brain

sciences
Systematic Review
The Role of Ketamine in the Treatment of Bipolar Depression:
A Scoping Review
Muhammad Youshay Jawad 1,2 , Saleha Qasim 1 , Menglu Ni 3,4 , Ziji Guo 3,5 , Joshua D. Di Vincenzo 1 ,
Giacomo d’Andrea 6 , Aniqa Tabassum 1 , Andrea Mckenzie 1 , Sebastian Badulescu 1 , Iria Grande 7,8,9,10,11
and Roger S. McIntyre 1,3,5,12, *

1 Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON M5T 2S8, Canada;
youshayjwd@gmail.com (M.Y.J.); salehaqasim96@gmail.com (S.Q.);
joshua.divincenzo@uhnresearch.ca (J.D.D.V.); aniqa.tabassum@uhn.ca (A.T.);
andrea.mckenzie@uhn.ca (A.M.); sebastian.badulescu@mail.utoronto.ca (S.B.)
2 Institute for Mental Health Policy Research, Centre for Addictions and Mental Health,
Toronto, ON M6J 1H4, Canada
3 Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada;
menglu.ni@mail.utoronto.ca (M.N.); ziji.guo@mail.utoronto.ca (Z.G.)
4 Department of Psychology, University of Toronto, Toronto, ON M5S 3G3, Canada
5 Brain and Cognition Discovery Foundation, Toronto, ON M5S 1M2, Canada
6 Department of Neuroscience, Imaging and Clinical Sciences, University “G. d’Annunzio”, 66100 Chieti, Italy;
giacomo.dandrea1993@gmail.com
7 Bipolar and Depressive Disorders Unit, Hospital Clinic de Barcelona, C. Villarroel, 170,
08036 Barcelona, Spain; igrande@clinic.cat
8 Departament de Medicina, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB),
C. Casanova, 143, 08036 Barcelona, Spain
9 Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), C. Villarroel, 170, 08036 Barcelona, Spain
10 Institute of Neurosciences (UBNeuro), P. de la Vall d’Hebron, 171, 08035 Barcelona, Spain
11 Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III,
28029 Madrid, Spain
12 Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada
Citation: Jawad, M.Y.; Qasim, S.; Ni, * Correspondence: roger.mcintyre@bcdf.org
M.; Guo, Z.; Di Vincenzo, J.D.;
d’Andrea, G.; Tabassum, A.; Abstract: Bipolar depression remains a clinical challenge with a quarter of patients failing to respond
Mckenzie, A.; Badulescu, S.; Grande, to initial conventional treatments. Although ketamine has been extensively studied in unipolar
I.; et al. The Role of Ketamine in the depression, its role in bipolar disorder remains inconclusive. The aim of our scoping review was to
Treatment of Bipolar Depression: A comprehensively synthesize the current clinical literature around ketamine use in bipolar depression.
Scoping Review. Brain Sci. 2023, 13,
A total of 10 clinical studies (5 randomized controlled trials and 5 open label studies) were selected.
909. https://doi.org/10.3390/
The preliminary evidence, albeit weak, suggests that ketamine is a promising treatment and calls for
brainsci13060909
further interest from the research community. Overall, ketamine treatment appeared to be tolerable
Academic Editor: with minimal risk for manic/hypomanic switching and showed some effectiveness across parameters
Rebecca Strawbridge of depression and suicidality. Moreover, ketamine is a potential treatment agent in patients with
Received: 6 May 2023
treatment-resistant bipolar depression with promising data extracted from extant controlled trials
Revised: 26 May 2023 and real-world effectiveness studies. Future studies are needed to identify ketamine’s role in acute
Accepted: 30 May 2023 and maintenance treatment phases of bipolar depression. Moreover, future researchers should study
Published: 4 June 2023 the recurrence prevention and anti-suicidal effects of ketamine in the treatment of bipolar depression.

Keywords: ketamine; bipolar depression; mood disorders; psychedelics; bipolar disorder

Copyright: © 2023 by the authors.

Licensee MDPI, Basel, Switzerland.
This article is an open access article
1. Introduction
distributed under the terms and
conditions of the Creative Commons
Bipolar disorder (BD) is a serious and debilitating psychiatric disorder affecting mul-
Attribution (CC BY) license (https:// tiple domains of mood, emotions, and cognition [1]. Overall, BD has a global prevalence
creativecommons.org/licenses/by/ of >1% and constitutes a major healthcare burden [2,3]. Patients with BD often have two
4.0/). distinct mood episodes, i.e., mania/hypomania and depression [4]. Using the criteria for

Brain Sci. 2023, 13, 909. https://doi.org/10.3390/brainsci13060909 https://www.mdpi.com/journal/brainsci

