Research

JAMA Psychiatry | Original Investigation

Efficacy and Safety of Ketamine vs Electroconvulsive Therapy

Among Patients With Major Depressive Episode
A Systematic Review and Meta-analysis
Taeho Greg Rhee, PhD; Sung Ryul Shim, PhD; Brent P. Forester, MD, MSc; Andrew A. Nierenberg, MD; Roger S. McIntyre, MD;
George I. Papakostas, MD; John H. Krystal, MD; Gerard Sanacora, MD, PhD; Samuel T. Wilkinson, MD

Supplemental content
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; I2 = 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.

Author Affiliations: Author

affiliations are listed at the end of this
article.
Corresponding Author: Greg Rhee,
PhD, Department of Public Health
Sciences, University of Connecticut
School of Medicine, 263 Farmington
JAMA Psychiatry. 2022;79(12):1162-1172. doi:10.1001/jamapsychiatry.2022.3352 Ave, Farmington, CT 06030 (tgrhee.
Published online October 19, 2022. Corrected on December 7, 2022. research@gmail.com).

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 Ketamine Compared With Electroconvulsive Therapy for Major Depressive Episode
M
ajor depressive disorder is one of the most common
and disabling mental disorders, affecting 15.7 mil-
lion adults 18 years and older in the United States,1,2
and is the subject of extensive prevention and treatment
efforts.3,4 Unfortunately, more than 30% of individuals who
experience major depressive episodes (MDEs) do not achieve
remission after several trials of antidepressants.5,6 Such treat-
ment-resistant depression (TRD) is associated with prema-
ture mortality, including suicide.7-9
Endorsed by multiple professional guidelines (eg,
American Psychiatric Association),10-12 electroconvulsive
therapy (ECT) is considered the gold standard treatment for
TRD because of its proven high efficacy.13 However, ECT has
been underused,14,15 due in part to health care professional
barriers (eg, lack of well-trained ECT practitioners across the
regions and lack of physical space) and patient barriers (eg,
stigma or public attitude and transportation difficulties).16
Furthermore, this treatment has long been associated with
adverse cognitive effects, although the risk for these
adverse effects has reduced by recent procedural changes
(eg, right unilateral with ultra-brief pulse width). Because of
cognitive adverse effects and other issues (ie, difficulty of
administration), physician-scientists have sought to iden-
tify alternative treatment modalities that approach ECT-
equivalent efficacy with more tolerable adverse effect and
acceptability profiles.
Since 2000, an increasing number of small- to medium-
sized clinical trials have shown that low doses of (R,S)-
ketamine delivered intravenously can have rapid and robust
antidepressant effects in TRD.17-21 While conventional anti-
depressant medications and adjunctive second-generation
antipsychotics target monoaminergic neurotransmission
(ie, serotonin, norepinephrine, and dopamine), ketamine
is a glutamate N-methyl- D -aspartate (NMDA) receptor
antagonist.14 Ketamine has shown rapid and robust antide-
pressant effects in patients with MDE, 22-24 and adverse
effects are generally mild and self-limiting.25,26 However,
unlike its S-enantiomer (esketamine), ketamine is not cur-
rently approved by regulatory agencies (eg, the US Food and
Drug Administration) for the treatment of depression.27
Establishing the efficacy of ketamine as compared with ECT
remains an important clinical question. Several review ar-
ticles have highlighted the importance of resolving this
issue,26,28,29 but no study has yet quantified the overall treat-
ment effect sizes of efficacy and safety outcomes between
ketamine and ECT. The aim of this study is to conduct a sys-
tematic review and meta-analysis of the clinical trials that com-
pare the efficacy and safety of ketamine and ECT.
Methods
Search Strategy and Reporting Criteria
The protocol pertaining to this study was registered on PROS-
PERO (CRD42022338045). A systematic search was conducted
from database inception to April 19, 2022. PubMed, MEDLINE,
t h e C o c h r a n e L i b r a r y, a n d E m b a s e we re s e a rc h e d
systematically using Medical Subject Headings (MeSH) terms
jamapsychiatry.com
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Original Investigation Research
Key Points
Question Is ketamine as effective as electroconvulsive therapy
(ECT) in patients with major depressive episode?
Findings This systematic review and meta-analysis of 6 trials with
340 patients suggests that ECT may be superior to ketamine in
improving depression severity. Findings also suggest that
ketamine and ECT each have unique adverse effect profiles.
Meaning Although ECT may be more efficacious than ketamine in
the acute phase, treatment options should be individualized and
patient-centered, considering different adverse effect profiles and
patient preferences.
and text keywords. We also manually searched all relevant
studies in clinical trial registries funded by the National
Institutes of Health, European Union clinical trial registries,
and Google Scholar. No language restrictions were imposed.
Sample search strategies are provided in eTable 1 in the
Supplement.
This study followed the Preferred Reporting Items for Sys-
tematic Reviews and Meta-analyses (PRISMA) reporting
guideline (eTable 2 in the Supplement).30 Our study used
publicly available data and did not include human participant
research. As per 45 CFR §46.102(f ), this study was not
submitted for institutional review board approval and did not
require informed consent procedures.
Study Selection
Inclusion criteria were established prior to article reviews and
were as follows: (1) patients with a diagnosis of depression using
standardized diagnostic criteria (eg, DSM-5 or International Sta-
tistical Classification of Diseases and Related Health Problems,
Tenth Revision [ICD-10]); (2) intervention/comparator groups
consisting of ECT and ketamine; and (3) severity of depres-
sive symptoms as an efficacy outcome using standardized mea-
sures (eg, Montgomery-Åsberg Depression Rating Scale
[MADRS] and Hamilton Depression Rating Scale [HDRS]); and
(4) human-based clinical trials. We also considered suicidal
ideation and cognition or memory measures as efficacy out-
comes. Further, we considered safety-related events as sec-
ondary outcomes (eg, reports of adverse events: suicide at-
tempts or deaths, headache, muscle pain, vertigo, diplopia/
nystagmus, dissociative or depersonalization symptoms, and
nausea). Exclusion criteria were (1) nonhuman studies and
(2) no use of standardized measures for depression or the pri-
mary outcomes of interest.
Data Extraction
Titles and abstracts were independently screened by 2
reviewers (T.G.R. and S.R.S.), and articles identified as
potentially relevant by at least 1 reviewer were retrieved and
duplicates were removed. Full-text articles were indepen-
dently screened by 2 reviewers (T.G.R. and S.R.S.); discrep-
ancies were resolved through group discussions. Data from
