Journal of Psychiatric Research 137 (2021) 232–241
Contents lists available at ScienceDirect
Journal of Psychiatric Research
journal homepage: www.elsevier.com/locate/jpsychires
Review article
The effectiveness, safety and tolerability of ketamine for depression in
adolescents and older adults: A systematic review
Joshua D. Di Vincenzo a, b, i, Ashley Siegel a, i, Orly Lipsitz a, i, Roger Ho d, e, Kayla M. Teopiz a,
Jason Ng a, Leanna M.W. Lui a, Kangguang Lin f, Bing Cao g, Nelson B. Rodrigues a, i,
Hartej Gill a, h, i, Roger S. McIntyre a, b, c, i, Joshua D. Rosenblat a, c, i, *
a
Mood Disorders Psychopharmacology Unit, University Health Network, 399 Bathurst St, M5T 2S8, Toronto, ON, Canada
Department of Pharmacology and Toxicology, University of Toronto, Medical Sciences Building, 1 King’s College Circle, ON, M5S 1A8, Toronto, ON, Canada
Department of Psychiatry, University of Toronto, 250 College Street, 8th Floor, M5T 1R8, Toronto, ON, Canada
d
Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, NUHS Tower Block, Level 9, 119228,
Singapore
e
Institute of Health Innovation and Technology (iHealthtech), National University of Singapore, MD6, 14 Medical Drive #14-01, 117599, Singapore
f
Department of Affective Disorders, The Affiliated Hospital of Guangzhou Medical University, Guangzhou (Guangzhou Huiai Hospital), China
g
Key Laboratory of Cognition and Personality (SWU), Faculty of Psychology, Ministry of Education, Southwest University, Chongqing, 400715, PR China
h
Institute of Medical Science, University of Toronto, Medical Sciences Building, 1 King’s College Cir, M5S 1A8, Toronto, ON, Canada
i
Canadian Rapid Treatment Center of Excellence, Mississauga, ON, Canada
b
c
A R T I C L E I N F O
A B S T R A C T
Keywords:
Ketamine
Esketamine
Depression
Adolescent
Elderly
Geriatric
The majority of antidepressant medication trials have focused on adult populations (ages 18–65), with much less
research in older and younger populations. Moreover, key differences in the efficacy and safety of antidepres­
sants have been identified between these age groups. Ketamine has emerged as a promising new treatment for
treatment resistant depression (TRD). The objective of this review is to summarize and synthesize the extant
literature on the effectiveness, safety and tolerability of ketamine for depression in special age populations (age
≤18 and ≥ 60). Following PRISMA guidelines, a systematic review was performed, searching EMBASE, PsycInfo,
and PubMed from inception through July 2020. Studies reporting the use of any ketamine formulation with
variable routes of administration to treat clinically diagnosed depression in adolescents or older adults were
included. Thirteen studies were included in the analysis and ten observed rapid (≤2 week latency) antidepressant
effects following ketamine treatments, with better outcomes following larger, repeated doses, and in open-label
rather than blinded settings. Two case reports in adolescents assessed measures of suicidal ideation and both
found ketamine to effectuate rapid anti-suicidal effects. Ketamine appears to be safe and well-tolerated in ad­
olescents and older adults. The small quantity, high heterogeneity, and generally low quality of available studies
precludes statistical syntheses and significantly limits the strength of our conclusions. Preliminary proof-ofconcept studies are promising, however, rigorously designed randomized controlled trials (RCTs) are still
required to ascertain effectiveness, safety and tolerability in these groups.
1. Introduction
Major depressive disorder (MDD) manifests in all age groups; agespecific lifetime prevalence increases during adolescence, remaining
high (~20–22%) throughout adulthood before declining to 14.4% in
older adults (aged ≥ 60) (Hasin et al., 2018; Merikangas et al., 2010).
Moreover, the manifestations and outcomes of MDD vary between age
groups. Depressive symptoms in adolescence and into adulthood predict
future educational and social impairments (Fletcher, 2008; Thapar et al.,
2012), as well as non-communicable diseases including diabetes, sub­
stance use disorders and obesity (Armbrecht et al., 2020; Hasler et al.,
2005; Keenan-Miller et al., 2007). Older adults experience dispropor­
tionately high levels of functional impairment from depressive symp­
toms, and have higher relapse and recurrence rates, compared to
* Corresponding author. Mood Disorders Psychopharmacology Unit, Poul Hansen Family Centre for Depression, University Health Network, 399 Bathurst Street,
Toronto, ON, M5T 2S8, Canada.
E-mail address: joshua.rosenblat@uhn.ca (J.D. Rosenblat).
https://doi.org/10.1016/j.jpsychires.2021.02.058
Received 15 November 2020; Received in revised form 22 January 2021; Accepted 20 February 2021
Available online 1 March 2021
0022-3956/© 2021 Elsevier Ltd. All rights reserved.
J.D. Di Vincenzo et al.
Journal of Psychiatric Research 137 (2021) 232–241
younger counterparts (Lyness et al., 1999; Mitchell and Subramaniam,
2005). Furthermore, MDD is a risk factor for suicide, which occurs at the
highest rates in older adults, and is the second leading cause of death
globally among individuals aged 15–29 (Conejero et al., 2018; “WHO |
Suicide data,” 2019).
Two antidepressant drugs (ADs) – fluoxetine and escitalopram, both
selective serotonin reuptake inhibitors (SSRIs) – have been approved by
the Food and Drug Administration (FDA) to treat MDD in adolescents.
Unfortunately, a recent network meta-analysis could not conclude that
any of the 14 ADs included offered a benefit for adolescent MDD
(Cipriani et al., 2016). Furthermore, ADs may significantly increase risk
of harm-related adverse events in adolescents (March, 2004), leading
the FDA to mandate a black box warning on SSRIs due to increased
suicidality.
In accordance with recommendations for midlife adults, SSRIs are
considered first-line pharmacotherapy for older adults (aged ≥ 60) with
depression. Notwithstanding, many older adults treated with conven­
tional ADs including SSRIs and serotonin–norepinephrine reuptake in­
hibitors (SNRIs) do not achieve full recovery, and ADs are associated
with tolerability and important safety concerns for this age group (e.g.
hyponatremia and QTc prolongation) (Bose et al., 2008; Fick et al.,
2019; Rapaport et al., 2003; Rochester et al., 2018; Schneider et al.,
2003; Taylor, 2014; Viramontes et al., 2016).