Brain Sci. 2023, 13, 909 2 of 21

mood episodes and their duration, severity, and occurrence, BD is broadly classified into
BD-I, BD-II, and cyclothymia in the Diagnostic and Statistical Manual of Mental Disorders
(DSM) 5th edition [1].
BD-I is diagnosed following a manic episode, in which the individual may feel a
significant increase in energy or irritability in mood for a week or longer; BD-II involves
depressive and euthymic phases, along with hypomanic phases, which are characterized by
less severe manic symptoms that need only last four days in a row rather than a week; and
cyclothymic disorder, which is a milder form of bipolar disorder involving many “mood
swings” with hypomania and depressive symptoms that occur rather frequently [4,5]. In
addition to DSM criteria, individuals with BD often present on a spectrum of multiple
clinical symptoms (e.g., mood, cognition, emotions, etc.) and patient-reported outcomes
(e.g., sleep, fatigue, occupational deficits, etc.) [4,6]. Moreover, suicidality remains one of
the most serious consequences of BD. It is estimated that suicide rates for patients with
BD are approximately 20 times higher than the general population, with a quarter of them
resulting in serious harm [7–9].
Though mania/hypomania are the defining features of BD, patients typically spend
relatively more time experiencing depressive symptoms [4,10]. Despite the significant
burden of bipolar depression, there are only a handful of Food and Drug Administration
(FDA)-approved treatments for this specific condition (i.e., olanzapine and fluoxetine com-
bination, quetiapine, lurasidone, cariprazine, and lumateperone) [11]. The mechanisms of
these pharmacotherapies are diverse and multifaceted, as many act on multiple receptors at
a time and in unique ways, which reflects our incomplete understanding of the pathophysi-
ology of BD. For example, quetiapine is mainly an inhibitor of 5-HT2a and D2 receptors, but
also acts on D1 and H1 histamine receptors, among others, contributing to its adverse effects
(e.g., drowsiness, weight gain) [12]; olanzapine is an inverse agonist of 5HT2a receptors,
antagonist of D1 , D2 , D3 , and D4 dopamine receptors, H1 receptors, and also binds to
alpha-1 adrenergic and some postsynaptic muscarinic receptors [13], with similar adverse
effects to quetiapine; and lumateperone is a newer agent which acts as a 5-HT2a antagonist,
D2 presynaptic partial agonist and postsynaptic antagonist, serotonin reuptake inhibitor,
and glutamate modulator with fewer off-target effects and a more favorable side-effect
profile compared to previous antipsychotics [14,15]. Moreover, lithium, which is the oldest
pharmacotherapy for managing BD, has a poorly understood mechanism of action, yet
is still a first-line treatment when it comes to suicidality and rapid mood cycling [16]. It
has been estimated that 25% of patients are resistant to current treatments for bipolar
depression, posing huge economic, clinical, and personal burdens [17]. In view of this,
there is an urgent need to develop treatment modalities that can help in not only remitting
depressive symptoms among those who fail to respond to initial treatments but can also
help in tackling any residual symptoms, often pertaining to cognition [18].
The pathophysiological mechanisms underlying bipolar disorder involve abnormal-
ities in various specific brain regions. For example, GABAergic inhibitory circuits in the
cortex are known to be dysfunctional in patients with BD, and these deficits can be reversed
with mood stabilizers such as lithium, valproate, and atypical antipsychotics such as olanza-
pine [19]. Indeed, it could be posited that GABAergic receptor-mediated inhibitory deficits
in BD could increase the proclivity for disinhibited behaviors (i.e., risk taking, hedonism,
and sleeplessness). Such a relationship has been previously reported in healthy subjects
with greater anxiety traits [20] and in patients with schizophrenia experiencing greater
psychotic symptoms [21]. The hippocampus is another key brain region implicated in BD
pathophysiology, and is a nexus for learning, memory, and cognition. Preclinical studies
using mouse models for psychiatric disorders have found that hippocampal dentate gyrus
cells were arrested at a “hyperexcitable” stage with similar molecular and physiological
properties to those of the immature neurons, conferring working memory deficits and
hyper-locomotor activity, which has been posited as an endophenotype of BD [22–25].
Thus, with both above examples converging on increased glutamatergic activity by aber-
rant inhibitory mechanisms, modulating intermediaries of glutamatergic signaling, such as
Brain Sci. 2023, 13, 909 3 of 21

N-methyl-D-aspartic acid (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic

acid (AMPA) receptors could be promising targets for treating BD.
In the last decade, research on N-methyl-D-aspartic acid (NMDA) antagonists (i.e., ke-
tamine and esketamine) has shown promising results in managing treatment-resistant
unipolar depression [26,27]. Though ketamine infusion is not FDA-approved for depres-
sion treatment, its S-enantiomer (i.e., esketamine) has been FDA-approved for managing
treatment-resistant depression [26]. Key benefits of ketamine and esketamine include the
rapid-acting antidepressant effects (i.e., within hours of an intravenous infusion) [28], and
the absence of metabolic side effects compared to other pharmacotherapies for bipolar
depression such as olanzapine/fluoxetine combination therapy, which causes weight gain
and can take 4–8 weeks before it is effective [1]. Moreover, IV ketamine produces rapid
acting (within 2-, 4-, and 24-h post-dose) anti-suicidal effects that can last for up to a week,
which offers the potential of a promising intervention for treating severe acute suicidal
ideation [29], especially important for BD given the aforementioned high burden of suicidal-
ity. However, evidence supporting the use of ketamine/esketamine in bipolar depression
remains inconclusive [11]. There is some preclinical evidence that glutaminergic agents
can act not only as antidepressants, but also as mood stabilizing agents in patients with
BD [30]. However, clinical studies that could confirm and expand this preclinical notion
remain to be conducted.
As such, our scoping review is focused on synthesizing the available literature on
the use of ketamine/esketamine in bipolar depression, with a focus on its safety and
efficacy/effectiveness across multiple domains (i.e., depressive symptoms, suicidality,
cognition, and anxiety). Furthermore, we set forth to highlight research and clinical gaps
that could help future researchers to study ketamine treatment in BD better.

2. Methods
This review was conducted in accordance with the guidelines of Preferred Report-
ing Items for Systematic reviews and Meta-Analyses (PRISMA) for scoping reviews [31].
The protocol was registered as a priority on the open science framework (OSF; DOI
10.17605/OSF.IO/CS6TJ).

2.1. Eligibility Criteria

The present study aimed to synthesize the clinical literature on the use of ketamine
or esketamine in the treatment of bipolar depression. As such, we included all studies that
delineated the efficacy/effectiveness or safety of ketamine use in patients with BD. Since
bipolar and unipolar depression differ in their patient characteristics, clinical presentation,
treatment strategies, and prognosis, we excluded studies that did not distinguish between
these two phenotypes [1,32,33]. Hence, the studies that are composed only of patients with
BD were included herein (both BD-I and BD-II). Moreover, studies were required to report
at least one outcome directly related to clinical practice (i.e., change in depression, anxiety,
or suicidality measurements or adverse/tolerability effects). The efficacy/effectiveness
measures needed to be measured on standardized clinical scales (e.g., Montgomery–Åsberg
Depression Rating Scale (MADRS), Scale for Suicide Ideation (SSI), etc.) [17,32]. Efficacy
was defined as the group level change in the measured domain (e.g., depression, suicidality,
anxiety, etc.) under ideal and controlled conditions. On the other hand, effectiveness was
defined as change in measured psychological domains from group baseline in a real-world
or open label scenarios.
Additionally, included studies were required to be original research reporting quan-
titative results; qualitative, abstracts, case reports/series, and secondary sources were
excluded.
In accordance with the PRISMA statement [31], the foregoing criteria were formalized
in the following PIECOS outline:
Population: Adults aged 18 years and older.
Brain Sci. 2023, 13, 909 4 of 21

Intervention: Intravenous (IV) racemic ketamine, intranasal (IN) esketamine, or IV

arketamine.
Exposures: Clinical diagnosis of BD according to DSM-IV or 5 editions.
Comparison group(s): placebo or none.
Outcome(s): Studies must assess at least one clinically relevant factor (i.e., efficacy,
effectiveness, tolerability, or adverse effects) across one or more domains of bipolar depres-
sion (i.e., depressive symptoms, cognition, anxiety, and suicidality).
Studies: Quantitative and original studies of direct clinical relevance such as: random-
ized controlled trials (RCTs), open-label studies, retrospective chart reviews, or observa-
tional clinical studies.

