantly superior response and remission
rates; cognitive outcomes did not differ between ECT and
ketamine trials.
Meaning ECT may be superior to ketamine in adults in a major
depressive episode.
from Ekstrand et al4 and Sharma et al.5 We used version 2 of
the Cochrane risk-of-bias tool for RCTs6 to assess risk of bias.
Two authors (N.V. and A.F.) independently performed the lit-
erature search, study screening, data abstraction, and quality
appraisal. Disagreements, if any, were resolved through dis-
cussion and consensus with a third author (V.M.); if neces-
sary, a senior author (C.A.) was also involved in resolving
conflicts.
Results
Five RCTs 4,5,7-9 (pooled N = 278) met our search criteria
(Figure 1 and eTable 1 in Supplement 1). In the main analysis,
posttreatment depression ratings showed a trend for lower
scores with ECT compared with ketamine (SMD, −0.39; 95%
CI, −0.81 to 0.02; I2 = 45%; 5 RCTs4,5,7-9; n = 278) (Figure 2).
Importantly, in a sensitivity analysis that specifically ex-
cluded 3 RCTs7-9 for reasons related to questionable methods
and reporting, described in detail in our earlier review,10 post-
treatment depression ratings in the remaining RCTs4,5 were sig-
nificantly lower with ECT than with ketamine (SMD, −0.45; 95%
CI, −0.75 to −0.14; I2 = 6%; 2 RCTs; n = 211) (Figure 3).
The pooled ECT vs ketamine RR was 1.27 (95% CI, 1.06-
1.53; I2 = 0%; 3 RCTs4,5,9; n = 229) (eFigure 1 in Supplement 1)
for a study-defined response rate and 1.43 (95% CI, 1.12-1.82;
I2 = 0%; 2 RCTs4,5; n = 211) (eFigure 2 in Supplement 1) for a
study-defined remission rate. ECT was significantly superior
to ketamine in both regards, and heterogeneity was low in both
analyses.
The pooled SMD for difference in number of sessions re-
quired for response was 0.68 (95% CI, −0.80 to 2.16; I2 = 87%;
2 RCTs4,5; n = 139) (eFigure 3 in Supplement 1) favoring ECT.
The pooled SMD for difference in sessions to remission was 0.57
(95% CI, −0.65 to 1.79; I2 = 78%; 2 RCTs4,5; n = 119) (eFigure 4
in Supplement 1), again favoring ECT. In both analyses, num-
ber of trials was small, heterogeneity was high, CIs were wide,
and SMD was statistically nonsignificant.
Posttreatment cognition scores showed little difference
between ketamine and ECT groups (SMD, 0.13; 95% CI, −0.57
jamapsychiatry.com
Ketamine vs ECT for Depression Brief Report Research

to 0.83; I 2 = 1%; 2 RCTs 5,7 ; n = 34) (eFigure 5 in Supple- RCTs4,7,8; n = 230) (eFigure 7 in Supplement 1) for musculo-
ment 1). The pooled ketamine vs ECT RR was 0.38 (95% CI, skeletal pain; ketamine was superior to ECT in both regards.
0.18-0.79; I2 = 73%; 3 RCTs4,7,8; n = 230) (eFigure 6 in Supple- The pooled ketamine vs ECT RR for dissociative symptoms was
ment 1) for headache and 0.25 (95% CI, 0.15-0.42; I2 = 0%; 3 6.45 (95% CI, 1.92-21.64; I2 = 32%; 3 RCTs4,7,8; n = 230) (eFig-
ure 8 in Supplement 1); ECT was superior to ketamine for this
outcome.
Figure 1. PRISMA Flowchart Four trials had high7-9 or unclear risk of bias4 related to
randomization processes. All 5 trials had high risk of bias
262 Records identified through 2 Additional records identified
database searching through other sources related to deviations from intended interventions given the
lack of blinding of participants and treatment personnel and
given that such deviations are likely to affect outcomes.
214 Screened after duplicates removed Three trials4,7,8 were judged to be at high risk of bias due to
differences between groups on proportion of missing out-
199 Excluded come data. Two trials4,8 had high risk of bias in measurement
75 Review articles of outcomes due to nonblinding of outcome raters. Finally, 2
69 Nonrelevant objectives
25 No original data trials 5,9 were at high risk of bias in selection of reported
23 Case series/reports results as they were unregistered/retrospectively registered
7 Non-English articles
on a trial registry (eTable 2 in Supplement 1).

15 Full-text articles assessed for eligibility

10 Excluded
4 Ketamine adjust to ECT
2 Protocols
2 Non-RCTs
2 No original data
5 Studies included in quantitative synthesis
ECT indicates electroconvulsive therapy; RCT, randomized clinical trial.
Discussion
Overall, in 5 RCTs (N = 278), 4,5,7-9 ECT, compared with
ketamine, was not associated with statistically significantly
lower depression scores 1 week posttreatment; however,
in a sensitivity analysis that excluded RCTs with question-
able methods and reporting, 10 ECT was associated with
significantly lower depression scores posttreatment. The
effect sizes in these analyses were small to medium and

Figure 2. Posttreatment Depression Scores for Electroconvulsive Therapy (ECT) vs Ketamine in Patients
With Major Depressive Episode: Main Analysis4,5,7-9