included articles were independently extracted by 2 review-
ers (T.G.R. and S.R.S.) using a pilot-tested data extraction
form and then corroborated, with discrepancies resolved
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 Research Original Investigation
through group discussions. Information to be extracted was
established a priori and included the following: study char-
acteristics, participant characteristics and subgroups,
sample source and collection period, modes of ascertain-
ment, methods of data analysis, selection of cases and con-
trols, and quantitative data pertaining to any primary and
secondary outcomes along with adjusted factors. To ensure
the absence of overlapping data and to maintain the meta-
integrity, data and references for each included study were
carefully cross-checked.
Assessment of Bias and Methodological Quality
The risk of bias and methodological quality were evaluated
using the Cochrane Collaboration Risk of Bias tool version 2.31,32
We assessed 5 parameters, including (1) randomization pro-
cess, (2) deviations from the intended interventions, (3) miss-
ing outcome data, (4) measurement of the outcome, and
(5) selection of the reported result. Each domain was classi-
fied as having a high, low, or unclear risk of bias. We used
Cochrane Library’s Review Manager software, RevMan ver-
sion 5.4.1,33 when assessing biases and methodological quali-
ties. We also assessed publication bias (or small-study ef-
fects) using a funnel plot.34 We used the Egger test (ie, linear
regression test of funnel plot asymmetry) and Begg and
Mazumdar test (ie, rank correlation test of funnel plot asym-
metry) when assessing the publication bias.
Statistical Analysis
We used a Hedges g standardized mean difference (SMD) for
improvement in severity of depressive symptoms because
different studies used different standardized measures. The
weight of each study was determined using an inverse-
variance method.34 Relative risk (RR) was used for safety-
related outcomes as they were all binary outcomes, and we
used the Mantel-Haenszel method. 34 We used both the
Cochran Q statistic and I2 statistic to quantify the proportions
of heterogeneity due to within- and between-study
variations.34 To adequately estimate the overall effect sizes,
SMDs or RRs with their corresponding 95% CIs were calcu-
lated using fixed- or random-effects models depending on the
model assumptions.34 More specifically, a random-effects
model was used when the I2 statistic was greater than 50%,
and a fixed-effects model was used when I2 statistic was less
than 50%. We reported both random- and fixed-effects mod-
els when the I2 statistic was 50%. Because some studies re-
ported multiple effect sizes for severity of depressive symp-
toms, we used a 2-stage meta-analysis. In the first stage, we
obtained the overall effect size estimate of multiple mea-
sures within the study using a 3-level meta-analysis. In the sec-
ond stage, we pooled and obtained the overall effect size es-
timate using 1 effect size from each study. This approach avoids
potential duplication of the samples included.
We also conducted moderator analyses using meta-
regression analyses by study sample size, age, male sex (%),
region, randomization status, presence of psychotic fea-
tures, and treatment type (ie, right unilateral, bilateral, or
mixed types for ECT). When identifying potential modera-
tors, we used the variance of the true effects using a
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Ketamine Compared With Electroconvulsive Therapy for Major Depressive Episode
restricted maximum likelihood estimator.34 We used the
statistical software R version 4.2.1 (R Foundation for Statis-
tical Computing) for all analyses using the meta, rmeta, and
metafor packages.35 A 2-sided P < .05 was considered statis-
tically significant.
Results
Characteristics of the Studies Included
The literature search yielded 1248 articles, of which 60 were
eligible after screening titles and abstracts and removing du-
plicates. Of these eligible studies, 56 were further excluded af-
ter full-text screening. Two independent investigators (T.G.R.
and S.R.S.) discovered 2 additional studies by manually search-
ing clinical trial databases and reference lists. Details of study
selection are provided in eFigure 1 in the Supplement. Over-
all, 6 clinical trial studies36-41 with 340 patients (n = 162 for ECT
and n = 178 for ketamine) were included in the review (Table 1).
Five trials were conducted at single sites, and 1 study37 was a
multicenter trial (6 clinics). From these studies, 6 effect sizes
for depression severity were identified for meta-analysis. Two
studies (33.3%) were conducted in Europe, and 4 other stud-
ies (66.7%) were conducted in Asia or the Middle East. Five
studies followed randomized clinical trial designs, and 1
study,36 conducted in Germany, used a naturalistic, open-
label clinical trial design.
Sample sizes ranged from 18 to 186, with mean age of the
participants ranging from 37.5 to 52.5 years. A period for com-
pleting a series of treatment sessions for either ECT or ket-
amine was within a month. All studies recruited patients who
were ECT candidates; 5 of 6 studies only enrolled patients with
MDE, with 1 study41 recruiting patients with either unipolar
or bipolar depression. Table 1 provides details (including the
frequency and duration of treatment sessions) and summa-
ries of applicable findings for all included studies.
Efficacy Outcome: Depressive Symptoms
The primary efficacy outcome of interest was the improve-
ment of depressive symptoms (Figure 1). When stratified by
individual measure, ECT was superior to ketamine across dif-
ferent depressive symptom measures (SMD, −0.59 [95% CI,
−0.85 to −0.33] for MADRS; SMD, −0.83 [95% CI, −1.22 to −0.44]
for HDRS; SMD, −0.86 [95% CI, −1.50 to −0.22] for Beck De-
pression Inventory) (Figure 1A). The overall pooled SMD for
ECT, when compared with ketamine, was −0.69 (95% CI, −0.89
to −0.48; Cochran Q, P = .15; I2 = 39%), indicating that ECT was
more efficacious than ketamine (Figure 1B).
Efficacy Outcome: Suicidal Ideation
Only 1 study40 investigated the trajectory of suicidal ide-
ation. Using the Beck Scale for Suicidal Ideation, baseline scores
were not statistically different across the 3 intervention groups
(ie, ECT, oral ketamine, and intramuscular ketamine). While
each group showed significant reductions in scores on Beck
Scale for Suicidal Ideation at the end of the study, the group
differences were not found at the 1-week and 1-month
follow-up periods (P = .99 and P = .69, respectively).
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 Table 1. Characteristics of the Included Clinical Trials (n = 6)
Sample size,
Study No. (% male Age, mean,
Source (country) designa sex) y Condition Ketamine ECT Durationb Key finding
Basso et al,36 Open-label 50 (48) 49.6 TRD, no history of 0.5 mg/kg IV (n = 25) 3 times a UBP (0.3 ms) RUL ECT with 2-4 wk ECT and ketamine administration were equally effective;