2.2. Search Strategy and Study Inclusion

A comprehensive search of online databases (i.e., MEDLINE(R), Embase Classic +
Embase, APA PsycINFO, Ovid Healthstar, Journal@Ovid Full Text, Cochrane, Google
Scholar, and CINAHL) was completed from inception to 28 April 2023, using the follow-
ing search string: ((bipolar disorder) OR (bipolar depression)) AND (((arketamine) OR
(esketamine)) OR (ketamine)). Database search results were imported into the Covidence
platform (https://www.covidence.org/) for deduplication, screening, and risk of bias
assessment. Two reviewers (M.Y.J., S.Q.) independently screened the imported titles and
abstracts, then assessed the remaining full texts for eligibility. Conflicts in judgment were
resolved by discussion with a third reviewer (R.S.M.).

2.3. Data Extraction and Analysis

The following data points were extracted in a pilot-test Excel table wherever possible:
lead author, study design, study participants, intervention (and control, if any), primary
objectives, main findings, and limitations. Efficacy/effectiveness was defined as differ-
ence in measured domain (e.g., depression, suicidality, etc.) from baseline measured on
standardized clinical scales (such as Hamilton Depression Rating Scale, Scale for Suicide
Ideation, etc.). Safety, tolerability data and switching to mania/hypomania, and discontin-
uation rates were operationalized as adverse effects with an associative statistic (e.g., odds
ratio, prevalence, etc.). The extracted data points were synthesized qualitatively across the
lines of efficacy/effectiveness in ameliorating depressive or suicidality symptoms, overall
tolerability, and risk for mania/hypomania.

2.4. Risk of Bias Assessment

Assessments of methodological quality were independently conducted by two review-
ers (M.Y.J. and S.Q.) using Cochrane’s risk of bias tools [34]. Since we included both blinded
RCTs and unblinded follow-up/observational studies or open label trials, the standard
Risk of Bias (RoB) tool for randomized-controlled trials and the tool for Risk of Bias in
Non-randomized Studies of Interventions (ROBINS-I) were applied, respectively [35,36].

3. Results
3.1. Search Results
A total of 1994 studies were identified in our initial search. After the removal of
duplicates, 1191 studies were left to screen against title and abstract. Following title and
abstract screening, 30 studies were eligible for full text analysis and 10 studies were included
in the present review. Details relevant to study selection are outlined in Figure 1.
Brain Sci. 2023, 13, 909
Brain Sci. 2023, 13, x FOR PEER REVIEW  55 ofof 
2121 
 

 
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension 
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension
for scoping review flowchart for included studies.
for scoping review flowchart for included studies.  

3.2. Study Characteristics and Quality Appraisal

3.2. Study Characteristics and Quality Appraisal 
As a whole, our review identified 5 RCTs and 5 open label trials investigating the role
As a whole, our review identified 5 RCTs and 5 open label trials investigating the role 
ofof IV ketamine in BD. We did not find any study using IN esketamine or IV arketamine in 
IV ketamine in BD. We did not find any study using IN esketamine or IV arketamine
inmanaging 
managingdepressive 
depressive symptoms 
symptoms across 
across bipolar
bipolar depression.
depression. TheThe most
most commonly
commonly used
used 
dosage
dosage  was 0.5
was  mg/kg.
0.5  Almost all
mg/kg. Almost  all participants
participants inin open
open label studies
label  concurrently
studies  used
concurrently  used 
various mood stabilizing agents (e.g., lamotrigine, valproate, lithium, etc.) or antipsychotics
various mood stabilizing agents (e.g., lamotrigine, valproate, lithium, etc.) or antipsychot-
(e.g., olanzapine, quetiapine, etc.). Two out of five RCTs (Grunebaum et al. and Abbar
ics (e.g., olanzapine, quetiapine, etc.). Two out of five RCTs (Grunebaum et al. and Abbar 
etet al.) allowed participants to continue with their usual medications while the remaining 
al.) allowed participants to continue with their usual medications while the remaining
three RCTs allowed the participants only to take lithium and valproate. A few detailed
three RCTs allowed the participants only to take lithium and valproate. A few detailed 
characteristics of studies are delineated in Table 1, including lead author, study type,
characteristics of studies are delineated in Table 1, including lead author, study type, total 
total participants, dosage and mode of intervention, dosage and mode of control (for
participants, dosage and mode of intervention, dosage and mode of control (for RCTs), 
RCTs), concurrent medications, psychometric tools being used, primary objectives, findings,
concurrent medications, psychometric tools being used, primary objectives, findings, re-
reports of mania/hypomania, and limitations.  
ports of mania/hypomania, and limitations. 
Brain Sci. 2023, 13, 909 6 of 21

Table 1. Characteristics of included studies.

Any Report
Sr. Lead Total Intervention Concomitant Primary Psychometric of Hypo-
Study Type Control Findings Limitations
No. Author Participants (Dosage) Medications Objective Tool Used manic/Manic
Switching
Significant differences
in HAMD scores after
Therapeutic
1 week.
effects and
(mean Use of self-
38 patients Patients associated
reduction = 49.8%, comparison
with continued brain
p < 0.05). However, (no control).
treatment- their original alterations 17-item
relapse of symptoms Short duration
Open label resistant 0.5 mg/kg; medication following Hamilton
Zhuo et al., in 2nd week. By the None (3-weeks).
1. study bipolar Total 10 None regimen multi- Depression
2020 21st day, more severe reported
(3-week) disorder infusions including infusion Scale
depressive symptoms Excluded
(TRBD); mood ketamine (HAMD-17)
were reported patients with
22 males and stabilizers and augmenta-
compared to the suicidal
16 females. antipsychotics. tion in
baseline. (Baseline ideation.
patients with
HAMD score:
TRBD.
36.5 ± 2.8 and at 21st
day: 39.0 ± 2.4).
Brain Sci. 2023, 13, 909 7 of 21

Table 1. Cont.

