Journal of Affective Disorders 346 (2024) 49–56

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Journal of Affective Disorders

journal homepage: www.elsevier.com/locate/jad

Review Article

Comparative efficacy, tolerability and acceptability of intravenous racemic

ketamine with intranasal esketamine, aripiprazole and lithium as
augmentative treatments for treatment-resistant unipolar depression: A
systematic review and network meta-analysis
Itsuki Terao a, *, Takahiro Tsuge b, c, Kaori Endo d, Wakako Kodama e
a
Department of Psychiatry, Ikokoro Clinic Nihonbashi, Chuo-ku, Tokyo 103-0012, Japan
b
Department of Rehabilitation, Kurashiki Medical Center, Kurashiki, Okayama 710-8522, Japan
c
Department of Epidemiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Shikata-cho, Okayama 700-8558, Japan
d
National Coalition of independent scholars, 125 Putney Rd, Battleboro, VT, 05301, USA
e
Department of Psychiatry, Negishi Hospital, Fuchu-shi, Tokyo 183-0042, Japan

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Intravenous racemic ketamine is a promising treatment for treatment-resistant depression. However,
Ketamine its clinical utility compared with intranasal esketamine and the other well-studied conventional pharmacological
Esketamine interventions (i.e., aripiprazole and lithium) as augmentative treatments for treatment-resistant unipolar
lithium
depression in adults remains unclear. Therefore, we aimed to compare the efficacy, tolerability and acceptability
Aripiprazole
Treatment resistance
of intravenous racemic ketamine with intranasal esketamine, aripiprazole and lithium under such conditions.
Network meta-analysis Methods: The Cochrane Library, PubMed, CINHAL and ClinicalTrials.gov databases were systematically searched
from their inception to 10 May 2023. Randomised controlled trials evaluating these drugs were included. A
random-effects network meta-analysis was also performed.
Results: In the primary analysis, all four drugs were significantly more effective than placebo. In addition,
intravenous racemic ketamine was significantly more effective and acceptable than intranasal esketamine and
aripiprazole. Intravenous racemic ketamine was not significantly different from placebo in tolerability, whereas
intranasal esketamine and aripiprazole were significantly less tolerable than placebo. Lithium did not differ
significantly from intravenous racemic ketamine in efficacy, tolerability and acceptability.
Limitations: The sample size of patients treated with intravenous racemic ketamine was small.
Conclusions: Intravenous racemic ketamine may be a better augmentative treatment for treatment-resistant
unipolar depression than intranasal esketamine and aripiprazole. Whether intravenous racemic ketamine or
lithium is superior is unclear currently. A larger head-to-head trial of intravenous racemic ketamine versus
conventional augmentative treatments for treatment-resistant unipolar depression is needed.

1. Introduction
Antidepressant medication is the mainstay of treatment for major
depressive disorder (MDD); however, the response rate to first antide­
pressants medication is only 47 % (Rush et al., 2009). Although there is
no universal definition (Gaynes et al., 2020), treatment-resistant
depression (TRD) is typically defined as MDD that fails to achieve
remission even with adequate doses of antidepressants for a sufficient
period of time (Thase and Rush, 1997). It has been suggested that TRD is
associated with poorer outcomes, including increased suicide and hos­
pitalisation (Touloumis, 2021). Therefore, treatment options for TRD
need to be refined.
Augmentation therapy is an important option for TRD, and lithium is
the most thoroughly studied mood stabiliser, aripiprazole is the most
intensively studied antipsychotic and ketamine is relatively well studied
among N-methyl-D-aspartate (NMDA) receptor modulators (Nunez et al.,
2022; Scott et al., 2022; Strawbridge et al., 2019). In recent years, ke­
tamine has attracted attention as a promising new treatment (Young,

* Corresponding author at: Department of Psychiatry, Ikokoro Clinic Nihonbashi, 2-6-6 Nihobashihoridomecho, Chuo-ku, Tokyo 103-0012, Japan.
E-mail address: terao0125@gmail.com (I. Terao).