Ketamine is an N-methyl D-aspartate (NMDA) receptor antagonist
and dissociative anesthetic. At subanesthetic doses, ketamine is safe and
rapidly efficacious at treating depression and suicidal ideation in adults
with MDD, including treatment resistant depression (TRD; i.e. resistant
to ≥2 adequate AD trials) (Coyle and Laws, 2015; McIntyre et al., 2020;
Murrough et al., 2013; Wilkinson et al., 2018). While SSRIs and SNRIs
are usually only effective after weeks of continued administration, ke­
tamine is shown to have rapid therapeutic effects (Lipsitz et al., 2020;
Zanos and Gould, 2018). Furthermore, for decades, ketamine has been
safely and routinely used at higher doses as an anesthetic in both pe­
diatric and general populations (Roelofse, 2010). Given ketamine’s
favourable safety and efficacy profiles in adults, as well as the rapidity
and robustness of its action, even in TRD, there is impetus to ascertain
these observations by reviewing extant literature in adolescents and
older adults.
The aim of this systematic review is to assess the safety, tolerability,
and effectiveness of ketamine formulations for the treatment of MDD
and TRD in adolescents and older adults (aged ≥ 60).
In the current review, this special population is adolescents and older
adults. A PRISMA flow diagram (Fig. 1) was used to organize the search
results and Mendeley Desktop 1.19.4 was used to manage references and
deduplication. Due to the high heterogeneity and small number of
available studies (which includes non-randomized studies and case se­
ries/reports), statistical synthesis was not possible; for these reasons,
PRISMA guidelines were not strictly followed, but informed the design
of the protocol.
2. Methods
3.1. Search results
2.1. Search strategy
After deduplication of 761 total search results, 643 unique records
were identified in the preliminary search, 440 of which were excluded
following title and abstract review. Following full-text review of 203
records, 157 were excluded if they were not interventional or observa­
tional studies, or if they did not include a special population. 46 records
met the inclusion criteria, six of which included adolescent or older
adult populations. Seven additional studies were identified via manual
searching and included in the analysis, including one study which is
currently in press (Lipsitz et al., 2021). In total, 13 records met the in­
clusion criteria for this study: five in adolescents and eight in older
adults (Tables 3 and 4). Of the five studies in adolescents, one was a
randomized controlled trial (RCT; Bloch et al., 2020), one was a pro­
spective open-label study (Cullen et al., 2018), and three were case re­
ports (Dwyer et al., 2017; Weber et al., 2018; Zarrinnegar et al., 2019).
Eight studies including older adults consisted of two RCTs (George et al.,
2017; Ochs-Ross et al., 2020), one prospective open-label study (Irwin
et al., 2013), and five case series/reports (Gálvez et al., 2014; Lipsitz
et al., 2021; Medeiros da Frota Ribeiro and Riva-Posse, 2017; Srivastava
et al., 2015; Szymkowicz et al., 2014). In total, the three RCTs were
assessed to be of high quality (Table 1), whereas the two
non-randomized studies were deemed to be low quality due to lack of a
comparator (Table 2), and case series/reports are low quality due to lack
2.2. Study selection/eligibility criteria
Interventional and observational studies including clinical trials,
retrospective studies, case reports/series, and open-label studies were
eligible for inclusion in the first search if they were conducted in humans
and published in English. Original studies were included if ketamine was
administered to treat symptoms of depression, and if they contained
individuals belonging to a special population. Studies were excluded
from the first search if ketamine was not indicated specifically to treat
depression, if ketamine was administered adjunctively, if they did not
include results (i.e. trial protocols), if they or were review papers, con­
ference papers, or poster series (to prevent capturing the same study
twice).
In the second search, focused on adolescents and older adults for this
current review, the inclusion and exclusion criteria are the same as
stated above, with the additional exclusion of studies that did not
include individuals aged ≤18 or ≥60, and did not assess safety or
depression outcomes as a primary endpoint.
2.3. Quality appraisal
Risk of bias (RoB) was determined for all randomized studies using
the Cochrane RoB 2 tool as recommended in the Cochrane Handbook for
Systematic Review of Interventions (Table 1) (Higgins et al., 2020). The
RoB 2 assesses risk of bias across 5 domains: bias arising from the
randomization process; bias due to deviations from intended in­
terventions; bias due to missing outcome data; bias in measurement of
the outcome; and bias in selection of the reported result. For
non-randomized studies, risk of bias was assessed using the Newcastle
Ottawa Scale (Table 2) (Wells et al., n.d.).
3. Results
The search strategy involved two separate searches. The first search
was designed to be a broad scan of the literature with the purpose
identifying special populations (i.e. those typically excluded from clin­
ical trials) within the extant literature on ketamine as a treatment for
depression. To this end, the study author performed an open search on
the EMBASE, PsycInfo, and PubMed databases through July 2020, using
the keywords “ketamine” (including “esketamine,” “arketamine,”
“ketalar,” and “spravato”) and “depress*”, linked with Boolean opera­
tors (AND/OR) where necessary (Supplementary Table 1). Additional
searches on ClinicalTrials.gov and the first 10 pages of Google Scholar
were also performed. Furthermore, any relevant references identified in
articles from the preliminary search were included to capture additional
relevant extant literature. Once the first search was completed, the re­
cords identified were reviewed by the study authors and grouped into
five special populations according to relevant themes which emerged
during the review: 1) adolescents and elderly; 2) medically unstable/ill;
3) individuals with suicidal ideation; 4) individuals with a history of
substance use disorder; and 5) individuals with postpartum/hormonal
depression. The second search constituted a new systematic review
dedicated to one of the special populations identified in the first search.
233
J.D. Di Vincenzo et al.
Journal of Psychiatric Research 137 (2021) 232–241
Records iden�fied through
database searching
(n = 761 )
Addi�onal records iden�fied
through other sources
(n = 17 )
Records a�er duplicates removed
(n = 643 )
Records screened
(n = 643 )
Records excluded
(n = 440 )
Full-text ar�cles assessed
for eligibility
(n = 203 )
Full-text ar�cles excluded,
as they are not
interven�onal or
observa�onal studies
specifically inves�ga�ng
the efficacy, safety, or
tolerability of ketamine
for depressive symptoms
in special popula�ons
(n = 157 )
Studies included in
qualita�ve synthesis
(n = 46 )
Studies included in subpopula�on (adolescents &
older adults)
(n = 13 )
Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of search results.
Table 1
Risk of bias assessment for RCTs – Cochrane RoB2 results.
Study
Bias arising from the
randomization process
Bias due to deviations from
intended interventions
Bias due to missing
outcome data
Bias in the measurement of
the outcome
Bias in selection of the
reported result
Bloch et al.
(2020)
George et al.
(2017)
Ochs-Ross et al.
(2020)
Low
Low
Low
Low
Low
Low
Low
Low
Some concerns
Low
Low
Low
Low
Some concerns
Low
of generalizability.