Any Report
Sr. Lead Total Intervention Concomitant Primary Psychometric of Hypo-
Study Type Control Findings Limitations
No. Author Participants (Dosage) Medications Objective Tool Used manic/Manic
Switching
The HDRS scores
To measure were reduced by an
the change in average of 11 points
Small sample
neurocogni- on the 3rd day and by
size.
tive 12 points on the 7th
No control
performance day post-infusion
group.
before and (24 ± 5, 13 ± 6, and
Possible
on the 3rd 17-item 12 ± 7, respectively).
practice effect
day after a Hamilton
on cognitive
18 patients Mood single dose Depression Eight patients had at
test
with baseline stabilizers of ketamine Rating Scale least 50% reduction of
performance
Hamilton throughout the infusion in (HDRS) HDRS scores on the
Non- (with no
Permoda- Depression A single dose duration of the patients with Neurocognitive 7th day compared to
randomized, None control group
2. Osip et al., Rating Scale of 0.5 mg/kg None study. a diagnosis tests: Trail the baseline.
uncontrolled reported to control the
2015 (HDRS) score over 45 min Antidepressants of bipolar making test
trial bias).
more than 18 were stopped 7 disorder and (TMT) and Performance on
(4 males and days before in depressed Stroop neurocognitive tests
Discontinuation
14 females). infusion. state taking color-word improved significantly
of antidepres-
mood interference on the 3rd day after
sants 7 days
stabilizing test infusion. The degree
before the
drugs and to of improvement in the
intervention
correlate it neurocognitive test
might have
with the an- scores correlated
fluctuated the
tidepressant positively with the
cognition.
effect of the degree of baseline
intervention. impairment on the
tests.
Brain Sci. 2023, 13, 909 8 of 21

Table 1. Cont.

Any Report
Sr. Lead Total Intervention Concomitant Primary Psychometric of Hypo-
Study Type Control Findings Limitations
No. Author Participants (Dosage) Medications Objective Tool Used manic/Manic
Switching
13 patients met the
criteria for response
Mood
(50% reduction in
stabilizers
53 patients HDRS scores) at 24 h
throughout the To
(13 males and 27 patients met Open label.
duration of the investigate
and the criteria at day 7. Uneven
study. Most of the 17-item
40 females) The criteria for None gender
the patients effectiveness Hamilton
with bipolar A single dose remission was met by reported proportion.
Rybakowski Open label were receiving of a single Depression
3. disorder of 0.5 mg/kg None 8 and 14 patients at (within the Antidepressants
et al., 2017 clinical trial more than one ketamine Rating Scale
with over 40 min day 1 and 7, 7-day were tapered
mood infusion in (HDRS)
depression respectively. period) off only 7 days
stabilizer. patients with
score of at before
Antidepressants bipolar
least 18 on The response was infusion.
were stopped 7 disorder.
HDRS Scale. significantly more
days before
frequent in males
infusion.
than females.
Brain Sci. 2023, 13, 909 9 of 21

Table 1. Cont.

Any Report
Sr. Lead Total Intervention Concomitant Primary Psychometric of Hypo-
Study Type Control Findings Limitations
No. Author Participants (Dosage) Medications Objective Tool Used manic/Manic
Switching
There was an
estimated decrease of
5.84 points on SSI at
day 1 for patients on
ketamine compared to
the midazolam group
(p = 0.074). Similar Small pilot
16 patients A feasibility results were reported sample
Patients
(10 females study to for improvement in (limited
continued to Clinician-
and 6 males) evaluate the HDRS-17 scale power).
take the rated SSI for
with scores Ketamine hy- Midazolam effect of (six-point decrease Lower than
psychometric suicidal
≥ 16 on drochloride 0.02 mg/kg ketamine with p = 0.109). recommended
drugs they ideation
Grunebaum Randomized HDRS-17 0.5 mg/kg in in 100 mL versus None dose of
4. were taking Hamilton
et al., 2017 clinical trial and a score 100 mL of of saline midazolam 4 out of 7 on ketamine reported midazolam
except for the Depression
of ≥ 4 on the saline over over 40 infusion on were classified as was used
benzodi- Rating Scale
scale for 40 min min suicidal responders (50% which might
azepines up to (HDRS-17)
suicidal ideation in response) compared have
24 h before
ideation bipolar to 1 out of 9 for minimized the
infusion.
(SSI). depression. midazolam (CI not effect of
significant). Similarly, midazolam.
3/7 in the ketamine
group were remitters
compared to 1/9
randomized to
midazolam.
Brain Sci. 2023, 13, 909 10 of 21

Table 1. Cont.

Any Report
Sr. Lead Total Intervention Concomitant Primary Psychometric of Hypo-
Study Type Control Findings Limitations
No. Author Participants (Dosage) Medications Objective Tool Used manic/Manic
Switching
After 1st infusion:
Rate of response and
remission reported as
21.1% (95%
CI = 0.9–21.2) and
15.8% (95%
Self- Patients CI = 0–33.9),
control continued to respectively.
Six (Results take the A pilot study
intravenous after the prescribed investigating After 6th infusion: Small sample
infusions of first antidepressant the antide- Rate of response and size.
Montgomery–
16 patients 0.5 mg/kg infusion regimen (at pressant, remission are 73.7% No control
Single arm Asberg
Zheng (13 males ketamine were least 4 weeks anti-suicidal (95% CI = 51.9–95.5) None group.
5. open label Depression
et al., 2020 and over 40 min com- before effects and and 63.2% (95% reported
trial Rating Scale
3 females). on a thrice pared screening and safety of six CI = 39.3–87.0), Short follow
(MADRS)
weekly basis with the infusion) along consecutive respectively. up period of
were admin- results with other infusions of only 2 weeks.
istered. after the psychotropic ketamine. Large and significant
sixth in- agents as decreases in both
fusion). augmentation. MADRS scores and
SSI-part-1 were noted:
5.8, p < 0.001 and 0.8,
p = 0.018. These
findings were
maintained across the
subsequent infusions.
Brain Sci. 2023, 13, 909 11 of 21

Table 1. Cont.