https://doi.org/10.1016/j.jad.2023.11.023
Received 31 August 2023; Received in revised form 3 November 2023; Accepted 7 November 2023
Available online 8 November 2023
0165-0327/© 2023 Elsevier B.V. All rights reserved.
I. Terao et al.
2023), and two meta-analyses of TRD at different stages of treatment
resistance have suggested its relative usefulness (Scott et al., 2022;
Strawbridge et al., 2019). Among the various ketamine formulations and
routs of administration, intranasal esketamine was approved by the
Food and Drug Administration (FDA) in 2019 (Marwaha et al., 2023).
Although intravenous racemic ketamine is invasive, expensive and
reportedly more likely to cause side effects than other administration
methods (Short et al., 2018), a growing body of evidence suggests its
efficacy for TRD (Li et al., 2016; Singh et al., 2016; Su et al., 2017;
Zehong et al., 2019), with evidence for other delivery systems and other
NMDA receptor modulators still scarce. In addition, Bhaji et al. (Bahji
et al., 2021) suggested that racemic ketamine is significantly more
effective and tolerable than esketamine for major depression, with no
significant difference in acceptability in separate meta-analyses. How­
ever, they included patients with bipolar depression in addition to major
depressive disorder, different routes of administration, monotherapy
plus augmentation therapy, and non-TRD in addition to TRD. Further­
more, the relative usefulness of intravenous racemic ketamine versus
well-studied conventional augmentation therapy in TRD has not been
reported.
Therefore, we aimed to assess the comparative efficacy, tolerability,
and acceptability of intravenous racemic ketamine with intranasal
esketamine, well-studied conventional pharmacotherapies (i.e., aripi­
prazole and lithium), and placebo as augmentation therapy in
treatment-resistant unipolar depression using a network meta-analysis.
2. Methods
This study was pre-registered in PROSPERO (number:
CRD42023425734) and was conducted in accordance with the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)
statement (Supplementary Table 1).
2.1. Search strategies
We searched the Cochrane Library, PubMed, CINHAL and ClinicalT
rials.gov databases from their inception to 10 May 2023, with no lan­
guage restrictions (detailed search formulae and additional filters are
provided in Supplementary Table 2). We also reviewed previous rele­
vant systematic reviews (Bahji et al., 2021; Nunez et al., 2022; Scott
et al., 2022; Vazquez et al., 2021) and screened for candidate studies.
Three reviewers (I.T., T.T. and K.E.) screened the titles and abstracts,
and the studies that were candidates for inclusion underwent full-text
reviews. Disagreements were resolved by discussions. Decisions were
recorded using Endnote 20.
2.2. Selection criteria
The inclusion criteria were (1) Randomised placebo-controlled trials
evaluating intravenous racemic ketamine, nasal esketamine, aripipra­
zole per os and lithium carbonate per os, and active-controlled trials
comparing these drugs for augmentation treatment of TRD. (2) The trials
focused on acute antidepressant effects as the primary outcome. (3)
Participants were aged 18 to 65 years with TRD. In this study, TRD was
defined as MDD diagnosed using standard diagnostic criteria with no
improvement after using one or more antidepressants at a sufficient dose
for a sufficient period of time, because non-response to the first anti­
depressant is significantly correlated with higher subsequent treatment
resistance (Schosser et al., 2012; Souery et al., 2007), and it would be
clinically useful to lower the threshold for the typical definition of
treatment-resistant depression, which is the failure to achieve remission
with two or more antidepressants.
Exclusion criteria were as follows: (1) Studies that focused on a
specific group of patients, such as those with somatic symptoms or
substance use disorders. (2) Studies that used concomitant psychological
interventions were excluded. (3) Studies with combined interventions
50
Journal of Affective Disorders 346 (2024) 49–56
with these medications were excluded.
2.3. Data extraction and quality assessment
I.T. extracted the relevant information and W.K. confirmed the data
received. To be more conservative, we tried to select the results of the
intention-to-treat analyses as much as possible. Authors were not con­
tacted for missing data for analysis. I.T., T.T. and K.E. assessed the risk of
bias using RoB 2.0 (Sterne et al., 2019), and I.T. and W.K. assessed the
certainty of evidence according to the Confidence in Network Meta-
Analysis (CINeMA) approach (Nikolakopoulou et al., 2020). Publica­
tion bias was assessed when the number of studies per treatment
exceeded 10 (Higgins et al., 2022).
2.4. Outcomes
Response rate was the primary outcome. In addition, the secondary
endpoints were discontinuation due to adverse events only (tolerability)
and discontinuation due to any reason (acceptability). Effect sizes for
each outcome were expressed as odds ratios. The following predefined
hierarchy was used for the primary endpoint. The Montgomery-Åsberg
Depression Rating Scale was used first, followed by the Hamilton Rating
Scale for Depression, and finally the Beck Depression Inventory. For the
single-dose ketamine studies, the rapid onset of antidepressant effects