jamapsychiatry.com
2020 (Germany) clinical trial psychosis, ECT week for 2 weeks; No. of spECTrum 5000 Q (n = 25) 3 however, the antidepressant effects of ketamine occurred
candidates infusions, mean (SD) [range]: times a week for 4 weeks; No. faster. Ketamine improved neurocognitive functioning,
6.76 (1.23) [6-9] of sessions, mean (SD) [range]: especially attention and executive functions; ECT was
12.36 (1.75) [9-16] related to a small overall decrease in cognitive
performance.
Ekstrand et al,37 Open-label, 186 (36) 52.5 Unipolar 0.5 mg/kg IV (n = 95) 3 times a RUL ECT (n = 91) 3 times a 4 wk Remission rates were statistically different (57/91 [62.6%]
2022 (Sweden) multicenter depression, ECT week for 2 weeks; No. of week for 4 weeks; No. of in ECT vs 44/95 [46.3%] in ketamine infusions; P = .03).
RCT candidates infusions, mean (SD) [range]: sessions, mean (SD) [range]: Ketamine, despite being inferior to ECT, can be a safe and
6.8 (3.3) [5-9] 7.8 (2.4) [6-10] valuable tool in treating unipolar depression.
Ghasemi et al,38 Blind RCT 18 (44) 37.6 DSM-IV MDE, ECT 0.5 mg/kg IV (n = 9), 3 BP (1.0 ms) BL ECT with 1 wk Within 24 h, depressive symptoms significantly improved
2014 (Iran) candidates infusions every 48 h in a week Thymatron DGx (n = 9); 3 in patients receiving the first dose of ketamine compared
sessions every 48 h in a week with ECT. Compared with baseline, this improvement
remained significant throughout the study. For depressive
symptoms after the second dose, ketamine was lower than
the second ECT. This study showed ketamine is as effective

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as ECT in improving depressive symptoms in MDE and has
more rapid antidepressant effects compared with ECT.
Kheirabadi Blind RCT 22 (59) 38.8 MDE, no history of 0.5 mg/kg IV over 40 min BL ECT with Thymatron DGx 2-3 wk Depressive symptoms in both groups improved with no
et al,39 2019 psychosis, ECT (n = 10) twice a week up to (n = 12) twice a week weekly statistically significant difference. Cognitive state was
(Iran) candidates complete remission; range: up to complete remission; more favorable (but not significant) in the ketamine group.
1-6 range: 1-6 Treatment with IV ketamine in people with MDE has the
same antidepressant effects as ECT treatment without any
memory deficiency.
Ketamine Compared With Electroconvulsive Therapy for Major Depressive Episode

Kheirabadi Open-label 39 (33-53) 39.1-41.6 DSM-V MDE, ECT 0.5 mg/kg IM (n = 15), 6-9 BL ECT with Thymatron DGx 3 wk Oral and IM ketamine probably have equal antidepressant
et al,40 2020 RCT candidates injections in 3 weeks (with a 2- (n = 12), 6-9 sessions in 3 in addition to more antisuicidal effects compared with ECT
(Iran) to 3-d interval); 1.0 mg/kg oral weeks; range: 6-9 but had fewer cognitive adverse effects and higher
(n = 12), every 2-3 d up to 6-9 preference by patients. Thereby, ketamine can be an
sessions in 3 weeks alternative method in the treatment of patients with
severe and/or suicidal MDE.
Sharma et al,41 Blind, RCT 25 (44) 38.8 ICD-10 criteria for 0.5 mg/kg IV (n = 12); 6 BP (1.5 ms) bifrontal or RUL 2 wk Compared with ketamine, ECT showed significantly greater
2020 (India) severe depression alternate-day sessions; range: ECT with Niviqure (n = 13) for reduction in HDRS and BDI scores. ECT patients had a
(bipolar or 1-6 6 alternate-day sessions; higher response rate than ketamine patients. This study
unipolar), ECT range: 1-6 favored ECT over ketamine for a better efficacy over 6
candidates treatment sessions in severe depression.
Abbreviations: BDI, Beck Depression Inventory; BL, bilateral session; BP, brief pulse; ECT, electroconvulsive pulse stimuli.

© 2022 American Medical Association. All rights reserved.

therapy; HDRS, Hamilton Depression Rating Scale; ICD-10, International Statistical Classification of Diseases and a
Every study setting was inpatient.
Related Health Problems, Tenth Revision; IM, intramuscular; IV, intravenous; MDE, major depressive episode; b
Denotes a period for completing a series of treatment sessions.
RCT, randomized clinical trial; RUL, right unilateral session; TRD, treatment-resistant depression; UBP, ultra-brief

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Original Investigation Research

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 Research Original Investigation Ketamine Compared With Electroconvulsive Therapy for Major Depressive Episode

Figure 1. Severity of Depressive Symptoms Between Electroconvulsive Therapy (ECT) and Ketamine in Patients With Major Depressive Episode

A Severity of depressive symptoms by measure

ECT Ketamine SMD Favors Favors

Study Total Mean (SD)
MADRS
Basso et al,36 2020 24 –17.420 (7.4900)
Ekstrand et al,37 2022 91 –22.300 (9.6100)
Total (95% CI) 115
Heterogeneity: τ2 = 0; χ2 = 0.03; df = 1; P = .86; I2 = 0%
HDRS
Ghasemi et al,38 2014 9 –21.880 (5.8500)
Kheirabadi et al,39 2019 12 –12.500 (3.5000)
Sharma et al,41 2020 13 –21.190 (5.8400)
Kheirabadi et al,40 2020 (IM) 12 –12.330 (5.0300)
Kheirabadi et al,40 2020 (oral) 12 –12.330 (5.0300)
Total (95% CI) 58
Heterogeneity: τ2 = 0.0475; χ2 = 5.1; df = 4; P = .28; I2 = 22%
BDI
Ghasemi et al,38 2014 9 –26.780 (8.7000)
Sharma et al,41 2020 13 –30.650 (5.7700)
Total (95% CI) 22
Heterogeneity: τ2 = 0.3225; χ2 = 2.5; df = 1; P = .11; I2 = 60%
Total Mean (SD) (95% CI) ECT ketamine
25 –13.000 (6.1500) –0.636 (–1.211 to –0.061)
95 –16.200 (11.3500) –0.577 (–0.870 to –0.283)
120 –0.589 (–0.850 to –0.327)
9 –20.670 (5.4200) –0.204 (–1.131 to 0.723)
10 –7.700 (2.9500) –1.415 (–2.371 to –0.458)
12 –14.500 (4.3800) –1.246 (–2.115 to –0.376)
15 –10.140 (4.4400) –0.451 (–1.221 to 0.319)
12 –8.170 (2.9800) –0.972 (–1.826 to –0.117)
58 –0.832 (–1.221 to –0.444)
9 –23.780 (9.5100) –0.313 (–1.245 to 0.618)
12 –20.450 (8.6800) –1.350 (–2.233 to –0.466)
21 –0.859 (–1.500 to –0.218)