Any Report
Sr. Lead Study Total Intervention Concomitant Primary Psychometric of Hypo-
Control Findings Limitations
No. Author Type Participants (Dosage) Medications Objective Tool Used manic/Manic
Switching
There was a significant
reduction of QIDS-SR16 scores
No control
from baseline to all subsequent
group.
timepoints (p < 0.001).
Small sample
In addition, a significant
size.
difference was observed in the
Four Patients were
QIDS-SR16 scores from
intravenous required to
post-infusion 1 to
infusions of bear the cost of
post-infusion 3 (p < 0.001) and Treatment
ketamine Quick the treatment
post-treatment assessment emergent
0.5–0.75 mg/kg Inventory for leading to a
visit (p < 0.05). hypomania
over a To evaluate Depression potential
66 patients in three
40-min the Symptomatology- selection or
with 35% of patients were classified patients
period. Patients real-word Self Report-16 expectancy
treatment- as responders (50% response) (4.5%)–
Open label Started with continued to effectiveness (QIDS-SR16 ) bias.
resistant and 20% patients achieved might be due
Fancy et al., Observa- 2 doses of take their of repeated
6. bipolar None remission at follow-up 1 week to co-
2023 tional 0.5 mg/kg prescribed ketamine Generalized Potential
disorder following the fourth infusion. administration
Study and psychotropic infusions for Anxiety confounding
(27 males of antide-
increased to medication. TRBD in a Disorder-7 by
and QIDS suicidality item score pressants.
0.75 mg/kg community (GAD-7) psychotropic
39 females). decreased significantly over
in the 3rd clinic setting. drugs or
time with treatment (p < 0.001). No case of
and 4th Sheehan medical
The difference was also mania
infusion in Disability Scale comorbidities
significant between reported.
case of as study was
post-infusion scores and
inadequate conducted on
post-treatment scores (p < 0.05).
response. patients under
treatment at
Anxiety scores also decreased
the community
significantly from baseline to
clinic.
post-infusion 3 and
post-treatment (p < 0.05 and
p < 0.001, respectively).
Brain Sci. 2023, 13, 909 12 of 21

Table 1. Cont.

Any Report
Sr. Lead Total Intervention Concomitant Primary Psychometric of Hypo-
Study Type Control Findings Limitations
No. Author Participants (Dosage) Medications Objective Tool Used manic/Manic
Switching
The effect sizes for
Small sample
To determine change in MADRS
size.
whether an were 0.52 (95%
N-methyl- confidence interval One
Normal saline
daspartate– (CI), 0.28–0.76) at 40 participant
could have
18 patients Patients were receptor Montgomery– min, 0.67 (95% CI, in ketamine
0.5 mg/kg masked proper
Randomized with 0.9% only allowed antagonist Åsberg 0.42– and one
Diazgranados infused in blinding.
7. controlled TRBD.(12 fe- Normal to take lithium produces Depression 0.91) at day 1, and 0.22 participant
et al., 2010 normal
trial males and saline or valproate rapid antide- Rating Scale (95% CI, −0.03 to 0.48) in control
saline. Tapering of
6 males). only. pressant (MADRS) at day group
some of the
effects in 14. The largest effect developed
current
subjects with was seen 2 days after mania.
medications
bipolar infusion
might have led
depression. (d = 0.80; 95% CI,
to bias.
0.55–1.04)
Depressive symptoms Small sample
as well as suicidal size.
ideation significantly
The efficacy improved in subjects Normal saline
of ketamine receiving ketamine could have
15 with 0.5 mg/kg Patients were
infusion in compared to placebo masked proper
Randomized bipolar infused in 0.9% only allowed
Zarate reducing (d = 0.89, 95% None blinding.
8. controlled disorder normal Normal to take lithium MADRS
et al., 2012 depressive C.I. = 0.61–1.16 and reported
trial (8 females saline. saline or valproate
symptoms in 0.98, 95% Tapering of
and 7 males). only)
bipolar C.I. = 0.64–1.33, some of the
depression respectively); this current
improvement medications
remained significant might have led
through Day 3. to bias.
Brain Sci. 2023, 13, 909 13 of 21

Table 1. Cont.

Any Report
Sr. Lead Total Intervention Concomitant Primary Psychometric of Hypo-
Study Type Control Findings Limitations
No. Author Participants (Dosage) Medications Objective Tool Used manic/Manic
Switching
Small sample
size.
Ketamine lowered One
fatigue scores participant Normal saline
Exploratory 36 bipolar To study compared to placebo in ketamine could have
0.5 mg/kg Patients were
analysis of depression anti-fatigue NIH-Brief from 40 min and one masked proper
infused in 0.9% only allowed
Saligan randomized patients properties of Fatigue post-treatment. The participant blinding.
9. normal Normal to take lithium
et al., 2016 crossover- (21 females ketamine in Inventory largest anti-fatigue in control
saline. saline or valproate
controlled and bipolar (NIH-BFI) effects between group Tapering of
only.
trial. 15 males). depression. placebo and ketamine developed some of the
was at day 2 (d = 0.58, mania. current
p < 0.05). medications
might have led
to bias.
Small sample
84.6% (n = 22;
size.
ketamine) vs. 28.0%
26 (n = 7; placebo)
Normal saline
participants To study the reported resolution of
could have
with bipolar 0.5 mg/kg Patients anti-suicidal Scale for suicidal symptoms
Randomized 0.9% masked proper
Abbar disorder infused in continued effects of Suicide (SSI < 4). The odds None
10. controlled Normal blinding.
et al., 2022 (Gender normal their as usual ketamine in Ideation ratio for resolution of reported
trial saline.
distribution saline. medication. a suicidal (SSI) suicidal ideation was
Patients were
not crisis. 14.1 (3.0 to 92.2,
allowed to take
reported). p < 0.001) in bipolar
cannabis and
disorder patients at
other current
day 3 post treatment.
medications.
Brain Sci. 2023, 13, 909 14 of 21

Overall, the quality appraisal of included studies showed concerns across multiple
domains of robustness. The component studies had a small number of participants that
could have led to limited statistical power to identify true efficacy/effectiveness of IV
ketamine use in BD patients. Moreover, studies reported on acute effects of IV ketamine use
(from 24 h to one week) and lacked the ability to provide information for long-term clinical
management. The reported follow-up period in most studies was two to three weeks,
limiting the validity of results in long-term usage. The ROBINS-I assessment showed mod-
erate concerns for confounding since patients were on multiple psychopharmacological
treatments with no control to measure the effectiveness robustly. The participants included
in many studies were hospitalized or had treatment-resistant disease which limits the
generalizability of results. Most studies either did not blind the individuals conducting the
outcome assessment (standardized self-reported depression scoring and cognitive tests) or
lacked information about blinding, leading to a moderate risk of bias in outcome measure-
ment. Moreover, the majority of open label trials had concerns due to participants dropping
out. The lack of control group made it difficult to rule out placebo effect completely.
On the other hand, all RCTs showed some concerns for missing data as assessed
through the ROB tool for RCTs. Moreover, none of the RCTs reported on the post-trial
statistics for the success of blinding that could have led to higher placebo rates in interven-
tional groups. The detailed domain level results for the quality appraisal are presented in
Figure 2, and further limitations of each constituent study are delineated in Table 1. It was
noted that even though most studies showed a significant decrease in depression scores
following ketamine infusion, the effect size varied. Hence, the response rates and remission
rates are discussed separately in the review and should be accounted for while deriving
conclusions.