and their rapid decay for depression were reported in a previous meta-
analysis (McGirr et al., 2015). Therefore, there was concern that varia­
tions in the time between the last dose and the measurement of efficacy
could strongly influence the results. For this reason, we decided to select
the result with the largest antidepressant effect for ketamine for two- or
few-dose ketamine trials that reported response rates at multiple time
points. In the crossover studies, the results of the first period before
crossover were evaluated.
2.5. Data analysis
Frequentist random-effects network meta-analyses were performed
using the “netmeta” package (Rücker G et al., 2022) and R version 4.2.1
software (R Core Team, 2022). Heterogeneity and inconsistency were
assessed using I2 and Q statistics, respectively. For continuity correction,
events with 0 were replaced with 0.5 before analysis. In the primary
analysis, a network meta-analysis was performed using data from all
included trials. A sensitivity analysis excluding single-dose trials was
performed to compare each active drug on the same basis as the
repeated-dose trials.
2.6. Subgroup analysis
As this systematic review focused on routes of administration and
narrower indications than previous meta-analyses evaluating ketamine
(Bahji et al., 2021; Scott et al., 2022; Strawbridge et al., 2019), it was
expected that the number of trials for the meta-analysis would not be
large enough to allow subgroup analyses stratified by potential cova­
riates such as risk of bias, stage of TRD, and baseline depression severity.
Therefore, we only planned subgroup analyses by study duration, which
we considered particularly important given the rapid onset and atten­
uation of ketamine’s antidepressant effects (McGirr et al., 2015), as
discussed above (McGirr et al., 2015). Subgroups for trial duration were
defined when the time point used for analysis was within 1 week and
when the time point was over 1 week. For tolerability and acceptability,
we used the results reported in the endpoints; for subgroup analyses
evaluating tolerability and acceptability for 1 week or less, we excluded
trials that did not describe tolerability and acceptability for this period.
2.7. Protocol amendments
We registered protocol amendments on the PROSPERO website with
I. Terao et al.
the reasons for the amendments. In addition, after the completion of the
systematic review, the time point for classifying subgroup analyses was
changed from 8 days to 1 week. Initially, 8 days was used to include at
least one intranasal esketamine trial (Daly et al., 2018) in the subgroup
analysis with a shorter duration, but we found that response rates of less
than 1 week were reported from that trial.
3. Results
3.1. Identification of relevant studies
A literature search identified 2550 candidate studies, and 22 studies
were included after screening and full-text review (Baumann et al.,
1996; Berman et al., 2009; Berman et al., 2007; Chen et al., 2023; Daly
et al., 2018; Fava et al., 2012; Fedgchin et al., 2019; Ionescu et al., 2019;
Joffe et al., 1993; Kamijima et al., 2013; Kamijima et al., 2018; Katona
et al., 1995; Li et al., 2016; Marcus et al., 2008; Nierenberg et al., 2003;
Popova et al., 2019; Singh et al., 2016; Su et al., 2017; Takahashi et al.,
2021; Yoshimura et al., 2014; Zehong et al., 2019; Zusky et al., 1988),
Supplementary Fig. 1, Table 1). The 23 studies excluded by the full-text
review are described in Supplementary Table 3, together with the rea­
sons for their exclusion. The number of studies and participants for the
included active drugs were as follows: intravenous racemic ketamine
(Ionescu et al., 2019; Li et al., 2016; Singh et al., 2016; Su et al., 2017;
Zehong et al., 2019), 157 in five studies; intranasal esketamine (Chen
et al., 2023; Daly et al., 2018; Fedgchin et al., 2019; Popova et al., 2019;
Takahashi et al., 2021), 565 in five studies; aripiprazole, 1217 in seven
studies (Berman et al., 2009; Berman et al., 2007; Fava et al., 2012;
Kamijima et al., 2013; Kamijima et al., 2018; Marcus et al., 2008;
Yoshimura et al., 2014); and lithium, 92 in six studies (Baumann et al.,
1996; Joffe et al., 1993; Katona et al., 1995; Nierenberg et al., 2003;
Yoshimura et al., 2014; Zusky et al., 1988). The mean age for each study
ranged from 36.8 to 50 years. The proportion of male patients ranged
from 12.5 to 77 %. The time points measured ranged from 40 min to 6
weeks. Most of the included studies tested repeated doses, while three
used single doses of intravenous racemic ketamine (Li et al., 2016; Su
et al., 2017; Zehong et al., 2019). Except for one head-to-head trial
(aripiprazole versus lithium) (Yoshimura et al., 2014), all other trials
were placebo-controlled. Baseline depression severity tended to be
higher in the nasal esketamine trials. Most of the lithium trials were
older and often used tricyclic antidepressants, while the others used
second-generation antidepressants. All the studies of intravenous
racemic ketamine included only patients who were nonresponsive to
two or more antidepressants, whereas the studies of the other drugs
included patients who were nonresponsive to one or more
antidepressants.
3.2. Risk of bias assessment
No study was rated as “high risk”. The 10 studies were “low risk”,
while the other 12 had “some concerns” (Supplementary Fig. 2). The
most common concerns were inadequate description of the random­