–3 –2 –1 0 1 2
SMD (95% CI)

B Overall effect size for severity of depressive symptoms

SMD Favors Favors

Study N (95% CI) ECT ketamine
Basso et al,36 2020 50 –0.636 (–1.211 to –0.061)
Ekstrand et al,37 2022 186 –0.577 (–0.870 to –0.283)
Ghasemi et al,38 2014 18 –0.259 (–0.916 to 0.398)
Kheirabadi et al,39 2019 22 –1.415 (–2.371 to –0.458)
Sharma et al,41 2020 25 –1.297 (–1.916 to –0.677)
Kheirabadi et al,40 2022 39 –0.684 (–1.256 to –0.112)
Total (95% CI) –0.685 (–0.890 to –0.476)
Heterogeneity: τ2 = 0.0368; χ2 = 8.15; df = 5; P = .15; I2 = 39%

–3 –2 –1 0 1 2
SMD (95% CI)

Analyses were done using a fixed-effects model and inverse variance. For the
study by Kheirabadi et al (2020),40 we distinguish intramuscular ketamine and
oral ketamine without duplications. A 2-stage model was used in B. In the first
stage, we obtained the overall effect size estimate of multiple measures within
the studies by Ghasemi et al,38 Sharma et al,41 and Kheirabadi et al (2020)40
using a 3-level meta-analysis. In the second stage, we pooled and obtained the
overall effect size estimate using 1 effect size from each study. BDI indicates
Beck Depression Inventory; HDRS, Hamilton Depression Rating Scale;
MADRS, Montgomery-Åsberg Depression Rating Scale; SMD, standardized
mean difference.

Cognition and Memory
One study 36 assessed neurocognitive performance as an
outcome. The authors concluded that patients in the ket-
amine group performed better than those in the ECT group,
with a small to moderate effect size (Cohen d, 0.40;
P = .04). In individual domains, the ketamine group outper-
formed the ECT group in terms of attention, verbal memory,
and executive functions with moderate to large effect
sizes. 36 There was no group difference for immediate
memory or visual memory.36 The other study39 reported
memory performance using a Wechsler Memory Scale and
reported no group differences for memory performance.
Safety Outcomes
Only 4 of 6 studies (66.7%)37-40 explicitly reported adverse
events. Of these, only 1 study37 reported serious adverse
events, including suicide attempts and suicide deaths.
In this study, the number of patients reporting any
serious adverse events was not statistically significant
between groups (23 of 90 in ECT vs 14 of 91 in ketamine;
P = .09).37 In the same study,37 suicide attempts (6 of 90 in
ECT vs 4 of 91 in ketamine) and suicide deaths (1 of 90 in
ECT vs 0 of 91 in ketamine) were not different between
groups.
Figure 2 presents individual types of adverse events.
The ketamine group had lower risks than the ECT group for
headache (RR, 0.37 [95% CI, 0.18-0.76]) and muscle pain
(RR, 0.23 [95% CI, 0.13-0.38]) (Figure 2A). On the other
hand, transient dissociative or depersonalization symptoms
were more common in ketamine compared with ECT (RR,
5.04 [95% CI, 3.03-8.36]). Electroconvulsive therapy had
lower risks than ketamine for blurred vision (RR, 26.47

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 Ketamine Compared With Electroconvulsive Therapy for Major Depressive Episode Original Investigation Research

Figure 2. Individual Safety Outcomes Between Electroconvulsive Therapy (ECT) and Ketamine in Patients With Major Depressive Episode

A Adverse events with lower risk for ketamine

Ketamine ECT RR MH, random Lower risk Lower risk

Study Events Total Events Total (95% CI) for ketamine for ECT Weight, %
Headache
Ekstrand et al,37 2022 20 91 72 90 0.275 (0.184-0.410) 46.7
Kheirabadi et al,39 2019 6 10 12 12 0.619 (0.385-0.995) 44.1
Kheirabadi et al,40 2020 1 27 3 12 0.148 (0.017-1.283) 9.2
Total (95% CI) 128 114 0.371 (0.181-0.762) 100
Heterogeneity: τ2 = 0.2458; χ2 = 7.31; df = 2; P = .03; I2 = 73%

Ketamine ECT RR MH,

Study Events Total Events Total fixed (95% CI)
Muscle pain
Ekstrand et al,37 2022 13 91 48 90 0.268 (0.156-0.459) 79.3
Kheirabadi et al,39 2019 0 10 11 12 0.052 (0.003-0.778) 17.3
Kheirabadi et al,40 2020 0 27 1 12 0.152 (0.007-3.466) 3.4
Total (95% CI) 128 114 0.227 (0.134-0.382) 100
Heterogeneity: τ2 = 0; χ2 = 1.46; df = 2; P = .48; I2 = 0%
0.001 0.01 0.1 1 10
RR MH, random or fixed (95% CI)

B Adverse events with lower risk for ECT

Ketamine ECT RR MH, fixed Lower risk Lower risk
Study Events Total Events Total (95% CI) for ketamine for ECT Weight, %
Blurred vision
Ekstrand et al,37 2022 18 91 0 90 36.596 (2.239-598.170) 52.3
Kheirabadi et al,39 2019 6 10 0 12 15.476 (0.983-243.775) 47.7
Total (95% CI) 101 102 26.471 (3.618-193.665) 100
Heterogeneity: τ2 = 0; χ2 = 0.18; df = 1; P = .67; I2 = 0%
Diplopia/nystagmus
Ekstrand et al,37 2022 28 91 2 90 13.846 (3.399-56.410) 63.8
Kheirabadi et al,39 2019 4 10 0 12 10.714 (0.649-176.930) 14.5
Kheirabadi et al,40 2020 2 27 0 12 2.273 (0.118-43.940) 21.7
Total (95% CI) 128 114 10.883 (3.522-33.627) 100
Heterogeneity: τ2 = 0; χ2 = 1.17; df = 2; P = .56; I2 = 0%
Vertigo
Ekstrand et al,37 2022 63 91 22 90 2.832 (1.921-4.175) 98.0
Kheirabadi et al,39 2019 4 10 0 12 10.714 (0.649-176.930) 2.0
Total (95% CI) 101 102 2.991 (2.034-4.397) 100
Heterogeneity: τ2 = 0; χ2 = 0.85; df = 1; P = .36; I2 = 0%
Dissociative or depersonalization symptoms
Ekstrand et al,37 2022 55 91 14 90 3.885 (2.335-6.465) 92.5
Kheirabadi et al,39 2019 6 10 0 12 15.47 (0.983-243.775) 3.0
Kheirabadi et al,40 2020 23 27 0 12 21.364 (1.407-324.365) 4.5
Total (95% CI) 128 114 5.036 (3.033-8.361) 100
Heterogeneity: τ2 = 0.3991; χ2 = 2.32; df = 2; P = .31; I2 = 14%
0.1 1 10 100 1000
RR MH, fixed (95% CI)