Table 2
Risk of bias assessment for non-randomized studies – Newcastle-Ottawa Scale
results. Maximum number of stars possible for each domain denoted in brackets.
Study
Selection (/4)
Comparability (/2)
Outcome (/3)
Lipsitz et al. (2021)
Cullen et al. (2018)
Irwin et al. (2013)
***
***
***
0
0
0
**
***
**
3.2. Prospective studies in adolescents
Two prospective studies assessing the antidepressant effects of ke­
tamine in adolescents were identified (Bloch et al., 2020; Cullen et al.,
2018). The most recent was a blinded, midazolam-controlled crossover
RCT with a two-week washout period assessing the efficacy, safety, and
tolerability of IV ketamine in adolescents with treatment resistant MDD
and a Children’s Depression Rating Scale-Revised (CDRS-R) score > 40
(NCT02579928; Bloch et al., 2020). Participants showed a greater
response on the Montgomery–Åsberg depression rating scale (MADRS) 1
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J.D. Di Vincenzo et al.
Journal of Psychiatric Research 137 (2021) 232–241
Table 3
Study demographics.
Adolescents
Author (year)
Type of study
N
Age (years)
Diagnosis
TRD?
Bloch et al. (2020)
RCT
(Crossover)
Open label
study
Case report
17
13–17
MDD
Yes - Resistant to ≥ 1 AD
13
12–18
MDD
Yes - Resistant to ≥ 2 ADs
1
16
MDD; ADHD; Crohn’s disease
Case report
1
14
Zarrinnegar et al.
(2019)
Case report
1
15
Depression with suicidality; postconcussion syndrome; chronic migraines;
and complex regional pain syndrome of
the lower extremities
MDD; GAD; PTSD
Yes - Escitalopram (alone and with aripiprazole
augmentation); bupropion; lithium
Yes - Fluoxetine and aripiprazole; duloxetine
George et al.
(2017)
Ochs-Ross et al.
(2020)
Irwin et al. (2013)
RCT
16
≥60
RCT
138
≥65
Open label
study
Mean (SD)
= 63 (±18)
Lipsitz et al.
(2021); IN PRESS
Szymkowicz et al.
(2014)
Open label
chart review
Case series
16
ITT; 8
PP
53
Medeiros da Frota
Ribeiro et al.
(2017)
Gálvez et al.
(2014)
Case series
2
Mean (SD)
= 67 (±6)
Mean (SD)
= 72.25
(±5.38)
64a & 72b
Case report
1
Srivastava et al.
(2015)
Case report
1
Cullen et al.
(2018)
Dwyer et al.
(2017)
Weber et al.
(2018)
Older
Adults
4
Yes - Sertraline, fluvoxamine, imipramine,
venlafaxine, lorazepam, clonazepam, prazosin; and
augmentation with aripiprazole, olanzapine,
chlorpromazine, ziprasidone
MDD or Bipolar Depression; current
episode ≥ 4 weeks in duration
MDD
Yes - Resistant to ≥ 1 AD
HADS score of ≥15 or a HADS depression
subscale score of ≥8 at screening and at
the start of ketamine treatment
MDD
No
MDD
Yes - Resistant to multiple ADs and ECT
MDDa; BD type 1b
Yes - Resistant to multiple ADsab and ECTb
62
Recurrent melancholic MDD; history
included hypertension, hypothyroidism,
and a cerebrovascular accident
65
N/A - “fourth episode of depressive
illness”; Baseline HAMD of 17 indicated
mild depression
Yes - Resistant to reboxetine, mianserin, dothiepin,
venlafaxine, sertraline, mirtazapine, duloxetine,
and nortriptyline, including augmentation with
antipsychotics (quetiapine, olanzapine) or lithium
Yes - Resistant to escitalopram (alone and with
amisulpride augmentation); duloxetine +
amisulpride, agomelatine, and agomelatine +
amisulpride
Yes - Resistant to ≥ 2 ADs
Yes – Resistant to multiple ADs
Note: RCT = Randomized controlled trial; MDD = Major depressive disorder; AD = Antidepressant drug; ADHD = Attention deficit hyperactivity disorder; GAD =
Generalized anxiety disorder; PTSD=Post-traumatic stress disorder; ITT=Intention-to-treat; PP=Per-protocol; SD=Standard deviation; HADS=Hospital anxiety and
depression scale; BD=Bipolar disorder; ECT = Electro-convulsive therapy; HAMD=Hamilton depression rating scale.
a
= Case 1.
b
= Case 2.
day after they received ketamine compared to 1 day after midazolam or
baseline. Aside from these raw MADRS scores, comparative statistical
analyses of this study’s primary outcome have not been reported. Sec­
ondary outcomes assessed via implicit association tasks (IATs) for this
trial were reported independently in a poster session (Dwyer et al.,
2019) where it was shown that ketamine reduced depression (Cohen’s d
= 0.65) and suicide/death (Cohen’s d = 0.50) IATs, but not self-harm or
anxiety IATs, compared to midazolam. No serious adverse events were
reported in this trial and no adverse events led to discontinuation.
Adverse events, assessed 1 h after each infusion via the Clinician
Administered Dissociative States Scale (CADSS), occurred in 15/17
(88.24%) participants post-ketamine, and 13/16 (81.25%)
post-midazolam, with a higher prevalence of multiple symptoms re­
ported after ketamine compared to midazolam. These adverse effects are
commonly reported in studies using ketamine to treat depression in
adults and are typically transient, however their durations were not
reported in this trial (Short et al., 2018). This group is also currently
conducting a 3-week RCT followed by a 6-month open-label extension
phase (NCT03889756; estimated n = 24) to assess safety and tolerability
of IV ketamine in the same demographic, estimated to be completed in
the fourth quarter of 2022.
In a smaller study, adolescents with treatment resistant MDD and
CDRS-R > 40 received six open-label, intravenous ketamine infusions
over two weeks (Cullen et al., 2018). Ketamine treatment had a signif­
icant effect on the primary outcome, change from baseline in CDRS-R at
the end of the 2 week study period; secondary analyses of MADRS,
BDI-II, and CGI scores also revealed significant reductions at 2 weeks
post-ketamine treatment, although measures of anhedonia did not
change significantly. The greatest reductions in mean BDI-II and MADRS
scores were observed after the first treatment, whereas CDRS-R scores
declined gradually after each treatment. After 2 weeks, 5/13 (38%)
participants exhibited a response (≥50% reduction in depressive
symptoms), three of whom also achieved remission (CDRS-R ≤28).