isation process, allocation concealment, or lack of prior protocol regis­
trations. Most studies of intravenous racemic ketamine and intranasal
esketamine were rated as “low risk”, whereas studies of aripiprazole and
lithium were rated as “some concerns”.
3.3. Network meta-analyses results
3.3.1. Results of the primary analyses
The results of the primary analyses are shown in Tables 2a, 2b and 2c
for efficacy, tolerability and acceptability, respectively. The time points
and outcomes used in the efficacy analyses are listed in Table 1. The
efficacy of all drugs was significantly superior to placebo. In addition,
intravenous racemic ketamine was significantly more effective than
intranasal esketamine or aripiprazole. The efficacy of intravenous
51
Journal of Affective Disorders 346 (2024) 49–56
racemic ketamine was higher than that of lithium, although no statistical
significance was found. Intravenous racemic ketamine and lithium were
not significantly different from placebo in tolerability, whereas intra­
nasal esketamine and aripiprazole were significantly worse tolerated
than placebo. In acceptability, intravenous racemic ketamine was
significantly superior to intranasal esketamine, aripiprazole and pla­
cebo. No significant differences were found in the other comparisons.
Although the duration of the studies varied considerably, statistically
significant heterogeneity and inconsistency was not found in any of the
analyses.
3.3.2. Results of the sensitivity analyses
The results of the sensitivity analyses are shown in Supplementary
Tables 4a: efficacy, 4b: tolerability, and 4c: acceptability. The efficacy of
all drugs was significantly superior to that of placebo. Although intra­
venous racemic ketamine had the highest odds ratio compared with
placebo, there was no significant difference in efficacy between all
active drugs. Notably, intravenous racemic ketamine was not only not
significantly less tolerable than the other drugs and placebo but was
significantly more acceptable than the other drugs and placebo. Intra­
nasal esketamine and aripiprazole were significantly less well tolerated
than placebo. There were no significant differences in the other com­
parisons. No significant heterogeneity or inconsistency was found.
3.3.3. Results of the subgroup analyses including trials within 1 week
The results of the subgroup analyses including trials within 1 week
are shown in Supplementary Tables 5a (efficacy), 5b (tolerability), and
5c (acceptability). The efficacy of all drugs except lithium were signif­
icantly superior to that of placebo, with the highest odds ratio compared
with placebo for intravenous racemic ketamine. No significantly
different comparisons were found for tolerability and acceptability, in
which aripiprazole was not included because no studies reported safety
at this period. No significant heterogeneity was observed in any of the
analyses. Inconsistency was not assessed because it was not possible to
form closed loops in the network.
3.3.4. Results of the subgroup analyses including trials longer than 1 week
The results of the subgroup analyses including trials longer than 1
week are shown in Supplementary Tables 6a: efficacy, 6b: tolerability,
and 6c: acceptability. Comparisons where significant differences existed
were analogous of the sensitivity analysis. All drugs were significantly
more effective than placebo. Intranasal esketamine and aripiprazole
were significantly less well tolerated than placebo. In acceptability,
intravenous racemic ketamine was significantly superior to the other
drugs and placebo. No significant differences were found in the other
comparisons. No significant heterogeneity or inconsistency was found in
any of the analyses.
3.3.5. Certainty of evidence
The certainty of evidence for intravenous racemic ketamine was as
follows: moderate certainty in comparison with placebo and low cer­
tainty in comparison with intranasal esketamine, aripiprazole and
lithium (Supplementary Table 7). The most common factors down­
grading the certainty of evidence were “within-study bias”, “impreci­
sion, and “reporting bias”. “Reporting bias” was assessed as “some
concern” in all comparisons, as asymmetry could not be detected in the
funnel plots due to the small number of studies, and publication bias
could not be assessed (Higgins et al., 2022). If both “imprecision” and
“reporting bias” were present in each comparison, the certainty was only
downgraded by one because we judged them to be interconnected for
the small number of included studies (Higgins et al., 2022).
4. Discussion
The present study reports the results of both the first meta-analysis
focusing on the augmentative antidepressant effect of intravenous
 I. Terao et al.
Table 1
Characteristics of the included studies. HAMD: Hamilton Depression Rating Scale, MADRS: Montgomery Åsberg Depression Rating Scale, NA: not available,SGAs: Second generation antidepressants, TCAs: Tricyclic
antidepressants.
Study Failed Combined Outcome Intervention Time of Time point Sample Mean % Baseline Baseline Responders Drop out Drop out
antidepressant antidepressants measure measurement selected for size age male depression depression (%) due to due to
trials for reponse rate the primary severity: row severity (%: adverse any
efficacy scores mean value/ effects (%) reason
analysis maximum (%)
value)