C No difference between ECT and ketamine

Ketamine ECT RR MH, random Lower risk Lower risk
Study Events Total Events Total (95% CI) for ketamine for ECT Weight, %
Nausea
Ekstrand et al,37 2022 25 91 23 90 1.075 (0.662-1.747) 55.1
Kheirabadi et al,39 2019 3 10 9 12 0.400 (0.147-1.089) 37.1
Kheirabadi et al,40 2020 0 27 1 12 0.152 (0.007-3.466) 7.8
Total (95% CI) 128 114 0.640 (0.252-1.624) 100
Heterogeneity: τ2 = 0.3484; χ2 = 4.24; df = 2; P = .12; I2 = 53%
0.001 0.01 0.1 1 10
RR MH, random (95% CI)

Fixed indicates fixed-effects model; MH, Mantel-Haenszel method; random, random-effects model; RR, relative risk.

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 Research Original Investigation Ketamine Compared With Electroconvulsive Therapy for Major Depressive Episode

Table 2. Moderator Analysis by Age, Sex, Sample Size, Region, Randomization, Type of ECT Treatment,
and Presence of Psychotic Features Using Meta-Regression Analysesa

Moderator k Coefficient (95% CI) SMD (95% CI) P value

No. of total patients 6 0.002 (−0.003 to 0.006) .51b
Age 6 0.018 (−0.030 to 0.066) .47b
Male sex (%) 6 −4.490 (−4.687 to 1.708) .36b
Region .25c
Asia/Middle East 4 NA −0.839 (−1.171 to −0.507)
Europe 2 NA −0.589 (−0.850 to −0.327)
Randomization .86c
Yes 5 NA −0.692 (−0.912 to −0.472) Abbreviations: ECT, electroconvulsive
No 1 NA −0.636 (−1.211 to −0.061) therapy; k, number of effect sizes;
Type of ECT .12c NA, not applicable;
SMD, standardized mean difference
Right unilateral 2 NA −0.589 (−0.850 to −0.327) (Hedges g).
Bilateral 3 NA −0.655 (−1.048 to −0.262) a
Coefficient refers to the
Mixed 2 NA −1.297 (−1.916 to −0.677) meta-regression coefficient.
Psychotic features .78c A restricted maximum likelihood
was used.
Yes 2 NA −0.709 (−0.974 to −0.443) b
Continuous moderators.
No 4 NA −0.649 (−0.974 to −0.324) c
Categorical moderators.

intervention; this is partly due to difficulties in implement-

Figure 3. Risk-of-Bias Assessment for Individual Studies
ing blinding among participants and personnel. Further, 1
Risk-of-bias domain study37 explicitly reported potential missing outcome bias
Study D1 D2 D3 D4 D5 Overall due to a higher dropout rate in the ketamine group than that
Basso et al,36 2020 – + + + + – Judgment of the ECT group. None of the included studies had selective
Ekstrand et al,37 2022 + ! ! + + – – High reporting (ie, reporting bias) or other biases per study proto-
Ghasemi et al,38 2014 + ! ! + + ! ! Some concerns cols, resulting in low risks for domains 4 and 5. In addition,
Kheirabadi et al,39 2019 + ! ! + + ! + Low we did not find any potential publication bias (eFigure 2 in
Kheirabadi et al,40 2020 + ! + + + ! the Supplement) using the Egger test (P = .32) and Begg and
Sharma et al,41 2020 + + + + + + Mazumdar test (P = .57).

The risk-of-bias domains are described as follows: D1 indicates bias arising from
the randomization process; D2, bias due to deviations from the intended
intervention; D3, bias due to missing outcome data; D4, bias in measurement of
the outcome; D5, bias in selection of the reported result. (See eTable 3 in the
Supplement for details.)
[95% CI, 3.62-193.67]), vertigo (RR, 2.99 [95% CI, 2.03-
4.40]), and diplopia/nystagmus (RR, 10.88 [95% CI, 3.52-
33.63]) (Figure 2B).
Moderator Analysis
e also considered potential moderating roles of the follow-
ing variables using meta-regression and meta–analysis of
variance models: number of patients, age, male sex (%),
geographic region, randomization status, treatment type,
and presence of psychotic features (Table 2). We did not
find any moderating effects of these factors on the main
treatment effects.
Quality Assessment and Risk of Bias
Methodological quality of the included studies was low to
moderate (Figure 3), and we provided our justification in
eTable 3 in the Supplement. Except for 1 study,36 all studies
used randomization, 4 of which had robust allocation con-
cealment to reduce selection bias. Four of 6 studies (66.7%)
had some concerns regarding deviations from intended
Discussion
The present systematic review and meta-analysis includes
11 effect sizes for depression severity from 6 studies with
340 patients with a DSM or ICD-10 diagnosis of MDE. To our
knowledge, this is the first meta-analysis to quantify the
efficacy and safety of ketamine vs ECT in patients with
MDE. At the end of completing a series of treatment ses-
sions, we found that ECT was more efficacious than ket-
amine in reducing depression severity. While the meta-
analysis suggests that ECT may be superior to ketamine in
terms of efficacy, treatment options should still be individu-
alized and patient-centered because ketamine’s faster anti-
depressant effects may still be desirable for certain patients
with severe MDE who require quick recovery from the
severity of depression. For instance, 3 studies36,38,39 qualita-
tively reported that ketamine had more rapid antidepres-
sant effects than ECT during the initial course of treatment
sessions, whereas 1 study41 found that patients receiving
E C T r e c ove r e d m o r e q u i c k l y t h a n t h o s e r e c e iv i ng
ketamine.42,43 Additionally, ketamine and ECT have unique
adverse effect profiles.
When reviewing articles systematically, we found that 2
studies37,39 had long-term follow-up (ie, 3 months or longer)
after the trial completed. One study39 found no difference in