ECT Ketamine SMD IV, random Favors Favors

Study Mean (SD) Total No. Mean (SD) Total No. (95% CI) ECT ketamine Weight, %
Ekstrand et al,8 2022 12.2 (11.1) 91 16.9 (13.1) 95 –0.38 (–0.68 to –0.09) 37.8
Ghasemi et al,9 2014 15.7 (7.5) 9 10.9 (7.5) 9 0.61 (–0.34 to 1.56) 13.4
Kheirabadi et al,6 2019 13.6 (3.1) 12 16.9 (3.3) 10 –0.99 (–1.89 to –0.09) 14.5
Kheirabadi et al,7 2020 9.5 (5.4) 12 10.9 (5.1) 15 –0.26 (–1.02 to 0.50) 18.0
Sharma et al,5 2020 3.9 (3.2) 13 8.8 (7.4) 12 –0.84 (–1.67 to –0.02) 16.3
Total (95% CI) 137 141 –0.39 (–0.81 to 0.02) 100.0

Heterogeneity: τ2 = 0.10; χ2 = 7.26; df = 4; P = .12; I2 = 45%

–4 –2 0 2 4
Test for overall effect: z = 1.86 (P = .06)
SMD IV, random (95% CI)

IV indicates inverse variance; SMD, standardized mean difference.

Figure 3. Posttreatment Depression Scores for Electroconvulsive Therapy (ECT) vs Ketamine in Patients
With Major Depressive Episode: Sensitivity Analysis Excluding Methodologically Weaker Trials4,5

ECT Ketamine SMD IV, random Favors Favors

Study Mean (SD) Total No. Mean (SD) Total No. (95% CI) ECT ketamine Weight, %
Ekstrand et al,8 2022 12.2 (11.1) 91 16.9 (13.1) 95 –0.38 (–0.68 to –0.09) 86.8
Sharma et al,5 2020 3.9 (3.2) 13 8.8 (7.4) 12 –0.84 (–1.67 to –0.02) 13.2
Total (95% CI) 104 107 –0.45 (–0.75 to –0.14) 100.0

Heterogeneity: τ2 = 0.01; χ2 = 1.06; df = 1; P = .30; I2 = 6%

–4 –2 0 2 4
Test for overall effect: z = 2.87 (P = .004)
SMD IV, random (95% CI)

IV indicates inverse variance; SMD, standardized mean difference.

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© 2023 American Medical Association. All rights reserved.

 Research Brief Report Ketamine vs ECT for Depression

similar in magnitude; heterogeneity in both analyses was
small to moderate. Importantly, ECT was associated
with significantly higher response and remission rates but
not with significantly faster onset of either response or
remission.
These findings supplement those presented in the meta-
analysis by Rhee et al1 but suggest that the advantage for ECT
over ketamine may be smaller than shown by them, support-
ing our recommendation for a trial of ketamine before a trial
of ECT for patients with MDE. A caveat is that this recommen-
dation is supported by only a small number of patients in a
small number of trials.
Finally, given the possibility that patients with bipolar
depression may not respond as well to ketamine as those
with major depressive disorder, 11 we believe that future
RCTs of ECT vs ketamine for patients with MDE should
report outcomes separately for bipolar depression and
major depressive disorder, at least in supplementary materi-
als if not in main analyses, so that future meta-analyses can
pool outcomes separately for bipolar disorder and major
depressive disorder.
Limitations
Key limitations were the small number of eligible studies, small
sample sizes in most studies, poor methodological quality of
most studies, and high risk of bias in all. No study examined
retrograde amnestic deficits, arguably the most problematic
adverse effect of ECT.
Conclusions
The findings of this study suggest that ECT may be superior
to ketamine for improving depressive symptoms in adults with
an MDE. However, the advantage is small, and therefore, for
many patients, especially those who want to be protected
against cognitive risks, a trial of ketamine may be worth con-
sidering before a trial of ECT.

ARTICLE INFORMATION
Accepted for Publication: February 1, 2023.
Published Online: April 12, 2023.
doi:10.1001/jamapsychiatry.2023.0562
Author Contributions: Dr Menon had full access to
all of the data in the study and takes responsibility
for the integrity of the data and the accuracy of the
data analysis.
Concept and design: Menon, Andrade.
Acquisition, analysis, or interpretation of data:
All authors.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important
intellectual content: Menon, Andrade.
Statistical analysis: Menon, Andrade.
Administrative, technical, or material support:
Menon, Varadharajan, Faheem.
Supervision: Andrade.
Conflict of Interest Disclosures: Dr Menon reports
traveling to deliver guest lectures and conduct
workshops, funded by the organizers of the
programs in the cities in which they were
conducted. Dr Andrade reports publishing an
e-newsletter supported by Sun Pharmaceuticals
(payments are made directly to registered
charities); previously publishing print newsletters
for free distribution as an educational service to
medical professionals in India, for which production
costs were reimbursed by the pharmaceutical
organizations responsible for the distribution:
Sun Pharmaceutical Industries and Intas
Pharmaceuticals; traveling to deliver guest lectures
and conduct workshops, funded by the organizers
of the programs in the cities in which they were
conducted; consulting for Sun Pharmaceutical
Industries and Intas Pharmaceuticals for nominal
compensation in the form of academic support
towards slide preparation or purchase of materials
such as textbooks or directly to charities; receiving
payments for developing educational materials for
scientific initiatives and programs, such as for
Behavioral and Neurosciences Foundation of India,
PsyBase India, Texas Tech University, Nordic
Association for Convulsive Therapy, and American
Society of Clinical Psychopharmacology. No other
disclosures were reported.
Data Sharing Statement: See Supplement 2.
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