Intranasal
esketamine 56 or
Chen et al., 84 mg twice per
2023 1–5 SGA MADRS week 4 weeks 4 weeks 126 36.8 68.0 36.5 60.8 19.3 5.6 14.3
Placebo 126 37.8 71.0 35.9 59.8 16.0 1.6 15.9
Intranasal
Takahashi esketamine 28,
et al., 56 or 84 mg
2021 1–4 SGAs MADRS twice weekly 4 weeks 4 weeks 122 43.4 53.3 37.4 62.3 37.5 8.2 9.0
Placebo 80 43.3 51.0 37.7 62.8 37.5 3.8 10.0
Intranasal
esketamine 28,
Daly et al., 56 or 84 mg for
2018 2 or more NA MADRS days 1,4 2 h,1,8 days 2h 34 44.4 41.2 33.2 55.3 50.0 2.9 11.8
Placebo 33 44.4 46.0 35.0 58.3 18.2 0.0 3.0
Intranasal
Fedgchin esketamine 56 or
et al., 84 mg twice
2019 1 or more SGAs MADRS weekly 4 weeks 4 weeks 229 46.1 35.0 37.6 62.7 53.7 3.5 10.9
52

Placebo 113 46.8 32.0 37.5 62.5 38.9 1.8 5.3

Intranasal
Popova esketamine 56 or
et al., 84 mg twice
2019 2 or more SGAs MADRS weekly 4 weeks 4 weeks 115 45.0 34.0 37.0 61.7 69.3 7.9 11.4
Placebo 109 46.4 42.0 37.3 62.2 52.0 0.9 8.3
Intravenous
racemic
Ionescu ketamine 0.5
et al., mg/kg twice
2019 3 or more TCAs or SGAs HAMD-28 weekly 3 weeks 3 weeks 13 45.5 46.0 31.6 36.3 25.0 16.7 33.3
Placebo 13 45.3 77.0 26.3 30.2 33.3 0.0 33.3
Intravenous
racemic
ketamine 0.2 or
Cao et al., 0.5 mg/kg, single 0, 40 min, 2, 4

Journal of Affective Disorders 346 (2024) 49–56

2019 2 or more NA HAMD-17 infusion h, 1, 2, 4, 6 days 4h 37 47.0 15.6 23.6 45.4 43.2 0 0.0
Placebo 18 50.0 38.5 23.7 45.6 11.1 0 0.0
Intravenous
racemic
ketamine 0.2 or 1–4 days (Exact
Su et al., 0.5 mg/kg, single time not
2017 3 or more NA HAMD-17 infusion specified.) 1–4 days 47 46.8 38.0 23.0 44.2 42.6 2.1 2.1
Placebo 24 48.6 17.0 23.3 44.8 12.5 0.0 0.0
Intravenous
racemic
ketamine 0.5
Singh et al., mg/kg twice or
2016 2 or more SGAs MADRS thrice weekly 15 days 15 days 35 44.6 31.0 34.4 57.3 62.1 8.6 34.3
(continued on next page)
 I. Terao et al.
Table 1 (continued )
Study Failed Combined Outcome Intervention Time of Time point Sample Mean % Baseline Baseline Responders Drop out Drop out
antidepressant antidepressants measure measurement selected for size age male depression depression (%) due to due to
trials for reponse rate the primary severity: row severity (%: adverse any
efficacy scores mean value/ effects (%) reason
analysis maximum (%)
value)