3.3. Efficacy of Ketamine Use in Bipolar Depression

Our search identified 5 RCTs that delineated the efficacy of IV racemic ketamine in the
treatment of acute bipolar depression. The crossover double blinded RCT by Diazgranados
et al. randomized 18 participants with BD (concurrent treatment with lithium or valproate)
to receive one infusion of ketamine (0.5 mg/kg) or normal saline (as control) [37]. The
study showed a statistically significant reduction in depression among ketamine users
when compared to placebo (d = 0.52, 95% CI= 0.28–0.76, p < 0.05) after 40 min of infusion.
The antidepressant effect remained statistically differentiated from placebo subgroups for
up to three days post-infusion. The maximum response rates (50% reduction in depressive
measurement) were 71% and 6% among ketamine and placebo subgroups up to three days
post-treatment, respectively [37]. Another RCT with similar patient characteristics and
study design reported an antidepressant effect among 15 participants receiving IV ketamine
when compared to placebo (d = 0.89, 95% CI = 0.61–1.16, p < 0.05) 40 min post-infusion. The
study reported approximately similar response rates compared to previous RCT (i.e., 79%
in the ketamine group and 0% in the placebo group) over the period of the trial. Moreover,
anti-suicidal effects were observed with the use of ketamine when compared to placebo
in the same study (d = 0.98, 95% confidence interval = 0.64–1.33, p < 0.05) 40 min post-
infusion [38]. However, an RCT by Grunebaum et al. in 16 BD patients did not show
any statistically significant anti-suicidal effect of IV ketamine compared to IV midazolam
(control) [39]. This was the only RCT that used IV midazolam as control while studying
patients with BD and suicidal ideations. Notwithstanding, a recent RCT by Abbar et al.
comprising 52 BD patients with suicidality reported a statistically significant resolution of
suicidal symptoms (Scale for Suicide Ideation measurement < 4) among ketamine users
when compared to control (IV saline) by day 3 (OR = 14.1, 95%CI = 3.0 to 92.2, p < 0.001) [40].
Lastly, an RCT by Saligan et al. reported on anti-fatigue properties of IV ketamine
among 36 patients with bipolar depression maintained on either lithium or valproate.
When controlled for non-fatigue depressive symptoms (such as anhedonia, hopelessness,
psychomotor retardation, etc.), the study suggested a statistically significant difference
measured on NIH-Brief Fatigue Inventory between patients randomized to ketamine and
Brain Sci. 2023, 13, 909 15 of 21

Brain Sci. 2023, 13, x FOR PEER REVIEW 
  placebo(IV normal saline) with the highest difference on day two post-treatment (d14 
= of  21 
0.58,
p < 0.05) [41].

 
Figure 2. Risk of bias assessment results for the included literature at the domain level, wherein
Figure 2. Risk of bias assessment results for the included literature at the domain level, wherein (A) 
(A) shows results for randomized controlled studies as per Cochrane’s Risk of Bias tool (RoB), and
shows results for randomized controlled studies as per Cochrane’s Risk of Bias tool (RoB), and (B) 
(B) shows results for open label studies as per Cochrane’s Risk of Bias in Non-randomized Studies-
shows results for open label studies as per Cochrane’s Risk of Bias in Non-randomized Studies-of 
Interventions 
of (ROBINS-I) 
Interventions (ROBINS-I)tool. 
tool.Icons 
Iconswere 
weregenerated 
generatedusing 
usingthe 
theopen-source 
open-source RobVis 
RobVis ShinyApp: 
ShinyApp:
https://www.riskofbias.info/welcome/robvis-visualization-tool. 
https://www.riskofbias.info/welcome/robvis-visualization-tool.

In a nutshell, the small number of participants in the included RCTs makes the scien-
3.3. Efficacy of Ketamine Use in Bipolar Depression 
tific literature severely limited related to the role of ketamine treatment in acute and/or
Our search identified 5 RCTs that delineated the efficacy of IV racemic ketamine in 
maintenance treatment of bipolar depression (with or without suicidality), relevant patient
the treatment of acute bipolar depression. The crossover double blinded RCT by Diazgra-
characteristics (gender and degree of bipolar depression), and combination treatment with
nados et al. randomized 18 participants with BD (concurrent treatment with lithium or 
mood stabilizing agents (e.g., lithium, lamotrigine, etc.). Moreover, in all RCTs, patients
valproate) to receive one infusion of ketamine (0.5 mg/kg) or normal saline (as control) 
were tapered off their ongoing psychopharmacological treatments to receive mood stabi-
[37]. The study showed a statistically significant reduction in depression among ketamine 
lizers only. This could have led to fluctuation in their depressive measures and in turn,
users when compared to placebo (d = 0.52, 95% CI= 0.28–0.76, p < 0.05) after 40 min of 
measurement bias in outcome measures.
infusion. The antidepressant effect remained statistically differentiated from placebo sub-
groups for up to three days post-infusion. The maximum response rates (50% reduction 
in depressive measurement) were 71% and 6% among ketamine and placebo subgroups 
up to three days post-treatment, respectively [37]. Another RCT with similar patient char-
acteristics and study design reported an antidepressant effect among 15 participants re-
ceiving IV ketamine when compared to placebo (d = 0.89, 95% CI = 0.61–1.16, p < 0.05) 40 
min post-infusion. The study reported approximately similar response rates compared to 
Brain Sci. 2023, 13, 909 16 of 21