Three responders sustained a response at the end of a 6-week follow up
phase, of whom two were in remission. No severe adverse events were
reported. Nausea was reported in three participants (emesis in one) and
treated with ondansetron. Importantly, a protocol change was imple­
mented with respect to the dose of ketamine administered: the first 5
participants (including 4 overweight) did not respond to ketamine dosed
according to 0.5 mg/kg ideal body weight (average dose received = 0.35
mg/kg actual body weight), so subsequent participants received keta­
mine at 0.5 mg/kg of actual body weight. Indeed, the adolescents who
received higher doses due to having a higher body-mass index (BMI)
reported the best outcomes.
3.3. Retrospective studies in adolescents
Three retrospective studies assessing the antidepressant effects of
intravenous ketamine infusions in adolescents were identified, all of
which are single case reports in adolescents with TRD and multiple
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Journal of Psychiatric Research 137 (2021) 232–241
Table 4
Methods and main efficacy, safety, and tolerability outcomes of studies included in the current review.
Adolescents
Older
Adults
Author (year)
Intervention
(Formulation, Dose,
Regimen)
Concomitant
Medications
Assessments
Main Outcomes
Safety/Tolerability/Adverse
Events
Bloch et al.
(2020)
IV Ketamine; 0.5 mg/kg
over 40 min; single
administration.
Stable for ≥4 weeks
MADRS; CADSS
No SAEs reported; CADSS
scores indicate more
significant dissociation 1 h
after ketamine infusion
compared to midazolam.
Cullen et al.
(2018)
IV Ketamine; 0.5 mg/kg
over 40 min; 6 infusions
over 2 weeks.
Dose stable for ≥2
months; or
discontinued with
adequate washout
time depending on the
class of drug
CDRS-R; MADRS; CGI;
BDI-II; SHAPS; TEPS
MADRS [mean (SD)]:
Baseline [32.9 (9.1)];
1 day post-ketamine [mean
(95%CI) = 15.44
(10.51–20.37)]; 1 day postmidazolam [mean (95% CI)
= 24.13 (18.21–30.04)].
CDRS-R mean difference
from baseline after 2 weeks
(SD): − 19.8 (14.8); t = 4.8;
p = 0.0004;
Average % change from
baseline on CDRS-R after 2
weeks (SD) = − 42.5%
(31%).
Dwyer et al.
(2017)
IV Ketamine; 0.5 mg/kg
over 40 min; 7 infusions
over an 8-week
hospitalization (days 1,
3, 7, 14, 21, 28, 50).
Lithium (level 0.49),
aripiprazole (25 mg
daily), and mixed
amphetamine salts XR
(30 mg daily)
MADRS; CDRS; SSI-5;
BHS; CADSS
Weber et al.
(2018)
IV Ketamine; 7mcg/kg/
min; continuously
infused over 5 days
(titrated to 4, then 2mcg/
kg/min, then
discontinued on day 5).
Fluoxetine and
aripiprazole
NRS assessed pain; No
specific rating scales
or assessments
mentioned for
depressive symptoms
(simply referred to
“psychiatric
assessments")
Zarrinnegar
et al. (2019)
IV Ketamine; 0.5 mg/kg
over 40 min; 6 infusions
over 3 weeks (days 3, 5,
7, 10, 17, 24).
No ADs mentioned;
pre-infusion
chlorpromazine for
nausea
MADRS; CDRS-R; SSI
George et al.
(2017)
SC ketamine; 0.1, 0.2,
0.3, 0.4, and 0.5 mg/kg;
≥1 week apart.
Prescribed
medications were
allowed, given no
changes in the 4 weeks
leading up to trial
MADRS; CADSS
Response and remission
were more frequent after
ketamine (68.8%
participants) compared to
29% and 14%, respectively,
after midazolam; MADRS
scores tended to return to
baseline on day 7.
Ochs-Ross
et al. (2020)
Intranasal esketamine;
28 mg, 56 mg, or 84 mg;
twice weekly for 4
weeks.
One of: duloxetine,
escitalopram,
sertraline, or
venlafaxine XR
MADRS; CGI-S; PHQ9; SDS
Improvement on the MADRS
from baseline to day 28 was
numerically greater in the
esketamine group compared
to placebo, but this was not
statistically significant;
Least square means
difference (95% CI) = − 3.6
(− 7.20, 0.07), 2-tailed p
value = 0.059.
Symptomatic improvement
1 day post-ketamine for
depression (61% MADRS
reduction; 32% CDRS
reduction), suicidal ideation
(88% SSI-5 reduction), and
hopelessness (57% BHS
reduction); improvements
were sustained for 61 days.
Clinician-reported
improvement of depression
on day 1 of infusion; selfreported improvement in SI
on day 2 and discharge on
day 5. Returned after 5
months with relapse of
depression and SI, and
received another 5-day
infusion with similar results.
CDRS-R and MADRS scores
decreased gradually by
30–40% to moderate levels
and were sustained; greatest
improvement seen on SSI
(~75% reduction).
No SAEs reported; transient
dissociative symptoms
(CADSS) and blood pressure
elevations resolved within an
hour after treatment; one
participant with high
suicidality at enrollment
reported worsening of suicidal
thoughts at post-treatment
which was not reflected in the
clinical assessments.
No SAEs reported; Mild intrainfusion dissociative
symptoms (maximum CADSS:
7/92) completely resolved
after 80 min; Mild nausea
treated with ondansetron.
No SAEs reported; nystagmus
and visual changes occurred
when dose was briefly titrated
up to 8mcg/kg/min on day 3,
however these symptoms
resolved after returning to
7mcg/kg/min.
No SAEs reported; symptoms
of derealisation and nausea
were controlled with low dose
chlorpromazine pretreatment.
No SAEs reported; dose
response relationship between
ketamine and dissociative
effects was observed; CADSS
scores peaked 10–15 min after
injection and resolved after 40
min. Mild, transient
hemodynamic changes were
observed; Mild neurologic
symptoms (mainly dizziness)
were reported in 5 patients
and resolved within 2 h after
treatment; Slight liver enzyme
elevations observed in 1
participant at trial end; 1
participant reported mild
urologic symptoms (urge to
urinate more often).
SAEs reported in 3 receiving
esketamine (anxiety, blood
pressure increase, hip fracture
- deemed not related to
esketamine exposure) and 2
receiving placebo (gait
disturbance, dizziness). 4
treatment emergent adverse
events led to discontinuation
in the esketamine group, and 2
in the placebo group.
(continued on next page)
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Journal of Psychiatric Research 137 (2021) 232–241
Table 4 (continued )
Author (year)
Intervention
(Formulation, Dose,
Regimen)
Concomitant
Medications
Assessments
Main Outcomes
Safety/Tolerability/Adverse
Events
Irwin et al.