Placebo 32 43.2 34.4 36.2 60.3 10.3 3.1 93.8

Intravenous
racemic
ketamine 0.2 or
Li et al., 0.5 mg/kg, single 40, 80 min, 2, 4
2016 3 or more SGAs HAMD-17 infusion h 80 min 32 43.9 31.3 21.8 41.9 40.6 0.0 0.0
Placebo 16 49.9 18.8 22.8 43.8 6.3 0.0 0.0
Kamijima Aripiprazole 6.3
et al., 1–3 SGAs MADRS (mean flexible 6 weeks 6 weeks 208 38.3 62.0 24.9 41.5 37.5 1.9 7.2
2018 dose) mg daily
Placebo 203 39.5 65.0 25.2 42.0 25.6 1.5 9.9
Aripiprazole 3 or
Kamijima
9.8 (mean
et al., 1–3 SGAs MADRS 6 weeks 6 weeks 391 38.7 58.0 25.2 42.0 40.7 2.6 8.7
flexible dose) mg
2013
daily
Placebo 195 39.0 59.0 25.5 42.5 28.2 1.0 6.2
Fava et al., Aripiprazole 2 30 days (± 3 30 days (±
1 or more SGAs MADRS 56 45.1 36.0 30.7 51.2 18.5 0.0 3.6
2012 mg daily days) 3 days)
Placebo 169 45.4 34.0 31.2 52.0 17.4 0.0 1.2
Berman Aripiprazole 10.7
1,2,3,4,5,6
et al., 1 or more SGAs MADRS (mean flexible 6 weeks 177 45.1 39.0 26.6 44.3 46.6 6.2 16.9
weeks
2009 dose) mg daily
53

Placebo 172 45.6 55.0 27.1 45.2 26.6 1.7 13.4

Marcus Aripiprazole 11
et al., 2 or more SGAs MADRS (mean flexible 6 weeks 6 weeks 191 44.6 65.0 25.2 42.0 32.4 3.7 15.2
2008 dose) mg daily
Placebo 190 44.4 62.0 27.0 45.0 17.4 1.1 14.7
Berman Aripiprazole 11.8
1,2,3,4,5,6
et al., 2 or more SGAs MADRS (mean flexible 6 weeks 182 46.5 38.5 26.0 43.3 33.7 3.3 12.0
weeks
2007 dose) mg daily
Placebo 176 44.2 35.8 25.9 43.2 23.8 2.2 9.0
Nierenberg
Lithium (dosage
et al., 1–4 TCAs HAMD-17 6 weeks 6 weeks 18 37.2 50.0 21.4 41.2 11.1 0.0 0.0
unknown)
2003
Placebo 17 39.7 58.8 21.7 41.7 17.6 0.0 0.0
Baumann
et al., Lithium 800 mg

Journal of Affective Disorders 346 (2024) 49–56

1996 1 or more SGAs HAMD-21 daily 1 week 1 week 10 40.0 30.0 NA NA 60.0 0.0 20.0
Placebo 14 43.0 28.6 NA NA 14.3 0.0 14.3
Katona
et al., Lithium 800 mg
1995 1 or more SGAs and TCAs HAMD-17 daily 6 weeks 6 weeks 29 39.5 31.0 17.9 34.4 51.7 6.9 20.7
Placebo 32 40.5 54.5 19.3 37.1 25.0 6.3 28.1
Joffe et al., Lithium 1200 mg
1993 1 or more TCAs HAMD-17 daily 2 weeks 2 weeks 17 37.4 52.9 20.2 38.8 52.9 0.0 0.0
Placebo 16 37.4 37.5 18.7 36.0 18.8 0.0 0.0
Lithium
Zusky et al., 300–900 mg
1988 1 or more TCAs HAMD-17 daily 1,2,3 weeks 3 weeks 9 46.8 12.5 19.4 37.3 37.5 12.5 12.5
Placebo 9 44.8 25.0 25.8 49.6 25.0 12.5 12.5
(continued on next page)
I. Terao et al. Journal of Affective Disorders 346 (2024) 49–56

Table 2a
The network meta-analysis results (odds ratios for response rates among each

Drop out

reason
due to
drug or placebo [95 % confidence interval]). Bold text indicates statistical sig­

10.0

10.0
(%)
any
nificance. Values above 1 suggest the superior efficacy of drugs in columns over
those in rows.

effects (%)
Drop out

adverse Intravenous . . . .
due to

racemic ketamine

10.0

10.0
3.20 [1.43; 7.16] Intranasal . . .
esketamine
Responders

2.90 [1.33; 6.27] 0.90 [0.59; Aripiprazole . .