3.4. Effectiveness of Ketamine Use in Bipolar Depression

A total of 5 studies were identified that investigated the use of IV ketamine in an open
label or retrospective clinical setting. An in-patient interventional study by Rybakowski
et al. investigated the role of ketamine among 53 patients with bipolar depression taking >1
mood stabilizing agents (i.e., carbamazepine, lithium, quetiapine, valproate, lamotrigine,
quetiapine, aripiprazole, and topiramate). Almost half of the participants showed response
to ketamine treatment (i.e., n = 27; 51%) with more males than females (i.e., 77% > 43%) after
7 days of treatment [42]. Another in-patient interventional study by Zhou et al. delineated
the effects of nine ketamine infusions over the period of 3 weeks among 38 patients with
bipolar depression. The findings suggested a significant decrease in depressive symptoms
after one week. However, the patients gradually relapsed into depression in the proceed-
ing two weeks with pre-treatment depressive measures after three weeks of the study
period [43]. Nevertheless, a recent open label study by Zheng et al. consisting of 6 ketamine
infusions across 12 days suggested significant effectiveness of ketamine treatment among
patients with bipolar depression even after study completion. Among 16 patients, 73.7%
and 63.2% showed response and remission rates after 12 days, respectively [44].
A recent real-world study from Canada investigated the use of IV racemic ketamine
(0.5–0.75 mg/kg; 4 infusions) over a two-week period among 66 patients with BD. The study
found significant effects in improving depression (Cohen’s f = 0.56, p < 0.001), suicidality
(Cohen’s f = 0.56, p < 0.001), and anxiety symptoms (Cohen’s f = 0.43, p < 0.001) post four
ketamine infusions across two weeks. Moreover, the study reported response and remission
rates of 35% and 20% across depressive measures at the end of study period (7 days after
the last infusion), respectively [45]. Lastly, a small open label study by Permoda-Osip
et al. simultaneously investigated antidepressant and pro-cognitive effects of ketamine in
patients with BD (n = 18). Cognition was assessed through the trail making (TMT) and the
Stroop color word interference tests. This study reported statistically significant (p < 0.001)
improvement in the TMT and Stroop tests 3 days after a single infusion of ketamine
(0.5 mg/kg) when compared to baseline. Moreover, the study reported 8 responders
(i.e., 50% decrease in depressive measures from baseline) after three days [46].

3.5. Safety and Tolerability of Ketamine Use in Bipolar Depression

Treatment with IV racemic ketamine was safe and mostly tolerable with transient
side effects (i.e., feeling dizzy, cognitive impairment, dissociation, nausea, headache, odd
sensations, flatulence, and blurred vision). These side effects lasted from 30 to 60 min and
none of these side effects led to treatment discontinuation [38,40–46].
There was a report of increased suicidality among two participants in an RCT by
Grunebaum et al., with one patient leading to a suicide attempt (post-infusion second
month) after IV ketamine in one of the RCTs on BD patients with baseline suicidal
thoughts [39]. No other studies reported any sudden increase in suicidal ideation.
Two studies reported manic/hypomanic switching with ketamine infusions among
patients with BD. Diazgranados et al. reported one patient in the ketamine group and one
patient in the control group (IV saline) who developed manic symptoms after infusion in a
total of 18 patients enrolled. However, the study did not delineate patient-specific charac-
teristics or time period for the occurrence of mania [37]. Moreover, the real-world study
by Fancy et al. described three patients (out of 66) with BD who developed hypomania
after the third or fourth ketamine infusion. All these patients were taking antidepressants
alongside IV ketamine treatment [45].

4. Discussion
According to our review, IV ketamine demonstrates weak preliminary evidence of effi-
cacy, tolerability, and safety in persons treated for bipolar depression. Moreover, ketamine
infusions did not appear to result in a higher rate of manic/hypomanic induction, dissocia-
tion, or psychosis when compared to persons with major depressive disorder [26,27,47].
Nevertheless, a limitation of the extant literature is that few studies are controlled and
Brain Sci. 2023, 13, 909 17 of 21

most of them are limited to single infusion studies, while the remainder are largely open-
label studies.
The therapeutic management of BD includes primarily three steps of treatment: acute
treatment to abate mania/hypomania or depression, maintenance treatment to prevent
manic/hypomanic or depressive episodes, and the treatment of subthreshold affective
symptoms as well as cognitive impairment [32]. As such, there is some evidence that IV
ketamine is effective in the treatment of the acute phase of bipolar depression. However,
there is little to no evidence of its use in maintenance treatment and optimization of residual
symptoms. Moreover, although IN esketamine is FDA-approved for unipolar depression
with extensive data around its long-term use, no such studies exist in the purview of bipolar
depression. This leads to a dearth of treatment options in patients with bipolar depression
who are not responsive to current treatment strategies (i.e., combination of mood stabilizing
agents and antipsychotics) [32]. It has been estimated that up to 25% of patients with
bipolar depression who do not respond to initial two-treatment interventions are often
termed to have treatment-resistant bipolar depression (TRBD).
As of now, there is no FDA-approved treatment for TRBD, leading to significant
emotional, somatic, functional, and financial toll among patients [17]. Furthermore, the lack
of consensus definition of TRBD further complicates the spectrum for treatment of patients
resistant to polypharmacological combination treatments. As such, the scientific community
should acknowledge and further define the TRBD domain that will eventually lead to
better evidence synthesis for treatments such as ketamine and psilocybin [17]. Lastly, all the
current interventions for bipolar depression take time to ameliorate depressive symptoms
and this lag in response leads to only a fraction of patients reporting any improvement in
the first week of treatment [17,32]. There is a dire need to study therapeutic targets that
may work rapidly with effects in a short period of time [18].
Our review suggests that IV ketamine can help ameliorate depressive and suicidal
symptoms in a shorter period of time (anywhere from one day to a week) among patients
with apparent TRBD. However, there was a report of an increase in suicidal ideation in
two participants in an RCT by Grunebaum et al. after ketamine infusion [39]. Although it
appears to be an isolated event, future research should focus on tolerability and long-term
use of IV ketamine in patients with BD presenting with suicidality. Moreover, there is a
need to differentiate the anti-suicidal role of ketamine across BD-I, BD-II, and cyclothymic
patients. As of now, preliminary evidence suggests the cautious use of IV ketamine in
BD patients to reduce suicidal ideation with constant post-treatment monitoring may be
considered in select cases.
Moreover, there is some weak evidence from a real-world study that IV ketamine
might be beneficial in improving cognitive deficits among patients with BD [46]. Overall,
IV ketamine was mostly tolerable in the majority of patients within our included studies.
However, there is an important caveat when it comes to manic/hypomanic switching. It
appears from current literature that IV ketamine might lead to manic/hypomanic switching
in patients who are currently on antidepressant treatment. Three out of five RCTs tapered
the BD patients of antidepressant treatment before infusing ketamine, and hence the use of
IV ketamine and antidepressants together remains poorly understood. Even though the
evidence is lacking, it is clinically suggested that patients should be put on mood-stabilizing
agents (e.g., lamotrigine, valproate, lithium, etc.) and tapered off antidepressants before
initiating treatment with ketamine infusions. In a case where antidepressant plus ketamine
treatment is needed, extra monitoring might help avoid any adverse event.