(2013)
Oral Ketamine (in cherry
syrup); 0.5 mg/kg; daily
for 28 days.
Permitted
HADS; MMSE; BPI-SF
(VAS); M.I.N.I. PLUS
(ASC, SRA); MQOL;
KPSS
No SAEs reported; mild
increases in complaints about
diarrhea, trouble sleeping, and
trouble sitting still were
reported in one subject each,
with declining severities over
the course of the study.
Lipsitz et al.
(2021);
IN PRESS
IV Ketamine; 0.5–0.75
mg/kg over 40–45 min;
four doses over 1–2
weeks.
Permitted
QIDS-SR16; GAD-7;
CADSS
HADS declined gradually,
reaching a significant
difference from baseline at
day 14 (mean Δ = 3.5, d =
1.14, 95% CI = 1.09–5.90, p
= 0.01), and sustaining it at
study end (Day 28; mean Δ
= 4, d = 1.34, 95% CI =
2.3–5.9, p = 0.001);
Response rate = 57%.
Significant reduction on the
QIDS-SR16 after repeated
ketamine infusions (F(4, 92)
= 7.412, p < .001). Mean
(SD) QIDS-SR16 was 17.12
(5.33) at baseline and
decreased to 12.52 (5.79)
following four infusions.
Szymkowicz
et al. (2014)
IV Ketamine; 0.5 mg/kg
of ideal body weight over
40 min; 2–6 infusions.
Prescribed
medications were
continued
MADRS
Medeiros da
Frota Ribeiro
et al. (2017)
IV Ketamine; 0.5 mg/kg
over 40 min; single
administration; biweekly
for first 2–3 weeks, then
weekly or every other
week for up to 8 more
weeks.
N/A
QIDS-SR; BDI-II (case
1 only)
Gálvez et al.
(2014)
SC Ketamine; 0.1 mg/kg
and 0.2 mg/kg bolus;
single administration ≥1
week apart.
Nortriptyline 125 mg/
day
MADRS
Srivastava
et al. (2015)
IV Ketamine; 0.5 mg/kg
over 40 min; 4 infusions
over 2 weeks.
Agomelatine
HAMD
No patient achieved
response at any time (≥50%
reduction in MADRS). All
participants MADRS scores
returned to baseline by
study end.
Gradual decline from
baseline (Case 1 = 14; Case
2 = 20) in QIDS-SR over
initial two weeks, sustaining
a score of ~7 until
discontinuation. Case 2
returned with relapse of
depression and SI after 5
weeks (QIDS-SR = 20) and
was treated again with nine
semi-weekly ketamine
infusions.
Baseline MADRS range:
20–25. Reductions after 0.1
mg/kg ketamine
(ΔMADRS⩰-15) and 0.2 mg/
kg ketamine (ΔMADRS⩰20), but not after midazolam
(ΔMADRS⩰-5). Patient
remained at MADRS = 0 for
5 months following 0.2 mg/
kg dose.
Rapid response was
observed after the first dose
(HAMD pre-infusion = 17;
HAMD 4 h post-infusion =
3); the patient maintained
remission through the end of
the trial and until follow-ups
ceased.
Several SAEs occurred during
infusions and most resolved
following the infusion, the
majority of which related to
CADSS domains (i.e. dizziness,
vision disturbances,
drowsiness, confusion,
depersonalization,
derealisation, and
hallucination). Increases in
systolic blood pressure,
diastolic blood pressure, and
heart rate were common in
both participants with and
without baseline
hypertension;
antihypertensive drugs were
administered as needed. No
dropouts were attributed to
treatment emergent adverse
events. Drowsiness was the
most common adverse event.
No SAEs reported; dissociation
and sedation were reported,
but resolved shortly following
the infusion.
No SAEs reported; transient
psychotomimetic effects
observed, which resolved
shortly after infusion.
No SAEs reported; transient
blurred vision and
lightheadedness were reported
and resolved within an hour
post-treatment.
No SAEs reported; transient
dissociation and cognitive
deficits were observed but
resolved within 2 h posttreatment.
Note: IV=Intravenous; mg = Milligrams; kg = Kilograms; MADRS = Montgomery–Åsberg depression rating scale; CADSS=Clinician-administered dissociative states
scale; SD=Standard deviation; CI=Confidence interval; SAE=Severe adverse event; CDRS-R = Children’s depression rating scale-revised; CGI=Clinical global im­
pressions; BDI-II=Beck depression inventory II; SHAPS=Snaith-Hamilton pleasure scale; TEPS = Temporal experience of pleasure scale; XR = extended release; SI =
suicidal ideation; SSI-5=Scale for suicidal ideation-5; SC = subcutaneous; BHS=Beck hopelessness scale; mcg = Micrograms; min = Minute; NRS=Numerical rating
scale; PHQ-9 = Patient health questionnaire-9; SDS=Sheehan disability scale; MMSE = Mini-mental state examination; BPI-SF=Brief pain inventory-short form;
VAS=Visual analog scale; M.I.N.I. PLUS = Mini-international neuropsychiatric interview-plus; ASC = Adverse symptom checklist; SRA=Suicide risk assessment;
237
J.D. Di Vincenzo et al.
Journal of Psychiatric Research 137 (2021) 232–241
MQOL = McGill quality of life questionnaire; KPSS=Karnofsky performance status scale; GAD-7 = Generalized anxiety disorder-7 scale; QIDS-SR = Quick inventory of
depressive symptoms-self report; HAMD=Hamilton depression rating scale.
comorbidities requiring hospitalization for suicidality (Dwyer et al.,
2017; Weber et al., 2018; Zarrinnegar et al., 2019). Two studies used
repeated doses of ketamine over 3 and 7 weeks and reported similar
outcomes, albeit with varying treatment trajectories (Dwyer et al., 2017;
Zarrinnegar et al., 2019). One patient who received 7 infusions over an 8
week hospitalization responded rapidly after the first dose, improving
and maintaining this response over 60 days (Dwyer et al., 2017).
Interestingly, another patient, receiving the same dose at 6 infusions
over 3 weeks, showed gradual antidepressant (MADRS and CDRS-R) and
antisuicidal (SSI) responses, but CDRS-R never fell below 40 and the
patient subjectively denied improvement until 2 weeks after the final
infusion (Zarrinnegar et al., 2019). Nevertheless this patient improved
sufficiently to be discharged 1 month after the final infusion and
continued to do well over the ensuing months. The third report describes
an atypical dosing regimen consisting of a 5-day, continuous IV infusion
of ketamine to which the patient’s symptoms of depression and suicidal
ideation responded (per clinician and self-reports) on the first day, with
continued improvement over the subsequent 4 days of treatment (Weber
et al., 2018). Five months after discharge from the first 5-day infusion,
the patient returned with suicidal ideation and once again received
successful treatment with a 5-day IV ketamine infusion. In all three cases
no adverse events were reported and ketamine was well-tolerated, with
mild nausea treated as-needed with low-dose antiemetics.