1.37]
40.0 1.92 [0.70; 5.22] 0.60 [0.28; 0.66 [0.32; Lithium .

40.0
(%)

1.28] 1.36]
5.33 [2.56; 1.67 [1.19; 1.85 [1.44; 2.78 [1.40; Placebo
11.10] 2.33] 2.37] 5.50]
mean value/
severity (%:

I2 = 23.8 %; p value of Q statistics = 0.17 in total, 0.14 in heterogeneity and 0.63

depression

maximum
Baseline

in inconsistency.
value)

42.3

42.3

Table 2b
severity: row

The network meta-analysis results (odds ratios for drop-out rates due to side
depression
Baseline

effects among each drug or placebo [95 % confidence interval]). Bold text in­
scores

dicates statistical significance. Values above 1 suggest the inferior tolerability of

22.0

22.0

drugs in columns over those in rows.

Intravenous . . . .
male

30.0

40.0

racemic ketamine
%

0.63 [0.13; 3.12] Intranasal . . .

Mean

esketamine
40.0

39.0
age

0.86 [0.19; 3.96] 1.36 [0.51; Aripiprazole . .

3.63]
1.57 [0.24; 10.12] 2.48 [0.58; 1.83 [0.48; Lithium .
Sample

10.58] 6.90]
size

10

10

1.92 [0.47; 7.79] 3.03 [1.41; 2.24 [1.21; 1.23 [0.36; Placebo
6.53] 4.14] 4.20]
the primary
selected for

I2 = 0 %; p value of Q statistics = 0.99 in total, 0.99 in heterogeneity and 0.65 in

Time point

4 weeks
analysis
efficacy

inconsistency.

Table 2c
for reponse rate

The network meta-analysis results (odds ratios for drop-out rates due to any
measurement

reason among each drug or placebo [95 % confidence interval]). Bold text in­
4 weeks
Time of

dicates statistical significance. Values above 1 suggest the inferior acceptability

of drugs in columns over those in rows.
Intravenous . . . .
racemic ketamine
dose) mg daily

dose) mg daily
(mean flexible

(mean flexible
Aripiprazole 9

0.19 [0.06; 0.59] Intranasal . . .

Intervention

Lithium 458

esketamine
0.21 [0.07; 0.60] 1.07 [0.64; Aripiprazole . .
1.78]
0.28 [0.07; 1.08] 1.45 [0.54; 1.35 [0.54; Lithium .
3.86] 3.41]
HAMD-17
Outcome

0.24 [0.09; 0.62] 1.25 [0.82; 1.17 [0.88; 0.86 [0.36; Placebo
measure

1.90] 1.56] 2.10]

I2 = 2 %; p value of Q statistics = 0.43 in total, 0.37 in heterogeneity and 0.83 in

inconsistency.
antidepressants

racemic ketamine in unipolar TRD in adults and the first network meta-
Combined

analysis comparing intravenous racemic ketamine with intranasal

SGAs

esketamine, aripiprazole, lithium and placebo in such conditions. Bhaji

et al. (Bahji et al., 2021) suggested that racemic ketamine is more
effective than esketamine for major depression, as described in the
antidepressant

Introduction section, and we extended the meta-analysis by restricting

the condition of indication, method of intervention, route of adminis­
Failed

trials

tration, and adding comparisons with well-studied conventional

Table 1 (continued )