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 Ketamine Compared With Electroconvulsive Therapy for Major Depressive Episode
depression severity during the 3-month follow-up between
the ketamine and ECT groups. The other study37 reported
that the remission rates were not different between groups
by the 12-month follow-up period. It appears that the treat-
ment effects may wane similarly in both groups over time.
To our knowledge, a largely unexplored area is the evalua-
tion of long-term strategies addressing maintenance, remis-
sion, and relapse issues between these 2 groups. For ECT,
the best strategy for relapse prevention appears to be con-
tinuing ECT, continuing pharmacotherapy, or using some
combination of both.44-46 Large and well-controlled studies
examining relapse prevention approaches in ketamine are
lacking. However, a large randomized withdrawal study of
esketamine, a very similar therapy, suggests that continuing
treatment at a less frequent interval is an effective relapse
prevention approach.47 Future research is needed to further
optimize long-term treatment outcomes for both ketamine
and ECT to prevent relapse, which is of key importance for
clinical practice.48,49
For cognition and memory performances, 1 study36 re-
ported that the ketamine group outperformed the ECT group
in cognition, but the effect size was small to moderate. An-
other study39 reporting memory performance found no dif-
ference between patients with ketamine and those with ECT,
though this study was likely underpowered to detect such dif-
ferences (total sample size of 32). Because of underpowered
study designs, no firm conclusions regarding cognition and
memory performance can be made in this meta-analysis.
Future research should address this issue.
An important consideration for clinicians and patients
with serious depression is the comparative tolerability and
safety of ketamine vs ECT. The provision of ketamine only
involves the administration of a low dose of anesthesia
medicine, while the provision of ECT involves the adminis-
tration of a full dose of anesthesia plus an electrical stimu-
lus that induces a seizure. Hence, it is expected that ket-
amine would be better tolerated and safer than ECT. The
studies included in this meta-analysis were limited in the
exploration of this question. Only 1 of the studies reported
formal serious adverse events. Additionally, both ketamine
and ECT had unique adverse effect profiles (ie, ketamine
had lower risks for headache and muscle pain whereas
ECT had lower risks for blurred vision, vertigo, diplopia/
nystagmus, and dissociative or depersonalization symp-
toms). No study assessed the relative tolerability or accept-
ability of these different adverse effect profiles. Future
studies should consider patient tolerability and acceptabil-
ity with respect to these 2 potential treatments. In addition,
given the short-term nature of the studies included in this
meta-analysis, all of the adverse events reported were
acute. Thus, future research should assess long-term
adverse events resulting from either ketamine or ECT and
weigh the potential long-term benefits and risks of these
treatment options.
ARTICLE INFORMATION Published Online: October 19, 2022.
Accepted for Publication: August 26, 2022. doi:10.1001/jamapsychiatry.2022.3352
jamapsychiatry.com
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Original Investigation Research
Limitations
Several methodological limitations deserve comment. First,
most of the studies had relatively small sample sizes and lacked
long-term follow-up assessments, and thus, the study de-
signs may be underpowered. There are 2 ongoing random-
ized clinical trials identified through the US clinical trial reg-
istry that may address this limitation in the near future. The
Canadian Biomarker Integration Network in Depression
(CAN-BIND) study50 plans to recruit 240 patients with unipo-
lar or bipolar depression (accounting for a 20% dropout rate)
to conduct a randomized, single-blinded crossover trial. In this
trial, patients will be randomized to receive 0.5-mg/kg intra-
venous ketamine or ECT thrice weekly for 3 to 4 weeks. The
other study, ECT Versus Ketamine in Patients With Treatment-
Resistant Depression (ELEKT-D),51 aims to recruit 400 pa-
tients with unipolar TRD. This is an unblinded, open-label ran-
domized trial to compare 0.5-mg/kg intravenous ketamine (2
times a week up to a total of 6 treatment sessions) and ECT (3
times a week up to a total of 9 treatment sessions) over 3 to 5
weeks. These studies are expected to be completed by March
2023 and December 2022, respectively. Additionally, no study
has yet directly compared ECT with esketamine, which has sub-
stantially larger evidence from regulatory clinical trials and has
received approval for treating TRD.
A second limitation is that the included studies were also
slightly different in inclusion and exclusion criteria (eg, inclu-
sion of bipolar depression and presence of psychotic fea-
tures), which require careful interpretations of the findings.
For example, while ECT is particularly effective in patients with
psychotic depression,52 examining differences in the predic-
tive value for response rates between ketamine and ECT by
such patient characteristics may lead to more personalized
medicine.26
A third limitation is that the included studies may have
used different ketamine and/or ECT treatment protocols (eg,
frequency and routes of administration), all of which could
have influenced efficacy and safety outcomes. Although our
moderator analyses accounted for some of these issues (eg,
type of treatment modalities and geographic region), there
may still be moderating or confounding factors (eg, fre-
quency [eg, twice vs thrice weekly], stimulus width [eg,
brief pulse vs ultra-brief pulse] for ECT, and medications
used for anesthesia).
Conclusions
This meta-analysis suggests that ECT may be superior to
ketamine for improving acute depression severity, but
several major methodological limitations reported above
should be considered. At least 2 large, ongoing comparative
studies will lend further data on this important question
that has significant relevance to patients, health care pro-