4.1. Future Research

There is a relative lack of adequately powered RCTs in bipolar disorder evaluating the
role of IV ketamine or IN esketamine in treating psychopathological domains of bipolar
depression. Future researchers should aim to discern the therapeutic usefulness of gluta-
matergic agents in the acute phase of bipolar depression and maintenance treatment of
bipolar disorders. Future studies should include a large, complex sample, as well as the use
Brain Sci. 2023, 13, 909 18 of 21

of validated self-report measures to fully understand the role of ketamine in preventing

future depressive episodes. It is important to map out clinical predictors that can determine
greater effectiveness and/or risk of manic/hypomanic switching among patients with BD.
Moreover, although ketamine treatment appears to be safe in BD patients, its safety and
tolerability regarding manic/hypomanic switch should be further explored. Lastly, it may
also be necessary to consider the potential confounding factors that can arise when study-
ing a patient population with multiple comorbidities, and on many types of psychotropic
medications. This could be a limitation to be vigilant of. These future studies are essential
to understand the mechanisms of glutamatergic agents in bipolar depression and TRBD.
Although we excluded the studies that had both unipolar and bipolar depression
patients, there are some real-world studies including a mix of mood disorder (both unipolar
and bipolar depression) patients providing us with some prefatory evidence related to
effectiveness of IV ketamine in treating select domains of bipolar depression. These studies
have shown some benefits in treating anhedonia, a mood disorder with mixed features,
anxiety, and functional deficits (i.e., work productivity and attendance) often being shown
by patients with BD [48–52]. These studies can act as a starting point for future researchers
to design robust clinical trials to better understand whether ketamine infusions can lead
to betterment in patient reported outcomes (e.g., sleep, functional outcomes, emotional
disturbances, etc.).

4.2. Limitations
Our scoping review is limited primarily due to moderately low quality RCTs and
real-world data. The overall quality of evidence poses serious limitations as most of the
studies included in the synthesis had a small sample size and a short follow-up period
that could study only acute effects. The lack of blinding in the open label studies failed to
rule out placebo effect. The varying gender ratio and mixed sample populations (including
hospitalized patients, patients with TRBD, and self-sponsoring community clinic patients)
further limits the generalizability of results. The missing outcome data and lacking sta-
tistical calculations for outcomes in RCTs further diminished our ability to synthesize the
exact antidepressant efficacy of IV ketamine use in BD patients. Moreover, there was no
post-trial assessment for the success of blinding among control groups in the included
RCTs. The blinding techniques varied between IV saline and IV midazolam that could
have further reduced the validity of these studies with results that might not be exactly
additive for a review. As such, more operative blinding techniques are needed to conduct
robust RCTs with ketamine/esketamine treatments in patients with BD. Therefore, findings
across efficacy/effectiveness and safety profiles of ketamine from our review should be
interpreted cautiously when it comes to the use of ketamine in patients with BD.

5. Conclusions
Our review suggests that IV ketamine is a promising acute treatment in adults liv-
ing with bipolar depression. There is also some preliminary evidence that IV ketamine
might have significant anti-suicidal effects in select BD patients presenting with suicidality.
However, the cited evidence is limited to short-term studies with most of them being
pilot projects. The findings, thus, prove the feasibility of related research and the safety of
short-term IV ketamine treatment with minimal risk of manic/hypomanic switching. The
evidence is not sufficient to draw clinical guidelines comprehensively. The limitations of
the studies made it difficult to rule out a placebo effect, and whether the antidepressant
response is sustainable or transient remains unknown too. Furthermore, to translate the
findings to clinical practice, the selected sample in the future studies needs to be more
representative of the general population. The wide exclusion criteria, acuity of depression,
concurrent administration of other pharmacotherapies, and limited sample size in the
current literature highlights the need for more comprehensive studies to draw important
conclusions regarding the effectiveness and feasibility of ketamine use in clinical practice.
Brain Sci. 2023, 13, 909 19 of 21

Overall, extant evidence suggests the potential of ketamine in the treatment of bipolar
depression and select comorbidities (e.g., anxiety, cognitive deficits, substance use disorders,
etc.) in bipolar disorder. Larger multi-infusion studies in well-characterized cohorts of
persons living with bipolar disorder are needed to further inform treatment decisions. In
the interim, the use of IV ketamine in centers with core competencies in safely delivering
this treatment may be considered across difficult-to-treat patients with bipolar depression.

Author Contributions: Conceptualization, M.Y.J. and R.S.M.; methodology, M.Y.J. and S.Q.; software,
M.Y.J.; validation, M.Y.J., S.Q. and R.S.M.; formal analysis, M.Y.J., S.Q. and M.N.; investigation,
M.Y.J. and Z.G.; resources, M.Y.J. and J.D.D.V.; data curation, M.Y.J. and S.Q.; writing—original draft
preparation, M.Y.J. and S.Q.; writing—review and editing, M.Y.J., S.Q., G.d., A.T., A.M., S.B. and I.G.;
visualization, M.Y.J.; supervision, R.S.M.; project administration, R.S.M. All authors have read and
agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Conflicts of Interest: I.G. has received grants and served as consultant, advisor, or CME speaker
for the following identities: ADAMED, Angelini, Casen Recordati, Esteve, Ferrer, Gedeon Richter,
Janssen Cilag, Lundbeck, Lundbeck-Otsuka, Luye, SEI Healthcare, Viatris outside the submitted
work. I.G. thanks the support of the Spanish Ministry of Science and Innovation (MCIN) (PI19/00954)
integrated into the Plan Nacional de I + D + I and co-financed by the ISCIII-Subdirección General
de Evaluación y confinanciado por la Unión Europea (FEDER, FSE, Next Generation EU/Plan de
Recuperación Transformación y Resiliencia_PRTR); the Instituto de Salud Carlos III; the CIBER of
Mental Health (CIBERSAM); and the Secretaria d’Universitats i Recerca del Departament d’Economia
i Coneixement (2021 SGR 01358), CERCA Programme/Generalitat de Catalunya as well as the
Fundació Clínic per la Recerca Biomèdica (Pons Bartran 2022-FRCB_PB1_2022). Roger McIntyre
has received research grant support from CIHR/GACD/National Natural Science Foundation of
China (NSFC) and the Milken Institute; and speaker/consultation fees from Lundbeck, Janssen,
Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue,
Pfizer, Otsuka, Takeda, Neurocrine, Neurawell, Sunovion, Bausch Health, Axsome, Novo Nordisk,
Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, Abbvie, and Atai Life Sciences.
Roger McIntyre is a CEO of Braxia Scientific Corp.

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