NA

augmentative treatments. Intravenous racemic ketamine was signifi­

cantly more effective than intranasal esketamine and aripiprazole, but
Yoshimura

not significantly different from lithium in efficacy in the primary anal­

et al.,
2014

ysis. Although the significant superiority of intravenous racemic keta­

Study

mine over aripiprazole and intranasal ketamine in efficacy disappeared

54
I. Terao et al.
in the sensitivity analysis and subgroup analyses, which may be due to
insufficient sample size given the wide 95 % confidence interval for
intravenous racemic ketamine, it has the highest odds ratio compared
with placebo in all analyses and may indicate a potential advantage over
the other three drugs regardless of the number of doses or duration,
although no definitive conclusions can be drawn at this stage. Further­
more, in the primary analysis, the durations of the intravenous racemic
ketamine study were shorter than those of studies with other drugs,
ranging from 40 min to 3 weeks, suggesting a rapid onset of antide­
pressant effects. The major drawback of ketamine is relapse after a single
dose, and two repeated dose studies of intravenous racemic ketamine
were available in this study; in the sensitivity analysis only including
repeated dose studies, intravenous racemic ketamine was significantly
superior to placebo, supporting a previous review that repeated intra­
venous dosing of ketamine prevents relapse depression (Marcantoni
et al., 2020). Contrary to our initial expectation, intravenous racemic
ketamine was not significantly inferior to the other drugs or placebo in
terms of tolerability and acceptability regardless of whether included
studies were repeated dose only or not, and whether within 1 week or
over 1 week. Rather, intravenous racemic ketamine was significantly
more acceptable than aripiprazole and intranasal esketamine, except for
within 1 week, whereas aripiprazole and intranasal esketamine were
significantly less tolerable than placebo except for within 1 week, sug­
gesting a better safety profile of intravenous racemic ketamine than
intranasal esketamine and aripiprazole, although this should be inter­
preted with caution due to the shorter study duration of intravenous
racemic ketamine and the possibility that its dissociative effects prevent
maintenance of blindness (Acevedo-Diaz et al., 2020). The Singh et al.
(Singh et al., 2016) study had a very high dropout rate for any reason in
the placebo group (93.8 %), which was excluded as an outlier, and
further sensitivity analysis performed post hoc showed no significant
difference in acceptability between intravenous racemic ketamine and
the other drugs or placebo (data not shown). In summary, although not
robust, intravenous racemic ketamine may be superior to intranasal
esketamine, aripiprazole and placebo in terms of efficacy, tolerability
and acceptability. The comparison of intravenous racemic ketamine
with lithium generally showed no significant difference, and both were
small in number, so their superiority could not be determined at this
time.
5. Limitations
This study has several limitations: (1) Some adverse effects
commonly associated with ketamine, such as dissociation, nausea,
increased blood pressure and headache (Rhee et al., 2022), were not
well reported and could not be assessed. Similarly, psychotomimetic
effects, dependence and abuse of ketamine could not be assessed. (2) We
did not mention the acute anti-suicidal effect of ketamine (Witt et al.,
2020) because it was not reported for the other drugs. (3) We were
unable to include other evidence-based augmentative pharmacother­
apies for TRD due to staffing limitations. (4) The sample sizes included
in the analysis were small, especially for intravenous racemic ketamine
and lithium, resulting in a lack of robustness and power. (5) The
comparative results between the active drugs were mostly derived from
indirect evidence. Head-to-head trials are needed to improve the pre­
cision of the evidence. (6) The higher baseline severity of intranasal
esketamine may influence its lower efficacy, tolerability and accept­
ability compared to intravenous racemic ketamine. Apart from study
duration, the effect of other potential confounding factors could not be
assessed due to the small number of include studies. (7) We performed a
network meta-analysis, which inevitably violates the transitivity
assumption, e.g., different routes of administration and study durations.
In the absence of direct comparisons, we considered it was important to
gain a preliminary understanding of the comparative results by tenta­
tively sharing placebos to guide future research. Fortunately, the sta­
tistical heterogeneity was not significant. For the reasons given in (4) to
55
Journal of Affective Disorders 346 (2024) 49–56
(7), it is underlined that the results of the present analyses are not robust
and require careful interpretation.
6. Conclusion
Intravenous racemic ketamine may be a better augmentative treat­
ment option for TRD than intranasal esketamine, aripiprazole and pla­
cebo given its higher efficacy, tolerability and acceptability, whereas it
is unclear whether intravenous racemic ketamine or lithium is superior.
These findings will, to some extent, guide treatment selection in clinical
practice. However, the results are not robust due to the small number of
participants, various conceptual heterogeneities and lack of assessment
of ketamine-specific side effects, and it is hoped that the present findings
will serve as a springboard for a large-scale trial of intravenous racemic
ketamine that will re-examine its utility.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.jad.2023.11.023.
CRediT authorship contribution statement
All authors made substantial contributions to the conception and
design of the study, acquisition of the data, or analysis and interpreta­
tion of the data; took part in drafting the manuscript or revising it
critically for important intellectual content; gave final approval of the
version to be published; and agree to be accountable for all aspects of the
work.
Ethics approval statement and patient consent statement
As this study is a systematic review and meta-analysis, it does not
involve human subjects, and therefore, ethics approval and patient
consent statements are not applicable.
Funding statement
The authors received no financial support for the research, author­
ship, or publication of this article.
Declaration of competing interest
The Authors declare that there is no conflict of interest.
Data availability
The datasets analysed in the current study are available from the
corresponding author upon reasonable request.
Acknowledgments
None.
Clinical trial registration
This study has been registered with PROSPERO (number
CRD42023425734).
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