Severe adverse events occurred in five participants: anxiety, blood
pressure increases and hip fracture each occurred in one participant in
the esketamine group, with the latter deemed unlikely to be caused by
esketamine; gait disturbances and dizziness were each reported in one
participant in the placebo group. Discontinuation due to treatment
emergent adverse events occurred in 5.6% of the esketamine group
versus 3.1% of the placebo group. Esketamine was well-tolerated with
mild, transient CADSS elevations and no adverse cognitive or hemody­
namic effects. Interestingly, the lead investigators anticipated that the
starting dose (28 mg) would not be efficacious, and therefore did not
assess the time to response in this study, which could factor into the
improved response and remission rates observed in the open-label
continuation phase.
The third prospective study in older adults is a 28-day open-label
proof-of-concept trial of daily oral ketamine to treat depression and
anxiety in hospice patients (Irwin et al., 2013). Notably, the age range of
participants (36–88 years) was not strictly limited to older adults as per
our initial inclusion criteria, however extant literature regarding keta­
mine in older adults is scant therefore this study was included in the
systematic review. 16 participants consented and 14 received ketamine,
with 6 dropouts (4 due to non-response to ketamine, 2 due to reasons
unrelated to ketamine). In a per-protocol analysis the 8 participants who
completed the study all experienced gradual improvement of depressive
symptoms and sustained a response (HADS improvement ≥30%) to
ketamine on the HADS by study end (day 28), with a mean (SD) time to
response of 14.4 (19.1). The response rate of all participants who
received ketamine was 57% after day 28. Secondary outcome measures
found no effect of ketamine on pain, functional status, cognition, sui­
cidality, or quality of life. No severe adverse events were reported in this
trial and no discontinuations due to tolerability issues were reported.
3.4. Prospective studies in older adults
Three prospective studies were identified which assessed the safety,
tolerability, or efficacy of ketamine formulations in older adults with
depression, including two RCTs (George et al., 2017; Ochs-Ross et al.,
2020) and one open-label study (Irwin et al., 2013), all featuring
different routes of administration and dosing regimens.
George et al. (2017) performed a pilot RCT assessing escalating,
subcutaneous doses of ketamine in older adults with treatment resistant
MDD or bipolar disorder (BPD) and a MADRS score ≥20. Multiple
medical comorbidities were present in the study population, including
Parkinson’s, multiple sclerosis, and polymyalgia rheumatica, although
individuals with psychotic illnesses were excluded. MADRS scores at 4 h,
and 1, 3 and 7 days were analyzed as the primary outcome. Cumula­
tively, 11/16 participants attained response (MADRS improvement
≥50%) and remission (MADRS <10) after receiving a ketamine dose,
compared to 4/14 brief responders and 2/14 brief remitters following
midazolam control. Secondary analyses revealed a main effect of dose
and significant quadratic trend across time points representing a return
to baseline symptoms at day 7 post-treatment. No severe or clinically
significant adverse events were reported in this trial and dose titrations
up to 0.5 mg/kg were all well-tolerated. A dose-response relationship
between ketamine and CADSS score was observed, and symptoms
resolved without intervention within an hour post-infusion.
Ochs-Ross et al. (2020) conducted an RCT to assess the effects of
escalating doses of intranasal esketamine twice weekly for four weeks
adjunctive to a newly-initiated oral AD, compared to a placebo
adjunctive to a newly-initiated oral AD, in participants with treatment
resistant MDD (MADRS >24). After day 28, the change in MADRS scores
from baseline (primary endpoint) was not significantly different be­
tween esketamine and placebo groups, although the esketamine group
showed a numerically greater antidepressant response. Response
(MADRS improvement ≥50%) and remission (MADRS ≤12) rates were
27% and 17.5% in the esketamine group, and 13.3% and 6.7% in the
placebo group, respectively. In this study, 111/138 (80.4%) participants
(88 RCT non-responders and 23 responders) continued on to a long term
open-label phase, and by the end of the ensuing 4-week induction phase,
response and remission rates (69.5% and 46.3%, respectively) were
comparable to those observed in adults aged 18–65 (NCT02418585).
3.5. Retrospective studies in older adults
Five retrospective case studies have reported on ketamine use to treat
depression in older adults, with 1–53 cases per article (Gálvez et al.,
2014; Lipsitz et al., 2021; Medeiros da Frota Ribeiro and Riva-Posse,
2017; Srivastava et al., 2015; Szymkowicz et al., 2014).
Lipsitz et al. (2021) present the largest case series of ketamine for
older adults with TRD. In this study, data was analyzed from 53 older
adults ranging from 60 to 82 years of age, who received up to four IV
ketamine infusions over one to two weeks for a total of 235 adminis­
trations among the sample. Across the sample, depressive symptoms
significantly improved from baseline to each post-infusion data point,
with a main effect of infusion on Quick Inventory of Depressive
Symptoms-Self-Report-16 (QIDS-SR16) scores (Cohen’s f = 0.60). Of the
available data, 3 participants (10%) met remission criteria (QIDS-SR16
score ≤ 5), and 7 (27%) responded (≥50% symptomatic improvement
from baseline). At the third infusion, 27/47 (58.7%) participants
received a dose increase from 0.5 mg/kg to 0.75 mg/kg with no reports
of safety/tolerability issues. Drowsiness was the most common adverse
event, occurring at 50% (n = 73) of infusions. Treatment-emergent
hypertension was reported in 36 participants (69%) at ≥1 infusion,
and 10 (19%) required intervention with an antihypertensive. Average
CADSS scores were elevated at each infusion but were significantly
attenuated from the first infusion to each subsequent infusions. In total,
three (5.6%) participants dropped out of the four-infusion protocol: one
after the first infusion due to worsening anxiety; two after the second
infusion due to worsening anxiety and intolerable dissociative symp­
toms. Severe adverse events relating to the dissociative properties of
ketamine were reported during several infusions, most of which became
moderate or mild post-infusion.
Szymkowicz et al. (2014) recruited four inpatients who were
admitted to a psychiatric unit for treatment- and ECT-resistant MDD
238
J.D. Di Vincenzo et al.