fessionals, and policy makers.
Correction: This article was corrected on December
7, 2022, to fix errors in Figure 2.
(Reprinted) JAMA Psychiatry December 2022 Volume 79, Number 12 1169
 Research Original Investigation
Author Affiliations: Department of Psychiatry,
School of Medicine, Yale University, New Haven,
Connecticut (Rhee, Krystal, Sanacora, Wilkinson);
VA New England Mental Illness, Research,
Education and Clinical Center (MIRECC), VA
Connecticut Healthcare System, West Haven
(Rhee); Department of Public Health Sciences,
School of Medicine, University of Connecticut,
Farmington (Rhee); Department of Health and
Medical Informatics, Kyungnam University College
of Health Sciences, Changwon,
Gyeongsangnam-do, Republic of Korea (Shim);
Department of Psychiatry, Harvard Medical School,
Boston, Massachusetts (Forester, Nierenberg,
Papakostas); Division of Geriatric Psychiatry,
McLean Hospital, Belmont, Massachusetts
(Forester); Dauten Family Center for Bipolar
Treatment Innovation, Massachusetts General
Hospital, Boston (Nierenberg, Papakostas);
Department of Psychiatry, University of Toronto,
Toronto, Ontario, Canada (McIntyre); Brain and
Cognition Discovery Foundation, Toronto, Ontario,
Canada (McIntyre); Clinical Trials Network and
Institute, Department of Psychiatry, Massachusetts
General Hospital and Harvard Medical School,
Boston (Papakostas).
Author Contributions: Dr Rhee 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. Drs Rhee and Shim contributed
equally to the work as co–first authors.
Concept and design: Rhee, Forester, Nierenberg,
McIntyre, Papakostas, Sanacora.
Acquisition, analysis, or interpretation of data:
Rhee, Shim, Krystal, Sanacora, Wilkinson.
Drafting of the manuscript: Rhee, Shim, McIntyre,
Wilkinson.
Critical revision of the manuscript for important
intellectual content: Rhee, Shim, Forester,
Nierenberg, Papakostas, Krystal, Sanacora,
Wilkinson.
Statistical analysis: Rhee, Shim, Papakostas.
Administrative, technical, or material support: Rhee,
Shim, Sanacora.
Supervision: Rhee, Forester, McIntyre, Papakostas,
Wilkinson.
Conflict of Interest Disclosures: Dr Rhee reported
support from the National Institute on Aging (NIA)
through Yale School of Medicine (T32AG019134);
funding from the NIA (R21AG070666), National
Institute of Mental Health (#R21MH117438), and
Institute for Collaboration on Health, Intervention,
and Policy (InCHIP) of the University of
Connecticut; serving as a review committee
member for Patient-Centered Outcomes Research
Institute (PCORI) and Substance Abuse and Mental
Health Services Administration (SAMHSA);
receiving honoraria payments from PCORI and
SAMHSA; having served as a stakeholder/
consultant for PCORI and received consulting fees
from PCORI; and currently serving as a co–
editor-in-chief of Mental Health Science and
pending to receive honorarium payments annually
from the publisher, John Wiley & Sons. Dr Forester
reported research grant funding from Biogen, Eisai,
Rogers Family Foundation, Spier Family Foundation
and the National Institutes of Health (NIH); serving
on the Pharmacy and Therapeutics Committee for
CVS Health; and serving as a consultant for Patina
Health. Dr Nierenberg reported grants from PCORI
(PaCR-2017C2-8169, XPPRN-1512-33786,
XPPRN-1512-33786), the Thomas P. Hackett, MD
Endowed Chair in Psychiatry at Massachusetts
1170 JAMA Psychiatry December 2022 Volume 79, Number 12 (Reprinted)
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Ketamine Compared With Electroconvulsive Therapy for Major Depressive Episode
General Hospital, and the Dauten Family Center for
Bipolar Treatment Innovation; being a consultant
for Abbott Laboratories, Alkermes, American
Psychiatric Association, Appliance Computing,
Mindsite, Basliea, BrainCells, Brandeis University,
Bristol Myers Squibb, Clintara, Corcept, Dey
Pharmaceuticals, Dainippon Sumitomo (now
Sunovion), Eli Lilly, EpiQ, Mylan, Forest,
Genaissance, Genentech, GlaxoSmithKline,
Hoffman LaRoche, Infomedic, Intra-Cellular
Therapies, Lundbeck, Janssen Pharmaceuticals,
Jazz Pharmaceuticals, Medavante, Merck,
Methylation Sciences, Naurex, NeuroRx, Novartis,
Otsuka, Pamlab, Parexel, Pfizer, PGx Health, Ridge
Diagnostics Shire, Schering-Plough, Somerset,
Sunovion, Takeda Pharmaceuticals, Targacept, and
Teva; consulting through the Massachusetts
General Hospital Clinical Trials Network and
Institute for AstraZeneca, BrainCells, Dainippon
Sumitomo/Sepracor, Johnson & Johnson,
Labopharm, Merck, Methylation Science, Novartis,
PGx Health, Shire, Schering-Plough, Targacept, and
Takeda/Lundbeck Pharmaceuticals; grant, research,
or other support from the American Foundation for
Suicide Prevention, Agency for Healthcare
Research and Quality, Brain and Behavior Research
Foundation, Bristol Myers Squibb, Cederroth,
Cephalon, Clexio, Cyberonics, Elan, Eli Lilly, Eisai,
Forest, GlaxoSmithKline, Janssen Pharmaceuticals,
Intra-Cellular Therapies, Lichtwer Pharma, Marriott
Foundation, Mylan, Myriad, National Institute of
Mental Health, Neuronetics, Pamlab, PCORI, Pfizer,
Sage, Shire, Stanley Foundation, Takeda, and
Wyeth-Ayerst; honoraria from Belvoir Publishing,
University of Texas Southwestern, Dallas, Brandeis
University, Bristol Myers Squibb, Hillside Hospital,
American Drug Utilization Review, American
Society for Clinical Psychopharmacology, Baystate
Medical Center, Columbia University, Controlled
Risk Insurance Company, Dartmouth Medical
School, Health New England, Harold Grinspoon
Charitable Foundation, Imedex, Israel Society for
Biological Psychiatry, Johns Hopkins University, MJ
Consulting, New York State, Medscape, MBL
Communications, Massachusetts General Hospital
Psychiatry Academy, National Association of
Continuing Education, Physicians Postgraduate
Press, State University of New York Buffalo,
University of Wisconsin, University of Pisa,
University of Michigan, University of Miami,
University of Wisconsin at Madison, World
Congress of Brain Behavior and Emotion, American
Professional Society of ADHD and Related
Disorders, International Society for Bipolar
Disorder, SciMed, Slack Publishing, Wolters Kluwer
Publishing, the American Society for Clinical