Journal of Psychiatric Research 137 (2021) 232–241
with multiple comorbidities, to receive repeated IV ketamine infusions
dosed by ideal body weight. No patient responded: Patient A terminated
treatments after 2 ketamine sessions due to intolerable dissociative
adverse events and lack of response; Patients B, C, and D received five,
six and six ketamine infusions, respectively, with transient and
well-tolerated dissociative adverse events, although their depressive
symptoms did not improve over the course of infusions.
Medeiros da Frota Ribeiro and Riva-Posse (2017) describe two older
adults with TRD who both received multiple IV infusions of ketamine
over several weeks. Case 1 received 11 infusions over 8 weeks and
gradually sustained a response on the QIDS-SR after the final infusion.
Case 2 received 6 ketamine infusions over the first three weeks and had
achieved a response on the QIDS-SR which was sustained for a total of 11
weeks with semi-weekly maintenance treatments, at which point the
patient was lost to follow up. Case 2 returned to the clinic 5 weeks later
with a QIDS-SR score of 18, achieving remission again 11 weeks after
reinstatement of semi-weekly ketamine treatments. No severe adverse
events were reported and all infusions were well-tolerated with transient
psychotomimetic symptoms spontaneously resolving after the infusion.
Gálvez et al. (2014) describe a 62-year-old woman with moderately
severe TRD (MADRS ≤34) and multiple comorbidities which were
managed with several medications. In a double-blind, multiple cross­
over, placebo controlled study, this patient received single subcutaneous
bolus doses of ketamine or midazolam placebo ≥1 week apart. The
patient sustained a rapid response to the 0.1 mg/kg ketamine dose for 2
weeks and attained remission (MADRS = 0) after the 0.2 mg/kg dose for
5 months, but not after midazolam. After relapsing, the patient received
12 additional open-label subcutaneous ketamine injections over 54 days
and gradually sustained a response after the final injection. All injections
of ketamine were well-tolerated with mild, transient light-headedness
and blurred vision.
Lastly, Srivastava et al. (2015) present a patient with mild TRD
(HAMD < 20) who received four IV infusions of ketamine over two
weeks. Rapid HAMD reductions were reported after each infusion and
remission (HAMD <7) was briefly achieved at multiple time points, with
a HAMD score of 10 after the final infusion. After discontinuing keta­
mine, the patient maintained remission throughout the ensuing year of
follow-ups on the same oral AD being taken throughout the study. In­
fusions were well-tolerated with mild psychotomimetic effects which
resolved within an hour of each infusion.
adverse events to ketamine reported in adolescents are similar to those
reported in adult counterparts: transient and tolerable dissociation
occurred which resolved spontaneously within an hour post-infusion;
nausea was controlled with ondansetron or chlorpromazine.
Safety is often the highest priority in clinical studies, therefore doses
of drugs given to adolescents and older adults are typically conserva­
tively estimated based on data drawn from general adult populations.
Importantly, it is known that higher doses of ketamine are required to
elicit a dissociative state in pediatrics than in adults (Green et al., 2011).
Indeed, Cullen et al. (2018) found that dosing ketamine at 0.5 mg/kg by
ideal body weight did not lead to a response in any adolescent. However,
participant response improved after adjusting the dose to be based on
actual body weight, and a post-hoc analysis revealed that BMI predicted
response, likely because participants with higher BMIs received higher
doses (Cullen et al., 2018). Weber et al. (2018) presented a continuous
infusion regimen of 7mcg/kg/min that produced a daily dose greater
than 725 mg in the 72 kg patient, which was effective at treating
depression and was tolerated well without serious adverse events.
Among retrospective and prospective studies in older adults, there is
contradicting evidence regarding the safety, tolerability, and efficacy of
ketamine formulations as antidepressants. The largest study, consti­
tuting over 60.5% (138/228) of older adults analyzed in this review, did
not find intranasal esketamine to be more efficacious than placebo after
28 days (Ochs-Ross et al., 2020), whereas a nearly-identical study con­
ducted in adults aged 18–65 did (Popova et al., 2019). Similar to the
cautious ketamine dosing strategy used in adolescents by Cullen et al.
(2018), Ochs-Ross et al. (2020) started esketamine administration at 28
mg in their study in older adults - half of the starting dose used by
Popova et al. (2019). Indeed, response and remission rates approached
those seen in adults when participants from the Ochs-Ross et al. (2020)
study continued receiving intranasal esketamine at higher doses in an
open-label follow-up study. This finding supports the hypothesis that
efficacious doses of esketamine were delayed in this trial, or possibly
that the AD adjunctively administered in this trial began working after
this time.
All other studies in older adults with depression used racemic keta­
mine. In agreement with previous studies, George et al. (2017) found
that subcutaneous ketamine injections produced a rapid antidepressant
effect. However, symptoms returned to baseline by day 7, suggesting
that multiple administrations within one week may be required to
produce a lasting response. Contrarily, in Irwin et al.’s (2013) study,
older adults given oral ketamine nightly for 28 nights reported a slow
but gradual decline in depressive symptoms, which reached statistical
significance after day 14 and at the final data point. However, it is
important to emphasize that Irwin et al. (2013) included participants
who were younger than 60 years and who may not have been diagnosed
with depression as per the DSM-V, therefore the results of this study are
less generalizable to older adults than George et al. (2017) and Ochs-­
Ross et al. (2020).
The findings of case reports on ketamine in older individuals have
conflicting results. The largest case series by Lipsitz et al. (2021), re­
ported that ketamine treatment safely elicited rapid and significant
antidepressant responses with a low attrition rate (~5%), congruent
with data from the general adult population as shown in a similar
analysis by the same group (Rodrigues et al., 2020). Conversely,
Szymkowicz et al. (2014) concluded that repeated intravenous ketamine
treatments offered an unfavorable risk-benefit profile in four older
adults with MDD, however, the participants were all extensively resis­
tant to ADs and ECT. Importantly, two of the four cases showed clinical
and/or neuroimaging signs suggesting neurophysiological impairments
that could potentially prevent a response to ketamine by inhibiting
synaptic plasticity, a key mechanism through which ketamine is hy­
pothesized to work (Kraus et al., 2017). By contrast, Gálvez et al. (2014),
Medeiros da Frota Ribeiro and Riva-Posse (2017) and Srivastava et al.
(2015) observed older individuals without signs of neurophysiological
impairments in whom single and repeated ketamine infusions produced
4. Discussion
The limited amount of available evidence supports the safety,
tolerability, and effectiveness of ketamine at treating depressive symp­
toms in adolescents, and older adults to a lesser extent, with better an­
tidepressant outcomes for individuals who received longer treatment
courses and higher doses. This systematic review presented 33 adoles­
cents, all of whom received racemic ketamine, and 228 older individuals
who received ketamine in various formulations and routes of adminis­
tration (esketamine, n = 138; ketamine, n = 90). Each of the three RCTs
were assessed as high quality with low risks of bias; the two open label
studies were deemed low quality with high risks of bias due to lack of
comparator or blinding; case reports were considered low quality due to
low generalizability.
Across prospective and retrospective studies, it is consistently
observed that ketamine elicits a rapid and robust antidepressant
response in adolescents with TRD. Similar to what has been reported in
adults (Murrough et al., 2013), ketamine outperformed midazolam
controls, with improvements reported within hours post-ketamine
infusion. Adolescents who received repeated administrations typically
sustained a response to ketamine for multiple weeks with maintenance
therapy (Cullen et al., 2018; Dwyer et al., 2017; Zarrinnegar et al.,
2019). No severe adverse events occurred, no signs of drug-liking,
addiction or dependence to ketamine were observed, and no partici­
pants withdrew due to ketamine-emergent adverse events. In general,
239
J.D. Di Vincenzo et al.
Journal of Psychiatric Research 137 (2021) 232–241
a response, within days, lasting several weeks to months.
For older adults, severe adverse events were reported in the two
studies with the largest samples. In the largest study, an RCT, two severe
adverse events (anxiety and blood pressure increase) were determined
to be related to esketamine exposure (Ochs-Ross et al., 2020). Further­
more, four treatment emergent adverse events led to discontinuation in
the esketamine group, compared to two in the placebo group. In the
second largest study, the case series by Lipsitz et al. (2021), severe
adverse events in the form of severe CADSS elevations were common
(~10%) during infusions, and typically waned to moderate or mild
levels shortly following the infusion. In general, adverse events appear
to be more common and less tolerated in older adults than in individuals
aged <60 years. Neurologic symptoms were more frequently reported in
older adults, however it is unknown whether these reports are attrib­
utable to ketamine or rather to age-associated cognitive decline. Other
adverse events reported in older adults but not in adolescents include:
mild liver enzyme elevations, mild urologic symptoms, diarrhea, trouble
sitting still, and trouble sleeping.
There are several limitations to this review. Most studies included
herein have small sample sizes and are single-centred; only Ochs-Ross
et al. (2020) conducted a multi-centre trial. Additionally, longitudinal
studies in adolescents and older adults receiving ketamine formulations
to treat depression are scant, so this review cannot speak to long-term
safety or efficacy. Further, due to the dearth of literature in these pop­
ulations, publication bias is an issue which precludes broad general­
izations of these findings to other adolescent or older adult populations.
Different studies also use different rating scales and definitions for
response or remission, which limits generalizability since adolescents
are often evaluated on the CDRS as opposed to the MADRS or BDI
typically used in adults aged >18. Moreover, many participants
included in this review received concomitant behavioural and/or
pharmacotherapies, which may have interacted with ketamine and
affected the results. Future research should look to address gaps in the
literature that remain with respect to longitudinal studies studying ke­
tamine formulations alone, and along with various concomitant treat­
ment modalities (pharmacotherapies and behavioural interventions) for
depression in adolescents and older adults. In addition to determining
whether ketamine is effective, safe and well-tolerated in adolescents and
elderly patients, it is also important to determine whether ketamine may
benefit specific dimensions or symptoms of depression (e.g. cogniti­
ve/functional impairment) as well as suicidality, as empirical evidence
may suggest (Lee et al., 2016; McIntyre et al., 2013).
In summary, this systematic review describes current evidence from
the extant literature regarding the safety, tolerability, and effectiveness
of ketamine formulations for the treatment of depression in adolescents
and older adults. The paucity, heterogeneity, and variable quality of
studies available for this review significantly limits our ability to
conduct statistical syntheses and draw strong conclusions. Nevertheless,
the results of the studies discussed herein generally support the pre­
vailing narrative that ketamine formulations are rapid-acting antide­
pressants capable of producing a response in treatment-resistant
individuals across all ages, although tolerability issues are more com­
mon in older adults. The literature would benefit from more high quality
RCTs and a greater quantity of data on the use of ketamine as an anti­
depressant in adolescents and older adults. Future research should focus
on optimizing ketamine dosages to improve tolerability in older adults,
as well as the efficacy in adolescents and older adults.
Leanna M.W. Lui: Writing – Review & Editing. Kangguang Lin:
Writing – Review & Editing. Bing Cao: Writing – Review & Editing.
Nelson B. Rodrigues: Writing – Review & Editing. Hartej Gill: Writing
– Review & Editing. Roger S. McIntyre: Writing – Review & Editing,
Supervision. Joshua D. Rosenblat: Conceptualization, Writing – Re­
view & Editing, Supervision, Project administration.
Joshua D. Di Vincenzo was primarily involved in the writing, anal­
ysis and synthesis of this review, under the supervision of Joshua D.
Rosenblat. All other authors contributed significantly to the content and
revision of this work. All authors approved the final version of the
manuscript for submission.
Declaration of competing interest
RSM has received research grant support from CIHR/GACD/Chinese
National Natural Research Foundation; speaker/consultation fees from
Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neuro­
crine, Sunovion, Bausch Health, Novo Nordisk, Kris Eisai, Minerva,
Intra-Cellular, and Abbvie. Dr. Roger McIntyre is a CEO of Champignon.
JDR has received research grant support from the Canadian Cancer
Society, Canadian Psychiatric Association, American Psychiatric Asso­
ciation, American Society of Psychopharmacology, University of Tor­
onto, University Health Network Centre for Mental Health, Joseph M.
West Family Memorial Fund and Timeposters Fellowship and industry
funding for speaker/consultation/research fees from Janssen, Allergan,
Lundbeck, Sunovion and COMPASS. JDR is the medical director of a
private clinic providing intravenous ketamine infusions and intranasal
esketamine for depression.
RCH has received research grant support from the National Medical
Research Council of Singapore, National Parks Board of Singapore and
National University of Singapore; speaker/consultation fees from
Lundbeck, Janssen, Pfizer and Otsuka.
Acknowledgement
We thank all team members for their contributions to the manu­
script. Special thanks to Glyneva Bradley-Ridout, Jiaqi Xiong, Yuetong
Song, and Linas Wilkialis for help in conducting the literature search and
data extraction.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.jpsychires.2021.02.058.
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Joshua D. Di Vincenzo: Conceptualization, Methodology, Software,
Validation, Formal analysis, Investigation, Resources, Data Curation,
Writing – Original Draft, Visualization, Project administration. Ashley
Siegel: Writing – Review & Editing. Orly Lipsitz: Writing – Review &
Editing. Roger Ho: Writing – Review & Editing. Kayla M. Teopiz:
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