Psychopharmacology (formerly NCDEU), Rush
Medical College, Yale University School of Medicine,
National Nuclear Data Center, Nova Southeastern
University, National Alliance on Mental Illness,
Institute of Medicine, Continued Medical Education
Institute, and the International Society for CNS
Clinical Trials and Methodology; serving currently or
formerly on the advisory boards of Appliance
Computing, BrainCells, Eli Lilly, Genentech, Johnson
& Johnson, Takeda/Lundbeck, Targacept, and
InfoMedic; stock options in Appliance Computing,
BrainCells, and Medavante; and copyrights to the
Clinical Positive Affect Scale and the Massachusetts
General Hospital Structured Clinical Interview for
the Montgomery-Åsberg Depression Scale
exclusively licensed to the Massachusetts General
Hospital Clinical Trials Network and Institute.
Dr McIntyre reported research grant support from
the Canadian Institutes of Health Research/Global
Alliance for Chronic Diseases/National Natural
Science Foundation of China (NSFC) and the Milken
Institute; speaker/consultation fees from Lundbeck,
Janssen, Alkermes, Neumora Therapeutics,
Boehringer Ingelheim, Sage, Biogen, Mitsubishi
Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine,
Sunovion, Bausch Health, Axsome, Novo Nordisk,
Kris, Sanofi, Eisai, Intra-Cellular, NewBridge
Pharmaceuticals, Abbvie, and Atai Life Sciences;
and being chief executive officer of Braxia Scientific
Corp. Dr Papakostas reported serving as a
consultant, sometimes on behalf of Massachusetts
General Hospital, for Abbott Laboratories, Acadia
Pharmaceuticals, Alkermes, Alfasigma USA,
AstraZeneca, Avanir Pharmaceuticals, Axsome
Therapeutics, Boston Pharmaceuticals, Brainsway,
Bristol Myers Squibb, Cala Health, Cephalon, Dey
Pharma, Eleusis Health Solutions, Eli Lilly,
Genentech, Genomind, GlaxoSmithKline, Evotec,
H. Lundbeck, Inflabloc Pharmaceuticals, Janssen
Global Services, Jazz Pharmaceuticals, Johnson &
Johnson, Methylation Sciences, Monopteros
Therapeutics, Mylan, Novartis Pharma, One Carbon
Therapeutics, Osmotica Pharmaceutical, Otsuka
Pharmaceuticals, Pamlab, Pfizer, Pierre Fabre
Laboratories, Praxis Precision Medicines, Ridge
Diagnostics (formerly known as Precision Human
Biolaboratories), Sage Therapeutics, Shire
Pharmaceuticals, Sunovion Pharmaceuticals, Taisho
Pharmaceutical, Takeda Pharmaceutical Company,
Theracos, and Wyeth; receiving honoraria (for
lectures or consultancy) from Abbott Laboratories,
Acadia Pharmaceuticals, Alkermes, Alfasigma USA,
Asofarma America Central Y Caribe, AstraZeneca,
Avanir Pharmaceuticals, Bristol Myers Squibb,
Brainsway, Cephalon, Dey Pharma, Eli Lilly, Evotec,
Forest Pharmaceuticals, GlaxoSmithKline, Inflabloc
Pharmaceuticals, Grunbiotics, Hypera, Jazz
Pharmaceuticals, H. Lundbeck, Medichem
Pharmaceuticals, Meiji Seika Pharma, Novartis
Pharma, Otsuka Pharmaceuticals, Pamlab, Pfizer,
Pharma Trade, Pierre Fabre Laboratories, Ridge
Diagnostics, Shire Pharmaceuticals, Sunovion
Pharmaceuticals, Takeda Pharmaceutical Company,
Theracos, Titan Pharmaceuticals, and Wyeth;
receiving research support (paid to hospital) from
Alfasigma USA, AstraZeneca, Bristol Myers Squibb,
Cala Health, Forest Pharmaceuticals, the National
Institute of Mental Health, Mylan, Neuralstem,
Pamlab, PCORI, Pfizer, Johnson & Johnson, Ridge
Diagnostics (formerly known as Precision Human
Biolaboratories), Sunovion Pharmaceuticals, Tal
Medical, and Theracos; and having served (not
currently) on the speaker’s bureau for Bristol Myers
Squibb and Pfizer. Dr Krystal reported serving as a
consultant for Aptinyx, Biogen, Idec, Bionomics,
Boehringer Ingelheim, Clearmind Medicine, Cybin,
Enveric Biosciences, Epiodyne, EpiVario, Janssen
Research & Development, Jazz Pharmaceuticals,
Otsuka America Pharmaceutical, Perception
Neuroscience, Praxis Precision Medicines, Spring
Care, and Sunovion Pharmaceuticals; serving as a
scientific advisory board member for Biohaven
Pharmaceuticals, BioXcel Therapeutics, Cerevel
Therapeutics, Delix Therapeutics, Eisai, EpiVario,
Freedom Biosciences, Jazz Pharmaceuticals,
Neumora Therapeutics, Neurocrine Biosciences,
Novartis, Praxis Precision Medicines, PsychoGenics,
Tempero Bio, and Terran Biosciences; having in the
past 3 years the patent “Mavoglurant in treating
gambling and gaming disorders” (application 63/
jamapsychiatry.com
 Ketamine Compared With Electroconvulsive Therapy for Major Depressive Episode
125,181 filed by the Yale University Office of
Cooperative Research); and having stock options
from Biohaven Pharmaceuticals Medical Sciences,
Clearmind Medicine, EpiVario, Neumora
Therapeutics, Tempero Bio, and Terran Biosciences.
Dr Sanacora reported receiving personal fees and
serving as a consultant to Allergan, Alkermes,
Ancora, Aptinx, AstraZeneca, Avanier
Pharmaceuticals, Axsome Therapeutics, Biogen,
Biohaven Pharmaceuticals, Boehringer Ingelheim
International, Bristol Myers Squibb, Cowen, EMA
Wellness, Engrail Therapeutics, Clexio, Denovo
Biopharma, Freedom, Gilgamesh, Hoffmann
La-Roche, Intra-Cellular Therapies, Janssen
Pharmaceuticals, Koa Health, Levo, Lundbeck,
Merck, miCure Therapeutics, Navitor
Pharmaceuticals, Neurocrine, Novartis, Noven
Pharmaceuticals, Otsuka, Perception Neuroscience,
Praxis Therapeutics, Relmada Therapeutics, Sage
Pharmaceuticals, Servier Pharmaceuticals, Seelos
Pharmaceuticals, Taisho Pharmaceuticals, Teva,
Transend, Valeant, Vistagen Therapeutics, and XW
Labs; receiving research contracts from
AstraZeneca, Bristol Myers Squibb, Eli Lilly, Johnson
& Johnson, Merck, and Usona over the past 36
months; holding equity in Biohaven
Pharmaceuticals; being a co-inventor on a US
patent (8,778,979) held by Yale University and a
co-inventor on US Provisional Patent Application
047162-7177P1 (00754) filed by the Yale University
Office of Cooperative Research. Dr Wilkinson
reported receiving contract funding from Janssen
Pharmaceuticals, Sage Therapeutics, and Oui
Therapeutics for the conduct of clinical trials
administered through Yale University as well as
consulting fees from Biohaven Pharmaceuticals,
Sage Therapeutics, Janssen Pharmaceuticals, and
Oui Therapeutics. No other disclosures were
reported.
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